WO2007044796A2 - Pyridazinone compounds as calcilytics - Google Patents

Pyridazinone compounds as calcilytics Download PDF

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WO2007044796A2
WO2007044796A2 PCT/US2006/039700 US2006039700W WO2007044796A2 WO 2007044796 A2 WO2007044796 A2 WO 2007044796A2 US 2006039700 W US2006039700 W US 2006039700W WO 2007044796 A2 WO2007044796 A2 WO 2007044796A2
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Prior art keywords
phenyl
methyl
pyridazin
fluoro
ethyl
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PCT/US2006/039700
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French (fr)
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WO2007044796A3 (en
Inventor
Irina Shcherbakova
Camille G. Wermuth
Frederick Jeannot
Paola Ciapetti
Virginie Roques
William L. Heaton
Jeff A. Breinholt
Rebecca L. Conklin
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Nps Pharmaceuticals, Inc.
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Publication of WO2007044796A2 publication Critical patent/WO2007044796A2/en
Publication of WO2007044796A3 publication Critical patent/WO2007044796A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Figure 1 is a graph, which depicts the effect of bolus i.v. injection of the compound of Example 2b on plasma PTH level in normal rats.
  • the present disclosure relates to novel calcilytic compounds, methods for preparing these compounds, oral bioavailability of these compounds, prolonged pharmacological effect of these compounds, pharmaceutical compositions containing these compounds, and their uses as calcium receptor antagonists.
  • extracellular Ca 2+ is under rigid homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation.
  • Extracellular Ca 2+ inhibits the secretion of parathyroid hormone ("PTH”) from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from C-cells.
  • PTH parathyroid hormone
  • Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca 2+ concentration.
  • PTH is the principal endocrine factor regulating Ca 2+ homeostasis in the blood and extracellular fluids.
  • PTH by acting on bone and kidney cells, increases the level of Ca 2+ in the blood. This increase in extracellular Ca 2+ then acts as a negative feedback signal, depressing PTH secretion.
  • the reciprocal relationship between extracellular Ca 2+ and PTH secretion provides for a mechanism maintaining bodily Ca 2+ homeostasis.
  • Extracellular Ca 2+ acts directly on parathyroid cells to regulate PTH secretion.
  • the existence of a parathyroid cell surface protein, which detects changes in extracellular Ca 2+ has been confirmed (see Brown et al., Nature, 366:574, (1993)).
  • this calcium receptor protein acts as a receptor for extracellular Ca 2+ , detects changes in the ion concentration of extracellular Ca 2+ and initiates a functional cellular response, namely PTH secretion.
  • Extracellular Ca 2+ may influence various cell functions, as reviewed in Nemeth et al., Cell Calcium, 11:319 (1990).
  • extracellular Ca 2+ plays a role in parafollicular (C-cells) and parathyroid cells (see Nemeth, Cell Calcium, 11 :319 (1990)).
  • the role of extracellular Ca 2+ on bone osteoclasts has also been studied (see, e.g., Zaidi, Bioscience Reports, 10:493 (1990)).
  • Compounds are known to mimic the effects of extra-cellular Ca 2+ on a calcium receptor molecule.
  • calcilytics are compounds able to inhibit calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca 2+ .
  • Calcilytics may be useful as lead molecules in the discovery, development, design, modification and/or construction of useful calcium modulators, which are active at Ca 2+ receptors. Such calcilytics may also be useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expression and/or secretion of which is regulated or affected by activity at one or more Ca 2+ receptors.
  • Target diseases or disorders for calcilytic compounds include diseases involving abnormal bone and mineral homeostasis.
  • Abnormal calcium homeostasis may be characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels.
  • calcium receptor antagonists offer a unique approach towards the pharmacotherapy of diseases associated with abnormal bone or mineral homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.
  • the present disclosure features calcilytic compounds.
  • Calcilytic compounds refer to compounds able to inhibit calcium receptor activity.
  • the ability of a compound to "inhibit calcium receptor activity” refers to the ability of a compound to cause a decrease in one or more calcium receptor activities evoked by extracellular Ca 2+ .
  • R 1 , R 2 , R 3 and R 4 are independently one of H, lower alkyl, cycloalk or a group of the formula CH(lower alkyl)(CH 2 ) n -R 5 or (CH 2 ) n -R 5 wherein n is 0, 1 , or 2, and R 5 is a heterocycle or an aryl group which may have 0 to 4 substituents in the ring. In alternative embodiments, the aryl group may have 0 to 5 substituents in the aryl ring.
  • Each substituent is at least one of: halogen, CN, CF 3 , OCF 3 , lower alkyl, NO 2 , NH 2 , NH(lower alk), N(lower alk) 2l NH[S(O) 2 lower alk], NH[S(O) 2 alkyl aryl], NH[S(O) 2 aryl], NH[S(O) 2 heterocycle], OS(O) 2 NH 2 , OS(O) 2 NH(lower alkyl), OS(O) 2 N(lower alkyl) 2 , lower alkoxy, OH, OC(O)-lower alk, OC(O)-lower alkyl-NH 2 , OC(0)-lower alkyl-NH(lower alk), OC(O)-lower alkyl-N(lower alk) 2 , OC(0)0-lower alk, OC(0)0-lower alkyl amino, OC(O)O-lower alkyl-
  • R 1 may be one of: lower alkyl, cycloalk, (CH 2 ) n -R 5 or CH(lower alkyl)(CH 2 ) n -R 5 , wherein n may be 2 or 1 in certain embodiments, and n may be 2, 1 or O in other embodiments.
  • R 5 is an aryl group which may have O to 3 substituents in the aryl ring. More particularly, in certain embodiments wherein R 1 is a group of the formula (CH 2 ) n -R 5 , n is 1 and R 5 is an aryl group, 1 to 3 substituents on the aryl ring may be one of: lower alkyl and halogen.
  • R 1 is a group of formula CH(lower alk)(CH 2 ) n -R 5 , n is 0 or 1, and R 5 is an aryl group
  • 1 to 3 substituents on the aryl ring may be one of: H, lower alkyl and halogen.
  • R 5 is a heterocycle wherein the heterocycle may be one of: thiophene, morpholine, piperidine, imidazole, thiazole, benzothiadiazole, benzoxadiazole.
  • R 2 may be one of: CH(lower alkyl)(CH 2 ) n -R 5 or (CH 2 ) n -R 5 wherein n may be 2 or 1 , or alternatively 0, and R 5 is an aryl group, 1 to 3 substituents in the aryl ring may be one of: lower alkyl and halogen.
  • R 3 may be (CH 2 ) n -R 5 wherein n may be 1 or 0, and R 5 is an aryl group, wherein 0 to 3 substituents in the aryl ring may be one of: lower alkoxy, OH and halogen.
  • R 4 may be lower alkyl or an aryl group, wherein 0 to 3 substituents in the aryl ring may be one of: lower alkyl and halogen.
  • AIk refers to either alkyl or alkenyl.
  • Lower alk refers to either lower alkyl or lower alkenyl.
  • alkenyl refers to an optionally substituted hydrocarbon group containing at least one carbon-carbon double bond between the carbon atoms and containing 2- 6 carbon atoms joined together.
  • the alkenyl hydrocarbon group may be straight- chain. In some embodiments, straight-chain alkenyl has 2 to 4 carbons.
  • Alkyl refers to an optionally substituted hydrocarbon group joined by single carbon-carbon bonds and having 1 to 6 carbon atoms joined together.
  • the alkyl hydrocarbon group may be straight-chain or contain one or more branches. In some embodiments, branched- and straight-chain alkyl groups have 1 to 4 carbons, each of which may be optionally substituted.
  • Alkyl substituents may be independently one of: lower alkyl, unsubstituted aryl, OH, NH 2 , NH-lower alkyl, or N(lower alkyl) 2 . In some embodiments, no more than two substituents are present.
  • alkyl may be a lower alkyl, which is unsubstituted branched- or straight-chain alkyl having 1 to 5 carbons. In other embodiments, alkyl may be a lower alkyl having 1 to 4 carbons.
  • Cycloalk refers to an optionally substituted cyclic alkyl or an optionally substituted non-aromatic cyclic alkenyl and includes monocyclic and multiple ring structures such as bicyclic and tricyclic.
  • the cycloalkyl may have, for example, 3 to 15 carbon atoms. In one embodiment, cycloalkyl has 3 to 5 carbon atoms.
  • Optional substituents for cycloalk are independently selected from the group described above for alkyl and alkenyl. In one embodiment, no more than three substituents are present.
  • the cycloalk is unsubstituted.
  • the cylcoalk may be an unsubstituted cyclic alkyl. Examples of suitable cycloalkyl groups include cyclopropyl and cyclobutyl.
  • Heterocycle refers to an optionally substituted aromatic or non-aromatic ringed moieties. Heterocyclic moieties typically comprise one ring or two fused rings, where the ring(s) is 5 to 6-membered and typically contains 1 to 3 non-carbon atoms.
  • Non-carbon atoms for heterocycle are independently selected from nitrogen, oxygen and sulfur.
  • Aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated ring system or fused conjugated ring system.
  • Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • the aryl may be either optionally substituted phenyl or optionally substituted pyridyl.
  • Alkoxy refers to oxygen joined to an unsubstituted alkyl 1 to 4 carbon atoms in length.
  • the oxygen is joined to an unsubstituted alkyl 1 to 2 carbons in length.
  • the alkoxy may be methoxy.
  • Metal refers to a monovalent metal cation.
  • the metal may be sodium or potassium.
  • the calcilytic compounds of Structure I can be prepared by reacting 1 ,3,5-substituted 2H-pyridazin-3-ones with an alkyl halide.
  • 1 ,3,5-Substituted 2H-pyridazin-3-ones may be prepared by Scheme I involving a method of reacting 4-aryl-2-oxo-butyric acids with 1-aryl-alkan-2-ones and hydrazine hydrate.
  • 4-Aryl-2-oxo-butyric acids may be prepared by reacting 4-aryl-2-hydroxy- but-3-enoic acids with sodium hydroxide.
  • 1 ,3,5-substituted 2H-pyridazin-3-ones may be prepared by Scheme Il involving a method of reacting 3,4,5-substituted 5- hydroxy-5H-furan-2-ones with hydrazine hydrate.
  • 3,4,5-Substituted 5-hydroxy-5H- furan-2-ones can be prepared using standard techniques known to those having skill in the art. For example, see WO 96/36623, entitled Diaryl-5-Oxygenated-2-(5H)-
  • the calcilytic compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration.
  • Systemic administration may be accomplished through oral administration.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
  • Additional information about standard pharmaceutical practice for formulating pharmaceutical compositions such as conventional techniques for making tablets and pills containing active ingredients are described in the standard reference, "Remington: the Science and Practice of Pharmacy," (21st ed. 2005). This standard reference is incorporated herein.
  • injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be achieved by transmucosal or transdermal methods.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, bile salts and fusidic acid derivatives for transmucosal administration.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various calcilytic compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC50, ECSQ, the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses may have to be administered.
  • the composition may be in unit dosage form.
  • a tablet or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered, and for transmucosal delivery, a buccal patch may be administered.
  • dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration may contain suitably from 0.01 to
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes may contain suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula
  • a topical formulation may contain suitably 0.01 to 5.0% of a compound of
  • the active ingredient may be administered as a single dose or in multiple does, for example, from 2 to 6 times per day, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • treatment includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • Diseases and disorders which might be treated or prevented, based upon the affected cells include bone and mineral-related diseases or disorders; hypoparathyroidism; those of the central nervous system such as seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage, such as occurs in cardiac arrest or neonatal distress, epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, and Tourette's syndrome; diseases involving excess water reabsorption by the kidney, such as syndrome of inappropriate ADH secretion (SIADH), cirrhosis, congestive heart failure, and nephrosis; hypertension; preventing and/or decreasing renal toxicity from cationic antibiotics (e.g., aminoglycoside antibiotics); gut motility disorders such as diarrhea and spastic colon; Gl ulcer diseases; Gl diseases with excessive calcium absorption
  • the present compounds are used to increase serum parathyroid hormone ("PTH") levels.
  • PTH serum parathyroid hormone
  • Increasing serum PTH levels may be helpful in treating diseases such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia of malignancy, and osteoporosis.
  • the present compounds are co-administered with an anti-resorptive agent.
  • agents include, but are not limited to estrogen, 1 ,25- (OH)2"Vitamin D3, calcitonin, selective estrogen receptor modulators, vitronectin receptor antagonists, V-H+-ATPase inhibitors, src SH2 antagonists, bisphosphonates and cathepsin K inhibitors.
  • Another aspect of the present disclosure provides a method of treating a patient comprising administering to the patient an amount of a present compound sufficient to increase the serum PTH level.
  • the method is carried out by administering an amount of the compound effective to cause an increase in duration and/or quantity of serum PTH level sufficient to have a therapeutic effect.
  • the compound administered to a patient causes an increase in serum PTH having a duration of up to one hour, about one to about twenty-four hours, about one to about twelve hours, about one to about six hours, about one to about five hours, about one to about four hours, about two to about five hours, about two to about four hours, or about three to about six hours.
  • the compound administered to a patient causes an increase in serum PTH having a duration of more than about twenty-four hours provided that it is co-administered with an anti resorptive agent.
  • the compound administered to a patient causes an increase in serum PTH of up to two-fold, two- to five-fold, five- to ten-fold, and at least 10-fold, greater than peak serum PTH in the patient. The peak serum level is measured with respect to a patient not undergoing treatment.
  • the composition of Formula (I) and their pharmaceutically acceptable salts and/or complexes, which may be active when given orally, can be formulated as syrups, tablets, capsules, and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier such as, for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier such as, for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • any routine encapsulation may be suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be utilized.
  • aqueous gums, celluloses, silicates or oils may be used to form a soft gelatin capsule shell.
  • Typical parenteral compositions include a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt or complex thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low-melting vegetable waxes or fats or their synthetic analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low-melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • composition may be in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • Microwave reactions were performed on Initiator TM (Biotage, Sweden) on continuous irradiation at 2450 MHz. All microwave reactions were carried out in heavy-walled Borosilicate tubes, sealed with cap fitted Teflon Septa.
  • HPLC High Pressure Liquid Chromatography analyses for 95+% purity confirmation were performed on a Gilson Series HPLC equipped with an Agilent DAD 170 (diode array detector), and a Macherey-Nagel Nucleodur C18 (5 ⁇ , 4.6x150 mm) column.
  • MS Mass Spectrometry analyses were performed on an Aqa single quad ThermoFinnigan spectrometer with an ESI (Electrospray Ionization) and were recorded in the positive-ion mode.
  • NMR Nuclear Magnetic Resonance
  • NMR resonances are reported in ⁇ (ppm) relative to tetramethylsilane (TMS) as internal standard with the following descriptors for the observed multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), and m (multiplet). J AB coupling constants are reported in Hz.
  • TMS tetramethylsilane
  • HPLC gradient 5% to 80% ACN in H 2 O: 98%.
  • Titanium (IV) chloride (0.44 ml, 4.07 mmol) was added to a solution of 4- (3-fluoro-phenyl)-2-oxo-butyric acid of Example 1c (2 g, 10.2 mmol) and 1-(2- methoxy-phenyl)-propan-2-one (1.58 ml, 10.2 mmol) in dry toluene (40.7 mL) at room temperature.
  • the reaction mixture was stirred overnight under argon, and then ice was added (50 g).
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuum.
  • HPLC gradient 20% to 80% ACN in H 2 O: 98%.
  • HPLC isocratic 80% ACN in H 2 O: >95%.
  • Example 1f Utilizing the procedure described in Example 1f except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one for 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 2a, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2- isopropyl-6-methyl-2H-pyridazin-3-one was prepared as a white solid (0.07 g, 24%).
  • HPLC isocratic 90% ACN in H 2 O: >95%.
  • HPLC gradient 20% to 80% ACN in H 2 O: >95%.
  • HPLC gradient from 20% to 80% ACN in H 2 O: >99%.
  • frans-Styrylacetic acid (0.46 g, 2.86 mmol) and triethylamine (0.7 ml_, 4.92 mmol) were added to a solution of 2-bromopropiophenone (0.35 ml_, 2.34 mmol) in anhydrous acetonitrile (11.7 mL).
  • the reaction mixture was stirred under argon overnight, and then 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.95 mL, 6.33 mmol) was added dropwise.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • the reaction mixture was poured into a mixture of an aqueous solution of 1 N hydrochloric acid (6.2 mL) and 7.8 mL of brine, and extracted with 40 mL of 1 :1 ethyl acetate/cyclohexane.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to yield 0.771 g of 5-hydroxy-5-methyl-4-phenyl- 3-((E)-styryl)-5H-furan-2-one compound as a yellow foam.
  • the resulting compound was used onto the next step without any further purification.
  • This first crop was triturated in hot 1 :1 ethanol/diethyl ether and filtered to give 6-methyl-4-phenethyl-5-phenyl-2H-pyridazin-3-one (0.2 g, 30%) as a bright yellow solid.
  • Butyryl chloride (1.65 mL, 15.93 mmol) was added dropwise at 0 0 C to a solution of phenol (1 g, 10.62 mmol) in dry pyridine (42 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. Methylene chloride (100 mL) was added to the reaction mixture followed by a NaHCO 3 saturated solution (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure and co-evaporated with toluene to yield butyric acid phenyl ester (1.64 g, 93%) as yellowish oil.
  • Phenyltrimethylammonium tribromide (10.5 g, 28.05 mmol) was added in two portions to a solution of 1-(2-methoxy-phenyl)-butan-1-one of step 8d (5 g, 28.05 mmol) in anhydrous tetrahydrofuran (56 ml_). The reaction mixture was stirred under argon at room temperature for 3.5 hours. Water (150 ml.) was then added and the mixture was extracted with dichloromethane (150 ml_). The organic layer was dried over sodium sulfate, filtered and evaporated.
  • Example 7a Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(2-methoxy-phenyl)-butan-1-one of Example 8e and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid of Example 8a, 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one was obtained as yellowish oil (9.06 g). The crude product was used in the next step without any further purification.
  • HPLC gradient 20% to 80% ACN in H 2 O: 98%.
  • reaction mixture was stirred under argon at 60 0 C overnight and cooled to room temperature.
  • Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL).
  • the organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuum.
  • HPLC gradient 20-80% ACN/H 2 O: > 99%.
  • Example 9c Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one for 5-hydroxy-4-(2-methoxy-phenyl)-5-methyl-3-((E)-styryl)-5H-furan-2-one of Example 9c, 5-(2-methoxy-phenyl)-6-methyl-4-styryl-2H-pyridazin-3-one and 5-(2-methoxy- phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one were obtained as a yellowish foam (inseparable mixture) (2.0 g, 30%).
  • Example 9d Utilizing the procedures described in Example 8h except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one and 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one for 5-(2- methoxy-phenyl)-6-methyl-4-styryl-2H-pyridazin-3-one and 5-(2-methoxy-phenyl)-6- methyl-4-phenethyl-2H-pyridazin-3-one of Example 9d, 2-isopropyl-5-(2-methoxy- phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one and 2-isopropyl-5-(2-methoxy- phenyl)-6-
  • Example 8i Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one of Example 9f, 5-(2-hydroxy-phenyl)-2-isopropyl-6-methyl-4-phenethyl-2H-pyridazin-
  • HPLC gradient 20-80% ACN/H 2 O: > 96%.
  • Ethyl magnesium bromide in diethyl ether (48.6 mL, 48.6 mmol) was added dropwise at 0 0 C to a solution of 3,N-dirnethoxy-N-methyl-benzamide of Example 10a (3.8 g, 19.46 mmol), in anhydrous diethyl ether (68 mL).
  • the reaction mixture was allowed to warm to room temperature and then stirred for 4 hours.
  • a saturated solution of ammonium chloride (42 mL) was added followed by extraction with ethyl acetate (100 mL). The organic layer was washed with 1 N citric acid (100 mL), NaHCO 3 saturated solution (100 mL), and brine (10OmL).
  • Example 8e Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one for 1-(3-methoxy-phenyl)-propan-1-one of Example 10b, 2-bromo-1-(3-methoxy-phenyl)-propan-1-one was obtained as colorless oil (3.8 g, 93%).
  • Example 7a Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(3-methoxy-phenyl)-propan-1-one of Example 10c and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, 3-[2-(3-fluoro- phenyl)-vinyl]-5-hydroxy-4-(3-methoxy-phenyl)-5-methyl-5H-furan-2-one was obtained as an orange foam. The crude product was used directly onto the next step without any further purification.
  • Example 10e 4-[2-(3-fluoro-phenyl)-vinyl]-2-isopropyl-5-(3-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one and 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(3- methoxy-phenyl)-6-methyl-2H- pyridazin-3-one were obtained and separated by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (9:1) (0.4 g, 59%) (98% of 4-[2-(3-fluoro- phenyl)-vinyl]-2-isopropyl-5-(3-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one and 2 % of 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(3-
  • Example 10g Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(3-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 10g, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(3-hydroxy-phenyl)-2- isopropyl-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.275 g, 62%).
  • IC 50 greater than 50 ⁇ M.
  • Example 10b Utilizing the procedures described in Example 10b except substituting 3, N-dimethoxy-N-rnethyl-benzamide for 3-f luoro-2, N-dimethoxy-N-methyl-benzamide of Example 11a, 1-(3-fluoro-2-methoxy-phenyl)-propan-1-one was obtained as a colorless oil (0.726 g, 17%).
  • Example 8e Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one for 1-(3-fluoro-2-methoxy-phenyl) ⁇ propan-1-one of Example 11b, 2-bromo-1-(3-fluoro-2-methoxy-phenyl)-propan-1-one was obtained as a colorless oil (0.922 g, 92%).
  • Example 7a Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(3-fluoro-2-methoxy-phenyl)-propan-1-one of Example 11c and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, 4-(3- fluoro-2-methoxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H-furan- 2-one was obtained as a brown gum. The crude product was used directly onto the next step without any further purification.
  • Example 8g Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one for 4-(3-fluoro-2-methoxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H- furan-2-one of Example 11d, 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- vinyl]-6-methyl-2H-pyridazin-3-one and 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro- phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one were obtained as an orange gum (inseparable mixture) (0.516 g, 41%).
  • Example 8g Utilizing the procedures described in Example 8g except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2 ⁇ isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-6- methyl-2H-pyridazin-3-one of Example 11g, 5-(3-fluoro-2-hydroxy-phenyl)-4-[2-(3- fluoro-phenyl)-ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one was obtained as a beige foam (0.141 g, 70%).
  • HPLC gradient 20-80% ACN/H 2 O: > 99%.
  • Example 10b Utilizing the procedures described in Example 10b except substituting 3,N-dimethoxy-N-methyl-benzamide for 2-fluoro-3,N-dimethoxy-N-rnethyl-benzamide of Example 12a, 1-(2-Fluoro-3-methoxy-phenyl)-propan-1-one was obtained as a colorless oil (2.43 g, 87%).
  • Example 8e Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one for 1-(2-fluoro-3-methoxy-phenyl)-propan-1-one of Example 12b, 2-bromo-1-(2-fluoro-3-methoxy-phenyl)-propan-1-one was obtained as a colorless oil (3.29 g, 96%).
  • Example 7a Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(2-fluoro-3-methoxy-phenyl)-propan-1-one of Example 12c and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, 4-(2- fluoro-3-methoxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H-furan- 2-one was obtained as a brown gum. The crude product was used directly onto the next step without any further purification.
  • Example 9f Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 5-(2- fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-isopropyl-6-methyl-2H- pyridazin-3-one of Example 12f, 5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.484 g, 91%).
  • HPLC gradient 20-80% ACN/H 2 O: > 99%.
  • Example 10b Utilizing the procedures described in Example 10b except substituting 3,N-dimethoxy-N-methyl-benzamide for 2,N-dimethoxy-N-methyl-benzamide of Example 13a and ethyl magnesium bromide for ⁇ -butyl magnesium chloride, 1-(2- methoxy-phenyl)-pentan-1-one was obtained as a colorless oil (5.73 g, 96%).
  • Example 7a Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(2-methoxy-phenyl)-pentan-1-one of Example 12c, 5-hydroxy-4-(2-methoxy-phenyl)-5-propyl-3-((E)-styryl)-5H-furan-2-one was obtained as a brown gum. The crude product was used directly onto the next step without any further purification.
  • Example 8g Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyI)-5H-furan-2-one for 5-hydroxy-4-(2-methoxy-phenyl)-5-propyl-3-((E)-styryl)-5H-furan-2-one of Example 12d, 5-(2-methoxy-phenyl)-6-propyl-4-((E)-styryl)-2H-pyridazin-3-one and 5-(2- methoxy-phenyl)-4-phenethyl-6-propyl-2H-pyridazin-3-one were obtained as a white solid (inseparable mixture) (1.22 g, 14%).
  • Example 12f 2-isopropyl-5-(2-methoxy-phenyl)-4-phenethyl-6-propyl-2H-pyridazin-3- one was obtained as a colorless oil (0.790 g, 90%).
  • Example 8i Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-isopropyl-5-(2-methoxy-phenyl)-4-phenethyl-6-propyl-2H-pyridazin-3-one of Example 12g , 5-(2-Hydroxy-phenyl)-2-isopropyl-4-phenethyl-6-propyl-2H-pyridazin- 3-one was obtained as a white solid (0.082 g, 25%).
  • Tetrabutylammonium bromide (0.023 g, 0.074 mmol), 2-chlorobenzyl bromide (0.320 g, 1.56 mmol) and 4 ⁇ [2-(3-fluoro-phenyl)-vinyl]-5 ⁇ (2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one of Example 14b (0.5 g, 1.48 mmol) were added to a suspension of potassium carbonate (0.513 g, 37.16 mmol) in anhydrous acetonitrile (10 ml_). The mixture was refluxed for 2 hours and concentrated under reduced pressure.
  • HPLC gradient 20-80% ACN/H 2 O: > 95%.
  • Example 15b Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(2-methyl- benzyl)-2H-pyridazin-3-one of Example 15b, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2-(2-methyl-benzyl)-2H-pyridazin-3-one was obtained as a white solid (0.126 g, 25%).
  • Example 16b Utilizing the procedures described in Example 8i except substituting Q- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(3-methyl- benzyl)-2H-pyridazin-3-one of Example16b, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2-(3-methyl-benzyl)-2H-pyridazin-3-one was obtained as a white solid (0.145 g, 31%).
  • HPLC gradient 20-80% ACN/H 2 O: > 99%.
  • Example 17b Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(4-methyl- benzyl)-2H-pyridazin-3-one of Example 17b, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2-(4-methyl-benzyl)-2H-pyridazin-3-one was obtained as a white solid (0.020 g, 5%).
  • Example 8i Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-isopropyl-5-(2-methoxy-phenyl)-4-phenethyl-6-phenyl-2H-pyridazin-3-one of Example 18h, 5-(2-hydroxy-phenyl)-2-isopropyl-4-phenethyl-6-phenyl-2H- pyridazin-3-one was obtained as a white solid (0.3 g, 62%).
  • IC 50 greater than 50 ⁇ M.
  • Example 8i Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-cycIohexylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one of Example 20b, 2-cyclohexylmethyl-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.294 g, 66%).
  • HPLC gradient 20-80% ACN/H 2 O: > 95%.
  • IC 50 greater than 50 ⁇ M.
  • HPLC isocratic 90% ACN/H 2 O: > 95%.
  • IC 50 greater than 50 ⁇ M.
  • Example 8e Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one of Example 8d for 1-(2-benzyloxy-phenyl)-2-bromo- propan-1-one of Example 22a, 1-(2-benzyloxy-phenyl)-2-bromo-propan-1-one was obtained as an colorless oil (0.2 g, 75%).
  • Example 8g Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-phenyl)-5-hydroxy-5-methyl-3-((E)-styryl)-5H-furan-2- one of Example 22c, 5-(2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3- one was obtained as a white solid (5.1 g, 25%).
  • Example 22e for 5-(2-benzyloxy-phenyl)-2-cyclopropylmethyl-6-methyl-4-((E)-styryl)- 2H-pyridazin-3-one of Example 23a 2-cyclopropylmethyl-5-(2-hydroxy-phenyl)-6- methyl-4-phenethyl-2H-pyridazin-3-one was obtained as a white solid (0.21 g, 58%).
  • Example 9e for 5-(2-benzyloxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl-4-((E)-styryl)- 2H-pyridazin-3-one of Example 24a 5-(2-benzyloxy-phenyl)-2-(3-methoxy-benzyl)-6- methyl-4-phenethyl-2H-pyridazin-3-one was obtained as a colorless oil (0.51 g, 94%).
  • Example 9e for 5-(2-benzyloxy-phenyl)-6-methyl-2-(1-phenyl-ethyl)-4-((E)-styryl)-2H- pyridazin-3-one of Example 25a 5-(2-benzyloxy-phenyl)-6-methyl-4-phenethyl-2-(1- phenyl-ethyl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.45 g, 92%).
  • Example 8g Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5- methyl-5H-furan-2-one of Example 26a, 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro- phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a white solid (3 g, 15%).
  • Example 22e Utilizing the procedures described in Example 22e except substituting 5- (2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 22d for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 26b and (2-bromo-ethyl)-benzene for 1-bromoethyl benzene, 5-(2- benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2-(1-phenyl-ethyl)-2H- pyridazin-3-one was obtained as a colorless gum (0.51 g, 82%).
  • HPLC gradient 20-80% ACN/H 2 O: > 99%.
  • Example 9e for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-(4-methoxy- benzyl)-6-methyl-2H-pyridazin-3-one of Example 27a 5-(2-benzyloxy-phenyl)-4-[2- (3-fluoro-phenyl)-ethyl]-2-(4-methoxy-benzyl)-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.56 g, 93%).
  • HPLC gradient 5-80% ACN/H 2 O: > 99%.
  • Example 9e for 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-4-[2-(3-fluoro- phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 28a 5-(2-benzyloxy-phenyl)- 2-(3,5-dimethoxy-ben2yl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.42 g, 95%).
  • HPLC gradient 5-80% ACN/H 2 O: > 94%.
  • the resulting crude product was purified on silica gel column chromatography using cyclohexane - ethyl acetate (gradient from 30% to 50% of ethyl acetate) to afford 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl- 2H-pyridazin-3-one (0.24 g, 15%) as a colorless gum.
  • Example 7a Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-phenyl)-2-bromo-propan-1-one and trans- styrylacetic acid for 4-(4-fluoro-phenyl)-but-3-enoic acid of Example 30a, 4-(2- benzyloxy-phenyl)-3-[2-(4-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H-furan-2-one was obtained as an orange gum (10 g). The crude product was used directly onto the next step without any further purification.
  • Example 8g Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-phenyl)-3-[2-(4-fluoro-phenyl)-vinyl]-5-hydroxy-5- methyl-5H-furan-2-one of Example 30b, the title compound was obtained as a yellowish oil (0.6 g, 11%).
  • Example 22e Utilizing the procedures described in Example 22e except substituting 5- (2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 22d for 5-(2-benzyloxy-phenyl)-4-[2-(4-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 30c, 5-(2-benzyloxy-phenyl)-4-[2-(4-fluoro-phenyl)-vinyl]-6-methyl-2- phenethyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.34 g, 55%).
  • HPLC gradient 5-80% ACN/H 2 O: > 99%.
  • HPLC gradient 5-80% ACN/H 2 O: > 96%.
  • HPLC gradient 5-80% ACN/H 2 O: > 95%.
  • Example 29b Utilizing the procedures described in Example 29b except substituting 5- (2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one of Example 26b for 5-(2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example of 14d, and 4-bromomethyl-benzo[1 ,2,5]thiadiazole for 1-bromomethyl-3,5- dimethoxy-benzene, 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-6-methyl-4- ((E)-styryl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.53 g, 54%).
  • HPLC gradient 5-80% ACN/H 2 O: > 95%.
  • Example 29b Utilizing the procedures described in Example 29b except substituting 5- (2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one of Example 29a for 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl- 2H-pyridazin-3-one of Example 35a, 2-benzo[1 ,2,5]thiadiazol-4-ylmethyI-5-(3-fluoro- 2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.2 g, 70%).
  • Example 8i Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one of Example 8h for 2-benzo[1,2,5]thiadiazol-4-ylmethyl-5-(3-fluoro-2-methoxy- phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one of Example 35b, 2- benzo[1 ,2,5]thiadiazol-4-ylmethyl-5-(3-fluoro-2-hydroxy-phenyl)-4-[2-(3-fluoro- phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.07 g,
  • Example 8g Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(3-fluoro-2-methoxy-phenyl)-5-hydroxy-5-methyl-3-((E)-styryl)-5H- furan-2-one of Example 36a, 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-4-((E)-styryl)- 2H-pyridazin-3-one was obtained as a white solid (0.25 g, 20%).
  • Example 29b Utilizing the procedures described in Example 29b except substituting 5- (2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one of Example 29a for 5-(3-fluoro-2-methoxy-phenyl)-6-methyl ⁇ 4-phenethyl-2H-pyridazin-3- one of Example 36c, and 4-brom ⁇ methy!-benzo[1,2,5]thiadiazole for (2-bromo-ethyl)- benzene, 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-2,4-diphenethyl-2H-pyridazin-3- one was obtained as a yellowish oil (0.31 g, 95%).
  • Example 8i Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one of Example 8h for 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-2,4-diphenethyl-2H- pyridazin-3-one of Example 36d, 5-(3-fluoro-2-hydroxy-phenyl)-6-methyl-2,4- diphenethyl-2H-pyridazin-3-one was obtained as a white foam (0.15 g, 52%).
  • HPLC gradient 20-80% ACN/H 2 O: > 95%.
  • Example 22a Utilizing the procedures described in Example 22a except substituting 1- (2-hydroxy-phenyl)-propan-1-one for 1-(3-fluoro-2-hydroxy-phenyl)-propan-1-one of Example 37a, 1-(2-benzyloxy-3-fluoro-phenyl)-propan-1-one was obtained as a colorless oil (3.55 g, 92%).
  • Example 8e Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one of Example 8d for 1-(2-benzyloxy-3-fluoro-phenyl)- propan-1-one of Example 37b, 1-(2-benzyloxy-3-fluoro-phenyl)-2-bromo-propan-1- one was obtained as a colorless oil (4.1 g, 88%).
  • Example 7a Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-3-fluoro-phenyl)-2-bromo-propan-1-one of Example 37c, and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, 4- (2-benzyloxy-3-fluoro-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H- furan-2-one was obtained as a brown oil (8 g). The crude product was used directly onto the next step without any further purification.
  • Example 8g Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-3-fluoro-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5- hydroxy-5-methyl-5H-furan-2-one of Example 37d, 5-(2-benzyloxy-3-fluoro-phenyl)-4- [(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a yellowish solid (0.4 g, 15%).
  • Example 8g Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyI)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-3-fluoro-phenyl)-5-hydroxy-5-methyl-3-((E)-styryl)-5H- furan-2-one of Example 38a, 5-(2-benzyloxy-3-fluoro-phenyl)-6-methyl ⁇ 4-((E)-styryl)- 2H-pyridazin-3-one was obtained as a yellowish solid (0.75 g, 30%).
  • HPLC gradient 5-95% ACN/H 2 O: > 99%.

Abstract

Various calcilytic compounds and pharmaceutical compositions containing these compounds are disclosed. Calcilytic compounds are compounds capable of inhibiting calcium receptor activity. Methods for preparing calcilytic compounds, oral bioavailability of calcilytic compounds, and their use as calcium receptor antagonists are also disclosed.

Description

PYRIDAZINONE COMPOUNDS AS CALCILYTICS
Brief Description of the Drawings
[0001] Figure 1 is a graph, which depicts the effect of bolus i.v. injection of the compound of Example 2b on plasma PTH level in normal rats.
Detailed Description
[0002] The present disclosure relates to novel calcilytic compounds, methods for preparing these compounds, oral bioavailability of these compounds, prolonged pharmacological effect of these compounds, pharmaceutical compositions containing these compounds, and their uses as calcium receptor antagonists. [0003] In mammals, extracellular Ca2+ is under rigid homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation. Extracellular Ca2+ inhibits the secretion of parathyroid hormone ("PTH") from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from C-cells. Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca2+ concentration. [0004] It is observed that PTH is the principal endocrine factor regulating Ca2+ homeostasis in the blood and extracellular fluids. PTH, by acting on bone and kidney cells, increases the level of Ca2+ in the blood. This increase in extracellular Ca2+ then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between extracellular Ca2+ and PTH secretion provides for a mechanism maintaining bodily Ca2+ homeostasis.
[0005] It is also observed that extracellular Ca2+ acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein, which detects changes in extracellular Ca2+, has been confirmed (see Brown et al., Nature, 366:574, (1993)). In parathyroid cells, this calcium receptor protein acts as a receptor for extracellular Ca2+, detects changes in the ion concentration of extracellular Ca2+ and initiates a functional cellular response, namely PTH secretion. [0006] Extracellular Ca2+ may influence various cell functions, as reviewed in Nemeth et al., Cell Calcium, 11:319 (1990). For example, extracellular Ca2+ plays a role in parafollicular (C-cells) and parathyroid cells (see Nemeth, Cell Calcium, 11 :319 (1990)). The role of extracellular Ca2+ on bone osteoclasts has also been studied (see, e.g., Zaidi, Bioscience Reports, 10:493 (1990)). [0007] Compounds are known to mimic the effects of extra-cellular Ca2+ on a calcium receptor molecule. However, calcilytics are compounds able to inhibit calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca2+. Calcilytics may be useful as lead molecules in the discovery, development, design, modification and/or construction of useful calcium modulators, which are active at Ca2+ receptors. Such calcilytics may also be useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expression and/or secretion of which is regulated or affected by activity at one or more Ca2+ receptors. Target diseases or disorders for calcilytic compounds include diseases involving abnormal bone and mineral homeostasis. [0008] Abnormal calcium homeostasis may be characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels. [0009] Thus, calcium receptor antagonists offer a unique approach towards the pharmacotherapy of diseases associated with abnormal bone or mineral homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis. [0010] The present disclosure features calcilytic compounds. "Calcilytic compounds" refer to compounds able to inhibit calcium receptor activity. The ability of a compound to "inhibit calcium receptor activity" refers to the ability of a compound to cause a decrease in one or more calcium receptor activities evoked by extracellular Ca2+.
[0011] The use of calcilytic compounds to inhibit calcium receptor activity and/or achieve a beneficial effect in a patient is described herein. More specifically, the present disclosure demonstrates the ability of calcilytic compounds to increase PTH secretion, thereby confirming that the parathyroid gland calcium receptor is a target site for these compounds. Also described herein are techniques, which may be used to obtain additional calcilytic compounds and prodrugs of calcilytic compounds. [0012] Examples of the featured calcilytic compounds representing 2,4,5,6- substituted 2H-pyridazin-3-ones are provided by the chemical formula depicted in Structure I and the accompanying description.
Figure imgf000005_0001
[0013] wherein:
[0014] R1, R2, R3 and R4 are independently one of H, lower alkyl, cycloalk or a group of the formula CH(lower alkyl)(CH2)n-R5 or (CH2)n-R5 wherein n is 0, 1 , or 2, and R5 is a heterocycle or an aryl group which may have 0 to 4 substituents in the ring. In alternative embodiments, the aryl group may have 0 to 5 substituents in the aryl ring. Each substituent is at least one of: halogen, CN, CF3, OCF3, lower alkyl, NO2, NH2, NH(lower alk), N(lower alk)2l NH[S(O)2lower alk], NH[S(O)2alkyl aryl], NH[S(O)2aryl], NH[S(O)2heterocycle], OS(O)2NH2, OS(O)2NH(lower alkyl), OS(O)2N(lower alkyl)2, lower alkoxy, OH, OC(O)-lower alk, OC(O)-lower alkyl-NH2, OC(0)-lower alkyl-NH(lower alk), OC(O)-lower alkyl-N(lower alk)2, OC(0)0-lower alk, OC(0)0-lower alkyl amino, OC(O)O-lower alkyl-NH(lower alk), OC(O)O-lower alkyl- N(lower alk)2, OC(O)NH-lower alk, OC(O)N(lower alk)2, OC(0)heterocycle, O-lower alkyl-P(O)(OH)2, O-lower alkyl-P(O)OH(O-lσwer alkyl-OC(O)O-lower alkyl), O-lower alkyl-P(O)(O-lower alkyl-OC(0)0-lower alk)2, OP(O)(OH)2, OP(0)(0-lower alkyl- aryl)2, OP(O)(O-lower alk)2, OP(O)(O-lower alkyl-OC(O)O-lower alk)2 and OP(O)(O- metal)2; or pharmaceutically acceptable salts, hydrates, tautomers, solvates or complexes thereof.
[0015] In certain embodiments, R1 may be one of: lower alkyl, cycloalk, (CH2)n-R5 or CH(lower alkyl)(CH2)n-R5, wherein n may be 2 or 1 in certain embodiments, and n may be 2, 1 or O in other embodiments. R5 is an aryl group which may have O to 3 substituents in the aryl ring. More particularly, in certain embodiments wherein R1 is a group of the formula (CH2)n-R5, n is 1 and R5 is an aryl group, 1 to 3 substituents on the aryl ring may be one of: lower alkyl and halogen. Also, in other embodiments wherein R1 is a group of formula CH(lower alk)(CH2)n-R5, n is 0 or 1, and R5 is an aryl group, 1 to 3 substituents on the aryl ring may be one of: H, lower alkyl and halogen. In other certain embodiments, R5 is a heterocycle wherein the heterocycle may be one of: thiophene, morpholine, piperidine, imidazole, thiazole, benzothiadiazole, benzoxadiazole.
[0017] In certain embodiments R2 may be one of: CH(lower alkyl)(CH2)n-R5 or (CH2)n-R5 wherein n may be 2 or 1 , or alternatively 0, and R5 is an aryl group, 1 to 3 substituents in the aryl ring may be one of: lower alkyl and halogen. [0018] In certain embodiments R3 may be (CH2)n-R5 wherein n may be 1 or 0, and R5 is an aryl group, wherein 0 to 3 substituents in the aryl ring may be one of: lower alkoxy, OH and halogen.
[0019] In certain embodiments R4 may be lower alkyl or an aryl group, wherein 0 to 3 substituents in the aryl ring may be one of: lower alkyl and halogen. [0020] "AIk" refers to either alkyl or alkenyl. "Lower alk" refers to either lower alkyl or lower alkenyl.
[0021] "Alkenyl" refers to an optionally substituted hydrocarbon group containing at least one carbon-carbon double bond between the carbon atoms and containing 2- 6 carbon atoms joined together. The alkenyl hydrocarbon group may be straight- chain. In some embodiments, straight-chain alkenyl has 2 to 4 carbons. [0022] "Alkyl" refers to an optionally substituted hydrocarbon group joined by single carbon-carbon bonds and having 1 to 6 carbon atoms joined together. The alkyl hydrocarbon group may be straight-chain or contain one or more branches. In some embodiments, branched- and straight-chain alkyl groups have 1 to 4 carbons, each of which may be optionally substituted. Alkyl substituents may be independently one of: lower alkyl, unsubstituted aryl, OH, NH2, NH-lower alkyl, or N(lower alkyl)2. In some embodiments, no more than two substituents are present. For example, alkyl may be a lower alkyl, which is unsubstituted branched- or straight-chain alkyl having 1 to 5 carbons. In other embodiments, alkyl may be a lower alkyl having 1 to 4 carbons.
[0023] "Cycloalk" refers to an optionally substituted cyclic alkyl or an optionally substituted non-aromatic cyclic alkenyl and includes monocyclic and multiple ring structures such as bicyclic and tricyclic. The cycloalkyl may have, for example, 3 to 15 carbon atoms. In one embodiment, cycloalkyl has 3 to 5 carbon atoms. Optional substituents for cycloalk are independently selected from the group described above for alkyl and alkenyl. In one embodiment, no more than three substituents are present. In another embodiment, the cycloalk is unsubstituted. For example, the cylcoalk may be an unsubstituted cyclic alkyl. Examples of suitable cycloalkyl groups include cyclopropyl and cyclobutyl.
[0024] "Heterocycle" refers to an optionally substituted aromatic or non-aromatic ringed moieties. Heterocyclic moieties typically comprise one ring or two fused rings, where the ring(s) is 5 to 6-membered and typically contains 1 to 3 non-carbon atoms.
Non-carbon atoms for heterocycle are independently selected from nitrogen, oxygen and sulfur.
[0025] "Aryl" refers to an optionally substituted aromatic group with at least one ring having a conjugated ring system or fused conjugated ring system. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. The aryl may be either optionally substituted phenyl or optionally substituted pyridyl.
[0026] "Alkoxy" refers to oxygen joined to an unsubstituted alkyl 1 to 4 carbon atoms in length. In one embodiment, the oxygen is joined to an unsubstituted alkyl 1 to 2 carbons in length. For example, the alkoxy may be methoxy. Θ
[0027] "Metal" refers to a monovalent metal cation. For example, the metal may be sodium or potassium.
[0028] Compounds which are particularly useful embodiments include:
[0029] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isopropyl-6-methyl-
2H-pyridazin-3-one;
[0030] δ-CS-fluoro^-hydroxy-phenylM-p-β-fluoro-phenyO-ethyll^-isopropyl-δ- methyl-2H-pyridazin-3-one;
[0031] 5-(2-hydroxy-phenyl)-6-methyl-2,4-diphenethyl-2H-pyridazin-3-one;
[0032] 2-(3,5-dimethoxy-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2H-pyridazin-3-one;
[0033] 2-benzo[1 ,2,5]thiadiazol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one;
[0034] 5-(3-fluoro-2-hydroxy-phenyl)-6-methyl-2,4-diphenethyl-2H-pyridazin-3- one;
[0035] 2-(3,5-dimethoxy-benzyl)-5-(2-hydroxy-phenyl)-6-methyl-4-phenethyl-2H- pyridazin-3-one;
[0036] 2-[2-(3,5-dimethoxy-phenyl)-ethyl]-5-(3-fluoro-2-hydroxy-phenyl)-6-methyl-
4-phenethyl-2H-pyridazin-3-one;
[0037] 2-(3,4-dimethoxy-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2H-pyridazin-3-one; [0038] 2-(3,5-dimethyl-isoxazol-4-ylmethyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one;
[0039] 2-benzo[1 ,3]dioxol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2H-pyridazin-3-one;
[0040] 5-(2-hydroxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-3-yl-ethyl)-2H- pyridazin-3-one;
[0041] 5-(2-hydroxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-2-yl-ethyl)-2H- pyridazin-3-one.
[0042] An expanded list of compounds which are also particularly useful embodiments include:
[0043] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isobutyl-6-methyl-2H- pyridazin-3-one;
[0044] 2-cyclopentyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-
2H-pyridazin-3-one;
[0045] 2-benzyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H- pyridazin-3-one;
[0046] 2-cyclopentylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one;
[0047] 6-ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isopropyl-2H- pyridazin-3-one;
[0048] 2-cyclopropylmethyl-5-(2-hydroxy-phenyl)-6-methyl-4-phenethyl-2H- pyridazin-3-one;
[0049] 5-(2-hydroxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl-4-phenethyl-2H- pyridazin-3-one;
[0050] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(4-methoxy-benzyl)-6- methyl-2H-pyridazin-3-one;
[0051] 4-[2-(4-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-phenethyl-
2H-pyridazin-3-one;
[0052] 2-benzo[1 ,2,5]thiadiazol-4-ylmethyl-5-(3-fluoro-2-hydroxy-phenyl)-4-[2-(3- fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one;
[0053] 2-(3,5-dimethoxy-benzyl)-5-(3-fluoro-2-hydroxy-phenyl)-4-[2-(3-fluoro- phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one;
[0054] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3,4,5- trimethoxy-benzyl)-2H-pyridazin-3-one; [0055] 2-[3,5-bis-(2-methoxy-ethoxy)-benzyl]-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one;
[0056] 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)- 6-methyl-2-phenethyl-
2H-pyridazin-3-one;
[0057] 4-[2~(3~fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(3-methoxy-benzyl)-6- methyl-2H-pyridazin-3-one;
[0058] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-piperidin-3- ylmethyl-2H-pyridazin-3-one;
[0059] 2-benzo[1 ,2,5]oxadiazol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one;
[0060] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(2-methyl- thiazol-4-ylmethyl)-2H-pyridazin-3-one;
[0061] 4-[2-(3,4-difluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2- phenethyl~2H-pyridazin-3-one.
[0062] A further expanded list of compounds which are also particularly useful embodiments include:
[0063] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3-methyl- butyl)-2H-pyridazin-3-one;
[0064] 5-(2-hydroxy-phenyl)-2-isopropyl-6-methyl-4-phenethyl-2H-pyridazin-3- one;
[0065] δ-CS-fluoro^-hydroxy-phenyO^-p-CS-fluoro-phenyO-ethylJ^-isopropyl-β- methyl-2H-pyridazin-3-one;
[0066] 5-(2-fluoro-3-hydroxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-6- methyl-2H-pyridazin-3-one;
[0067] 5-(2-hydroxy-phenyl)-2-isopropyl-4-phenethyl-6-propyl-2H-pyridazin-3- one;
[0068] 2-(2-chloro-benzyl)-4-t2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one;
[0069] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(2-methyl- benzyl)-2H-pyridazin-3-one;
[0070] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3-methyl- benzyl)-2H-pyridazin-3-one;
[0071] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(4-methyl- benzyl)-2H-pyridazin-3-one; [0072] 5-(2-hydroxy-phenyl)-6-methyl-4-phenethyl-2-(1-phenyl-ethyl)-2H- pyridazin-3-one;
[0073] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(1-phenyl- ethyl)-2H-pyridazin-3-one;
[0074] 2-[2-(3,5-dimethoxy-phenyl)-ethyl]-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one;
[0075] 2-benzo[1,3]dioxol-5-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2H-pyridazin-3-one;
[0076] 3-[4-(2-hydroxy-phenyl)-3-methyl-6-oxo-5-phenethyl-6H-pyridazin-1- ylmethyl]-Λ/-methyl-benzamide;
[0077] 3-{5-[2-(3-fluoro-phenyl)-ethyl]-4-(2-hydroxy-phenyl)-3-methyl-6-oxo-6H- pyridazin-1-ylmethyl}-Λ/-methyl-benzamide;
[0078] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(2-methoxy-ethyl)-6- methyl-2H-pyridazin-3-one;
[0079] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(2- morpholin-4-yl-benzyl)-2H-pyridazin-3-one;
[0080] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3- morpholin-4-yl-benzyl)-2H-pyridazin-3-one;
[0081] {5-[2-(3-fluoro-phenyl)-ethyl]-4-(2-hydroxy-phenyl)-3-methyl-6-oxo-6H- pyridazin-1-yl}-acetic acid methyl ester;
[0082] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(2-methoxy-benzyl)-6- methyl-2H-pyridazin-3-one;
[0083] 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3-phenyl- propyl)-2H-pyridazin-3-one.
[0084] By way of example, the calcilytic compounds of Structure I can be prepared by reacting 1 ,3,5-substituted 2H-pyridazin-3-ones with an alkyl halide.
1 ,3,5-Substituted 2H-pyridazin-3-ones may be prepared by Scheme I involving a method of reacting 4-aryl-2-oxo-butyric acids with 1-aryl-alkan-2-ones and hydrazine hydrate. 4-Aryl-2-oxo-butyric acids may be prepared by reacting 4-aryl-2-hydroxy- but-3-enoic acids with sodium hydroxide. Also, 1 ,3,5-substituted 2H-pyridazin-3-ones may be prepared by Scheme Il involving a method of reacting 3,4,5-substituted 5- hydroxy-5H-furan-2-ones with hydrazine hydrate. 3,4,5-Substituted 5-hydroxy-5H- furan-2-ones can be prepared using standard techniques known to those having skill in the art. For example, see WO 96/36623, entitled Diaryl-5-Oxygenated-2-(5H)-
Furanones as COX-2 Inhibitors. Scheme I
Figure imgf000011_0001
Scheme Il
Figure imgf000011_0002
[0085] In order to use a compound of Formula (I) or a pharmaceutically acceptable salt or complex thereof for the treatment of humans and other mammals, it is typically formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
[0086] The calcilytic compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration. Systemic administration may be accomplished through oral administration. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. [0087] Additional information about standard pharmaceutical practice for formulating pharmaceutical compositions such as conventional techniques for making tablets and pills containing active ingredients are described in the standard reference, "Remington: the Science and Practice of Pharmacy," (21st ed. 2005). This standard reference is incorporated herein.
[0088] Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
[0089] Systemic administration can also be achieved by transmucosal or transdermal methods. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories. [0090] For topical administration, the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art. [0091] The amounts of various calcilytic compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC50, ECSQ, the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
[0092] Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses may have to be administered.
[0093] The composition may be in unit dosage form. For oral application, for example, a tablet or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered, and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.
[0094] Each dosage unit for oral administration may contain suitably from 0.01 to
500 mg/Kg, and particularly from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt or complex thereof, calculated as the free base.
The daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes may contain suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula
(I). A topical formulation may contain suitably 0.01 to 5.0% of a compound of
Formula (I). The active ingredient may be administered as a single dose or in multiple does, for example, from 2 to 6 times per day, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
[0095] As used herein, "treatment" of a disease includes, but is not limited to prevention, retardation and prophylaxis of the disease.
[0096] Diseases and disorders which might be treated or prevented, based upon the affected cells, include bone and mineral-related diseases or disorders; hypoparathyroidism; those of the central nervous system such as seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage, such as occurs in cardiac arrest or neonatal distress, epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, and Tourette's syndrome; diseases involving excess water reabsorption by the kidney, such as syndrome of inappropriate ADH secretion (SIADH), cirrhosis, congestive heart failure, and nephrosis; hypertension; preventing and/or decreasing renal toxicity from cationic antibiotics (e.g., aminoglycoside antibiotics); gut motility disorders such as diarrhea and spastic colon; Gl ulcer diseases; Gl diseases with excessive calcium absorption such as sarcoidosis; autoimmune diseases and organ transplant rejection; squamous cell carcinoma; and pancreatitis.
[0097] In one embodiment, the present compounds are used to increase serum parathyroid hormone ("PTH") levels. Increasing serum PTH levels may be helpful in treating diseases such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia of malignancy, and osteoporosis.
[0098] In another embodiment, the present compounds are co-administered with an anti-resorptive agent. Such agents include, but are not limited to estrogen, 1 ,25- (OH)2"Vitamin D3, calcitonin, selective estrogen receptor modulators, vitronectin receptor antagonists, V-H+-ATPase inhibitors, src SH2 antagonists, bisphosphonates and cathepsin K inhibitors.
[0099] Another aspect of the present disclosure provides a method of treating a patient comprising administering to the patient an amount of a present compound sufficient to increase the serum PTH level. In one embodiment, the method is carried out by administering an amount of the compound effective to cause an increase in duration and/or quantity of serum PTH level sufficient to have a therapeutic effect. [00100] In various embodiments, the compound administered to a patient causes an increase in serum PTH having a duration of up to one hour, about one to about twenty-four hours, about one to about twelve hours, about one to about six hours, about one to about five hours, about one to about four hours, about two to about five hours, about two to about four hours, or about three to about six hours. [00101] In an alternative embodiment, the compound administered to a patient causes an increase in serum PTH having a duration of more than about twenty-four hours provided that it is co-administered with an anti resorptive agent. [00102] In additional different embodiments, the compound administered to a patient causes an increase in serum PTH of up to two-fold, two- to five-fold, five- to ten-fold, and at least 10-fold, greater than peak serum PTH in the patient. The peak serum level is measured with respect to a patient not undergoing treatment. [00103] The composition of Formula (I) and their pharmaceutically acceptable salts and/or complexes, which may be active when given orally, can be formulated as syrups, tablets, capsules, and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier such as, for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation may be suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be utilized. For example, aqueous gums, celluloses, silicates or oils may be used to form a soft gelatin capsule shell.
[00104] Typical parenteral compositions include a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
[00105] Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
[00106] A typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt or complex thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low-melting vegetable waxes or fats or their synthetic analogs.
[00107] Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
[00108] The composition may be in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
Examples
[00109] The following specific examples are included for illustrative purposes only and are not to be considered as limiting to this disclosure. The reagents and intermediates used in the following examples are either commercially available or can be prepared according to standard literature procedures by those skilled in the art of organic synthesis.
[00110] Microwave reactions were performed on Initiator TM (Biotage, Sweden) on continuous irradiation at 2450 MHz. All microwave reactions were carried out in heavy-walled Borosilicate tubes, sealed with cap fitted Teflon Septa. [00111] HPLC (High Pressure Liquid Chromatography) analyses for 95+% purity confirmation were performed on a Gilson Series HPLC equipped with an Agilent DAD 170 (diode array detector), and a Macherey-Nagel Nucleodur C18 (5μ, 4.6x150 mm) column.
[00112] MS (Mass Spectrometry) analyses were performed on an Aqa single quad ThermoFinnigan spectrometer with an ESI (Electrospray Ionization) and were recorded in the positive-ion mode.
[00113] NMR (Nuclear Magnetic Resonance) spectroscopy was performed on a Bruker Advance 300 spectrometer and on a Varian Gemini 300 spectrometer. Proton and carbon spectra were recorded at 300 MHz and 75 MHz, respectively, in deuterochloroform (CDCI3), methanol-^ (CH3OH-Cf4), or dimethylsulfoxide-d6 (DMSO- d6) solutions. NMR resonances are reported in δ (ppm) relative to tetramethylsilane (TMS) as internal standard with the following descriptors for the observed multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), and m (multiplet). JAB coupling constants are reported in Hz. Example 1
Preparation of 4-f2-(3-fluoro-phenyl)-ethvπ-5-(2-hvdroxy-phenyl)-2-isobutyl-6-methyl-
2H-pyridazin-3-one
Figure imgf000016_0001
[00114] a) Potassium 4-(3-fluoro-phenyl)-2-oxo-but-3-enoate
Figure imgf000016_0002
[00115] A 250 mL single necked flask was charged with pyruvic acid (5.67 ml, 80.6 mmol), ice (33 g) and potassium hydroxide (6.8 g, 121.2 mmol). 3- Fluorobenzaldehyde (10 g, 80.6 mmol) was then added to this cold solution followed by methanol (75 mL). The reaction mixture was stirred for 2 hours at room temperature before filtration. Potassium 4-(3-fluoro-phenyl)-2-oxo-but-3-enoate was collected as yellowish solid (12.4 g, 65%). [00116] 1H NMR (DMSO-d6): δ 7.5 - 6.8 (m). [00117] HPLC (gradient 5% to 80% acetonitrile in H2O): 100%.
[00118] b) 4-(3-Fluoro-phenyl)-2-hydroxy-but-3-enoic acid
Figure imgf000016_0003
[00119] Potassium borohydride (2.16 g, 40.2 mmol) was added to a solution of potassium 4-(3-fluoro-phenyl)-2-oxo-but-3-enoate of Example 1a (12.4 g, 52.9 mmol) in water (220 mL). The resulting solution was stirred at room temperature overnight, and then acidified with a 6N hydrochloric acid aqueous solution. The mixture was stirred for 3 hours and filtered. The solid obtained was washed with absolute ethanol (50 mL) and dried under high vacuum to afford 4-(3-fluoro-phenyI)-2-hydroxy-but-3- enoic acid (11.34 g, 100%) as a white solid. [00120] 1H NMR (DMSO-c/6): δ 7.33 - 6.34 (m, 6H), 4.76 - 4.71 (m, 1 H).
[00121] HPLC (gradient 5% to 80% ACN in H2O): 98%.
[00122] MS (ESI") (+ 1 % NEt3): 194.9 [C10H9FO3 -H]" (m/z).
[00123] c) 4-(3-Fluoro-phenyl)-2-oxo-butyric acid
Figure imgf000017_0001
[00124] Sodium hydroxide (5.2 g) was added to a solution of 4~(3-fluoro-phenyl)-2- hydroxy-but-3-enoic acid of Example 1b (11.34 g) in water (104 mL). The mixture was refluxed for 1.5 hours and cooled to room temperature and acidified with 6N hydrochloric acid aqueous solution to pH 1-2. The mixture was extracted with ethyl acetate (200 mL). The organic layer was dried and concentrated under reduced pressure to give 4-(3-fluoro-phenyl)-2-oxo-butyric acid (7 g, 45% overall yield) as a yellowish oil. [00125] MS (ESI") (+ 1 % Et3N): 195.0 [C10H9FO3 -H]" (m/z).
[00126] d) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one
Figure imgf000017_0002
[00127] Titanium (IV) chloride (0.44 ml, 4.07 mmol) was added to a solution of 4- (3-fluoro-phenyl)-2-oxo-butyric acid of Example 1c (2 g, 10.2 mmol) and 1-(2- methoxy-phenyl)-propan-2-one (1.58 ml, 10.2 mmol) in dry toluene (40.7 mL) at room temperature. The reaction mixture was stirred overnight under argon, and then ice was added (50 g). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was treated with hydrazine hydrate (0.85 ml, 17.55 mmol) in n-butanol (48 mL). The reaction mixture was stirred under reflux overnight, and then concentrated in vacuum to yield the crude product which was purified by flash chromatography on silica gel, eluting with cyclohexane - ethyl acetate (6:4). Triturating in diethyl ether afforded 4-
[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one (0.350 g, 10%) as a white solid.
[00128] 1H NMR (DMSOd6): δ 12.75 (s, 1H), 7.46 - 7.44 (m, 1 H), 7.24 - 7.16 (m,
2H), 7.05 - 6.95 (m, 3H), 6.74 - 6.64 (m, 2H), 3.74 (s, 3H), 2.66 - 2.61 (m, 2H), 2.52 -
2.36 (m, 2H), 1.84 (s, 3H).
[00129] HPLC (gradient 20% to 80% ACN in H2O): 98%.
[00130] MS (ESI+) (+ 0.1% HCOOH): 338.9 [C2oH19FN2θ2+H]+ (m/z)
[00131] e) 4-[2-(3-Fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl- 2H-pyridazin-3-one
Figure imgf000018_0001
[00132] A solution of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl- 2H-pyridazin-3-one of Example 1d (0.5 g, 1.47 mmol) in anhydrous dimethylformamide (3.7 mL) was treated with isobutyl iodide (0.36 ml_, 3.1 mmol) and potassium carbonate (0.51 g, 3.69 mmol). The reaction mixture was stirred under argon at 60 0C overnight, and then cooled to room temperature. Water (50 mL) was added followed, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting crude product was purified by flash chromatography on silica gel, eluting with cyclohexane - ethyl acetate (8:2) to afford 4-[2-(3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin- 3-one (0.53 g, 91%) as yellowish oil.
[00133] 1H NMR (DMSO-c/6): δ 7.44 - 7.41 (m, 1 H), 7.21 - 7.14 (m, 2H), 7.04 - 6.91 (m, 3H), 6.71 - 6.61 (m, 2H), 3.95 - 3.91 (m, 1 H), 3.84 - 3.80 (m, 1 H) 3.72 (s, 3H), 2.62 - 2.14 (m, 5H), 1.84 (s, 3H), 0.89 - 0.87 (m, 6H). [00134] HPLC (isocratic 80% ACN in H2O): >99%. [00135] MS (ESI+) (+ 0.1% HCOOH): 394.9 [C24H27FN2O2H-H]+ (m/z). [00136] f) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isobutyl-6-methyl- 2H-pyridazin-3-one
Figure imgf000019_0001
[00137] A solution of 4-[2-(3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one of Example 1e (0.436 g, 1.1 mmol) in dry methylene chloride (5.7 ml_) was cooled to -70 °C and boron tribromide (1M in dichloromethane) (3.3 ml_, 3.3 mmol) was added in one shot. The reaction mixture was allowed to warm to room temperature, and then was heated using a microwave oven (25 min at 1500C, pressure raised to 14 bars). Water (76 ml_) was then added, and the mixture was extracted with dichloromethane (127 ml_). The organic layer was dried over sodium sulfate and concentrated in vacuum to give a residue which was purified by flash chromatography on silica gel, eluting with dichloromethane - methanol (gradient from 2% to 6% of methanol). Triturating in diethyl ether afforded 4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isobutyl-6-methyl-2H-pyridazin-3-one (0.150 g, 35%) as a white solid.
[00138] 1H NMR (DMSO-CZ6): δ 9.72 (s, 1 H), 7.26 - 7.17 (m, 2H), 6.98 - 6.86 (m, 4H), 6.73 - 6.63 (m, 2H), 3.90 - 3.84 (m, 2H), 2.63 - 2.37 (m, 4H), 2.18 - 2.14 (m, 1H), 1.90 (s, 3H), 0.89 - 0.87 (m, 6H).
[00139] HPLC (gradient 20% to 80% ACN in H2O): >99%. [00140] MS (ESI+) (+ 0.1 % HCOOH): 380.9 [C23H25FN2O2H-H]+ (m/z).
Example 2
Preparation of 4-r2-(3-fluoro-phenyl)-ethyll-5-(2-hydroxy-phenyl)-2-isopropyl-6- methyl-2H-pyridazin-3-one
Figure imgf000019_0002
[00141] a) 4-[2-(3-Fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one
Figure imgf000020_0001
[00142] Utilizing the procedures described in Example 1a-e except substituting isobutyl iodide for isopropyl iodide in step 1e, 4-[2-(3-fluoro-phenyl)-ethyl]-2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was prepared as yellowish oil (0.18 g, 60%).
[00143] 1H NMR (DMSOd6): δ 7.44 - 7.42 (m, 1H), 7.22 - 7.14 (m, 2H), 7.03 - 6.93
(m, 3H), 6.71 - 6.61 (m, 2H), 5.20 - 5.15 (m, 1H), 3.72 (s, 3H), 2.62 - 2.37 (m, 4H),
1.87 (s, 3H), 1.31 - 1.27 (m, 6H).
[00144] HPLC (isocratic 80% ACN in H2O): >95%.
[00145] MS (ESI+) (+ 0.1 % HCOOH): 380.9 [C23H25FN2O2+^* (m/z).
[00146] b) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isopropyl-6- methyl-2H-pyridazin-3-one
Figure imgf000020_0002
[00147] Utilizing the procedure described in Example 1f except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one for 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 2a, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2- isopropyl-6-methyl-2H-pyridazin-3-one was prepared as a white solid (0.07 g, 24%). [00148] 1H NMR (DMSO-c/6): δ 9.75 (s, 1 H), 7.27 - 7.19 (m, 2H), 6.99 - 6.87 (m, 4H), 6.73 - 6.63 (m, 2H), 5.20 - 5.15 (m, 1 H), 2.65 - 2.39 (m, 4H), 1.93 (s, 3H), 1.30 - 1.28 (m, 6H). [00149] HPLC (gradient 20% to 80% ACN in H2O): >95%.
[00150] MS (ESI+) (+ 0.1 % HCOOH) : 366.8 [C22H23FN2O2+H]+ (m/z).
Example 3
Preparation of 4-r2-(3-fluoro-phenyl)-ethvn-5-(2-hydroxy-phenyl)-6-methyl-2-(3- methvl-butvl)-2H-pyridazin-3-one
Figure imgf000021_0001
[00151] a) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(3- methyl-butyl)-2H-pyridazin-3-one
Figure imgf000021_0002
[00152] Utilizing the procedures described in Example 1a-e except substituting isobutyl iodide for 1-bromo-3-methylbutane in step 1e, 4-[2-(3-fluoro-phenyl)-ethyl]-5-
(2-methoxy-phenyl)-6-methyl-2-(3-methyl-butyl)-2H-pyridazin-3-one was prepared as yellowish oil (0.54 g, 89%).
[00153] 1H NMR (DMSO-c/6): δ 7.47 - 7.41 (m, 1H), 7.22 - 7.14 (m, 2H), 7.05 - 6.93
(m, 3H), 6.71 - 6.61 (m, 2H), 4.08 - 4.01 (m, 2H), 3.72 (s, 3H), 2.61 - 2.36 (m, 4H),
1.84 (s, 3H), 1.61 - 1.36 (m, 3H), 0.93 - 0.91 (m, 6H).
[00154] HPLC (isocratic 90% ACN in H2O): >95%.
[00155] MS (ESI+) (+ 0.1 % HCOOH): 409.0 [C25H29FN2O^H]+ (m/z)
[00156] b) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3- methyl-butyl)-2H-pyridazin-3-one
Figure imgf000022_0001
[00157] Utilizing the procedures described in Example 1f except substituting 4-[2-
(3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(3-methyl-butyl)-2H- pyridazin-3-one of Example 3a, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2-(3-methyl-butyl)-2H-pyridazin-3-one was prepared as white solid (0.12 g,
28%).
[00158] 1H NMR (DMSO-c/6): δ 9.74 (s, 1 H), 7.27 - 7.20 (m, 2H), 6.98 - 6.88 (m,
4H), 6.73 - 6.62 (m, 2H), 4.06 - 4.04 (m, 2H), 2.65 - 2.37 (m, 4H), 1.91 (s, 3H), 1.59
(m, 3H), 0.93 - 0.92 (m, 6H).
[00159] HPLC (gradient 20% to 80% ACN in H2O) : >95%.
[00160] MS (ESI+) (+ 0.1% HCOOH) : 394.9 [C24H27FN2O^H]+ (m/z).
Example 4
Preparation of 2-cvclopentyl-4-f2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-6- methyl-2H-pyridazin-3-one
Figure imgf000022_0002
[00161] a) 2-Cyclopentyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one
Figure imgf000022_0003
[00162] Utilizing the procedures described in Example 1a-e except substituting isobutyl iodide for bromocyclopentane in step 1e, 2-cyclopentyl-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was prepared as yellowish oil (0.070 g, 70%).
[00163] 1H NMR (CDCI3): δ 7.41 (t, 1 H, J = 7.79), 7.12 (q, 1 H, J = 7.35), 7.05 -
6.98 (m, 2H), 6.88 - 6.74 (m, 3H), 6.62 (dt, 1 H, J1 = 9.04, J2 = 2.03), 5.53 - 5.42 (m,
1 H), 3.76 (s, 3H), 2.75 - 2.47 (m, 4H), 2.12 - 1.87 (m, 5H), 1.96 (s, 3H), 1.70 (broad s, 3H).
[00164] MS (ESI+) (+ 0.1% HCOOH): 407.26 [C25H27FN2O2+H]+ (m/z).
[00165] b) 2-Cyclopentyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one
Figure imgf000023_0001
[00166] Utilizing the procedures described in Example 1f except substituting 4-[2-
(3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyhdazin-3-one for 2-cyclopentyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 4a, 2-cyclopentyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.193 g,
62%).
[00167] 1H NMR (CDCI3): δ 7.30 (t, 1H, J = 7.79), 7.10 - 6.92 (m, 3H), 6.82 - 6.72
(m, 2H), 6.64 (d, 1H, J = 7.72), 6.53 (dt, 1 H, J1 = 8.99, J2 = 1.98), 5.49 - 5.38 (m,
1 H), 2.76 - 2.47 (m, 4H), 2.04 (s, 3H), 2.01 - 1.8 (m, 6H), 1.63 (broad s, 2H).
[00168] HPLC (gradient from 20% to 80% ACN in H2O): >99%.
[00169] MS (ESI+) (+ 0.1% HCOOH): 392.9 [C24H25FN2O2+H]+ (m/z).
Example 5
Preparation of 2-benzyl-4-[2-(3-fluoro-phenyl)-ethvπ-5-(2-hvdroxy-phenyl)-6-methyl-
2H-pvridazin-3-one
Figure imgf000024_0001
[00170] a) 2-Benzyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl- 2H-pyridazin-3-one
Figure imgf000024_0002
[00171] Utilizing the procedures described in Example 1a-e except substituting isobutyl iodide for benzyl bromide in step 1e, 2-benzyl-4-[2-(3-fluoro-phenyl)-ethyl]-5- (2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was prepared as a white solid (0.3 g, 84%).
[00172] 1H NMR (CDCI3): δ 7.54 (d, 2H, J = 8.48), 7.45 - 7.28 (m, 4H), 7.15 - 6.97 (m, 3H), 6.84 - 6.77 (m, 2H), 6.73 (d, 1 H, J = 7.72), 6.62 (dt, 1 H, J1 = 9.99, J2 = 1.98), 5.37 (dd, 2H, J1 = 42.11 , J2 = 13.65), 3.75 (s, 3H), 2.79 - 2.48 (m, 4H), 1.96 (s, 3H).
[00173] b) 2-Benzyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyI)-6-methyl- 2H-pyridazin-3-one
Figure imgf000024_0003
[00174] Utilizing the procedures described in Example 1f except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one for 2-benzyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 5a, 2-benzyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6~methyl-2H-pyridazin-3-one was prepared as a white solid (0.180 g, 64%). [00175] 1H NMR (CDCI3): δ 7.48 (d, 2H, J = 7.73), 7.36 - 7.27 (m, 5H), 7.08 - 6.93 (m, 3H), 6.81 - 6.72 (m, 2H), 6.63 (d, 1 H, J = 7.73), 6.54 (dt, 1 H1 J1 = 9.79, J2 = 1.89), 5.34 (dd, 2H, J1 = 58.50, J2 = 13.66), 2.77 - 2.47 (m, 4H), 2.02 (s, 3H). [00176] HPLC (gradient from 20% to 80% ACN in H2O) : >99%. [00177] MS (ESI+) (+ 0.1% HCOOH): 415.0 [C26H23FN2O2+H]+ (m/z).
Example 6
Preparation of 2-cvclopentylmethyl-4-[2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-
6-methvl-2H-pyridazin-3-one
Figure imgf000025_0001
[00178] a) 2-Cyclopentylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one
Figure imgf000025_0002
[00179] Utilizing the procedures described in Example 1a-e except substituting isobutyl iodide for bromomethyl cyclopentane in step 1e, 2-cyclopentylmethyl-4-[2-(3- fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was prepared as a colorless oil (0.442 g, 79%).
[00180] 1H NMR (CDCI3): δ 7.42 (td, 1 H, J1 = 7.72, J2 =1.71), 7.16 - 7.08 (m, 1 H),
7.05 - 6.92 (m, 2H), 6.84 - 6.79 (dd, 2H, J1 = 7.44, J2 = 1.79), 6.75 (d, 1 H, J = 7.53),
6.62 (dt, 1 H, J1 = 9.79, J2 = 2.07), 4.26 - 4.02 (m, 3H), 3.75 ( s, 3H), 2.77 - 2.45 (m,
4H), 1.94 (s, 3H), 1.83 - 1.50 (m, 6H), 1.45 - 1.32 (m, 2H).
[00181] MS (ESI+) (+ 0.1 % HCOOH): 421.23 [C26H29FN2O2H-H]+ (m/z). [00182] b) 2-Cyclopentylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)- 6-methyl-2H-pyridazin-3-one
Figure imgf000026_0001
[00183] Utilizing the procedures described in Example 1f except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one for 2-cyclopentylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl- 2H-pyridazin-3-one of Example 6a, 2-cyclopentylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]- 5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one was prepared as a white solid (0.345 g, 81%).
[00184] 1H NMR (CDCI3): δ 7.30 (td, 1 H, J1 = 8.1 , J2 =1.60), 7.10 - 7.00 (m, 2H), 6.94 (t, 1 H, J = 7.44), 6.80 - 6.71 (m, 2H), 6.65 (d, 1H, J = 7.53), 6.55 (dt, 1 H, J1 = 9.98, J2 = 1.79), 4.24 - 4.16 (m, 1 H), 4.04 - 3.97 (m, 1 H), 2.74 - 2.60 (m, 3H), 2.57- 2.44 (m, 2H), 2.03 (s, 3H), 1.75 - 1.45 (2 broad s, 6H), 1.40 - 1.28 (broad s, 2H). [00185] HPLC (gradient from 20% to 80% ACN in H2O) : >96% [00186] MS (ESI+) (+ 0.1% HCOOH): 407.0 [C25H27FN2O2+H]+ (m/z).
Example 7 Preparation of 6-methyl-4-phenethyl-5-phenyl-2H-pyridazin-3-one
Figure imgf000026_0002
[00187] a) 5-Hydroxy-5-methyl-4-phenyl-3-((E)-styryl)-5H-furan-2-one
Figure imgf000026_0003
[00188] frans-Styrylacetic acid (0.46 g, 2.86 mmol) and triethylamine (0.7 ml_, 4.92 mmol) were added to a solution of 2-bromopropiophenone (0.35 ml_, 2.34 mmol) in anhydrous acetonitrile (11.7 mL). The reaction mixture was stirred under argon overnight, and then 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.95 mL, 6.33 mmol) was added dropwise. The resulting solution was stirred for 1 hour under argon at room temperature, and then oxygen was bubbled through the mixture for 45 min. The reaction mixture was poured into a mixture of an aqueous solution of 1 N hydrochloric acid (6.2 mL) and 7.8 mL of brine, and extracted with 40 mL of 1 :1 ethyl acetate/cyclohexane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to yield 0.771 g of 5-hydroxy-5-methyl-4-phenyl- 3-((E)-styryl)-5H-furan-2-one compound as a yellow foam. The resulting compound was used onto the next step without any further purification.
[00189] MS (ESI+) (+ 0.1% HCOOH): 275.1 [C19Hi603-H20+H]+ (m/z). Analyses showed the dehydrated product (MS) and the presence of the expected compound (1H NMR).
[00190] b) 6-Methyl-4-phenethyl-5-phenyl-2H-pyridazin-3-one
Figure imgf000027_0001
[00191] Hydrazine hydrate (0.25 mL, 5.27 mmol) was added to a solution of 5- hydroxy-5-methyl-4-phenyl-3-((E)-styryl)-5H-furan-2-one of Example 7a (0.771 g, 2.63 mmol) in /7-butanol (20 mL). The resulting solution was refluxed overnight and concentrated in vacuum. The crude product was triturated in diethyl ether to give a yellow solid (0.24 g, first crop). This first crop was triturated in hot 1 :1 ethanol/diethyl ether and filtered to give 6-methyl-4-phenethyl-5-phenyl-2H-pyridazin-3-one (0.2 g, 30%) as a bright yellow solid.
[00192] 1H NMR (DMSO-d6): δ 12.87 (s, 1 H), 7.46 - 7.43 (m, 3H), 7.19 - 7.06 (m, 5H), 6.88 - 6.85 (m, 2H), 2.68 - 2.63 (m, 2H), 2.51 - 2.38 (m, 2H), 1.85 (s, 3H). [00193] HPLC (gradient 20% to 80% ACN in H2O): 98%. [00194] MS (ESI+) (+ 0.1% HCOOH): 290.9 [C19H18N2O+H]+ (m/z). [00195] IC50 greater than 50 μM. Example 8
Preparation of 6-ethyl-4-r2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-2-isopropyl-
2H-pyridazin-3-one
Figure imgf000028_0001
[00196] a) 4-(3-Fluoro-phenyl)-but-3-enoic acid
Figure imgf000028_0002
[00197] (2-Carboxyethyl)triphenylphosphonium bromide (2.7 g, 6.59 mmol) was added to a solution of 3-fluorobenzaldehyde (0.5 ml_, 4.71 mmol) in anhydrous tetrahydrofuran (23 ml_). The suspension was cooled to -78°C and potassium tert- butoxide (1.7 g, 15.08 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight under argon. Water (20 ml_) was added, and tetrahydrofuran was removed under reduced pressure. Water (20 ml_) was added to the resulting solution, and the aqueous layer was extracted with ethyl acetate (50 ml_). The aqueous layer was acidified with 37% aqueous solution of hydrochloric acid to pH 1 and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by flash chromatography on silica gel, eluting with cyclohexane - ethyl acetate (1 :1) to afford 4-(3-fluoro-phenyl)-but-3-enoic acid (0.5 g, 58%) as a yellowish solid.
[00198] b) Butyric acid phenyl ester
Figure imgf000028_0003
[00199] Butyryl chloride (1.65 mL, 15.93 mmol) was added dropwise at 00C to a solution of phenol (1 g, 10.62 mmol) in dry pyridine (42 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. Methylene chloride (100 mL) was added to the reaction mixture followed by a NaHCO3 saturated solution (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure and co-evaporated with toluene to yield butyric acid phenyl ester (1.64 g, 93%) as yellowish oil.
[00200] 1H NMR (DMSOd6): δ 7.42 - 7.37 (m, 2H), 7.26 - 7.21 (m, 1H), 7.10 - 7.07 (m, 2H), 2.53 (t, 2H, J = 7.26), 1.64 (q, 2H, J = 7.32), 0.95 (t, 3H, J = 7.43).
[00201] c) 1 -(2-Hydroxy-phenyl)-butan-1 -one
Figure imgf000029_0001
[00202] Anhydrous aluminum chloride (0.73 g, 5.48 mmol) was added to butyric acid phenyl ester of step 8b (1 g, 6.09 mmol). The reaction mixture was heated to 130°C for 2 hours, cooled and then dichloromethane (50 mL) was added. The organic layer was washed with 6N aqueous solution of hydrochloric acid (25 mL), water (4x25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to yield the crude product which was purified by flash chromatography on silica gel, eluting with cyclohexane - ethyl acetate (gradient from 10% to 20% of ethyl acetate) to afford 1-(2-hydroxy-phenyl)-butan-1-one (0.36 g, 36%) as yellowish oil. [00203] 1H NMR (DMSO-c/6): δ 11.98 (s, 1 H), 7.88 (m, 1 H), 7.52 - 7.47 (m, 1H), 6.95 - 6.90 (m, 2H), 3.03 (t, 2H, J = 7.32), 1.62 (q, 2H, J = 7.38), 0.95 (t, 3H, J = 7.35).
[00204] d) 1 -(2-Methoxy-phenyl)-butan-1 -one
Figure imgf000029_0002
[00205] Potassium carbonate (32.4 g, 234.21 mmol) and methyl iodide (17.5 mL, 281.18 mmol) were added to a solution of 1-(2-hydroxy-phenyl)-butan-1-one of step 8c (15.4 g, 93.72 mmol) in anhydrous dimethylformamide (187 mL). The reaction mixture was stirred under argon at 600C overnight. The mixture was cooled and extracted with ethyl acetate (500 mL). The organic layer was washed with water (3x200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by flash chromatography on silica gel with cyclohexane - ethyl acetate (95:5) to afford 1-(2-methoxy-phenyl)-butan-1-one (13.64 g, 81%) as yellowish oil.
[00206] 1H NMR (DMSO-d6): δ 7.51 - 7.46 (m, 2H)1 7.12 (m, 1H), 6.98 (t, 1H, J = 7.21), 3.84 (s, 3H), 2.85 (t, 2H, J = 7.14), 1.55 (q, 2H, J = 7.29), 0.85 (t, 3H, J = 7.39).
[00207] e) 2-Bromo-1-(2-methoxy-phenyl)-butan-1-one
Figure imgf000030_0001
[00208] Phenyltrimethylammonium tribromide (10.5 g, 28.05 mmol) was added in two portions to a solution of 1-(2-methoxy-phenyl)-butan-1-one of step 8d (5 g, 28.05 mmol) in anhydrous tetrahydrofuran (56 ml_). The reaction mixture was stirred under argon at room temperature for 3.5 hours. Water (150 ml.) was then added and the mixture was extracted with dichloromethane (150 ml_). The organic layer was dried over sodium sulfate, filtered and evaporated. The resulting crude product was purified on silica gel column chromatography using cyclohexane - ethyl acetate (8:2) as eluent to afford 2-bromo-1-(2-methoxy-phenyl)-butan-1-one compound (7.14 g, 99%) as yellowish oil.
[00209] 1H NMR (DMSO-d6): δ 7.58 - 7.52 (m, 2H), 7.17 (d, 1H, J=7.96), 7.06 - 7.01 (m, 1H), 5.41 (dd, 1H, J1 = 7.73, J2 = 5.94), 3.87 (s, 3H), 2.13 - 2.06 (m, 1H), 1.94 - 1.86 (m, 1 H), 0.97 (t, 3H, J = 7.28).
[00210] f) 5-Ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H- furan-2-one
Figure imgf000030_0002
[00211] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(2-methoxy-phenyl)-butan-1-one of Example 8e and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid of Example 8a, 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one was obtained as yellowish oil (9.06 g). The crude product was used in the next step without any further purification.
[00212] g) 6-Ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin- 3-one and 6-ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3- one
Figure imgf000031_0001
[00213] Hydrazine hydrate (3.7 ml_, 76.7 mmol) was added to a solution of 5-ethyl- 3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of step 8f (9.06 g, 25.6 mmol) in π-butanol (194 ml_). The reaction mixture was refluxed for 4 days and then concentrated in vacuum. The crude product was purified on silica gel column chromatography eluting with cyclohexane - ethyl acetate (7:3). The isolated product was triturated in diethyl ether to afford the inseparable mixture of 6-ethyl-4- [2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one and 6-ethyl-4-[2- (3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one as a white solid of (1.23 g, 15%).
[00214] HPLC (gradient 20% to 80% ACN in H2O): 98%.
[00215] MS (ESI+) (+ 0.1% HCOOH): 350.9 [C21H19FN2O2+H]+ and 352.9 [C21H2iFN2O2+H]+ (m/z).
[00216] h) 6-Ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)- 2H-pyridazin-3-one
Figure imgf000031_0002
[00217] A solution of 6-ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)- 2H-pyridazin-3-one and 6-ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)- 2H-pyridazin-3-one of step 8g (0.4 g, 1.13 mmol) in anhydrous dimethylformamide (2.8 mL) was treated with isopropyl iodide (0.33 mL, 3.39 mmol) and potassium carbonate (0.39 g, 2.83 mmol). The reaction mixture was stirred under argon at 600C overnight and cooled to room temperature. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting crude product was purified by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (9:1) to afford 6-ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2- isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3-one (0.3 g, 66%) as yellowish oil. [00218] 1H NMR (DMSOd6): δ 7.44 (m, 1 H)1 7.22 - 7.14 (m, 2H), 7.03 - 6.93 (m, 3H), 6.70 - 6.60 (m, 2H), 5.19 (m, 1H), 3.72 (s, 3H), 2.61 - 2.58 (m, 2H), 2.49 - 2.45 (m, 2H), 2.20 - 2.14 (m, 2H), 1.32 - 1.28 (m, 6H), 0.94 (t, 3H, J = 7.49). [00219] HPLC (gradient 20-80% ACN/H2O): > 99%. [00220] MS (ESI+) (+ 0.1% HCOOH) : 395.17 [C24H27FN2O2H-H]+ (m/z).
[00221] i) 6-Ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isopropyl- 2H-pyridazin-3-one
Figure imgf000032_0001
[00222] Boron tribromide (1M in dichloromethane) (1.3 mL, 1.3 mmol) was added in one shot at -700C to a solution of 6-ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl- 5-(2-methoxy-phenyl)-2H-pyridazin-3-one of step 8h (0.150 g, 0.44 mmol) in dry methylene chloride (5.7 mL). The reaction mixture was allowed to warm to room temperature and then was heated using a microwave oven (30 min at 1500C, pressure raised to 14 bars followed by 40 min at 1500C, pressure raised to 14 bars). Water (30 mL) was then added to the reaction mixture, followed by extraction with dichloromethane (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuum to give a residue which was purified by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (gradient from 10% to 20% of ethyl acetate) to afford 6-ethyl-4-[2-(3-fluoro-phenyl)-ethyI]-5-(2- hydroxy-phenyl)-2-isopropyl-2H-pyridazin-3-one (0.21 g, 77%) as an off-white foam.
[00223] 1H NMR (DMSO-d6): δ 9.73 (s, 1 H), 7.27 - 7.19 (m, 2H), 6.98 - 6.87 (m,
4H), 6.72 - 6.61 (m, 2H), 5.19 (m, 1H)1 2.66 - 2.60 (m, 2H), 2.40 - 2.25 (m, 4H), 1.32 -
1.29 (m, 6H), 0.96 (t, 3H, J = 7.40).
[00224] HPLC (gradient 20-80% ACN/H2O): > 99%.
[00225] MS (ESI+) (+ 0.1 % HCOOH): 380.9 [C23H25FN2O^H]+ (m/z).
Example 9
Preparation of 5-(2-hvdroxy-phenyl)-2-isopropyl-6-methyl-4-phenethyl-2H-pyridazin-
3-one
Figure imgf000033_0001
[00226] a) 1-(2-Methoxy-phenyl)-propan-1-one
Figure imgf000033_0002
[00227] Utilizing the procedures described in Example 8d except substituting 1-(2- hydroxy-phenyl)-butan-1-one for 1-(2-hydroxy-phenyl)-propan-1-one, 1-(2-methoxy- phenyl)-propan-1-one was obtained as yellowish oil (21.3 g, 98%). [00228] 1H NMR (CDCI3): δ 7.67 (dd, W1 J1 = 7.63, J2 = 1.6), 7.47 - 7.39 (m, 1H), 7.01 - 6.92 (m, 2H), 3.88 (s, 3H), 2.97 (q, 2H, J = 7.28), 1.15 (t, 3H, J= 7.25).
[00229] b) 2-Bromo-1-(2-methoxy-phenyl)-propan-1-one
Figure imgf000033_0003
[00230] Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one for 1-(2-methoxy-phenyl)-propan-1-one of Example 9a, 2-bromo-1-(2-methoxy-phenyl)-propan-1-one was obtained as an orange oil (20.9 g,
[00231] 1H NMR (CDCI3): δ 7.72 (dd, 1 H, J1 = 7.64, J2 = 1.79), 7.52 - 7.45 (m, 1H), 7.06 - 6.94 (m, 2H), 5.52 (q, 1 H, J = 6.78), 3.92 (s, 3H), 1.85 (d, 3H, J= 6.59).
[00232] c) 5-Hydroxy-4-(2-methoxy-phenyl)-5-methyl-3-((E)-styryl)-5H-furan-2-one
Figure imgf000034_0001
[00233] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(2-methoxy-phenyl)-propan-1-one of Example 9b, 5-Hydroxy-4-(2-methoxy-phenyl)-5-methyl-3-((E)-styryl)-5H-furan-2-one was obtained as a yellowish oil (6.85 g). The crude product was used directly onto the next step without any further purification.
[00234] d) 5-(2-Methoxy-phenyl)-6-methyl-4-styryl-2H-pyridazin-3-one and 5-(2- methoxy-phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one
Figure imgf000034_0002
[00235] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one for 5-hydroxy-4-(2-methoxy-phenyl)-5-methyl-3-((E)-styryl)-5H-furan-2-one of Example 9c, 5-(2-methoxy-phenyl)-6-methyl-4-styryl-2H-pyridazin-3-one and 5-(2-methoxy- phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one were obtained as a yellowish foam (inseparable mixture) (2.0 g, 30%).
[00236] MS (ESI+) (+ 0.1% HCOOH): 318.9 [C20H18N2O2+H]+ and 320.9 [C20H20N2O2+H]+ (m/z). [00237] e) 2-lsopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin- 3-one and 2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-4~phenethyl~2H-pyridazin-3- one
Figure imgf000035_0001
[00238] Utilizing the procedures described in Example 8h except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one and 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one for 5-(2- methoxy-phenyl)-6-methyl-4-styryl-2H-pyridazin-3-one and 5-(2-methoxy-phenyl)-6- methyl-4-phenethyl-2H-pyridazin-3-one of Example 9d, 2-isopropyl-5-(2-methoxy- phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one and 2-isopropyl-5-(2-methoxy- phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one were obtained and separated by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (9:1) (0.479 g, 85%) (81% of 2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryI)-2H- pyridazin-3-one and 19% of 2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-phenethyl- 2H-pyridazin-3-one).
[00239] 1H NMR (CDCI3) (2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)- styryl)-2H-pyridazin-3-one): δ 7.35 (d, 1 H, J = 16.2), 7.48 - 7.42 (m, 1 H), 7.28 (m, 5H), 7.09 - 7.02 (m, 3H), 7.63 (d,1 H, J = 16.21), 5.55 - 5.40 (m, 1H), 3.77 (s, 3H), 2.03 (s, 3H), 1.44 (dd, 6H, J1 = 6.59, J2 = 4.9).
[00240] 1H NMR (CDCI3) (2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-phenethyl- 2H-pyridazin-3-one): δ 7.29 (td, 1 H, J1 = 7.91 , J2 =1.69), 7.21 - 7.07 (m, 3H), 7.04 - 6.95 (m, 4H), 6.87 (dd, 1H, J1 = 7.44, J2 = 1.79), 5.46 - 5.31 (m, 1 H), 3.76 (s, 3H), 2.76 - 2.45 (m, 4H), 1.97 (s, 3H), 1.41 (dd, 6H, J1 = 6.5, J2 = 5.75).
[00241] f) 2-lsopropyl-5-(2-methoxy-phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3- one
Figure imgf000036_0001
[00242] To a solution of 2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)- 2H-pyridazin-3-one of Example 9e (0.38 g, 1.05 mmol) in ethanol (20 ml_), palladium 10% weight on carbon (0.038 g) was added. The resulting mixture was purged using hydrogen gas, and stirred for 2 hours. After filtration, the catalyst was washed with ethanol and the filtrate was concentrated in vacuum. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (9:1) to afford 2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one as a colorless oil (0.373 g, 98%).
[00243] 1H NMR (CDCI3): δ 7.29 (td, W1 J1 = 7.91 , J2 =1.69), 7.21 - 7.07 (m, 3H), 7.04 - 6.95 (m, 4H), 6.87 (dd, 1 H, J1 = 7.44, J2 = 1.79), 5.46 - 5.31 (m, 1H), 3.76 (s, 3H), 2.76 - 2.45 (m, 4H), 1.97 (s, 3H), 1.41 (dd, 6H, J1 = 6.5, J2 = 5.75).
[00244] g) 5-(2-Hydroxy-phenyl)-2-isopropyl-6-methyl-4-phenethyl-2H-pyridazin-3- one
Figure imgf000036_0002
[00245] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one of Example 9f, 5-(2-hydroxy-phenyl)-2-isopropyl-6-methyl-4-phenethyl-2H-pyridazin-
3-one was obtained as a white solid (0.275 g, 62%).
[00246] 1H NMR (CDCI3): δ 7.29 (t, 2H, J = 7.07), 7.15 - 7.02 (m, 4H), 6.98 - 6.86
(m, 3H), 6.79 (dd, W1 J1 = 7.41 , J2 = 1.51), 5.43 - 5.28 (m, 1H), 2.80 - 2.49 (m, 4H),
2.04 (s, 3H), 1.38 (t, 6H, J = 7.07).
[00247] HPLC (gradient 20-80% ACN/H2O): > 96%.
[00248] MS (ESI+) (+ 0.1 % HCOOH): 349.0 [C22H24N2O2+H]+ (m/z). Example 10
Preparation of 4-r2-(3-fluoro-phenyl)-ethyll-5-(3-hvdroxy-phenyl)-2-isopropyl-6- methyl-2H-pvridazin-3-one
Figure imgf000037_0001
[00249] a) 3,N-dimethoxy-N-methyl-benzamide
Figure imgf000037_0002
[00250] A solution of ethylchloroformate (3.14 ml_, 32.8 mmol) in anhydrous dichloromethane (6 mL) was added dropwise at 100C to a solution of m-anisic acid (5 g, 32.8 mmol) and triethylamine (4.6 mL, 32.8 mmol) in anhydrous dichloromethane (70 mL). The reaction mixture was stirred at 100C for 40 min, and then N1O- dimethylhydroxylamine hydrochloride (3.2 g, 32.8 mmol) and triethylamine (4.6 mL, 32.8 mmol) were added. The resulting mixture was stirred for 1 hour, water (150 mL) was added, and the reaction mixture was extracted with dichloromethane (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (gradient from 10% to 30% of ethyl acetate) to afford 3,N-dimethoxy-N-methyl-benzamide (3.85 g, 60%) as a colorless oil. [00251] 1H NMR (CDCI3): δ 7.30 - 7.13 (m, 3H), 6.97 - 6.92 (m, 1H), 3.78 (s, 3H), 3.53 (S, 3H), 3.30 (s, 3H).
[00252] b) 1-(3-Methoxy-phenyl)-propan-1-one
Figure imgf000037_0003
[00253] Ethyl magnesium bromide in diethyl ether (48.6 mL, 48.6 mmol) was added dropwise at 00C to a solution of 3,N-dirnethoxy-N-methyl-benzamide of Example 10a (3.8 g, 19.46 mmol), in anhydrous diethyl ether (68 mL). The reaction mixture was allowed to warm to room temperature and then stirred for 4 hours. A saturated solution of ammonium chloride (42 mL) was added followed by extraction with ethyl acetate (100 mL). The organic layer was washed with 1 N citric acid (100 mL), NaHCO3 saturated solution (100 mL), and brine (10OmL). The final organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (gradient from 10% to 30% of ethyl acetate) to afford 1- (3-methoxy-phenyl)-propan-1-one (3.85 g, 60%) as a colorless oil (2.85 g, 89%). [00254] 1H NMR (CDCI3): δ 7.52 - 7.43 (m, 2H), 7.31 (t, 1H, J = 7.91), 7.08 - 7.02 (m, 1 H), 3.80 (s, 3H), 2.94 (q, 2H, J = 7.16), 1.18 (t, 3H, J= 7.25)
[00255] c) 2-Bromo-1-(3-methoxy-phenyl)-propan-1-one
Figure imgf000038_0001
[00256] Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one for 1-(3-methoxy-phenyl)-propan-1-one of Example 10b, 2-bromo-1-(3-methoxy-phenyl)-propan-1-one was obtained as colorless oil (3.8 g, 93%).
[00257] 1H NMR (CDCI3): δ 7.62 - 7.53 (m, 2H), 7.39 (t, 1 H, J = 7.91), 7.16 - 7.11 (m, 1 H), 5.28 (q, 1 H, J = 6.59), 3.86 (s, 3H), 1.90 (d, 3H, J= 6.59)
[00258] d) 3-[2-(3-Fluoro-phenyl)-vinyl]-5-hydroxy-4-(3-methoxy-phenyl)-5-methyl- 5H-furan-2-one
Figure imgf000038_0002
[00259] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(3-methoxy-phenyl)-propan-1-one of Example 10c and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, 3-[2-(3-fluoro- phenyl)-vinyl]-5-hydroxy-4-(3-methoxy-phenyl)-5-methyl-5H-furan-2-one was obtained as an orange foam. The crude product was used directly onto the next step without any further purification.
[00260] e) 4-[2-(3-Fluoro-phenyl)-vinyl]-5-(3-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one and 4-[2-(3-fluoro-phenyl)-ethyl]-5-(3-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one
Figure imgf000039_0001
[00261] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one for 3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(3-methoxy-phenyl)-5-methyl-5H-furan-2- one of Example 10d, 4-[2-(3-fluoro-phenyl)-vinyl]-5-(3-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one and 4-[2-(3-fluoro-phenyl)-ethyl]-5-(3-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one were obtained as a brown oil (inseparable mixture) (1.26 g, 24%). [00262] MS (ESI+) (+ 0.1% HCOOH): 337.0 [C20H17FN2O2+H]+ and 339.1 [C20H19FN2O2 +H]+ (m/z)
[00263] f) 4-[2-(3-Fluoro-phenyl)-vinyl]-2-isopropyl-5-(3-methoxy-phenyl)-6-methyl- 2H-pyridazin-3-one and 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(3-methoxy- phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000039_0002
[00264] Utilizing the procedures described in Example 8h except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one and 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one for 4-[2- (3-fluoro-phenyI)-vinyl]-5-(3-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one and 4-[2- (3-fluoro-phenyl)-ethyl]-5-(3-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 10e, 4-[2-(3-fluoro-phenyl)-vinyl]-2-isopropyl-5-(3-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one and 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(3- methoxy-phenyl)-6-methyl-2H- pyridazin-3-one were obtained and separated by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (9:1) (0.4 g, 59%) (98% of 4-[2-(3-fluoro- phenyl)-vinyl]-2-isopropyl-5-(3-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one and 2 % of 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(3-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one).
[00265] 1H NMR (CDCI3) (4-[2-(3-fluoro-phenyl)-vinyl]-2-isopropyl-5-(3-methoxy- phenyl)-6-methyl-2H-pyridazin-3-one): δ 8.35 (d, 1 H, J = 16.01), 7.43 (t, 1 H, J = 7.91), 7.25 - 7.17 (m, 1 H), 7.07 - 6.98 (m, 2H), 6.95 - 6.785 (m, 2H), 6.77 (dt, 1H, J1 = 7.41 , J2 = 1.22), 6.74 - 6.71 (m, 1 H), 6.63 (d, 1 H , J = 16.2), 5.52 - 5.41 (m, 1H), 3.84 (s, 3H)1 2.07 (s, 3H), 1.41 (d, 6H, J = 6.78).
[00266] 1H NMR (CDCI3) (4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(3-methoxy- phenyl)-6-methyl-2H-pyridazin-3-one): δ 7.35 (t, 1 H, J = 7.82), 7.18 - 7.09 (m, 1 H), 6.97 - 6.90 (m, 1H), 6.86 - 6.76 (m, 2H), 6.65 (dt, 1H, J1 = 9.99, J2 = 2.07), 6.57 - 6.51 (m, 2H), 5.44 - 5.33 (m, 1 H), 3.81 (s, 3H), 2.83 - 2.54 (m, 4H), 2.00 (s, 3H), 1.41 (d, 6H1 J = 6.78).
[00267] g) 4-[2-(3-Fluoro-phenyl)-ethyl]-2-isopropyl-5-(3-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one
Figure imgf000040_0001
[00268] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 4-[2-(3- fluoro-phenyl)-vinyl]-2-isopropyl-5-(3-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 10f, 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(3-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.331 g, 85%). [00269] 1H NMR (CDCI3): δ 7.35 (t, 1H, J = 7.82), 7.18 - 7.09 (m, 1 H), 6.97 - 6.90 (m, 1 H)1 6.86 - 6.76 (m, 2H), 6.65 (dt, 1 H, J1 = 9.99, J2 = 2.07), 6.57 - 6.51 (m, 2H), 5.44 - 5.33 (m, 1H), 3.81 (s, 3H), 2.83 - 2.54 (m, 4H), 2.00 (s, 3H)1 1.41 (d, 6H, J = 6.78).
[00270] h) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(3-hydroxy~phenyl)-2-isopropyl-6- methyl-2H-pyridazin-3-one
Figure imgf000041_0001
[00271] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(3-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 10g, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(3-hydroxy-phenyl)-2- isopropyl-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.275 g, 62%).
[00272] 1H NMR (CDCI3): δ 7.30 (d, 1H, J = 7.91), 7.15 - 7.07 (m, 1 H), 6.94 - 6.89
(m, 1 H), 6.85 - 6.77 (m, 1 H), 6.71 (d, 1H1 J = 7.53), 6.62 (dt, 1 H, J1 = 9.99, J2 = 1.89),
6.48 (dt, I H1 J1 = 7.54, J2 = 1.13),6.36 - 6.33 (m, 1 H), 6.29 (s, 1 H), 2.84 - 2.51 (m,
4H), 1.99 (s, 3H), 1.39 (t, 6H, J = 6.59).
[00273] HPLC (gradient 20-80% ACN/H2O): > 99%.
[00274] MS (ESI+) (+ 0.1% HCOOH): 367.1 [C22H23FN2O2H-H]+ (m/z).
[00275] IC50 greater than 50 μM.
Example 11
Preparation of 5-(3-fluoro-2-hvdroxy-phenyl)-4-r2-(3-fluoro-phenyl)-ethyl1-2-isopropyl-
6-methyl-2H-pvridazin-3-one
Figure imgf000041_0002
[00276] a) 3-Fluoro-2,N-dimethoxy-N-methyl-benzamide
Figure imgf000042_0001
[00277] Utilizing the procedures described in Example 10a except substituting m- anisic acid for 3-fluoro-2-methoxy-benzoic acid, 3-fluoro-2,N-dimethoxy-N-methyl- benzamide was obtained as a colorless oil (0.497 g, 79%).
[00278] 1H NMR (CDCI3): δ 7.16 - 6.99 (m, 3H), 3.96 (d, 3H, J = 2.07), 3.47 (broad s, 3H), 3.36 (broad s, 3H).
[00279] MS (ESI+) (+ 0.1% HCOOH): 213.9 [C10H12FNO3+H]+ (m/z).
[00280] b) 1-(3-Fluoro-2-methoxy-phenyl)-propan-1-one
Figure imgf000042_0002
[00281] Utilizing the procedures described in Example 10b except substituting 3, N-dimethoxy-N-rnethyl-benzamide for 3-f luoro-2, N-dimethoxy-N-methyl-benzamide of Example 11a, 1-(3-fluoro-2-methoxy-phenyl)-propan-1-one was obtained as a colorless oil (0.726 g, 17%).
[00282] 1H NMR (CDCI3): δ 7.39 - 7.34 (m, 1 H), 7.25 - 7.17 (m, 1 H), 7.09 - 7.01 (m, 1H), 3.99 (s, 3H), 2.97 (q, 2H, J = 7.28), 1.18 (t, 3H, J = 7.16).
[00283] c) 2-Bromo-1-(3-fluoro-2-methoxy-phenyl)-propan-1-one
Figure imgf000042_0003
[00284] Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one for 1-(3-fluoro-2-methoxy-phenyl)~propan-1-one of Example 11b, 2-bromo-1-(3-fluoro-2-methoxy-phenyl)-propan-1-one was obtained as a colorless oil (0.922 g, 92%).
[00285] 1H NMR (CDCI3): δ 7.47 - 7.41 (m, 1 H), 7.29 - 7.21 (m, 1 H), 7.12 - 7.03 (m, 1 H), 5.39 (q, 1 H1 J = 6.72), 4.07 (d, 3H, J = 3.02), 1.87 (d, 3H, J = 6.59). [00286] d) 4-(3-Fluoro-2-methoxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy- 5-methyl-5H-furan-2-one
Figure imgf000043_0001
[00287] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(3-fluoro-2-methoxy-phenyl)-propan-1-one of Example 11c and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, 4-(3- fluoro-2-methoxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H-furan- 2-one was obtained as a brown gum. The crude product was used directly onto the next step without any further purification.
[00288] e) 5-(3-Fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl- 2H-pyridazin-3-one and 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6- methyl-2H-pyridazin-3-one
Figure imgf000043_0002
[00289] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one for 4-(3-fluoro-2-methoxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H- furan-2-one of Example 11d, 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- vinyl]-6-methyl-2H-pyridazin-3-one and 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro- phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one were obtained as an orange gum (inseparable mixture) (0.516 g, 41%).
[00290] MS (ESI+) (+ 0.1% HCOOH): 355.1 [C20H16F2N2O2+H]+ and 357.1 [C20H18F2N2O2+H]+ (m/z) [00291] f) 5-(3-Fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-isopropyl- 6-methyl-2H-pyridazin-3-one and 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro- phenyl)-ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one
Figure imgf000044_0001
[00292] Utilizing the procedures described in Example 8h except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one and 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one for 5-(3- fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one and 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H- pyridazin-3-one of Example 11e, 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro- phenyl)-vinyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one and 5-(3-fluoro-2-methoxy- phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one were obtained and separated by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (9:1) (0.252 g, 45%) (87.6% of 5-(3-fluoro-2-methoxy- phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one and 12.4 % of 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-6- methyl-2H-pyridazin-3-one).
[00293] 1H NMR (CDCI3) (5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- vinyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one): δ 7.36 (d, 1 H, J = 16.01), 7.25 - 7.09 (m, 3H), 7.07 - 7.02 (m, 1 H), 6.96 - 6.87 (m, 2H), 6.85 (dt, 1 H, J1 = 7.54, J2 = 1.32), 6.59 (d, 1H, J = 16.02), 5.51 - 5.39 (m, 1 H), 3.80 (d, 3H, J = 2.45), 2.04 (s, 3H), 1.42 (dd, 6H, Jf = 7.53, J2 = 6.78).
[00294] 1H NMR (CDCI3) (5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one): δ 7.21 - 7.10 (m, 2H), 7.08 - 6.99 (m, 1 H), 6.87 - 6.75 (m, 2H), 6.68 (dt, 1 H, J1 = 9. 89, J2 = 1.98), 6.55 (dt, 1 H, J1 = 7.54, J2 = 1.32), 5.44 - 5.29 (m, 1 H), 3.82 (d, 3H, J = 2.83), 2.88 - 2.67 (m, 3H), 2.49 - 2.35 (m, 1 H), 1.99 (s, 3H), 1.41 (dd, 6H, J1 = 6.59, J2 = 5.65).
[00295] g) 5-(3-Fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl- 6-methyl-2H-pyridazin-3-one
Figure imgf000045_0001
[00296] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 5-(3- fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-isopropyl-6-methyl-2H- pyridazin-3-one of Example 11f, 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one was obtained as yellowish oil (0.194 g, 88%).
[00297] 1H NMR (CDCI3): δ 7.21 - 7.10 (m, 2H), 7.08 - 6.99 (m, 1 H), 6.87 - 6.75 (m, 2H), 6.68 (dt, W1 J1 = 9. 89, J2 = 1.98), 6.55 (dt, 1 H, J1 = 7.54, J2 = 1.32), 5.44 - 5.29 (m, 1 H), 3.82 (d, 3H, J = 2.83), 2.88 - 2.67 (m, 3H), 2.49 - 2.35 (m, 1 H), 1.99 (s, 3H), 1.41 (dd, 6H, J1 = 6.59, J2 = 5.65).
[00298] h) 5-(3-Fluoro-2-hydroxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl- 6-methyl-2H-pyridazin-3-one
Figure imgf000045_0002
[00299] Utilizing the procedures described in Example 8g except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2~isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-6- methyl-2H-pyridazin-3-one of Example 11g, 5-(3-fluoro-2-hydroxy-phenyl)-4-[2-(3- fluoro-phenyl)-ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one was obtained as a beige foam (0.141 g, 70%).
[00300] 1H NMR (CDCI3): δ 7.21 - 7.05 (m, 2H), 6.96 - 6.86 (m, 1 H), 6.85 - 6.68
(m, 2H), 6.65 - 6.56 (m, 2H), 6.29 (broad s, 1 H), 5.42 - 5.27 (m, 1 H), 2.82 - 2.61 (m,
3H), 2.60 - 2.45 (m, 1 H), 2.03 (s, 3H), 1.41 - 1.32 (m, 6H).
[00301] HPLC (gradient 20-80% ACN/H2O): > 99%.
[00302] MS (ESI+) (+ 0.1% HCOOH): 385.1 [C22H22F2N2O2+H]+ (m/z). Example 12
Preparation of 5-(2-fluoro-3-hvdroxy-phenyl)-4-f2-(3-fluoro-phenyl)-ethyl1-2- isopropyl-6-methyl-2H-pvridazin-3-one
Figure imgf000046_0001
[00303] a) 2-Fluoro-3,N-dimethoxy-N-methyl-benzamide
Figure imgf000046_0002
[00304] Utilizing the procedures described in Example 10a except substituting m- anisic acid for 2-fluoro-3-methoxy-benzoic acid, 2-fluoro-3,N-dimethoxy-N-methyl- benzamide was obtained as an orange oil (3.27 g, 65%).
[00305] 1H NMR (CDCI3): δ 7.16 - 6.93 (m, 3H), 3.90 (d, 3H, J = 0.94), 3.56 (broad s, 3H), 3.34 (broad s, 3H).
[00306] b) 1-(2-Fluoro-3-methoxy-phenyl)-propan-1-one
Figure imgf000046_0003
[00307] Utilizing the procedures described in Example 10b except substituting 3,N-dimethoxy-N-methyl-benzamide for 2-fluoro-3,N-dimethoxy-N-rnethyl-benzamide of Example 12a, 1-(2-Fluoro-3-methoxy-phenyl)-propan-1-one was obtained as a colorless oil (2.43 g, 87%).
[00308] 1H NMR (CDCI3): δ 7.42 - 7.34 (m, 1 H), 7.15 - 7.07 (m, 2H), 3.91 (s, 3H), 3.06 - 2.95 (m, 2H), 1.20 (t, 3H, J = 7.20).
[00309] c) 2-Bromo-1-(2-fluoro-3-methoxy-phenyl)-propan-1-one
Figure imgf000047_0001
[00310] Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one for 1-(2-fluoro-3-methoxy-phenyl)-propan-1-one of Example 12b, 2-bromo-1-(2-fluoro-3-methoxy-phenyl)-propan-1-one was obtained as a colorless oil (3.29 g, 96%).
[00311] 1H NMR (CDCI3): 5 7.44 - 7.36 (m, 1 H), 7.19 - 7.11 (m, 2H), 5.28 (q, 1 H, J = 6.69), 3.92 (s, 3H), 1.87 (dd, 3H, J1 = 6.7, J2 = 1.04).
[00312] d) 4-(2-Fluoro-3-methoxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy- 5-methyl-5H-furan-2-one
Figure imgf000047_0002
[00313] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(2-fluoro-3-methoxy-phenyl)-propan-1-one of Example 12c and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, 4-(2- fluoro-3-methoxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H-furan- 2-one was obtained as a brown gum. The crude product was used directly onto the next step without any further purification.
[00314] e) 5-(2-Fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl- 2H-pyridazin-3-one and 5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6- methyl-2H-pyridazin-3-one
Figure imgf000047_0003
[00315] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyI)-5H-furan-2-one for 4-(2-fluoro-3-methoxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H- furan-2-one of Example 12d, 5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- vinyl]-6-methyl-2H-pyridazin-3-one and 5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro- phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one were obtained as a yellowish solid (inseparable mixture) (0.743 g, 17%).
[00316] MS (ESI+) (+ 0.1% HCOOH): 355.1 [C20H16F2N2O2+^* and 357.1 [C20H18F2N2O2+H]+ (m/z).
[00317] f) 5-(2-Fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-isopropyl- 6-methyl-2H-pyridazin-3-one and 5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro- phenyl)-ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one
Figure imgf000048_0001
[00318] Utilizing the procedures described in Example 8h except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one and 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one for 5-(3- fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one and 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H- pyridazin-3-one of Example 12e, 5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro- phenyl)-vinyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one and 5-(2-fluoro-3-methoxy- phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one were obtained and separated by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (9:1) (0.531 g, 95%).
[00319] 1H NMR (CDCI3) (5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- vinyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one): δ 7.38 (d, 1 H, J = 16.01), 7.28 - 7.17 (m, 2H), 7.14 - 7.03 (m, 2H), 6.97 - 6.86 (m, 2H), 6.76 - 6.68 (m, 1 H), 6.59 (d, 1 H, J = 16.01), 5.51 - 5.39 (m, 1 H), 3.97 (s, 3H), 2.09 (s, 3H), 1.47 - 1.39 (m, 6H). [00320] 1H NMR (CDCI3) (5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one): δ 7.18 - 7.09 (m, 2H), 7.08 - 7.00 (m, 1 H), 6.86 - 6.76 (m, 2H), 6.65 (dt, 1 H, J1 = 9. 92, J2 = 2.02), 6.51 - 6.44 (m, 1 H), 5.42 - 5.31 (m, 1 H), 3.95 (s, 3H), 2.82 - 2.50 (m, 4H), 2.03 (s, 3H), 1.45 -1.37 (m, 6H).
[00321] g) 5-(2-Fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl- 6-methyl-2H-pyridazin-3-one
Figure imgf000049_0001
[00322] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 5-(2- fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-isopropyl-6-methyl-2H- pyridazin-3-one of Example 12f, 5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.484 g, 91%).
[00323] 1H NMR (CDCI3): δ 7.18 - 7.09 (m, 2H), 7.08 - 7.00 (m, 1 H), 6.86 - 6.76 (m, 2H), 6.65 (dt, 1 H, J1 = 9. 92, J2 = 2.02), 6.51 - 6.44 (m, 1 H), 5.42 - 5.31 (m, 1 H), 3.95 (s, 3H), 2.82 - 2.50 (m, 4H), 2.03 (s, 3H), 1.45 -1.37 (m, 6H).
[00324] h) 5-(2-Fluoro-3-hydroxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl- 6-methyl-2H-pyridazin-3-one
Figure imgf000049_0002
[00325] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 5-(2-fluoro-3-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-6- methyl-2H-pyridazin-3-one of Example 12g, 5-(2-fluoro-3-hydroxy-phenyI)-4-[2-(3- fluoro-phenyl)-ethyl]-2-isopropyl-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.322 g, 71%). [00326] 1H NMR (CDCI3): δ 7.16 - 7.03 (m, 3H), 6.84 - 6.67 (m, 3H), 6.65 - 6.58
(m, 1 H), 6.41 - 6.34 (m, 1H), 5.47 - 5.31 (m, 1H), 2.81 - 2.64 (m, 3H), 2.55 - 2.42 (m,
1H), 2.02 (s, 3H), 1.41 (d, 6H, J =6.59).
[00327] HPLC (gradient 20-80% ACN/H2O): > 99%.
[00328] MS (ESI+) (+ 0.1% HCOOH): 385.1 [C22H22F2N2O2+H]+ (m/z).
Example 13
Preparation of 5-(2-hvdroxy-phenyl)-2-isopropyl-4-phenethyl-6-propyl-2H- pvridazin-3-one
Figure imgf000050_0001
[00329] a) 2,N-dimethoxy-N-methyl-benzamide
Figure imgf000050_0002
[00330] Utilizing the procedures described in Example 10a except substituting m- anisic acid for o-anisic acid, 2,N-dimethoxy-N-methyl-benzamide was obtained as a colorless solid (25.8 g, 87%).
[00331] 1H NMR (DMSO-d6): δ 7.36 (m, 1 H), 7.18 (m, 1 H), 7.04 (d, 1 H, J = 8.3), 6.95 (t, 1 H, J = 7.4), 3.75 (s, 3H), 3.42 (broad s, 3H), 3.17 (broad s, 3H).
[00332] b) 1-(2-Methoxy-phenyl)-pentan-1-one
Figure imgf000050_0003
[00333] Utilizing the procedures described in Example 10b except substituting 3,N-dimethoxy-N-methyl-benzamide for 2,N-dimethoxy-N-methyl-benzamide of Example 13a and ethyl magnesium bromide for π-butyl magnesium chloride, 1-(2- methoxy-phenyl)-pentan-1-one was obtained as a colorless oil (5.73 g, 96%). [00334] 1H NMR (DMSO-J6): δ 7.51 - 7.46 (m, 2H), 7.12 (d, 1H, J = 7.9), 7.01 - 6.96 (m, 1 H), 3.84 (s, 3H), 2.87 (t, 2H, J = 7.3), 1.54 - 1.46 (m, 2H), 1.31 - 1.23 (m, 2H), 0.84 (t, 3H, J =7.3).
[00335] c) 2-Bromo-1-(2-methoxy-phenyl)-pentan-1-one
Figure imgf000051_0001
[00336] Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one for 1-(2-methoxy-phenyl)-pentan-1-one of Example 13b, 2-bromo-1-(2-methoxy-phenyl)-pentan-1-one was obtained as a yellowish oil (5.88 g, 96%).
[00337] 1H NMR (DMSOd6): δ 7.58 - 7.52 (m, 2H), 7.17 (d, 1 H, J = 8.9), 7.03 (m, 1 H), 5.46 (dd, 1 H, J1 = 5.9, J2 = 8.0), 3.87 (s, 3H), 2.05 - 2.00 (m, 1 H), 1.89 - 1.85 (m, 1 H), 1.48 - 1.34 (m, 2H), 0.90 (t, 3H, J = 7.3).
[00338] d) 5-Hydroxy-4-(2-methoxy-phenyl)-5-propyl-3-((E)-styryl)-5H-furan-2-one
Figure imgf000051_0002
[00339] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(2-methoxy-phenyl)-pentan-1-one of Example 12c, 5-hydroxy-4-(2-methoxy-phenyl)-5-propyl-3-((E)-styryl)-5H-furan-2-one was obtained as a brown gum. The crude product was used directly onto the next step without any further purification.
[00340] e) 5-(2-Methoxy-phenyl)-6-propyl-4-((E)-styryl)-2H-pyridazin-3-one and 5- (2-methoxy-phenyI)-4-phenethyl-6-propyl-2H-pyridazin-3-one
Figure imgf000051_0003
[00341] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyI)-5H-furan-2-one for 5-hydroxy-4-(2-methoxy-phenyl)-5-propyl-3-((E)-styryl)-5H-furan-2-one of Example 12d, 5-(2-methoxy-phenyl)-6-propyl-4-((E)-styryl)-2H-pyridazin-3-one and 5-(2- methoxy-phenyl)-4-phenethyl-6-propyl-2H-pyridazin-3-one were obtained as a white solid (inseparable mixture) (1.22 g, 14%).
[00342] MS (ESI+) (+ 0.1% HCOOH): 347.2 [C22H22N2O2H-H]+ and 349.2 [C22H24N2O2H-H]+ (m/z)
[00343] f) 2-lsopropyl-5-(2-methoxy-phenyl)-6-propyl-4-((E)-styryl)-2H-pyridazin-3- one
Figure imgf000052_0001
[00344] Utilizing the procedures described in Example 8h except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one and 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one for 5-(2- methoxy-phenyl)-6-propyl-4-((E)-styryl)-2H-pyridazin-3-one and 5-(2-methoxy- phenyl)-4-phenethyl-6-propyl-2H-pyridazin-3-one of Example 12e, 2-isopropyl-5-(2- methoxy-phenyl)-6-propyl-4-((E)-styryl)-2H-pyridazin-3-one was obtained and purified by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (8:2) (0.870 g, 77%).
[00345] 1H NMR (DMSO-c/6): δ 8.17 (d, 1 H, J = 16.13), 7.49 (m, 1 H), 7.28 - 7.09 (m, 8H), 6.47 (d, 1 H, J = 16.09), 5.30 (m, 1 H), 3.72 (s, 3H), 2.23 - 2.18 (m, 2H), 1.43 (q, 2H, J = 7.3), 1.37 - 1.31 (m, 6H), 0.74 (t, 3H, J = 7.3). [00346] MS (ESI+) (+ 0.1% HCOOH): 389.04 [C25H28N2O2H-H]+ (m/z).
[00347] g) 2-lsopropyl-5-(2-methoxy-phenyl)-4-phenethyl-6-propyl-2H-pyridazin-3- one
Figure imgf000053_0001
[00348] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 2- isopropyl-5-(2-methoxy-phenyl)-6-propyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 12f , 2-isopropyl-5-(2-methoxy-phenyl)-4-phenethyl-6-propyl-2H-pyridazin-3- one was obtained as a colorless oil (0.790 g, 90%).
[00349] 1H NMR (DMSOd6): δ 7.44 - 7.42 (m, 1 H), 7.19 - 6.97 (m, 6H), 6.84 (m,
2H), 5.20 (m, 1 H), 3.72 (s, 3H), 2.59 - 2.31 (m, 4H), 2.17 - 2.12 (m, 2H), 1.44 - 1.37
(m, 2H), 1.32 - 1.28 (m, 6H), 0.73 (t, 3H, J = 7.3).
[00350] MS (ESI+) (+ 0.1 % HCOOH): 391.07 [C25H30N2O2+H]+ (m/z).
[00351] h) 5-(2-Hydroxy-phenyl)-2-isopropyl-4-phenethyl-6-propyl-2H-pyridazin-3- one
Figure imgf000053_0002
[00352] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-isopropyl-5-(2-methoxy-phenyl)-4-phenethyl-6-propyl-2H-pyridazin-3-one of Example 12g , 5-(2-Hydroxy-phenyl)-2-isopropyl-4-phenethyl-6-propyl-2H-pyridazin- 3-one was obtained as a white solid (0.082 g, 25%).
[00353] 1H NMR (DMSO-d6): δ 9.70 (s, 1H), 7.29 - 7.09 (m, 4H), 6.98 - 6.84 (m, 5H), 5.21 (m, 1H), 2.59 - 2.19 (m, 6H), 1.43 (q, 2H, J = 7.3), 1.32 - 1.29 (m, 6H), 0.74 (t, 3H1 J = 7.3).
[00354] HPLC (gradient 20-80% ACN/H2O): > 94%. [00355] MS (ESI+) (+ 0.1% HCOOH): 377.1 [C24H28N2O2H-H]+ (m/z).
Example 14 Preparation of 2-(2-chloro-benzyl)-4-r2-(3-fluoro-phenyl)-ethvN-5-(2-hvdroxy- phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000054_0001
[00356] a) 3-[2-(3-Fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5methyl- 5H-furan-2-one
Figure imgf000054_0002
[00357] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(2-methoxy-phenyl)-propan-1-one and trans- styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, the title compound was obtained as a brown gum. The crude product was used directly onto the next step without any further purification.
[00358] b) 4-[2-(3-Fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one
Figure imgf000054_0003
[00359] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one for 3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5methyI-5H-furan-2- one, the title compounds were obtained as a yellow foam (0.4 g, 17% over two steps). [00360] 1H NMR (CDCI3): δ 13.08 (s, 1 H); 8.23 (d, 1 H, J = 16.2Hz); 7.62-7.04 (m,
8H); 6.52 (d, 1 H, J = 16.2Hz); 3.79 (s, 3H), 1.90 (s, 3H).
[00361] MS (ESI+) (+0.1%HCOOH): 437.1 [C20H17FN2O2 +H]+ (m/z)
[00362] c) 2-(2-Chloro-benzyl)-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one
Figure imgf000055_0001
[00363] Tetrabutylammonium bromide (0.023 g, 0.074 mmol), 2-chlorobenzyl bromide (0.320 g, 1.56 mmol) and 4~[2-(3-fluoro-phenyl)-vinyl]-5~(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one of Example 14b (0.5 g, 1.48 mmol) were added to a suspension of potassium carbonate (0.513 g, 37.16 mmol) in anhydrous acetonitrile (10 ml_). The mixture was refluxed for 2 hours and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane - ethyl acetate (9:1) to give 2-(2-chloro-benzyl)-4-[2-(3- fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one (0.558 g, 81%).
[00364] 1H NMR (CDCI3): δ 8.31 (d, 1 H, J = 16.02), 7.48 - 7.40 (m, 2H)1 7.26 - 7.09 (m, 8H), 6.89 (m, 2H), 6.60 (d, 1 H, J = 16.02), 5.50 (dd, 2H, J1 = 15.2, J2 = 37.1), 3.80 (s, 3H), 2.03 (s, 3H).
[00365] d) 2-(2-Chloro-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one
Figure imgf000055_0002
[00366] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 2-(2- chloro-benzyl)-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 14c, 2-(2-chloro-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5- (2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.538 g, 93%).
[00367] 1H NMR (CDCI3): δ 7.42 (m, 2H), 7.24 (m, 2H), 7.10 - 7.01 (m, 4H), 6.80 - 6.75 (m, 3H), 6.60 (m, 1H), 5.50 (dd, 2H, J1 = 15.2, J2 = 47.6), 3.77 (s, 3H), 2.73 - 2.56 (m, 4H), 1.94 (s, 3H).
[00368] e) 2-(2-Chloro-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)- 6-methyl-2H-pyridazin-3-one
Figure imgf000056_0001
[00369] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-(2-chloro-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one of Example 14d, 2-(2-chloro-benzyl)-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.348 g, 68%).
[00370] 1H NMR (CDCI3): δ 7.37 - 6.54 (m, 12H), 6.01 (broad s, 1 H), 5.48 (dd, 2H,
J1 = 15.2, J2 = 52.2), 2.72 - 2.55 (m, 4H), 2.00 (s, 3H).
[00371] HPLC (gradient 20-80% ACN/H2O): > 95%.
[00372] MS (ESI+) (+ 0.1 % HCOOH): 449.2 [C26H22CIFN2O2+H]+ (m/z).
Example 15
Preparation of 4-r2-(3-fluoro-phenyl)-ethyl1-5-(2-hvdroxy-phenyl)-6-methyl-2- (2-methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000056_0002
[00373] a) 4-[2-(3-Fiuoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2-(2- methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000057_0001
[00374] Utilizing the procedures described in Example 14c except substituting 2- chlorobenzyl bromide for 2-methylbenzyl bromide, 4-[2-(3-fluoro-phenyl)-vinyl]-5-(2- methoxy-phenyl)-6-methyl-2-(2-methyl-benzyl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.590 g, 88%).
[00375] 1H NMR (DMSOd6): δ 8.15 (d, 1 H, J = 16.12), 7.55 - 7.49 (m, 1H), 7.39 -
7.29 (m, 1 H), 7.23 - 6.96 (m, 10H), 6.52 (d, 1H, J = 16.12), 5.32 (dd, 2H, J1 = 14.6, J2
= 29.4), 3.74 (s, 3H), 2.41 (s, 3H), 1.92 (s, 3H).
[00376] MS (ESI+) (+ 0.1% HCOOH): 441.1 [C28H25FN2O2^-H]+ (m/z).
[00377] b) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2~(2- methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000057_0002
[00378] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 4-[2-(3- fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2-(2-methyl-benzyl)-2H- pyridazin-3-one of Example 15a, 4-[2-(3-fluoro~phenyl)-ethyl]-5-(2-methoxy-phenyl)-
6-methyl-2-(2-methyl-benzyl)-2H-pyridazin-3-one was obtained as a colorless oil
(0.54O g, 91%).
[00379] 1H NMR (DMSO-d6): δ 7.41 - 7.49 (m, 1 H), 7.21 - 7.14 (m, 5H), 7.05 - 6.94
(m, 4H), 6.65 - 6.70 (m, 2H), 5.26 (dd, 2H, J1 = 14.6, J2 = 30.9), 3.72 (s, 3H), 2.65 -
2.46 (m, 4H), 2.39 (s, 3H), 1.84 (s, 3H).
[00380] MS (ESI+) (+ 0.1 % HCOOH): 443.2 [C28H27FN2O2+H]+ (m/z). [00381] c) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(2- methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000058_0001
[00382] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(2-methyl- benzyl)-2H-pyridazin-3-one of Example 15b, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2-(2-methyl-benzyl)-2H-pyridazin-3-one was obtained as a white solid (0.126 g, 25%).
[00383] 1H NMR (DMSO-d6): δ 9.77 (broad s, 1 H), 7.27 - 7.14 (m, 5H), 7.03 - 6.87
(m, 5H), 6.71 (m, 2H), 5.25 (m, 2H), 2.65 - 2.44 (m, 4H), 2.38 (s, 3H), 1.90 (s, 3H).
[00384] HPLC (gradient 20-80% ACN/H2O): > 99%
[00385] MS (ESI+) (+ 0.1 % HCOOH): 429.1 [C27H25FN2O^H]+ (m/z)
Example 16
Preparation of 4-r2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-6-methyl-2- (3-methyl-benzvl)-2H-pyridazin-3-one
Figure imgf000058_0002
[00386] a) 4-[2-(3-Fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2-(3- methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000058_0003
[00387] Utilizing the procedures described in Example 14c except substituting 2- chlorobenzyl bromide for 3-methylbenzyl bromide, 4-[2-(3-fluoro-phenyl)-vinyl]-5-(2- methoxy-phenyl)-6-methyl-2-(3-methyl-benzyl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.500 g, 76%).
[00388] 1H NMR (DMSOd6): δ 8.16 (d, 1 H, J = 16.11), 7.45 - 7.55 (m, 1 H), 7.31 -
6.97 (m, 11 H), 6.49 (d, 1 H, J = 16.12), 5.26 (m, 2H), 3.73 (s, 3H), 2.28 (s, 3H), 1.92
(s, 3H).
[00389] MS (ESI+) (+ 0.1% HCOOH): 441.15 [C28H25FN2O2+H]+ (m/z).
[00390] b) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(3- methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000059_0001
[00391] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 4-[2-(3- fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2-(3-methyl-benzyl)-2H- pyridazin-3-one of Example 16a, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)- 6-methyl-2-(3-methyl-benzyl)-2H-pyridazin-3-one was obtained as a colorless oil (0.480 g, 99%).
[00392] 1H NMR (DMSO-c/6): δ 7.41 - 7.47 (m, 1 H), 7.23 - 6.93 (m, 9H), 6.69 (m, 2H), 5.20 (m, 2H), 3.71 (s, 3H), 2.63 - 2.46 (m, 4H), 2.28 (s, 3H), 1.84 (s, 3H). [00393] MS (ESI+) (+ 0.1 % HCOOH): 443.3 [C28H27FN2O2+H]+ (m/z).
[00394] c) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3- methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000059_0002
[00395] Utilizing the procedures described in Example 8i except substituting Q- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(3-methyl- benzyl)-2H-pyridazin-3-one of Example16b, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2-(3-methyl-benzyl)-2H-pyridazin-3-one was obtained as a white solid (0.145 g, 31%).
[00396] 1H NMR (DMSOd6): δ 9.76 (broad s, 1H), 7.26 - 7.10 (m, 6H), 6.98 - 6.87
(m, 4H), 6.71 (m, 2H)1 5.20 (s, 2H), 2.67 - 2.38 (m, 4H), 2.28 (s, 3H), 1.90 (s, 3H).
[00397] HPLC (gradient 20-80% ACN/H2O): > 99%.
[00398] MS (ESI+) (+ 0.1% HCOOH): 429.1 [C27H25FN2O2+H]+ (m/z).
Example 17
Preparation of 4-r2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-6-methyl-2- (4-methyl-benzyl)-2H-pvridazin-3-one
Figure imgf000060_0001
[00399] a) 4-[2-(3-Fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2-(4- methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000060_0002
[00400] Utilizing the procedures described in Example 14c except substituting 2- chlorobenzyl bromide for 4-methylbenzyl bromide, the title compound was obtained as a yellowish oil (0.490 g, 75%).
[00401] 1H NMR (DMSO-c/6): δ 8.16 (d, 1 H, J = 16.09), 7.52 - 7.47 (m, 1H), 7.36 -
6.96 (m, 11 H), 6.49 (d, 1H, J = 16.16), 5.25 (m, 2H), 3.73 (s, 3H), 2.26 (s, 3H), 1.91
(s, 3H).
[00402] MS (ESI+) (+ 0.1 % HCOOH): 441.09 [C28H25FN2O2+!-!]* (m/z). [00403] b) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(4- methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000061_0001
[00404] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 4-[2-(3- fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2-(4-methyl-benzyl)-2H- pyridazin-3-one of Example 17a, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-
6-methyl-2-(4-methyl-benzyl)-2H-pyridazin-3-one was obtained as a colorless oil
(0.420 g, 90%).
[00405] 1H NMR (DMSO-d6): δ 7.44 (m, 1H), 7.26 - 7.13 (m, 6H), 7.02 - 6.94 (m,
3H), 6.70 - 6.61 (m, 2H), 5.19 (s, 2H), 3.71 (s, 3H), 2.62 - 2.48 (m, 4H), 2.26 (s, 3H),
1.84 (S1 3H).
[00406] MS (ESI+) (+ 0.1 % HCOOH): 443.2 [C28H27FN2O2+H]+ (m/z).
[00407] c) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(4- methyl-benzyl)-2H-pyridazin-3-one
Figure imgf000061_0002
[00408] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(4-methyl- benzyl)-2H-pyridazin-3-one of Example 17b, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2-(4-methyl-benzyl)-2H-pyridazin-3-one was obtained as a white solid (0.020 g, 5%).
[00409] 1H NMR (DMSO-d6): δ 9.76 (s, 1H), 7.24 - 7.13 (m, 6H), 6.98 - 6.87 (m, 4H), 6.71 (m, 2H), 5.19 (s, 2H), 2.63 - 2.46 (m, 4H), 2.26 (s, 3H), 1.90 (s, 3H). [00410] HPLC (gradient 20-80% ACN/H2O): > 99%. [00411] MS (ESI+) (+ 0.1% HCOOH): 429.1 [C27H25FN2O2+H]+ (m/z).
Example 18
Preparation of 5-(2-hvdroxy-phenyl)-2-isopropyl-4-phenethyl-6-phenyl-2H- pyridazin-3-one
Figure imgf000062_0001
[00412] a) 1-(2-Methoxy-phenyl)-2-phenyl-ethanone
Figure imgf000062_0002
[00413] Utilizing the procedures described in Example 10b except substituting 3,N-dimethoxy-N-methyl-benzamide for 2,N-dimethoxy-N-methyl~benzamide and ethyl magnesium bromide for benzylmagnesium chloride, 1-(2-methoxy-phenyl)-2- phenyl-ethanone was obtained as a yellowish oil (7.92 g, 97%). [00414] 1H NMR (DMSO-d6): δ 7.52 - 6.98 (m, 9H), 4.23 (s, 2H), 3.87 (s, 3H). [00415] MS (ESI+) (+ 0.1 % HCOOH): 227.04 [C15H14O2+H]+ (m/z)
[00416] b) 2-Bromo-1-(2-methoxy-phenyl)-2-phenyl-ethanone
Figure imgf000062_0003
[00417] Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one for 1-(2-methoxy-phenyl)-2-phenyl-ethanone of Example 18a, 2-bromo-1-(2-methoxy-phenyl)-2-phenyl-ethanone was obtained as a yellowish oil (4.27 g, 63%). [00418] 1H NMR (DMSO-d6): δ 7.56 - 6.96 (m, 9H), 6.75 (s, 1 H), 3.85 (s, 3H). [00419] c) 5-Hydroxy-4-(2-methoxy-phenyI)-5-phenyl-3-((E)-styryl)-5H-furan-2-one
Figure imgf000063_0001
[00420] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(2-methoxy-phenyl)-2-phenyl-ethanone of Example 18b, 5-hydroxy-4-(2-methoxy-phenyl)-5-phenyl-3-((E)-styryl)-5H-furan-2- one was obtained as a brown gum. The crude product was used directly onto the next step without further purification. [00421] MS (ESI+) (+ 0.1% HCOOH): 367.01 [C25H20O4-H2O+H]+ (m/z).
[00422] d) 5-(2-Methoxy-phenyl)-6-phenyl-4-((E)-styryl)-2H-pyridazin-3-one
Figure imgf000063_0002
[00423] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one for 5-hydroxy-4-(2-methoxy-phenyl)-5-phenyl-3-((E)-styryl)-5H-furan-2-one of Example 18c, 5-(2-methoxy-phenyl)-6-phenyl-4-((E)-styryl)-2H-pyridazin-3-one was obtained as a yellowish solid (0.85 g, 15%). [00424] MS (ESI+) (+ 0.1% HCOOH): 381.03 [C25H2oN202+H]+
[00425] e) 2-isopropyl-5-(2-methoxy-phenyl)-6-phenyl-4-((E)-styryl)-2H-pyridazin- 3-one
Figure imgf000063_0003
[00426] Utilizing the procedures described in Example 8h except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one for 5-(2- methoxy-phenyl)-6-phenyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 18d, 2- isopropyl-5-(2-methoxy-phenyl)-6-phenyl-4-((E)-styryl)-2H-pyridazin-3-one was obtained and purified by flash chromatography on silica gel eluting with cyclohexane
- ethyl acetate (95:5) (0.610 g, 68%).
[00427] 1H NMR (DMSOd6): δ 8.30 (d, 1 H, J = 16.12), 7.31 - 6.95 (m, 14H), 6.64
(d, 1 H, J = 16.10), 5.37 (m, 1 H), 3.45 (s, 3H), 1.37 (m, 6H).
[00428] MS (ESI+) (+ 0.1% HCOOH): 423.1 [C28H26IWH]+ (m/z).
[00429] f) 2-lsopropyl-5-(2-methoxy-phenyl)-4-phenethyl-6-phenyl-2H-pyridazin-3- one
Figure imgf000064_0001
[00430] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 2- isopropyl-5-(2-methoxy-phenyl)-6-phenyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 18e, 2-isopropyl-5-(2-methoxy-phenyl)-4-phenethyl-6-phenyl-2H-pyridazin-
3-one was obtained as a colorless oil (0.55 g, 89%).
[00431] 1H NMR (DMSO-d6): δ 7.20 - 6.87 (m, 14H), 5.29 (m, 1 H), 3.47 (s, 3H),
2.63 (nn, 4H), 1.33 (m, 6H).
[00432] MS (ESI+) (+ 0.1% HCOOH): 425.1 [C28H28N2O^H]+ (m/z).
[00433] g) 5-(2-Hydroxy-phenyl)-2-isopropyl-4-phenethyl-6-phenyl-2H-pyridazin-3- one
Figure imgf000064_0002
[00434] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-isopropyl-5-(2-methoxy-phenyl)-4-phenethyl-6-phenyl-2H-pyridazin-3-one of Example 18h, 5-(2-hydroxy-phenyl)-2-isopropyl-4-phenethyl-6-phenyl-2H- pyridazin-3-one was obtained as a white solid (0.3 g, 62%).
[00435] 1H NMR (DMSO-c/6): δ 9.68 (s, 1 H), 7.18 - 7.07 (m, 9H), 6.89 - 6.80 (m,
4H), 6.71 (m, 1 H), 5.29 (m, 1 H), 2.68 - 2.54 (m, 4H), 1.37 (d, 6H, J = 5.96).
[00436] HPLC (gradient 20-80% ACN/H2O): > 95%
[00437] MS (ESI+) (+ 0.1 % HCOOH): 411.2 [C27H26N2O2+^* (m/z)
[00438] IC50 greater than 50 μM.
Example 19
Preparation of 2-(3-chloro-benzyl)-4-r2-(3-fluoro-phenvπ-ethvn-5-(2-hvdroxy-phenyl)-
6-methyl-2H-pyridazin-3-one
Figure imgf000065_0001
[00439] a) 2-(3-Chloro-benzyl)-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one
Figure imgf000065_0002
[00440] Utilizing the procedures described in Example 14c except substituting 2- chlorobenzyl bromide for 3-chlorobenzyl bromide, 2-(3-chloro-benzyl)-4-[2-(3-fluoro- phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-rnethyl-2H-pyridazin-3-one was obtained as a beige solid (0.636 g, 93%).
[00441] 1H NMR (CDCI3): δ 8.27 (d, 1H, J = 16.21), 7.53 - 7.37 (m, 3H), 7.31 - 7.15 (m, 3H), 7.11 - 6.99 (m, 4H), 6.90 (dd, 2H, J1 = 9.33, J2 = 1.04), 6.57 (d, 1 H, J = 16.01), 5.36 (dd, 2H, J1 = 42.86, J2 = 13.86), 3.78 (s, 3H), 2.02 (s, 3H). [00442] b) 2-(3-Chloro-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one
Figure imgf000066_0001
[00443] Utilizing the procedures described in Example 9f, except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 2-(3- chloro-benzyl)-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 19a, 2-(3-chloro-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5- (2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.652 g, 100%).
[00444] 1H NMR (CDCI3): δ 7.48 (s, 1H), 7.46 - 7.36 (m, 2H), 7.32 - 7.27 (m, 2H), 7.18 - 6.96 (m, 3H), 6.84 - 6.76 (m, 2H), 6.72 (d, 1 H, J = 7.35), 6.60 (d, 1 H1 J = 9.99), 5.31 (dd, 2H, J1 = 45.68, J2 = 13.66), 3.76 (s, 3H), 2.78 - 2.45 (m, 4H), 1.96 (s, 3H).
[00445] c) 2-(3-chloro-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one
Figure imgf000066_0002
[00446] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-(3-chloro-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one of Example 19b, 2-(3-chloro-benzyl)-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.31O g, 52%).
[00447] 1H NMR (CDCI3): δ 7.46 (s, 1H), 7.38 - 7.20 (m, 4H), 7.10 - 6.91 (m, 3H), 6.83 - 6.71 (m, 2H), 6.64 (d, 1 H, J = 7.72), 6.54 (d, 1 H, J = 9.23), 6.13 (broad s, 1H), 5.28 (dd, 2H, J1 = 53.31, J2 = 13.75), 2.79 - 2.47 (m, 4H), 2.02 (s, 3H). [00448] HPLC (gradient 20-80% ACN/H2O): > 95%. [00449] MS (ESI+) (+ 0.1 % HCOOH): 449.2 [C26H22CIFN2O^H]+ (m/z). [00450] IC50 greater than 50 μM.
Example 20
Preparation of 2-cvclohexylmethyl-4-[2-(3-fluoro-phenvπ-ethyll-5-(2-hvdroxy-phenyl)-
6-methvl-2H-pyridazin-3-one
Figure imgf000067_0001
[00451] a) 2-Cyclohexylmethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one
Figure imgf000067_0002
[00452] Utilizing the procedures described in Example 14c except substituting 2- chlorobenzyl bromide for cyclohexylmethyl bromide, 2-cyclohexylmethyl-4-[2-(3- fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.482 g, 75%).
[00453] 1H NMR (CDCI3): δ 8.33 (d, 1 H, J = 16.01), 7.51 - 7.42 (m, 1 H), 7.24 - 7.13 (m, 1 H), 7.12 - 6.99 (m, 4H), 6.94 - 6.83 (m, 2H), 6.59 (d, 1 H, J = 16.02), 4.20 - 3.95 (m, 2H), 3.78 (s, 3H), 2.01 (s, 3H), 1.81 - 1.61 (m, 5H), 1.37 - 1.02 (m, 5H).
[00454] b) 2-Cyclohexylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one
Figure imgf000067_0003
[00455] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 2- cyclohexylmethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 20a, 2-cyclohexylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5- (2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.519 g, 97%).
[00456] 1H NMR (CDCI3): δ 7.42 (td, 1 H, J1 = 7.52, J2 = 1.57), 7.17 - 7.07 (m, 1 H), 7.06 - 6.95 (m, 2H), 6.87 - 6.71 (m, 3H), 6.62 (d, 1H, J = 9.99), 4.17 - 3.88 (m, 2H), 3.76 (s, 3H), 2.79 - 2.44 (m, 4H), 2.04 (s, 3H), 1.81 - 1.61 (m, 5H), 1.36 - 1.00 (m, 5H).
[00457] c) 2-cyclohexylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one
Figure imgf000068_0001
[00458] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one for 2-cycIohexylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one of Example 20b, 2-cyclohexylmethyl-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.294 g, 66%).
[00459] 1H NMR (CDCI3): δ 7.35 - 7.27 (m, 1H), 7.11 - 7.00 (m, 2H), 6.95 (t, 1H, J
= 7.44), 6.82 - 6.63 (m, 3H), 6.57 (d, 1 H, J = 9.8), 4.17 - 3.84 (m, 2H), 2.79 - 2.45 (m,
4H), 2.03 (s, 3H), 1.77 - 1.56 (m, 5H), 1.29 - 0.97 (m, 5H).
[00460] HPLC (gradient 20-80% ACN/H2O): > 95%.
[00461] MS (ESI+) (+ 0.1 % HCOOH): 421.2 [C26H29FN2O2H-H]+ (m/z).
[00462] IC50 greater than 50 μM.
Example 21
Preparation of 4-r2-(3-fluoro-phenyl)-ethvn-5-(2-methoxy-phenyl)-6-methyl-2-(1 - phenvl-ethyl)-2H-pyridazin-3-one
Figure imgf000069_0001
[00463] a) 4-[2-(3-Fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2-(1 - phenyl-ethyl)-2H-pyιϊdazin-3-one
Figure imgf000069_0002
[00464] Utilizing the procedures described in Example 14c except substituting 2- chlorobenzyl bromide for (i-bromoethyl)benzene, 4-[2-(3-fluoro-phenyl)-vinyl]-5-(2- methoxy-phenyl)-6-methyl-2-(1-phenyl-ethyl)-2H-pyridazin-3-one was obtained as a white solid (0.520 g, 79%).
[00465] 1H NMR (CDCI3): δ 8.27 (d, 1H, J = 16.2), 7.66 - 7.42 (m, 3H), 7.41 - 7.13 (m, 3H), 7.12 - 6.96 (m, 4H), 6.94 - 6.81 (m, 2H), 6.57 (d, 1 H, J = 16.21), 6.52 - 6.57 (m, 1H), 6.47 (q, 1 H, J = 6.78), 3.77 (d, 3H, J = 17.33), 2.02 (s, 3H), 1.83 (t, 3H, J = 6.50).
[00466] b) 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(1 - phenyl-ethyl)-2H-pyridazin-3-one
Figure imgf000069_0003
[00467] Utilizing the procedures described in Example 9f, except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one for 4-[2-(3- fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2-(1-phenyl-ethyl)-2H-pyridazin- 3-one of Example 21a, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2- (1-phenyl-ethyl)-2H-pyridazin-3-one was obtained as a white solid (0.44 g, 99%). [00468] 1H NMR (CDCI3): δ 7.61 - 7.52 (m, 2H), 7.46 - 7.27 (m, 4H), 7.17 - 6.94
(m, 3H), 6.89 - 6.69 (m, 3H), 6.66 - 6.57 (m, 1 H), 6.42 (qd, W1 J1 - 7.09, J2 = 1.93),
3.74 (d, 3H, J = 20.1), 2.84 - 2.41 (m, 4H), 1.98 (s, 3H), 1.83 (dd, 3H, J1 = 7.16, J2 =
5.6).
[00469] HPLC (isocratic 90% ACN/H2O): > 95%.
[00470] MS (ESI+) (+ 0.1 % HCOOH): 443.3 [C28H27FN2O2 +H]+ (m/z).
[00471] IC50 greater than 50 μM.
Example 22 Preparation of 5-(2-hvdroxy-phenyl)-6-methyl-214-diphenethyl-2H-pyridazin-3-one
Figure imgf000070_0001
[00472] a) Preparation of 1-(2-benzyloxy-phenyl)-propan-1-one
Figure imgf000070_0002
[00473] To a solution of 1-(2-hydroxy-phenyl)-propan-1-one (0.2 g, 1.33 mmol) in anhydrous acetonitrile (8 mL) were added potassium carbonate (0.46 g, 3.32 mmol) and benzyl bromide (0.17 mL, 1.46 mmol). The reaction mixture was refluxed for 3 hours under argon and concentrated under reduced pressure. Methylene chloride (50 mL) was added, the resulting organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product that was purified by flash chromatography on silica gel, with cyclohexane - ethyl acetate (90:10) to afford the title compound (0.22 g, 70%) as a colorless oil.
[00474] 1H NMR (DMSO-d6): δ 7.53 - 7.34 (m, 7H), 7.21 (d, 1 H, J = 7.9), 7.00 (m, 1 H), 5.20 (s, 2H), 2.88 (q, 2H1 J = 7.2), 0.96 (3H, t, J = 7.2).
[00475] b) Preparation of 1 -(2-benzyloxy-phenyl)-2-bromo-propan-1 -one
Figure imgf000071_0001
[00476] Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one of Example 8d for 1-(2-benzyloxy-phenyl)-2-bromo- propan-1-one of Example 22a, 1-(2-benzyloxy-phenyl)-2-bromo-propan-1-one was obtained as an colorless oil (0.2 g, 75%).
[00477] 1H NMR (DMSOd6): δ 7.61 - 7.33 (m, 7H), 7.25 (d, 1 H, J = 8.3), 7.04 (m, 1 H), 5.56 (q, 1 H, J = 6.6), 5.23 (s, 2H), 1.64 (3H, d, J = 6.6).
[00478] c) Preparation of 4-(2-benzyloxy-phenyl)-5-hydroxy-5-methyl-3-((E)- styryl)-5H-furan-2-one
Figure imgf000071_0002
[00479] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-phenyl)-2-bromo-propan-1-one, 4-(2- benzyloxy-phenyl)-5-hydroxy-5-methyl-3-((E)-styryl)-5H-furan-2-one was obtained as a yellowish foam (6.85 g). The crude product was used directly onto the next step without any further purification.
[00480] MS (ESI+) (+ 0.1 % HCOOH): 380.98 [C26H22θ4-H2O+H]+ (m/z).
[00481] d) Preparation of 5-(2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H- pyridazin-3-one
Figure imgf000072_0001
[00482] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-phenyl)-5-hydroxy-5-methyl-3-((E)-styryl)-5H-furan-2- one of Example 22c, 5-(2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3- one was obtained as a white solid (5.1 g, 25%).
[00483] 1H NMR (DMSOd6): δ 12.99 (s, 1H), 8.26 (d, 1H, J = 16.1), 7.48 - 7.07
(m, 14H), 6.49 (d, 1 H, J = 16.1), 5.12 (s, 2H), 1.90 (s, 3H).
[00484] MS (ESI+) (+ 0.1 % HCOOH): 394.97 [C26H22N2O2+H]+ (m/z).
[00485] e) Preparation of 5-(2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)- styryl)-2H-pyridazin-3-one
Figure imgf000072_0002
[00486] A solution of 5-(2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin~ 3-one (0.5 g, 1.26 mmol) of Example 22d in anhydrous acetonitrile (7.6 ml_) was treated with (2-bromo-ethyl)-benzene (0.18 mL, 1.33 mmol) and potassium carbonate (0.43 g, 3.16 mmol). The reaction mixture was refluxed overnight under argon, cooled to room temperature, and concentrated in vacuum. Water (50 mL) was added followed by methylene chloride (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel, eluting with cyclohexane - ethyl acetate (9:1) to afford 5-(2-benzyloxy-phenyl)-6-methyl-2- phenethyl-4-((E)-styryl)-2H-pyιϊdazin-3-one (0.4 g, 63%) as a yellowish oil.
[00487] 1H NMR (DMSOd6): δ 8.2 (d, 1 H, J = 16.1), 7.46 - 7.08 (m, 19H), 6.52 (d, 1 H, J = 16.1), 5.18 (s, 2H), 4.33 (dd, 2H, J1 = 8.0, J2 = 6.6), 3.06 (t, 2H, J = 8.0), 1.92 (s, 3H). [00488] MS (ESI+) (+ 0.1 % HCOOH): 499.19 [C34H30N2O2+H]+ (m/z).
[00489] f) Preparation of 5-(2-hydroxy-phenyl)-6-methyl-2,4-diphenethyl-2H- pyridazin-3-one
Figure imgf000073_0001
[00490] To a solution of 5-(2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)- styryl)-2H-pyridazin-3-one (0.34 g, 0.69 mmol) of Example 22e in ethyl acetate (65 ml_) was added palladium 10% weight on carbon (0.3 g). The resulting mixture was stirred in a Parr Apparatus using hydrogen pressure (60 psi) for 7 hours and filtered over a bed of celite. After filtration, the catalyst was rinsed using ethyl acetate, and the filtrate was concentrated in vacuum. The crude product was triturated in diethyl ether to afford 5-(2-hydroxy-phenyl)-6-methyl-2,4-diphenethyl-2H-pyridazin-3-one as a white solid (0.18 g, 66%).
[00491] 1H NMR (DMSO-d6): δ 9.75 (s, 1 H), 7.31 - 6.85 (m, 14H), 4.31 - 4.21 (m,
2H)1 3.03 (t, 2H, J = 7.8), 2.59 - 2.35 (m, 4H), 1.91 (s, 3H).
[00492] HPLC (gradient 20-80% ACN/H2O): > 99%
[00493] MS (ESI+) (+ 0.1 % HCOOH): 411.1 [C27H26N2O2+H]+ (m/z).
Example 23
Preparation of 2-cvclopropylmethyl-5-(2-hvdroxy-phenyl)-6-methyl-4-phenethyl-2H- pyridazin-3-one
Figure imgf000074_0001
[00494] a) Preparation of 5-(2-benzyloxy-phenyl)-2-cyclopropylmethyl-6-methyl-4- ((E)-styryl)-2H-pyridazin-3-one
Figure imgf000074_0002
[00495] Utilizing the procedures described in Example 8h except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one and 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-2H-pyridazin-3-one of
Example 8g for 5-(2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 22d and isopropyl iodide for bromomethyl cyclopropane, 5-(2-benzyloxy- phenyl)-2-cyclopropylmethyl-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.36 g, 63%).
[00496] 1H NMR (DMSOd6): δ 8.22 (d, 1H, J = 16.1), 7.46 - 7.08 (m, 14H), 6.53 (d, 1 H1 J = 16.1), 5.15 (s, 2H), 4.00 (d, 2H, J = 7.1), 1.94 (s, 3H), 1.34 (s, 1 H), 0.40 - 0.50 (m, 4H). [00497] MS (ESI+) (+ 0.1% HCOOH): 449.09 [C30H28N2O2 +H]+ (m/z).
b) Preparation of 2-cyclopropylmethyl-5-(2-hydroxy-phenyl)-6-methyl-4- phenethyl-2H-pyridazin-3-one
Figure imgf000075_0001
[00498] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyrida2in-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-2-cyclopropylmethyl-6-methyl-4-((E)-styryl)- 2H-pyridazin-3-one of Example 23a, 2-cyclopropylmethyl-5-(2-hydroxy-phenyl)-6- methyl-4-phenethyl-2H-pyridazin-3-one was obtained as a white solid (0.21 g, 58%).
[00499] 1H NMR (CDCI3): δ 7.34 - 7.27 (m, 1H), 7.18 - 7.06 (m, 3H), 7.02 - 6.87
(m, 4H), 6.77 (dd, 1H, J1 = 7.53, J2 ~ 1.51), 5.97 - 5.27 (m, 1 H), 4.16 - 3.92 (m, 2H),
2.85 - 2.48 (m, 4H), 2.02 (s, 3H), 1.50 - 1.34 (m, 1H), 0.59- 0.43 (m, 4H).
[00500] HPLC (gradient 5-80% ACN/H2O): > 93%
[00501] MS (ESI+) (+ 0.1% HCOOH): 361.1 [C23H24N2O2+H]+ (m/z).
Example 24
Preparation of 5-(2-hvdroxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl-4-phenethyl-2H- pyridazin-3-one
Figure imgf000075_0002
[00502] a) Preparation of 5-(2-benzyloxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl~ 4-((E)-styryl)-2H-pyridazin-3-one
Figure imgf000076_0001
[00503] Utilizing the procedures described in Example 22e except substituting (2- bromo-ethyl)-benzene for 3-methoxybenzyl bromide, 5-(2-benzyloxy-phenyl)-2-(3- methoxy-benzyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.55 g, 82%).
[00504] 1H NMR (CDCI3): δ 8.42 (d, 1H, J = 16.2), 7.47 - 7.39 (m, 1 H), 7.34 - 7.16 (m, 11 H), 7.15 - 7.06 (m, 5H), 6.91 - 6.85 (m, 1H), 6.70 (d, 1 H, J = 16.2), 5.45 (dd, 2H, J1 = 33.35, J2 = 13.9), 5.10 (s, 2H), 3.81 (s, 3H), 2.10 (s, 3H).
[00505] b) Preparation of 5-(2-benzyloxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl- 4-phenethyl-2H-pyridazin-3-one
Figure imgf000076_0002
[00506] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 9e for 5-(2-benzyloxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl-4-((E)-styryl)- 2H-pyridazin-3-one of Example 24a, 5-(2-benzyloxy-phenyl)-2-(3-methoxy-benzyl)-6- methyl-4-phenethyl-2H-pyridazin-3-one was obtained as a colorless oil (0.51 g, 94%).
[00507] 1H NMR (CDCI3): δ 7.43 - 7.35 (m, 1 H), 7.32 - 7.24 (m, 4H), 7.23 - 7.09 (m, 5H), 7.08 - 6.99 (m, 4H), 6.98 - 6.91 (m, 2H), 6.89 - 6.80 (m, 2H), 5.38 (dd, 2H, J1 = 30.1 , J2 = 13.9), 5.06 (s, 2H), 3.80 (s, 3H), 2.81 - 2.49 (m, 4H), 2.00 (s, 3H). [00508] c) Preparation of 5-(2-hydroxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl-4- phenethyl-2H-pyridazin-3-one
Figure imgf000077_0001
[00509] Utilizing the procedures described in Example 9g except substituting 5-(2- benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 9f for 5-(2-benzyloxy-phenyl)-2-(3-methoxy-benzyl)-6-methyI-4~phenethyl- 2H-pyridazin-3-one of Example 24b, 5-(2-hydroxy-phenyl)-2-(3-methoxy-benzyl)-6- methyl-4-phenethyl-2H-pyridazin-3-one was obtained as a white solid (0.23 g, 56%).
[00510] 1H NMR (CDCI3): δ 7.33 - 7.23 (m, 3H)1 7.18 - 7.04 (m, 5H), 7.00 - 6.81
(m, 5H), 6.74 (dd, 1H, J1 = 7.5, J2 = 1.5), 5.38 (dd, 2H, J1 = 45.5, J2 = 13.7), 3.80 (s,
3H), 2.85 - 2.49 (m, 4H), 1.99 (s, 3H).
[00511] HPLC (gradient 20-80% ACN/H2O): > 99%
[00512] MS (ESI+) (+ 0.1% HCOOH): 427.1 [C27H26N2O^H]+ (m/z).
Example 25
Preparation of 5-(2-hydroxy-phenyl)-6-methyl-4-phenethyl-2-(1-phenyl-ethyl)-2H- pyridazin-3-one
Figure imgf000077_0002
[00513] a) Preparation of 5-(2-benzyloxy-phenyl)-6-methyl-2-(1-phenyl-ethyl)-4- ((E)-styryl)-2H-pyridazin-3-one
Figure imgf000078_0001
[00514] Utilizing the procedures described in Example 22e except substituting (2- bromo-ethyl)-benzene for 1 -bromoethyl benzene, 5-(2-benzyloxy-phenyl)-6-methyl-2- (1-phenyl-ethyl)-4-((E)-styryl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.50 g, 77%).
[00515] 1H NMR (CDCI3): δ 8.34 (dd, IH1 J1 = 16.2, J2 = 2.4), 7.62 - 7.56 (m, 1 H), 7.54 - 7.48 (m, 1H), 7.45 - 7.29 (m, 4H), 7.28 - 7.18 (m, 9H), 7.15 - 7.11 (m, 2H), 7.08 - 7.03 (m, 2H), 6.67 (d, 1H, J = 16.2), 6.41 (qd, 1 H, J1 = 7.1 , J2 = 2.0), 5.08 (q, 2H, J = 13.8), 2.08 (s, 3H), 1.86 (dd, 3H, J1 = 7.0, J2 = 1.2).
[00516] b) Preparation of 5-(2-benzyloxy-phenyl)-6-methyl-4-phenethyl-2-(1- phenyl-ethyl)-2H-pyridazin-3-one
Figure imgf000078_0002
[00517] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 9e for 5-(2-benzyloxy-phenyl)-6-methyl-2-(1-phenyl-ethyl)-4-((E)-styryl)-2H- pyridazin-3-one of Example 25a, 5-(2-benzyloxy-phenyl)-6-methyl-4-phenethyl-2-(1- phenyl-ethyl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.45 g, 92%).
[00518] 1H NMR (CDCI3): δ 7.57 - 7.51 (m, 1H), 7.47 - 7.18 (m, 8H), 7.17 - 7.07 (m, 4H), 7.06 - 6.97 (m, 2H), 6.96 - 6.86 (m, 3H), 6.81 (dd, 1H, J1 = 7.3, J2 = 1.6), 6.41 (q, 1 H, J = 7.3), 5.03 (d, 2H, J = 17.7), 2.83 - 2.40 (m, 4H), 1.99 (d, 3H, J = 3.4), 1.82 (d, 3H1 J = 6.9).
[00519] c) Preparation of 5-(2-hydroxy-phenyl)-6-methyl-4-phenethyl-2-(1-phenyl- ethyl)-2H-pyridazin-3-one
Figure imgf000079_0001
[00520] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-6-methyl-4-phenethyl-2-(1-phenyl-ethyl)-2H- pyridazin-3-one of Example 25b, 5-(2-hydroxy-phenyl)-6-methyl-4-phenethyl-2-(1- phenyl-ethyl)-2H-pyridazin-3-one was obtained as a white solid (0.084 g, 24%).
[00521] 1H NMR (CDCI3): δ 7.52 - 7.46 (m, 2H), 7.31 - 7.18 (m, 4H), 7.12 - 7.04
(m, 3H), 6.99 - 6.91 (m, 2H), 6.90 - 6.84 (m, 2H), 6.80 (dd, 1 H, J1 = 7.5, J2 = 1.6),
6.38 (dd, 1H, J1 = UA , J2 = 6.9),6.20 (broad s, 1H), 2.86 - 2.43 (m, 4H), 2.03 (s, 3H),
1.79 (d, 3H1 J = 7.1).
[00522] HPLC (gradient 20-80% ACN/H2O): > 99%
[00523] MS (ESI+) (+ 0.1% HCOOH): 411.1 [C27H26N2O^H]+ (m/z).
Example 26
Preparation of 4-r2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-6-methyl-2-(1 - phenvl-ethyl)-2H-pyridazin-3-one
Figure imgf000079_0002
[00524] a) Preparation of 4-(2-benzyloxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5- hydroxy-5-methyl-5H-furan-2-one
Figure imgf000080_0001
[00525] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-phenyl)-2-bromo-propan-1-one and trans- styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, 4-(2-benzyloxy-phenyl)-3-[2- (3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H-furan-2-one was obtained as a yellowish oil (19.9 g). The crude product was used directly onto the next step without any further purification.
[00526] b) Preparation of 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6- methyl-2H-pyridazin-3-one
Figure imgf000080_0002
[00527] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5- methyl-5H-furan-2-one of Example 26a, 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro- phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a white solid (3 g, 15%).
[00528] 1H NMR (DMSOd6): δ 13.03 (s, 1 H), 8.22 (d, 1 H, J = 16.1), 7.46 - 6.92
(m, 13H), 6.47 (d, 1 H, J = 16.1), 5.15 (s, 2H), 1.9 (s, 3H).
[00529] MS (ESI+) (+ 0.1% HCOOH): 413.1 [C26H21 FN2O2+H]+ (m/z).
[00530] c) Preparation of 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6- methyl-2-(1-phenyl-ethyl)-2H-pyridazin-3-one
Figure imgf000081_0001
[00531] Utilizing the procedures described in Example 22e except substituting 5- (2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 22d for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 26b and (2-bromo-ethyl)-benzene for 1-bromoethyl benzene, 5-(2- benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2-(1-phenyl-ethyl)-2H- pyridazin-3-one was obtained as a colorless gum (0.51 g, 82%).
[00532] 1H NMR (CDCI3): δ 8.3 (d, 1 H, J = 16.2), 7.62 - 7.25 (m, 6H), 7.24 - 6.99 (m, 10H), 6.95 - 6.85 (m, 2H), 6.62 ( d, 1 H1 J = 16.2), 6.56 - 6.45(m, 1H), 5.09 (q, 2H, J = 13.0), 2.08 (s, 3H), 1.86 (d, 3H, J = 6.9).
[00533] d) Preparation of 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6- methyl-2-(1-phenyl-ethyl)-2H-pyridazin-3-one
Figure imgf000081_0002
[00534] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 9e for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2-(1- phenyl-ethyl)-2H-pyridazin-3-one of Example 26d, 5-(2-benzyloxy-phenyl)-4-[2-(3- fluoro-phenyl)-ethyl]-6-methyl-2-(1-phenyl-ethyl)-2H-pyridazin-3-one was obtained as a colorless oil (0.48 g, 95%). [00535] 1H NMR (CDCI3): δ 7.58 - 7.52 (m, 1H), 7.48 - 7.28 (m, 6H), 7.25 - 7.14 (m, 3H), 7.14 - 6.99 (m, 4H), 6.92 - 6.67 (m, 3H), 6.64 - 6.55(m, 1H), 6.41 (q, 1 H, J = 7.0), 5.05 (d, 2H, J = 16.7), 2.83 - 2.43 (m, 4H), 2.00 (d, 3H, J = 3.0), 1.83 (d, 3H, J = 6.9).
[00536] e) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2-(1-phenyl-ethyl)-2H-pyridazin-3-one
Figure imgf000082_0001
[00537] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2-(1- phenyl-ethyl)-2H-pyridazin-3-one, the title compound was obtained as a white solid (0.10 g, 26%).
[00538] 1H NMR (CDCI3): δ 7.54 - 7.47 (m, 2H), 7.34 - 7.21 (m, 4H), 7.11 - 6.90
(m, 3H), 6.83 - 6.73 (m, 2H), 6.67 (d, 1 H, J = 7.7), 6.57 (dd, 1 H, J1 = 9.9, J2 = 1.8),
6.38 (q, 1H, J = 7.0), 5.43 (s broad, 1H), 2.83 - 2.58 (m, 3H), 2.55 - 2.42 (m, 1H),
2.02 (s, 3H), 1.8 ( d, 3H1 J = 7.1).
[00539] HPLC (gradient 20-80% ACN/H2O): > 99%.
[00540] MS (ESI+) (+ 0.1 % HCOOH): 429.1 [C27H25FN2O2+H]+ (m/z).
Example 27
Preparation of 4-f2-(3-fluoro-phenyl)-ethvn-5-(2-hvdroxy-phenyl)-2-(4-methoxy- benzyl)-6-methvl-2H-pyridazin-3-one
Figure imgf000082_0002
[00541] a) Preparation of 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-(4- methoxy-benzyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000083_0001
[00542] Utilizing the procedures described in Example 14c except substituting 4- [2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 14b for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H- pyridazin-3-one of Example 26b and 2-chlorobenzyl bromide for 1-chloromethyl-4- methoxy-benzene, 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyI)-vinyl]-2-(4-methoxy- benzyl)-6-methyl-2H-pyridazin-3-one was obtained as a colorless gum (0.60 g, 94%).
[00543] 1H NMR (CDCI3): 5 8.28 (d, 1 H, J = 16.2), 7.52 - 7.37 (m, 3H), 7.24 - 7.14 (m, 6H), 7.09 - 6.98 (m, 4H), 6.94 - 6.84 (m, 4H), 6.58 (d, 1 H, J = 16.2), 5.36 (dd, 2H, J1 = 34.8, J2 = 13.5), 5.07 (dd, 2H, J1 = 13.9, J2 = 12.6), 3.80 (s, 3H), 2.05 (s, 3H).
[00544] b) Preparation of 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-(4- methoxy-benzyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000083_0002
[00545] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 9e for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-(4-methoxy- benzyl)-6-methyl-2H-pyridazin-3-one of Example 27a, 5-(2-benzyloxy-phenyl)-4-[2- (3-fluoro-phenyl)-ethyl]-2-(4-methoxy-benzyl)-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.56 g, 93%). [00546] 1H NMR (CDCI3): δ 7.48 - 7.31 (m, 4H), 7.21 - 6.98 (m, 6H), 6.92 - 6.67 (m, 6H), 6.62 - 6.55 (m, 1H), 5.30 (q, 2H, J = 15.3), 5.04 (s, 2H), 3.80 (s, 3H), 2.76 - 2.44 (m, 4H), 1.97 (s, 3H).
[00547] c) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(4- methoxy-benzyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000084_0001
[00548] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-(4-methoxy- benzyl)-6-methyl-2H-pyridazin-3-one of Example 27b, 4-[2-(3-fluoro-phenyl)-ethyl]-5- (2-hydroxy-phenyl)-2-(4-methoxy-benzyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.3 g, 77%).
[00549] 1H NMR (CDCI3): δ 9.78 (broad s, 1H), 7.34 - 7.16 (m, 4H), 7.00 - 6.83 (m,
6H), 6.74 - 6.61 (m, 2H), 5.16 (dd, 2H, J1 = 16.3, J2 = 13.7), 3.72 (s, 3H), 2.72 - 2.33
(m, 4H), 1.9 (s, 3H).
[00550] HPLC (gradient 5-80% ACN/H2O): > 99%.
[00551] MS (ESI+) (+ 0.1% HCOOH): 445.2 [C27H25FN2O3+H]+ (m/z).
Example 28
Preparation of 2-(3,5-dimethoxy-benzyl)-4-f2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy- phenyl)-6-methyl-2H-pvridazin-3-one
Figure imgf000084_0002
[00552] a) Preparation of 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-4-[2- (3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000085_0001
[00553] Utilizing the procedures described in Example 14c except substituting 4- [2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 14b for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H- pyridazin-3-one of Example 26b, and 2-chlorobenzyl bromide for 1-bromomethyl-3,5- dimethoxy-benzene, 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-4-[2-(3-fluoro- phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.45 g,
O ).
[00554] 1H NMR (CDCl3): δ 8.29 (d, 1 H, J = 16.2), 7.45 - 7.37 (m, 1H), 7.22 - 7.15 (m, 6H), 7.10 - 6.97 (m, 4H), 6.94 - 6.84 (m, 2H), 6.66 - 6.62 (m, 2H), 6.58 (d, 1 H, J = 16.2), 6.42 - 6.38 (m, 1 H), 5.35 (dd, 2H, J1 = 45.5, J2 = 13.9), 5.08 (dd, 2H, J1 = 13.5, J2 = 12.6), 3.78 (s, 6H), 2.05 (s, 3H).
[00555] b) Preparation of 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-4-[2- (3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000085_0002
[00556] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 9e for 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-4-[2-(3-fluoro- phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 28a, 5-(2-benzyloxy-phenyl)- 2-(3,5-dimethoxy-ben2yl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.42 g, 95%).
[00557] 1H NMR (CDCI3): δ 7.43 - 7.35 (m, 1 H)1 7.30 - 7.23 (m, 2H), 7.21 - 7.16 (m, 2H), 7.14 - 6.98 (m, 3H), 6.85 - 6.74 (m, 2H), 6.73 - 6.55 (m, 5H), 6.42 - 6.39 (m, 1H), 5.50 (dd, 2H, J1 = 43.3, J2 = 13.7), 5.05 (s, 2H), 3.78 (s, 6H), 2.78 - 2.45 (m, 4H), 1.97 ( s, 3H).
[00558] c) Preparation of 2-(3,5-dimethoxy-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5- (2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000086_0001
[00559] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-4-[2-(3-fluoro- phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one of Example 28b, 2-(3,5-dimethoxy- benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3- one was obtained as a white solid (0.2 g, 59%).
[00560] 1H NMR (CDCI3): δ 9.78 (broad s, 1 H), 7.31 - 7.16 (m, 2H), 7.01 - 6.83 (m,
4H), 6.74 - 6.61 (m, 2H), 6.49 - 6.41 (m, 3H), 5.18 (s, 2H), 3.71 (s, 6H), 2.73 - 2.33
(m, 4H), 1.91 (s, 3H).
[00561] HPLC (gradient 5-80% ACN/H2O): > 94%.
[00562] MS (ESI+) (+ 0.1% HCOOH): 475.1 [C28H27FN2O4+H]+ (m/z).
Example 29
Preparation of 2-benzoF1 ,2,51thiadiazol-4-ylmethyl-4-f2-(3-fluoro-phenyl)-ethyll-5-(2- hvdroxy-phenyl)-6-methvl-2H-pvridazin-3-one
Figure imgf000087_0001
[00563] a) Preparation of 5-(2-benzyloxy-phenyl)-4-[2-(3~fluoro-phenyl)-ethyl]-6- methyl-2H-pyridazin-3-one
Figure imgf000087_0002
[00564] To a solution of 5-(2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H- pyridazin-3-one (1.6 g, 3.87 mmol) of Example 26b in ethyl acetate (50 mL) was added platinum oxide (0.16 g). The reaction mixture was stirred for 1.5 hours under hydrogen and filtered over celite. The filtrate was concentrated under reduced pressure. The resulting crude product was purified on silica gel column chromatography using cyclohexane - ethyl acetate (gradient from 30% to 50% of ethyl acetate) to afford 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl- 2H-pyridazin-3-one (0.24 g, 15%) as a colorless gum.
[00565] 1H NMR (CDCI3): δ 12.57 (broad s, 1 H), 7.45 - 7.37 (m, 1 H), 7.63 - 7.18 (m, 5H), 7.17 - 7.01 (m, 3H), 6.86 - 6.73 (m, 3H), 6.92 (dt, I H, J1 = 9.9, J2 = 1.9), 5.07 (s, 2H), 2.86 - 2.69 (m, 3H), 2.62 - 2.50 (m, 1 H)1 2.01 (s, 3H).
[00566] b) Preparation of 2-benzo[1 ,2,5]thiadiazol-4-ylmethyl-5-(2-benzyloxy- phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000088_0001
[00567] To a solution of 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6- methyl-2H-pyridazin-3-one (0.24 g, 0.59 mmol) of Example 29a in anhydrous dimethylformamide (3.5 ml_) were added 4-bromomethyl-benzo[1 ,2,5]thiadiazole (0.14 g, 0.65 mmol) and cesium carbonate (0.57 g, 1.77 mmol). The reaction mixture was stirred overnight at room temperature under argon. Water (20 ml) and ethyl acetate (20 ml) were added, the resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified on silica gel column chromatography eluting with cyclohexane - ethyl acetate (8:2) to afford 2-benzo[1 ,2,5]thiadiazol-4-ylmethyl-5-(2- benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one (0.23 g, 82%) as a yellowish oil.
[00568] 1H NMR (DMSO-d6): δ 8.04 (d, 1 H, J = 8.2), 7.63 - 6.64 (m, 15 H), 5.77 (dd, 2H, J1 = 15.8, J2 = 32.9), 5.13 (s, 2H), 2.70 - 2.42 (m, 4H), 1.86 (s, 3H). MS (ESI+) (+ 0.1 % HCOOH): 563.0 [C33H27FN4O2S+H]+ (m/z).
[00569] c) Preparation of 2-benzo[1,2,5]thiadiazol-4-ylmethy)-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000088_0002
[00570] To a solution of 2-benzo[1,2,5]thiadiazol-4-ylmethyl-5-(2-benzyloxy- phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one (0.2 g, 0.355 mmol) of Example 29b in glacial acetic acid (6 mL) was added 37% hydrochloric acid (2.9 ml_). The reaction mixture was stirred at 800C for 6 h and neutralized with 5N sodium hydroxide solution. The resulting aqueous layer was extracted with ethyl acetate (2 x 25mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting white solid was triturated successively in diethyl ether and cyclohexane to afford 2- benzo[1 ,2,5]thiadiazol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)- 6-methyl-2H-pyridazin-3-one (0.1 g, 60%) as a white solid.
[00571] 1H NMR (CDCI3): δ 7.95 (d, 1H, J = 8.6), 7.63 - 7.18 (m, 3H), 7.16 - 6.99 (m, 2H), 6.92 (d, IH1 J = 8.6), 6.88 - 6.79 (m, 3H), 6.66 - 6.56 (m, 1H), 5.93 (dd, 2H, J1 = 31.2, J2 = 15.2), 4.87 (broad s, 1H), 2.88 - 2.53 (m, 4H), 2.00 (s, 3H). [00572] HPLC (gradient 5-80% ACN/H2O): > 94%. [00573] MS (ESI+) (+ 0.1% HCOOH): 473.1 [C26H21 FN4O2S+H]+ (m/z).
Example 30
Preparation of 4-r2-(4-fluoro-phenyl)-ethvπ-5-(2-hvdroxy-phenyl)-6-methyl-2- phenethyl-2H-pyridazin-3-one
Figure imgf000089_0001
[00574] a) Preparation of 4-(4-fluoro-phenyl)-but-3-enoic acid
Figure imgf000089_0002
[00575] Utilizing the procedures described in Example 8a except substituting 3- fluorobenzaldehyde for 4-fluorobenzaldehyde, 4-(4-fluoro-phenyl)-but-3-enoic acid was obtained as an orange solid (3.3 g, 91%).
[00576] 1H NMR (CDCI3): δ 11.11 (broad s, 1H), 7.38 - 7.28 (m, 1H), 7.19 - 6.88 (m, 3H), 6.47 (d, 1H, J = 16.0), 6.19 (d, 1H, J = 16.0), 3.28 (dd, 2H, J1 = 7.0, J2 = 1.4).
[00577] b) Preparation of 4-(2-benzyloxy-phenyl)-3-[2~(4-fluoro-phenyl)-vinyl]-5- hydroxy~5-methyl-5H-furan-2-one
Figure imgf000090_0001
[00578] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-phenyl)-2-bromo-propan-1-one and trans- styrylacetic acid for 4-(4-fluoro-phenyl)-but-3-enoic acid of Example 30a, 4-(2- benzyloxy-phenyl)-3-[2-(4-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H-furan-2-one was obtained as an orange gum (10 g). The crude product was used directly onto the next step without any further purification.
[00579] c) Preparation of 5-(2-benzyloxy-phenyl)-4-[2-(4-fluoro-phenyl)-vinyl]-6- methyl-2H-pyridazin-3-one
Figure imgf000090_0002
[00580] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-phenyl)-3-[2-(4-fluoro-phenyl)-vinyl]-5-hydroxy-5- methyl-5H-furan-2-one of Example 30b, the title compound was obtained as a yellowish oil (0.6 g, 11%).
[00581] 1H NMR (DMSOd6): δ 12.98 (broad s, 1 H), 8.24 (d, 1H, J = 16.1), 7.48 - 7.07 (m, 13H), 6.40 (d, 1H, J = 16.1), 5.1 (s, 2H), 1.89 (s, 3H).
[00582] d) Preparation of 5-(2-benzyloxy-phenyl)-4-[2-(4-fluoro-phenyl)-vinyl]-6- methyl-2-phenethyl-2H-pyridazin-3-one
Figure imgf000091_0001
[00583] Utilizing the procedures described in Example 22e except substituting 5- (2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 22d for 5-(2-benzyloxy-phenyl)-4-[2-(4-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 30c, 5-(2-benzyloxy-phenyl)-4-[2-(4-fluoro-phenyl)-vinyl]-6-methyl-2- phenethyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.34 g, 55%).
[00584] 1H NMR (CDCI3): δ 8.34 (d, 1H, J = 16.2), 7.46 - 7.16 (m, 13H), 7.11 - 7.03 (m, 3H), 6.93 (t, 2H, J = 8.6), 6.54 (d, 1 H, J = 16.0), 5.09 (s, 2H), 4.50 - 4.42 (m, 2H), 3.24 - 3.15 (m, 2H), 2.04 (s, 3H).
[00585] e) Preparation of 4-[2-(4-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2-phenethyl-2H-pyridazin-3-one
Figure imgf000091_0002
[00586] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[2-(4-fluoro-phenyl)-vinyl]-6-methyl-2- phenethyl-2H-pyridazin-3-one of Example 3Od, 4-[2-(4-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2-phenethyl-2H-pyridazin-3-one was obtained as a grey solid (0.17 g, 62%).
[00587] 1H NMR (CDCI3): δ 8.45 (broad s, 1 H), 7.36 - 7.17 (m, 7H), 6.96 (t, 1 H, J = 7.1), 6.85 - 6.67 (m, 5H), 4.53 - 4.27 (m, 2H), 3.11 (t, 2H, J = 8.1), 2.74 - 2.47 (m, 4H), 2.07 (s, 3H). [00588] HPLC (gradient 5-80% ACN/H2O): > 95%. [00589] MS (ESI+) (+ 0.1 % HCOOH): 429.0 [C27H25FN2O^H]+ (m/z).
Example 31
Preparation of 2-(3,4-dimethoxy-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl1-5-(2-hydroxy- phenyl)-6-methvl-2H-pyridazin-3-one
Figure imgf000092_0001
[00590] a) Preparation of 5-(2-benzyloxy-phenyl)-2-(3,4-dimethoxy-benzyl)-4-[2- (3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000092_0002
[00591] Utilizing the procedures described in Example 14c except substituting A- [2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 14b for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H- pyridazin-3-one of Example 26b, and 2-chlorobenzyl bromide for 4-bromomethyl-1 ,2- dimethoxy-benzene, 5-(2-benzyloxy-phenyl)-2-(3,4-dimethoxy-benzyl)-4-[2-(3-fluoro- phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.43 g, 62%).
[00592] 1H NMR (CDCI3): δ 8.28 (d, 1H, J = 16.2), 7.45 - 7.36 (m, 1H), 7.22 - 7.15 (m, 6H), 7.13 - 6.98 (m, 6H), 6.94 - 6.81 (m, 3H), 6.59 (d, 1H, J = 16.2), 5.35 (dd, 2H, J1 = 38.9, J2 = 13.5), 5.07 (s, 2H), 3.88 (d, 3H, J = 2.8), 2.05 (s, 3H).
[00593] b) Preparation of 2-(3,4-dimethoxy-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5- (2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000093_0001
[00594] Utilizing the procedures described in Example 22f except substituting 5- (2-ben2yloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-2-(3,4-dimethoxy-benzyl)-4-[2-(3-fluoro- phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 31a, 2-(3,4-dimethoxy- benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3- one was obtained as a white solid (0.28 g, 77%).
[00595] 1H NMR (CDCI3): δ 7.34 - 7.28 (m, 1 H), 7.14 - 6.92 (m, 5H), 6.85 - 6.71
(m, 3H), 6.65 (d, 1 H1 J = 7.7), 6.55 (d, 1 H1 J = 9.8), 6.06 (broad s, 1 H), 5.27 (dd, 2H,
J1 = 53.6, J2 = 13.5), 3.85 (s, 6H), 2.80 - 2.46 (m, 4H), 2.01 (s, 3H).
[00596] HPLC (gradient 5-80% ACN/H2O): > 99%.
[00597] MS (ESI+) (+ 0.1 % HCOOH): 475.0 [C28H27FN2O4+H]+ (m/z).
Example 32
Preparation of 4-r2-(3-fluoro-phenyl)-ethvn-5-(2-hvdroxy-phenyl)-6-methyl-2-(3,4,5- trimethoxy-benzvl)-2H-pyridazin-3-one
Figure imgf000093_0002
[00598] a) Preparation of 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6- methyl-2-(3,4,5-trimethoxy-benzyl)-2H-pyridazin-3-one
Figure imgf000094_0001
[00599] Utilizing the procedures described in Example 14c except substituting 4- [2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 14b for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H- pyridazin-3-one of Example 26b, and 2-chlorobenzyl bromide for 5-chloromethyl- 1 ,2,3-trimethoxy-benzene, 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6- methyl-2-(3,4,5-trimethoxy-benzyl)-2H-pyridazin-3-one was obtained as a yellowish foam (0.36 g, 51%).
[00600] 1H NMR (CDCI3): δ 8.28 (d, 1 H, J = 16.2), 7.47 - 7.38 (m, 1H), 7.23 - 7.13 (m, 6H), 7.11 - 6.98 (m, 4H), 6.94 - 6.85 (m, 2H), 6.75 (s, 2H), 6.60 (d, 1 H, J = 16.2), 5.37 (dd, 2H, J1 = 33.4, J2 = 13.4), 5.08 (s, 2H), 3.81 (s, 9H), 2.05 (s, 3H).
[00601] b) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- rnethyl-2-(3,4,5-trimethoxy-benzyl)-2H-pyridazin-3-one
Figure imgf000094_0002
[00602] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2- (3,4,5-trimethoxy-benzyl)-2H-pyridazin-3-one of Example 26a, 4-[2-(3-fluoro-phenyl)- ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3,4,5-trimethoxy-benzyl)-2H-pyridazin-3-one was obtained as a grey solid (0.17 g, 57%). [00603] 1H NMR (CDCI3): δ 7.35 - 7.27 (m, 1 H), 7.11 - 6.92 (m, 3H), 6.83 - 6.73
(m, 4H), 6.67 (d, 1 H1 J = 7.5), 6.56 (d, 1 H, J = 9.8), 5.75 (s, 1 H), 5.26 (dd, 2H, J1 =
38.0, J2 = 13.3), 3.84 (s, 9H), 2.82 - 2.47 (m, 4H), 2.02 (s, 3H).
[00604] HPLC (gradient 5-80% ACN/H2O): > 96%.
[00605] MS (ESI+) (+ 0.1% HCOOH): 504.9 [C29H29FN2O5H-H]+ (m/z).
Example 33
Preparation of 2-r2-(3,5-dimethoxy-phenyl)-ethyll-4-r2-(3-fluoro-phenylVethvn-5-(2- hvdroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000095_0001
[00606] a) Preparation of 5-(2-benzyloxy-phenyl)-2-[2-(3,5-dimethoxy-phenyl)- ethyl]-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000095_0002
[00607] Utilizing the procedures described in Example 14c except substituting 4- [2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 14b for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H- pyridazin-3-one of Example 26b, and 2-chlorobenzyl bromide for 1 -(2-bromo-ethyl)- 3,5-dimethoxy-benzene, 5-(2-benzyloxy-phenyl)-2-[2-(3,5-dimethoxy-phenyl)-ethyl]-4- [2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a yellowish gum (0.4 g, 78%).
[00608] 1H NMR (CDCI3): δ 8.33 (d, 1H, J = 16.2), 7.46 - 7.37 (m, 1H), 7.28 - 7.16 (m, 6H), 7.14 - 7.01 (m, 4H), 6.96 - 6.86 (m, 2H), 6.62 (d, 1H, J = 16.2), 6.66 - 6.54 (m, 2H), 6.39 - 6.34 (m, 1 H), 5.10 (s, 2H), 4.56 - 4.37 (m, 2H), 3.79 (s, 6H), 3.15 (t, 2H1 J = 8.1), 2.06 (s, 3H).
[00609] b) Preparation of 2-[2-(3,5-dimethoxy-phenyl)-ethyl]-4-[2-(3-fluoro-phenyl)- ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000096_0001
[00610] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-2-[2-(3,5-dimethoxy-phenyl)-ethyl]-4-[2-(3- fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 33a, 2-[2-(3,5- dimethoxy-phenyl)-ethyl]-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl- 2H-pyridazin-3-one was obtained as a white solid (0.23 g, 73%).
[00611] 1H NMR (CDCI3): δ 7.36 - 7.27 (m, 1 H), 7.14 - 7.04 (m, 1H), 7.03 - 6.93
(m, 3H), 6.84 - 6.75 (m, 3H), 6.69 (d, 1 H, J = 7.5), 6.59 (d, 1H, J = 9.7), 6.46 (s, 1 H),
6.34 (s, 1 H), 4.48 - 4.28 (m, 2H)1 3.78 (s, 6H), 3.09 (t, 2H, J = 8.01), 2.85 - 2.48 (m,
4H), 2.03 (s, 3H).
[00612] HPLC (gradient 5-80% ACN/H2O): > 95%.
[00613] MS (ESI+) (+ 0.1 % HCOOH): 489.3 [C29H29FN2O4^-H]+ (m/z).
Example 34
Preparation of 2-(3,5-dimethoxy-benzyl)-5-(2-hvdroxy-phenyl)-6-methyl-4-phenethyl-
2H-pyridazin-3-one
Figure imgf000096_0002
[00614] a) Preparation of 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-6- methyl-4-((E)-styryl)-2H-pyridazin-3-one
Figure imgf000097_0001
[00615] Utilizing the procedures described in Example 29b except substituting 5- (2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one of Example 26b for 5-(2-benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example of 14d, and 4-bromomethyl-benzo[1 ,2,5]thiadiazole for 1-bromomethyl-3,5- dimethoxy-benzene, 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-6-methyl-4- ((E)-styryl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.53 g, 54%).
[00616] 1H NMR (DMSO-d6): δ 8.22 (d, 1 H, J = 16.1), 7.51 - 7.13 (m, 14 H), 6.52 (m, 4H), 5.26 (m, 2H), 5.16 (s, 2H), 3.72 (s, 6H), 1.96 (s, 3H).
[00617] b) Preparation of 2-(3,5-dimethoxy-benzyl)-5-(2-hydroxy-phenyl)-6-methyl- 4-phenethyl-2H-pyridazin-3-one
Figure imgf000097_0002
[00618] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-2-(3,5-dimethoxy-benzyl)-6-methyl-4-((E)- styryl)-2H-pyridazin-3-one of Example 34a, 2-(3,5-dimethoxy-benzyl)-5-(2-hydroxy- phenyI)-6-methyl-4-phenethyl-2H-pyridazin-3-one was obtained as a white solid (0.15 g, 33%).
[00619] 1H NMR (DMSO-d6): δ 9.74 (broad s, 1 H), 7.311 - 6.88 (m, 9H), 6.47 (m,
3H), 5.20 (s, 2H), 3.73 (s, 6H), 2.67 - 2.38 (m, 4H), 1.93 (s,3H).
[00620] HPLC (gradient 5-80% ACN/H2O): > 95%.
[00621] MS (ESI+) (+ 0.1% HCOOH): 457.4 [C28H28N2O4+H]+ (m/z). Example 35
Preparation of 2-benzof 1 ,2.51thiadiazol-4-ylmethyl-5-(3-fluoro-2-hvdroxy-phenyl)-4-r2- (3-fluoro-phenyl)-ethyll-6-methyl-2H-pvridazin-3-one
Figure imgf000098_0001
[00622] a) Preparation of 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- ethyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000098_0002
[00623] To a solution of 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)- vinyl]-6-methyl-2H-pyridazin-3-one (0.26 g, 0.73 mmol) of Example 11e in ethyl acetate (10 ml_) was added palladium on carbon (10%) (0.26 g). The reaction mixture was stirred under hydrogen at atmospheric pressure for 3 hours, and then filtered over celite. The filtrate was concentrated under reduced pressure to afford 5-(3- fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one (0.2 g, 76%) as a white solid.
[00624] 1H NMR (DMSO-d6): δ 12.9 (s, 1 H), 7.42 - 6.71 (m, 7H), 3.74 (d, 3H, J = 2.2), 2.74 - 2.55 (m, 3H), 2.30 - 2.24 (m, 1 H), 1.88 (s, 3H).
[00625] b) Preparation of 2-benzo[1 ,2,5]thiadiazol-4-ylmethyl-5-(3-fluoro-2- methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000099_0001
[00626] Utilizing the procedures described in Example 29b except substituting 5- (2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one of Example 29a for 5-(3-fluoro-2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl- 2H-pyridazin-3-one of Example 35a, 2-benzo[1 ,2,5]thiadiazol-4-ylmethyI-5-(3-fluoro- 2-methoxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.2 g, 70%).
[00627] 1H NMR (DMSOd6): δ 8.05 (d, 1 H, J = 8.7), 7.73 (dd, 1 H, J1 = 8.7, J2 = 6.8), 7.44 - 7.14 (m, 4H), 6.97 (m, 1H), 6.76 (m, 3H), 5.81 (dd, 2H, J1 = 15.6, J2 = 49.4), 3.77 (d, 3H, J = 2.3), 2.77 - 2.65 (m, 3H), 2.40 - 2.33 (m, 1 H), 1.90 (s, 3H).
[00628] c) Preparation of 2-benzo[1 ,2,5]thiadiazol-4-ylmethyl-5-(3-fluoro-2- hydroxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000099_0002
[00629] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one of Example 8h for 2-benzo[1,2,5]thiadiazol-4-ylmethyl-5-(3-fluoro-2-methoxy- phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one of Example 35b, 2- benzo[1 ,2,5]thiadiazol-4-ylmethyl-5-(3-fluoro-2-hydroxy-phenyl)-4-[2-(3-fluoro- phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.07 g,
Ό .
[00630] 1H NMR (DMSOd6): δ 9.96 (broad s, 1 H), 8.05 (d, 1 H, J = 8.7), 7.72 (dd, 1 H, J1 = 8.7, J2 = 7.0), 7.31 - 7.20 (m, 3H), 6.93 (m, 2H), 6.73 (m, 3H), 5.79 (dd, 2H, J1 = 15.7, J2 = 24.0), 2.72 - 2.56 (m, 3H), 2.46 - 2.42 (m, 1H)1 1.92 (s, 3H). [00631] HPLC (gradient 20-80% ACN/H2O): > 95%.
[00632] MS (ESI+) (+ 0.1 % HCOOH): 491.3 [C26H2oF2N402S+H]+ (m/z).
Example 36
Preparation of 5-(3-fluoro-2-hvdroxy-phenyl)-6-methyl-2.4-diphenethyl-2H-pyridazin-
3-one
Figure imgf000100_0001
[00633] a) Preparation of 4-(3-fluoro-2-methoxy-phenyl)-5-hydroxy-5-methyl-3- ((E)-styryl)-5H-furan-2-one
Figure imgf000100_0002
[00634] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 2-bromo-1-(3-fluoro-2-methoxy-phenyl)-propan-1-one, 4-(3- fluoro-2-methoxy-phenyl)-5-hydroxy-5-methyl-3-((E)-styryl)-5H-furan-2-one was obtained as yellowish oil (1.34 g). The crude product was used directly onto the next step without any further purification.
[00635] b) Preparation of 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-4-((E)-styryl)- 2H-pyridazin-3-one
Figure imgf000100_0003
[00636] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(3-fluoro-2-methoxy-phenyl)-5-hydroxy-5-methyl-3-((E)-styryl)-5H- furan-2-one of Example 36a, 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-4-((E)-styryl)- 2H-pyridazin-3-one was obtained as a white solid (0.25 g, 20%).
[00637] 1H NMR (DMSO-d6): δ 13.07 (broad s, 1 H), 8.3 (d, 1 H, J = 16.2), 7.50 - 7.05 (m, 8H), 6.49 (d, 1 H, J = 15.9), 3.73 (d, 3H, J = 1.8), 1.93 (s, 3H).
[00638] c) Preparation of 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-4-phenethyl-2H- pyridazin-3-one
Figure imgf000101_0001
[00639] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyrida2in-3-one of
Example 9e for 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3- one of Example 36b, 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-4-phenethyl-2H- pyridazin-3-one was obtained as a colorless oil (0.25 g, 99%).
[00640] 1H NMR (CDCI3): δ 7.26 - 6.99 (m, 7H), 6.44 (d, 1 H, J = 7.6), 3.83 (d, 3H, J = 2.7), 2.81 (m, 3H), 2.47 - 2.27 (m, 1 H), 1.98 (s, 3H).
[00641] d) Preparation of 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-2,4-diphenethyl- 2H-pyridazin-3-one
Figure imgf000101_0002
[00642] Utilizing the procedures described in Example 29b except substituting 5- (2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one of Example 29a for 5-(3-fluoro-2-methoxy-phenyl)-6-methyl~4-phenethyl-2H-pyridazin-3- one of Example 36c, and 4-bromσmethy!-benzo[1,2,5]thiadiazole for (2-bromo-ethyl)- benzene, 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-2,4-diphenethyl-2H-pyridazin-3- one was obtained as a yellowish oil (0.31 g, 95%).
[00643] 1H NMR (DMSO-d6): 5 7.29 - 7.13 (m, 10H), 6.91 (m, 2H), 6.74 (d, 1 H1 J = 7.6), 4.32 (m, 2H), 3.73 (d, 3H, J = 2.3), 3.07 (t, 2H, J = 7.6), 2.76 - 2.51 (m, 3H), 2.25 (m, 1 H), 1.89 (s, 3H).
[00644] e) Preparation of 5-(3-fluoro-2-hydroxy-phenyl)-6-methyl-2,4-diphenethyl- 2H-pyridazin-3-one
Figure imgf000102_0001
[00645] Utilizing the procedures described in Example 8i except substituting 6- ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-5-(2-methoxy-phenyl)-2H-pyridazin-3- one of Example 8h for 5-(3-fluoro-2-methoxy-phenyl)-6-methyl-2,4-diphenethyl-2H- pyridazin-3-one of Example 36d, 5-(3-fluoro-2-hydroxy-phenyl)-6-methyl-2,4- diphenethyl-2H-pyridazin-3-one was obtained as a white foam (0.15 g, 52%).
[00646] 1H NMR (DMSOd6): δ 9.91 (broad s, 1 H), 7.35 - 7.13 (m, 9H), 6.89 (m,
3H), 6.71 (d, 1 H, J = 7.5), 4.30 (m, 2H), 3.06 (t, 2H, J = 7.7), 2.60 (m, 3H), 2.38 (m,
1H), 1.92 (s, 3H).
[00647] HPLC (gradient 20-80% ACN/H2O): > 95%.
[00648] MS (ESI+) (+ 0.1 % HCOOH): 429.3 [C27H25FN2O2 +H]+ (m/z).
Example 37
Preparation of 2-(3,5-dimethoxy-benzyl)-5-(3-fluoro-2-hvdroxy-phenyl)-4-r2-(3-fluoro- phenyl)-ethyll-6-methyl-2H-pvridazin-3-one
Figure imgf000102_0002
[00649] a) Preparation of 1-(3-fluoro-2-hydroxy-phenyl)-propan-1-one
Figure imgf000103_0001
[00650] A solution of 1-(3-fluoro-2-methoxy-phenyl)-propan-1-one (0.14 g, 0.78 mmol) in anhydrous methylene chloride (7.7 mL) was cooled to -78°C. Boron tribromide (1M in methylene chloride) (0.92 mL, 0.92 mmol) was then added dropwise while maintaining the reaction mixture temperature below -70°C. The resulting solution was allowed to warm to room temperature for 5 minutes and poured in cold water (30 mL). The aqueous layer was extracted using methylene chloride (2 x 5OmL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford the title compound (0.12 g, 99%) as a yellow solid.
[00651] 1H NMR (DMSOd6): δ 11.96 (s, 1H), 7.72 (m, 1H), 7.50 (m, 1H), 6.94 (m, 1H), 3.13 (q, 2H, J = 7.2), 1.09 (t, 3H, J= 7.2).
[00652] b) Preparation of 1-(2-benzyloxy-3-fluoro-phenyl)-propan-1-one
Figure imgf000103_0002
[00653] Utilizing the procedures described in Example 22a except substituting 1- (2-hydroxy-phenyl)-propan-1-one for 1-(3-fluoro-2-hydroxy-phenyl)-propan-1-one of Example 37a, 1-(2-benzyloxy-3-fluoro-phenyl)-propan-1-one was obtained as a colorless oil (3.55 g, 92%).
[00654] 1H NMR (DMSO-d6): δ 7.44 - 7.18 (m, 8H), 5.12 (s, 2H), 2.84 (q, 2H, J = 7.2), 0.96 (t, 3H1 J = 7.2).
[00655] c) Preparation of 1-(2-benzyloxy-3-fluoro-phenyl)-2-bromo-propan-1-one
Figure imgf000104_0001
[00656] Utilizing the procedures described in Example 8e except substituting 1-(2- methoxy-phenyl)-butan-1-one of Example 8d for 1-(2-benzyloxy-3-fluoro-phenyl)- propan-1-one of Example 37b, 1-(2-benzyloxy-3-fluoro-phenyl)-2-bromo-propan-1- one was obtained as a colorless oil (4.1 g, 88%).
[00657] 1H NMR (CDCI3): δ 7.55 - 7.17 (m, 8H), 5.46 (q, 1 H, J = 6.6), 5.14 (dd, 2H, J1 = 11.0, J2 = 37.1), 1.59 (d, 3H1 J = 6.6).
[00658] d) Preparation of 4-(2-benzyloxy-3-fluoro-phenyl)-3-[2-(3-fluoro-phenyl)- vinyl]-5-hydroxy-5-methyl-5H-furan-2-one
Figure imgf000104_0002
[00659] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-3-fluoro-phenyl)-2-bromo-propan-1-one of Example 37c, and frans-styrylacetic acid for 4-(3-fluoro-phenyl)-but-3-enoic acid, 4- (2-benzyloxy-3-fluoro-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H- furan-2-one was obtained as a brown oil (8 g). The crude product was used directly onto the next step without any further purification.
[00660] e) Preparation of 5-(2-benzyloxy~3-fluoro-phenyl)-4-[(E)-2-(3-fluoro- phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000105_0001
[00661] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-3-fluoro-phenyl)-3-[2-(3-fluoro-phenyl)-vinyl]-5- hydroxy-5-methyl-5H-furan-2-one of Example 37d, 5-(2-benzyloxy-3-fluoro-phenyl)-4- [(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a yellowish solid (0.4 g, 15%).
[00662] 1H NMR (DMSOd6): δ 13.06 (s, 1 H), 8.23 (d, 1 H1 J = 16.0), 7.51 - 6.74 (m, 12H), 6.4 (d, 1 H, J = 16.0), 5.0 (m, 2H), 1.88 (s, 3H).
[00663] f) Preparation of 5-(2-benzyloxy-3-fluoro-phenyl)-2-(3,5-dimethoxy- benzyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000105_0002
[00664] Utilizing the procedures described in Example 14c except substituting 4- [2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 14b for 5-(2-benzyloxy-3-fluoro-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6- methyl-2H-pyridazin-3-one of Example 37e, and 2-chlorobenzyl bromide for 1- bromomethyl-3,5-dimethoxy~benzene, 5-(2-benzyloxy-3-fluoro-phenyl)-2-(3,5- dimethoxy-benzyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.44 g, 82%). [00665] 1H NMR (CDCI3): δ 8.26 (d, 1 H, J = 16.0), 7.29 - 7.02 (m, 8H), 7.01 - 6.78 (m, 4H), 6.67 - 6.61 (m, 2H), 6.43 - 6.39 (m, 1H), 6.34 (d, 1 H, J = 16.0), 5.33 (dd, 2H, J1 = 21.5, J2 = 13.6,) 5.01 (dd, 2H, J1 = 41.2, J2 = 11.4), 3.78 (s, 6H), 1.99 ( s, 3H).
[00666] g) Preparation of 2-(3,5-dimethoxy-benzyl)-5-(3-fluoro-2-hydroxy-phenyl)- 4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000106_0001
[00667] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-3-fluoro-phenyl)-2-(3,5-dimethoxy-benzyl)-4-[2-(3- fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 37f, 2-(3,5-dimethoxy- benzyl)-5-(3-fluoro-2-hydroxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-2H- pyridazin-3-one was obtained as a white foam (0.1 g, 27%).
[00668] 1H NMR (DMSOd6): δ 9.96 (s, 1 H), 7.25 (m, 2H), 6.92 (m, 2H), 6.71 (m,
3H), 6.46 (m, 3H), 5.20 (s, 2H), 3.73 (s, 6H), 2.71 - 2.55 (m, 3H), 2.44 - 2.37 (m, 1H),
1.92 (s, 3H).
[00669] HPLC (gradient 5-95% ACN/H2O): > 89%.
[00670] MS (ESI+) (+ 0.1 % HCOOH): 493.3 [C28H26F2N2O4 +H]+ (m/z).
Example 38
Preparation of 2-r2-(3,5-dimethoxy-phenyl)-ethyl1-5-(3-fluoro-2-hvdroxy-phenyl)-6- methyl-4-phenethyl-2H-pyridazin-3-one
Figure imgf000106_0002
[00671] a) Preparation of 4-(2-benzyloxy-3-fluoro-phenyl)-5-hydroxy-5-methyl-3- ((E)-styryl)-5H-furan-2-one
Figure imgf000107_0001
[00672] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-3-fluoro-phenyl)-2-bromo-propan-1-one, A- (2-benzyloxy-3-fluoro-phenyl)-5-hydroxy-5-methyl-3-((E)-styryl)-5H-furan-2-one was obtained as a brown oil (8 g). The crude product was used directly onto the next step without any further purification.
[00673] b) Preparation of 5-(2-benzyloxy-3-fluoro-phenyl)-6-methyl-4-((E)-styryl)- 2H-pyridazin-3-one
Figure imgf000107_0002
[00674] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyI)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-3-fluoro-phenyl)-5-hydroxy-5-methyl-3-((E)-styryl)-5H- furan-2-one of Example 38a, 5-(2-benzyloxy-3-fluoro-phenyl)-6-methyl~4-((E)-styryl)- 2H-pyridazin-3-one was obtained as a yellowish solid (0.75 g, 30%).
[00675] 1H NMR (DMSO-d6): δ 12.99 (broad s, 1 H), 8.27 (d, 1 H, J = 16.0), 7.48 - 7.06 (m, 13H), 6.42 (d, 1 H, J = 16.0), 4.98 (dd, 2H, J1 = 11.4, J2 = 39.3), 1.87 (s, 3H).
[00676] c) Preparation of 5-(2-benzyloxy-3-fluoro-phenyl)-2-[2-(3,5-dimethoxy- phenyl)-ethyl]-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one
Figure imgf000108_0001
[00677] Utilizing the procedures described in Example 14c except substituting 4- [2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 14b for 5-(2-benzyloxy-3-fluoro-phenyl)-6-methyl-4-((E)-styryl)-2H- pyridazin-3-one of Example 38b, and 2-chlorobenzyl bromide for 1 -(2-bromo-ethyl)- 3,5-dimethoxy-benzene, 5-(2-benzyloxy-3-fluoro-phenyl)-2-[2-(3,5-dimethoxy- phenyl)-ethyl]-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one was obtained as a yellowish oil (0.48 g, 69%).
[00678] 1H NMR (CDCI3): δ 8.36 (d, 1H, J = 16.2), 7.31 - 7.20 (m, 6H), 7.19 - 7.08 (m, 6H), 6.90 - 6.84 (m, 1H), 6.56 - 6.52 (m, 2H), 6.47 (d, 1 H, J = 16.1), 6.39 - 6.34 (m, 1 H), 5.01 (dd, 2H, J1 = 45.4, J2 = 11.4), 4.50 - 4.41 (m, 2H), 3.80 (s, 6H), 3.18 - 3.09 (m, 2H), 2.00 (s, 3H).
[00679] d) Preparation of 2-[2-(3,5-dimethoxy-phenyl)-ethyl]-5-(3-fluoro-2-hydroxy- phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one
Figure imgf000108_0002
[00680] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-3-fluoro-phenyl)-2-[2-(3,5-dimethoxy-phenyl)-ethyl]- 6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 38c, 2-[2-(3,5-dimethoxy- phenyl)-ethyl]-5-(3-fluoro-2-hydroxy-phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3- one was obtained as a white solid (0.17 g, 42%). [00681] 1H NMR (DMSO-d6): δ 9.92 (s, 1H), 7.22 (m, 4H), 6.90 (m, 3H), 6.70 (m,
1H), 6.39 (m, 3H), 4.29 (m, 2H), 3.73 (s, 6H), 3.00 (t, 2H, J = 7.6), 2.65 - 2.51 (m,
3H), 2.40 - 2.34 (m, 1 H), 1.91 (s, 3H).
[00682] HPLC (gradient 5-95% ACN/H2O): > 99%.
[00683] MS (ESI+) (+ 0.1 % HCOOH): 489.3 [C29H29F2N2O4 +H]+ (m/z).
Example 39
Preparation of 4-f2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-2-(3-methoxy- benzyl)-6-methyl-2H-pvridazin-3-one
Figure imgf000109_0001
[00684] a) Preparation of 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]- 2-(3-methoxy-benzyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000109_0002
[00685] To a suspension of potassium carbonate (0.124 g, 1.50 mmol) in anhydrous acetonitrile (4 ml) were added dibenzo-18-crown-6 (0.036 g, 0.10 mmol), 1-bromomethyl-3-methoxy-benzene (0.145 g, 0.72 mmol) and 5-(2-benzyloxy- phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 26b (0.247 g, 0.60 mmol). The resulting reaction mixture was refluxed under microwaves at 1300C for 2 hours and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with cyclohexane - dichloromethane (7:3) to give 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-2-(3-methoxy- benzyl)-6-methyl-2H-pyridazin-3-one (0.284 g, 88%). [00686] 1H NMR (CDCI3): δ 8.29 (d, 1 H, J = 16.2), 7.44 - 7.38 (m, 1H), 7.29 - 7.21 (m, 2H), 7.09 - 7.01 (m, 6H), 6.91 - 6.83 (m, 3H), 6.59 (d, 1 H, J = 16.2), 5.40 (dd, 2H, J1 = 12.0, J2 = 33.7), 5.08 (s, 2H), 3.80 (s, 3H), 2.05 (s, 3H), 1.42 (s, 3H).
[00687] b) Preparation of 4-[2-(3-fluoro-phenyl)-ethyI]-5-(2-hydroxy-phenyl)-2-(3- methoxy-benzyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000110_0001
[00688] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-2-(3- methoxy-benzyl)-6-methyl-2H-pyridazin-3-one of Example 39a, 4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl-2H-pyridazin-3- one was obtained as a white solid (0.145 g, 61%).
[00689] 1H NMR (CDCI3): δ 7.32 - 7.23 (m, 2H), 7.08 - 6.93 (m, 5H), 6.85 - 6.74
(m, 3H), 6.67 (d, 1 H, J = 7.9), 6.57 (d, 1 H, J = 9.8), 5.31 (dd, 2H, J1 = 13.9, J2 =
47.5), 2.77 - 2.49 (m, 4H), 2.00 (s, 3H).
[00690] HPLC (gradient 5-95% ACN/H2O): > 99%.
[00691] MS (ESI+) (+ 0.1% HCOOH): 445.3 [C27H25FN2θ3+H]+ (m/z).
Example 40
Preparation of 2-benzoM ,31dioxol-4-ylmethyl-4-f2-(3-fluoro-phenyl)-ethyll-5-(2- hvdroxy-phenyl)-6-methyl-2H-pvridazin-3-one
Figure imgf000110_0002
[00692] a) Preparation of 4-bromomethyl-benzo[1 ,3]dioxole
Figure imgf000111_0001
[00693] To a solution of 4-hydroxymethyl-benzo[1 ,3]dioxole (1.00 g, 6.6 mmol) and carbon tetrabromide (3.50 g, 10.5 mmol) in anhydrous tetrahydrofuran (30 ml.) was added at 00C triphenylphosphine (2.80 g, 10.5 mmol) in solution in tetrahydrofuran (10 mL). The resulting reaction mixture was stirred at room temperature for 2 hours. Water (30 mL) was added followed by ethyl acetate (30 mL). The organic layer was washed first with a concentrated aqueous sodium hydrogenocarbonate solution (30 mL) and then brine (30 mL), dried over anhydrous potassium carbonate and concentrated in vacuum. The resulting crude product was purified by flash chromatography on silica gel, eluting with cyclohexane - dichloromethane (7:3) to afford the title compound (1.23 g, 87%) as colorless oil.
[00694] 1H NMR (CDCI3): δ 6.86 - 6.75 (m, 3H), 6.02 (s, 2H), 4.47 (s, 2H).
[00695] b) Preparation of 2-benzo[1 ,3]dioxol-4-ylmethyl-5-(2-benzyloxy-phenyl)-4- [(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000111_0002
[00696] Utilizing the procedures described in Example 39a except substituting 1- bromomethyl-3-methoxy-benzene for 4-bromomethyl-benzo[1 ,3]dioxole, 2- benzo[1 ,3]dioxol-4-ylmethyl-5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]- 6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.463 g, 84%).
[00697] 1H NMR (CDCI3): δ 8.31 (d, 1 H, J = 16.2), 7.45 - 7.40 (m, 1 H), 7.23 - 7.18 (m, 6H), 7.10 - 7.00 (m, 4H), 6.92 - 6.76 (m, 5H), 6.60 (d, 1 H, J = 16.2), 5.98 (s, 2H), 5.43 (s, 2H), 5.08 (s, 2H), 2.05 (s, 3H). [00698] c) Preparation of 2-benzo[1 ,3]dioxol-4-ylmethyl-4-[2-(3-fluoro-phenyI)- ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyriciazin-3-one
Figure imgf000112_0001
[00699] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 2-benzo [1,3]dioxol-4-ylmethyl-5-(2-benzyloxy-phenyl)-4-[(E)-2-(3- fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 40b, 2- benzo[1 ,3]dioxol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one was obtained as a white solid (0.189 g, 49%).
[00700] 1H NMR (DMSO-d6): δ 9.74 (s, 1H), 7.29 - 7.18 (m, 2H), 6.99 - 6.64 (m,
9H), 6.03 (s, 2H), 5.22 (dd, 2H, J1 = 14.7, J2 = 18.6), 2.70 - 2.36 (m, 4H), 1.90 (s,
3H).
[00701] HPLC (gradient 5-95% ACN/H2O): > 90%
[00702] MS (ESI+) (+ 0.1 % HCOOH): 459.4 [C27H23FN2O4+H]+ (m/z).
Example 41
Preparation of 2-benzof 1 ,31dioxol-5-ylmethyl-4-f2-(3-fluoro-phenyl)-ethyl1-5-(2- hydroxy-phenyl)-6-methyl-2H-pvridazin-3-one
Figure imgf000112_0002
[00703] a) Preparation of 2-benzo[1,3]dioxol-5-ylmethyl-5-(2-benzyloxy-phenyl)-4~ [(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000113_0001
[00704] To a solution of 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6- methyl-2H-pyridazin-3-one of Example 26b (0.247 g, 0.60 mmol), 5-hydroxymethyl- benzo[1 ,3]dioxole (0.076 g, 0.50 mmol) and triphenylphosphine (0.170 g, 0.65 mmol) in anhydrous tetrahydrofuran (5 mL) was added diethylazodicarboxylate 40% in toluene (0.30 mL, 0.65 mmol). The resulting reaction mixture was heated at 600C for 12 hours and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with cyclohexane - dichloromethane (7:3) affording the title compound (0.193 g, 70%) as a white foam.
[00705] 1H NMR (CDCI3): δ 8.27 (d, 1 H, J = 16.0), 7.44 - 7.38 (m, 1 H), 7.20 - 7.15 (m, 6H), 7.08 - 6.99 (m, 6H), 6.91 - 6.77 (m, 3H), 6.58 (d, 1 H, J = 16.2), 5.94 (s, 2H), 5.31 (dd, 2H, J1 = 13.7, J2 = 36.9), 5.07 (s, 2H), 2.05 (s, 3H). [00706] MS (ESI+) (+ 0.1 % HCOOH): 547.2 [C34H27FN2O4^-H]+ (m/z).
[00707] b) Preparation of 2-benzo[1 ,3]dioxol-5-ylmethyl-4-[2-(3-fluoro-phenyl)- ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000113_0002
[00708] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 2-benzo [1 ,3]dioxol-5-ylmethyl-5-(2-benzyloxy-phenyl)-4-[(E)-2-(3- fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 41a, 2- benzo[1 ,3]dioxol-5-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one was obtained as a white solid (0.109 g, 67%). [00709] 1H NMR (CDCl3): δ 7.32 - 7.27 (m, 2H), 7.08 - 6.93 (m, 4H), 6.79 - 6.73
(m, 2H)1 6.64 (d, 1H, J = 7.5), 6.54 (d, 1 H, J = 10.0), 5.92 (s, 2H), 5.22 (dd, 2H, J1 =
13.4, J2 = 54.0), 2.73 - 2.47 (m, 4H), 2.01 (s, 3H).
[00710] HPLC (gradient 5-95% ACN/H2O): > 99%.
[00711] MS (ESI+) (+ 0.1 % HCOOH): 459.3 [C27H23FN2O4+H]+ (m/z).
Example 42
Preparation of 2-f3,5-bis-(2-methoxy-ethoxy)-benzvn-4-f2-(3-fluoro-phenyl)-ethvn-5- (2-hvdroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000114_0001
[00712] a) Preparation of [3,5-bis-(2-methoxy-ethoxy)-phenyl]-methanoI
Figure imgf000114_0002
[00713] To a suspension of potassium carbonate (3.10 g, 22.0 mmol) in anhydrous acetone (50 ml) were successively added dibenzo-18-crown-6 (0.40 g, 1.0 mmol), 5-hydroxymethyl-benzene-1 ,3-diol (1.40 g, 10.0 mmol) and toluene-4-sulfonic acid 2-methoxy ethyl ester (5.10 g, 22.0 mmol). The resulting reaction mixture was refluxed for 12 hours and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with cyclohexane - ethyl acetate (6:4) affording [3,5-bis-(2-methoxy-ethoxy)-phenyl]-methanol (1.17 g, 45%) as a colorless oil.
1H NMR (CDCI3): δ 6.54 (d, 2H, J = 2.2), 6.45 (s, 1 H), 4.61 (s, 2H), 4.09 (t, 4H, J 4.6), 3.73 (t, 4H, J = 4.6), 3.44 (s, 6H).
[00714] b) Preparation of 1-bromornethyl-3,5-bis-(2-methoxy-ethoxy)-benzene
Figure imgf000115_0001
[00715] Utilizing the procedures described in Example 40a except substituting 4- hydroxymethyl-benzo[1 ,3]dioxole for [3,5-bis-(2-methoxy-ethoxy)-phenyl]-methanol, 1-bromomethyl-3,5-bis-(2-methoxy-ethoxy)-benzene was obtained as a colorless oil (0.982 g, 67%).
[00716] 1H NMR (CDCI3): δ 6.56 (d, 2H, J = 2.2), 6.45 (s, 1 H), 4.39 (s, 2H), 4.09 (t, 4H, J = 4.5), 3.73 (t, 4H, J = 4.5), 3.44 (s, 6H).
[00717] c) Preparation of 5-(2-benzyloxy-phenyl)-2-[3,5-bis-(2-methoxy-ethoxy)- benzyl]-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000115_0002
[00718] Utilizing the procedures described in Example 39a except substituting 1- bromomethyl-3-methoxy-benzene for 1 -bromomethyl-3,5-bis-(2-methoxy-ethoxy)- benzene of Example 42b, 5-(2-benzyloxy-phenyl)-2-[3,5-bis-(2-methoxy-ethoxy)- benzyl]-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.590 g, 90%).
[00719] 1H NMR (CDCI3): δ 8.28 (d, 1 H, J = 16.2), 7.43 - 7.37 (m, 1 H), 7.23 - 7.15 (m, 5H), 7.09 - 7.00 (m, 4H), 6.91 - 6.86 (m, 2H), 6.68 (s, 2H), 6.59 (d, 1 H, J = 16.0), 6.47 (s, 1 H), 5.33 (dd, 2H, J1 = 14.0, J2 = 69.7), 5.10 (s, 2H), 4.10 (t, 4H, J = 4.7), 3.72 (t, 4H, J = 4.7), 3.42 (s, 6H), 2.05 (s, 3H), 2.04 (s, 3H).
[00720] d) Preparation of 2-[3,5-bis-(2-methoxy-ethoxy)-benzyl]-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000116_0001
[00721] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyrida2in-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-2-[3,5-bis-(2-methoxy-ethoxy)-benzyl]-4- [(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 42c, 2-[3,5- bis-(2-methoxy-ethoxy)-benzyl]-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy~phenyl)-6- methyl-2H-pyridazin-3-one was obtained as a white solid (0.353 g, 69%).
[00722] 1H NMR (CDCI3): δ 7.30 - 7.24 (m, 1H), 7.07 - 6.91 (m, 3H), 6.78 - 6.72
(m, 2H), 6.63 (d, 3H, J = 2.2), 6.53 (d, 1 H1 J = 9.8), 6.43 (t, 1 H1 J = 2.2), 5.23 (dd, 2H,
J1 = 13.7, J2 = 71.2), 4.05 (t, 4H, J = 4.5), 3.70 (t, 4H, J = 4.5), 3.41 (s, 6H), 2.74 -
2.46 (m, 4H), 2.00 (s, 3H).
[00723] HPLC (gradient 5-95% ACN/H2O): > 95%.
[00724] MS (ESI+) (+ 0.1% HCOOH): 563.4 [C32H35FN2O6H-H]+ (m/z).
Example 43
Preparation of 4-r2-(3-fluoro-phenyl)-ethvn-5-(2-hvdroxy-phenyl)-2-(2-methoxy-ethyl)-
6-methvl-2H-pyridazin-3-one
Figure imgf000116_0002
[00725] a) Preparation of 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]~ 2-(2-methoxy-ethyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000117_0001
[00726] Utilizing the procedures described in Example 41a except substituting 5- hydroxymethyl-benzo[1 ,3]dioxole for 2-methoxyethanol, 5-(2-benzyloxy-phenyl)-4- [(E)-2-(3-fluoro-phenyl)-vinyl]-2-(2-methoxy-ethyl)-6-methyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.264 g, 80%).
[00727] 1H NMR (CDCI3): δ 8.30 (d, 1 H, J = 16.2), 7.44 - 7.38 (m, 1H), 7.23 - 7.15 (m, 6H), 7.09 - 7.00 (m, 6H), 6.92 - 6.87 (m, 2H), 6.60 (d, 1H, J = 16.2), 5.08 (s, 2H), 4.57 - 4.35 (m, 2H), 3.88 (t, 2H, J = 5.9), 3.40 (s, 3H), 2.05 (s, 3H).
[00728] b) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2~hydroxy-phenyl)-2-(2- methoxy-ethyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000117_0002
[00729] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-2-(2- methoxy-ethyl)-6-methyl-2H-pyridazin-3-one of Example 43a, 4-[2-(3-fluoro-phenyl)- ethyl]-5-(2-hydroxy-phenyl)-2-(2-methoxy-ethyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.123 g, 57%).
[00730] 1H NMR (CDCI3): δ 7.30 (td, 1 H, J1 = 1.7, J2 = 8.1), 7.10 - 6.93 (m, 3H),
6.81 - 6.74 (m, 2H), 6.66 (d, 1 H, J = 7.7), 6.56 (d, 1 H, J = 10.1), 4.49 - 4.26 (m, 2H),
3.82 (t, 2H, J = 5.7), 3.37 (s, 3H), 2.77 - 2.47 (m, 4H), 2.02 (s, 3H). [00731] HPLC (gradient 5-95% ACN/H2O): > 99%.
[00732] MS (ESI+) (+ 0.1 % HCOOH): 383.3 [C22H23FN2O^H]+ (m/z). Example 44
Preparation of 4-r2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-6-methyl-2-(2- morpholin-4-yl-ethyl)-2H-pvridazin-3-one
Figure imgf000118_0001
[00733] a) Preparation of 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]- 6-methyl-2-(2-morpholin-4-yl-ethyl)-2H-pyridazin-3-one
Figure imgf000118_0002
[00734] Utilizing the procedures described in Example 41a except substituting 5- hydroxymethyl-benzo[1 ,3]dioxole for Λ/-(2-hydroxyethyl)morpholine, 5-(2-benzyloxy- phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2-(2-morpholin-4-yl-ethyl)-2H- pyridazin-3-one was obtained as a yellowish oil (0.281 g, 76%).
[00735] 1H NMR (CDCI3): δ 8.27 (d, 1 H, J = 16.0), 7.70 - 7.39 (m, 1H), 7.22 - 7.17 (m, 6H), 7.09 - 7.01 (m, 4H), 6.92 - 6.87 (m, 2H), 6.59 (d, 1H, J = 16.2), 5.08 (s, 2H), 4.43 - 4.37 (m, 2H), 3.70 (t, 2H, J = 4.3), 2.87 (t, 2H, J = 7.2), 2.61 (t, 2H, J = 4.5), 2.04 (s, 3H). [00736] MS (ESI+) (+ 0.1 % HCOOH): 526.4 [C32H32FN3O3+^* (m/z)
[00737] b) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2-(2-morpholin-4-yl-ethyl)-2H-pyridazin-3-one
Figure imgf000119_0001
[00738] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2- (2-morpholin-4-yl-ethyl)-2H-pyridazin-3-one of Example 44a, 4-[2-(3-fluoro-phenyl)- ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(2-morpholin-4-yl-ethyl)-2H-pyridazin-3-one was obtained as a beige solid (0.105 g, 34%).
[00739] 1H NMR (CDCI3): δ 7.30 (td, W1 J1 = 1.7, J2 = 8.1), 7.11 - 6.92 (m, 3H),
6.82 - 6.67 (m, 3H), 6.57 (d, 1 H, J = 10.0), 4.31 - 4.25 (m, 2H), 3.68 (t, 4H, J = 4.5),
2.86 - 2.46 (m, 10H), 2.01 (s, 3H).
[00740] HPLC (gradient 5-95% ACN/H2O): > 99%.
[00741] MS (ESI+) (+ 0.1% HCOOH): 438.4 [C25H28FN3O3H-H]+ (m/z).
Example 45
Preparation of {5-r2-(3-fluoro-phenyl)-ethyl1-4-(2-hvdroxy-phenyl)-3-rnethyl-6-oxo-6H- pyridazin-1-yl}-acetic acid methyl ester
Figure imgf000119_0002
[00742] a) Preparation of {4-(2-benzyloxy-phenyl)-5-[(E)-2-(3-fluoro-phenyl)-vinyl]- 3-methyl-6-oxo-6H-pyridazin-1-yl}-acetic acid methyl ester
Figure imgf000120_0001
[00743] Utilizing the procedures described in Example 39a except substituting 1- bromomethyl-3-methoxy-benzene for methyl bromoacetate, {4-(2-benzyloxy-phenyl)- 5-[(E)-2-(3-fluoro-phenyl)-vinyl]-3-methyl-6-oxo-6H-pyridazin-1 -yl}-acetic acid methyl ester was obtained as a yellowish solid (0.405 g, 77%).
[00744] 1H NMR (CDCI3): 5 8.31 (d, 1 H, J = 16.2), 7.45 - 7.39 (m, 1 H)1 7.23 - 7.18 (m, 6H), 7.12 - 7.01 (m, 4H), 6.93 - 6.87 (m, 2H), 6.59 (d, 1 H, J = 16.2), 5.10 (s, 2H), 4.98 (dd, 2H, J1 = 16.4, J2 = 52.6), 3.82 (s, 3H), 2.05 (s, 3H). [00745] MS (ESI+) (+ 0.1 % HCOOH): 485.4 [C29H25FN2O^H]+ (m/z).
[00746] b) Preparation of {5-[2-(3-fluoro-phenyl)-ethyl]-4-(2-hydroxy-phenyl)-3- methyl-6-oxo-6H-pyridazin-1-yl}-acetic acid methyl ester
Figure imgf000120_0002
[00747] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for {4-(2-benzyloxy-phenyl)-5-[(E)-2-(3-fluoro-phenyl)-vinyl]-3-methyl-6- oxo-6H-pyridazin-1-yl}-acetic acid methyl ester of Example 45a, {5-[2-(3-fluoro- phenyl)-ethyl]-4-(2-hydroxy-phenyl)-3-methyl-6-oxo-6H-pyridazin-1-yl}-acetic acid methyl ester was obtained as a white solid (0.302 g, 91%).
[00748] 1H NMR (CH3OH-d4): δ 7.34 - 7.29 (m, 1 H), 7.20 - 7.13 (m, 1H), 6.98 - 6.91 (m, 2H), 6.87 - 6.78 (m, 2H), 6.74 (d, 1 H1 J = 7.4), 6.66 - 6.62 (m, 1H), 4.94 (dd, 2H, J1 = 16.8, J2 = 36.9), 3.80 (s, 3H), 2.76 - 2.49 (m, 4H), 2.02 (s, 3H). [00749] HPLC (gradient 5-95% ACN/H2O): > 99%. [00750] MS (ESI+) (+ 0.1% HCOOH): 397.2 [C22H21 FN2O4+H]+ (m/z).
Example 46
Preparation of 3-(5-r2-(3-fluoro-phenyl)-ethyl1-4-(2-hvdroxy-phenyl)-3-methyl-6-oxo- 6H-pyridazin-1-ylmethyl>-Λ/-methyl-benzamide
Figure imgf000121_0001
[00751] a) Preparation of 3-bromomethyl-Λ/-benzamide
Figure imgf000121_0002
[00752] To a suspension of α-bromo-m-toluic acid (3.00 g, 14.0 mmol) in anhydrous toluene (15 ml_) were successively added thionylchloride (1.80 ml, 25.1 mmol) and one drop of dimethylformamide. The resulting reaction mixture was heated at 600C for 2 h and after cooling concentrated under reduced pressure. The crude product was solubilized in tetrahydrofurane (15 ml_) before addition of triethylamine (3.9 ml, 28.0 mmol) and of a solution of methylamine 2M in tetrahydrofurane (10.5 ml_, 21 mmol). The reaction mixture was stirred at room temperature for 3 h, dropped in a concentrated aqueous sodium hydrogenocarbonate solution (50 ml_). The aqueous phase was extracted with ethyl acetate (2 x 30 ml_). The organic fractions were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting crude product was purified by flash chromatography on silica gel, eluting with dichloromethane - methanol (1 :9) to afford 3-bromomethyl-Λ/-benzamide (0.446 g, 13%) as a yellowish solid.
[00753] 1H NMR (CDCI3): δ 7.80 (s, 1 H), 7.70 (d, 2H, J = 7.7), 7.51 (d, 2H1 J = 7.7), 7.42 (d, 2H, J = 7.6), 6.35 (broad s, 1 H), 4.60 (s, 2H), 3.01 (d, 3H, J = 4.8).
[00754] b) Preparation of 3-{5-[(E)-2-(3-fluoro-phenyl)-vinyl]-4-(2-methoxy-phenyl)- 3-methyl-6-oxo-6H-pyridazin-1-ylmethyl}-Λ/-methyl-benzamide
Figure imgf000122_0001
Utilizing the procedures described in Example 39a except substituting 5-(2- benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 26b for 4-[(E)-2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 46b, and 1-bromomethyl-3-methoxy-benzene for 3- bromomethyl-Λ/-benzamide of Example 46a, 3-{5-[(E)-2-(3-fluoro-phenyl)-vinyl]-4-(2- methoxy-phenyl)-3-methyl-6-oxo-6H-pyridazin-1-ylmethyl}-Λ/-methyl-benzamide was obtained as a white solid (0.207 g, 86%).
[00755] 1H NMR (CDCI3): δ 8.24 (d, 1 H, J = 16.2), 7.91 (s, 1 H), 7.74 (d, 1 H, J = 7.7), 7.68 (d, 1 H, J = 6.6), 7.51 - 7.41 (m, 2H), 7.24 - 7.01 (m, 5H), 6.91 (d, 1 H, J = 9.6), 6.58 (d, 1 H, J = 16.0), 6.26 (broad s, 1 H), 5.42 (dd, 2H, J1 = 13.7, J2 = 41.0), 3.78 (s, 3H), 3.02 (d, 3H, J = 4.9), 2.03 (s, 3H). [00756] MS (ESI+) (+ 0.1 % HCOOH): 484.2 [C29H26FIs^H]+ (m/z).
[00757] c) Preparation of 3-{5-[2-(3-fluoro-phenyl)-ethyl]-4-(2-methoxy-phenyl)-3- methyl-6-oxo-6H-pyhdazin-1-ylmethyl}-Λ/-methyl-benzamide
Figure imgf000122_0002
[00758] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 9e for 3-{5-[(E)-2-(3-fluoro-phenyl)-vinyl]-4-(2-methoxy-phenyl)-3-methyl-6- oxo-6H-pyridazin-1-ylmethyl}-Λ/-methyl-benzamide of Example 46b, 3-{5-[2-(3-fluoro- phenyl)-ethyl]-4-(2-methoxy-phenyl)-3-methyl-6-oxo-6H-pyridazin-1-ylmethyl}-Λ/- methyl-benzamide was obtained as a white solid (0.157 g, 79%). [00759] 1H NMR (CDCI3): δ 7.90 (S1 1H)1 7.76 (d, 1H, J = 7.9), 7.65 (d, 1H, J = 7.7), 7.42 (t, 2H, J = 7.7), 7.14 - 7.98 (m, 2H), 6.83 - 6.76 (m, 2H), 6.71 (d, 1 H, J = 7.7), 6.59 (d, 1 H, J = 9.8), 6.52 (broad s, 1 H), 5.35 (dd, 2H, J1 = 13.6, J2 = 42.2), 3.75 (s, 3H), 3.00 (d, 3H, J = 4.8), 2.76 - 2.47 (m, 4H), 1.96 (s, 3H).
[00760] d) Preparation of 3-{5-[2-(3-fluoro-phenyl)-ethyl]-4-(2-hydroxy-phenyl)-3- methyI-6-oxo-6H-pyridazin-1-ylmethyl}-/V-methyl-benzamide
Figure imgf000123_0001
[00761] Utilizing the procedures described in Example 1e except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-5~(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 1d for 3-{5-[2-(3-fluoro-phenyl)-ethyl]-4-(2-methoxy-phenyl)-3-methyl-6-oxo- 6H-pyridazin-1-ylmethyl}-Λ/-methyl-benzamide of Example 46c, 3-{5-[2-(3-fluoro- phenyl)-ethyl]-4-(2-hydroxy-phenyl)-3-methyl-6-oxo-6H-pyridazin-1-ylmethyl}-Λ/- methyl-benzamide was obtained as a white solid (0.106 g, 70%).
[00762] 1H NMR (CDCI3): δ 8.63 (broad s, 1H), 7.74 (s, 1H), 7.56 (d, 1H, J = 7.7),
7.50 (d, 1H, J = 7.7), 7.28 - 7.17 (m, 2H), 7.08 - 6.97 (m, 2H), 6.89 (t, 2H, J = 7.5),
6.76 - 6.69 (m, 2H), 6.11 (d, 1H, J = 7.7), 6.52 (d, 1H, J = 10.0), 5.23 (dd, 2H, J1 =
13.7, J2 = 43.9), 2.81 (d, 3H, J = 4.9), 2.69 - 2.49 (m, 4H), 1.98 (s, 3H).
[00763] HPLC (gradient 5-95% ACN/H2O): > 90%.
[00764] MS (ESI+) (+ 0.1% HCOOH): 472.4 [C28H26FN3O3H-H]+ (m/z).
Example 47
Preparation of 3-[4-(2-hydroxy-phenyl)-3-methyl-6-oxo-5-phenethyl-6H-pyridazin-1- ylmethyli-AZ-methyl-benzamide
Figure imgf000123_0002
[00765] a) Preparation of 3-[4-(2-methoxy-phenyl)-3-methyl-6-oxo-5-phenethyl- 6H-pyridazin-1-ylmethyl]-Λ/-methy)-benzamide
Figure imgf000124_0001
[00766] Utilizing the procedures described in Example 39a except substituting 5- (2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 26b for 5-(2-methoxy-phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one of Example 9d, and 1-bromomethyl-3-methoxy-benzene for 3-bromomethyl-Λ/- benzamide of Example 46a, 3-[4-(2-methoxy-phenyl)-3-methyl-6-oxo-5-phenethyl~ 6H-pyridazin-1-ylmethyl]-Λ/-methyl-benzamide was obtained as a white solid (0.231 g, 94%).
[00767] 1H NMR (CDCI3): δ 7.90 (s, 1H), 7.74 (d, 1 H, J = 7.7), 7.66 (d, 1H, J = 7.7), 7.44 - 7.37 (m, 2H), 7.18 - 7.10 (m, 3H), 7.03 - 6.91 (m, 4H), 6.81 (dd, 1H, J1 = 1.5, J2 = 7.4), 6.28 (broad s, 1H), 5.36 (dd, 2H, J1 = 13.8, J2 = 44.0), 3.75 (s, 3H), 3.01 (d, 3H, J - 4.9), 2.74 - 2.44 (m, 4H), 1.95 (s, 3H). [00768] MS (ESI+) (+ 0.1 % HCOOH): 468.3 [C29H29N3O+^* (m/z)
[00769] b) Preparation of 3-[4-(2-hydroxy-phenyl)-3-methyl-6-oxo-5~phenethyl-6H- pyridazin-1-ylmethyl]-/V-methyl-benzamide
Figure imgf000124_0002
[00770] Utilizing the procedures described in Example 1f except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 1c for 3-[4-(2-methoxy-phenyl)-3~methyl-6-oxo-5-phenethyl-6H-pyridazin- 1-ylmethyl]-Λ/-methyl-benzamide of Example 47a, 3-[4-(2-hydroxy-phenyl)-3-methyl- 6-oxo-5-phenethyl-6H-pyridazin-1-ylmethyl]-N-methyl-benzamide_was obtained as a white solid (0.127 g, 57%). [00771] 1H NMR (CDCI3): δ 7.75 (s, 1H), 7.69 (broad s, 1H), 7.57 (t, 2H, J = 7.5),
7.31 - 7.22 (m, 2H), 7.14 - 7.03 (m, 4H)1 6.95 - 6.86 (m, 3H), 6.76 (d, 1 H, J = 7.5),
6.53 - 6.49 (m, 1 H), 5.28 (dd, 2H, J1 = 13.6, J2 = 73.2), 2.83 (d, 3H, J = 4.7), 2.78 -
2.49 (m, 4H), 2.01 (s, 3H).
[00772] HPLC (gradient 5-95% ACN/H2O): > 93%
[00773] MS (ESI+) (+ 0.1 % HCOOH): 454.4 [C28H27N3O3H-H]+ (m/z).
Example 48
Preparation of 2-(3-dimethylamino-benzyl)-4-f2-(3-fluoro-phenvπ-ethvn-5-(2-hvdroxy- phenyl)-6-methvl-2H-pyridazin-3-one
Figure imgf000125_0001
[00774] a) Preparation of 2-(3-bromo-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000125_0002
[00775] Utilizing the procedures described in Example 39a except substituting 5- (2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 26b for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 1d, and 1-bromomethyl-3-methoxy-benzene for 3- bromobenzyl bromide and, 2-(3-bromo-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.450 g,
'O ).
[00776] 1H NMR (CDCI3): δ 7.65 (t, 1H, J = 8.3), 7.46 - 7.37 (m, 3H), 7.25 - 7.18 (m, 1 H), 7.14 - 6.96 (m, 3H), 6.82 - 6.71 (m, 3H), 6.62 (d, 1 H, J = 9.9), 5.30 (dd, 2H, J1 = 13.8, J2 = 45.6), 3.73 (s, 6H), 2.82 - 2.50 (m, 4H), 1.96 (s, 3H). [00777] b) Preparation of 2-(3-dimethylamino-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]- 5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000126_0001
[00778] To a solution of 2-(3-bromo-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 48a (0.450 g, 0.88 mmol) in toluene (5 ml_), were successively added sodium tert-butoxide (0.211 g, 2.20 mmol), tris(dibenzylidene acetone dipalladium chloroform adduct (0.036 g, 0.04 mmol), xantphos (0.066 g, 0.12 mmol) and dimethylamine 2M in THF (1.10 mL, 2.20 mmol). The reaction mixture was refluxed under microwaves at 1200C for 20 min. After cooling, the reaction mixture was concentrated in vacuum. The resulting crude product was purified by flash chromatography on silica gel, eluting with dichloromethane - ethyl acetate (85:15) to afford 2-(3-dimethylamino-benzyl)-4-[2-(3- fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one (0.308 g, 74%) as a white solid.
[00779] MS (ESI+) (+ 0.1 % HCOOH): 472.3 [C29H30FN3O^H]+ (m/z).
[00780] c) Preparation of 2-(3-dimethylamino-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]- 5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000126_0002
[00781] A solution of 2-(3-dimethylamino-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 48d (0.320 g, 0.78 mmol) in hydrobromic acid (10 mL) was refluxed under microwaves at 1200C for 40 min. After cooling, the reaction mixture was dropped in a concentrated aqueous sodium hydrogenocarbonate solution (50 mL). The aqueous phase was extracted with ethyl acetate (2 x 30 ml). The organic fractions were washed with brine (30 mL), dried over anhydrous potassium carbonate and concentrated in vacuum. The resulting crude product was purified by flash chromatography on silica gel, eluting with dichloromethane - methanol (9:1) to afford 2-(3-dimethylamino-benzyl)-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one (0.180 g, 67%) as a white solid.
[00782] 1H NMR (CH3OH-d4): δ 7.31 (t, 1 H, J = 8.3), 7.19 - 7.09 (m, 2H), 6.97 - 6.90 (m, 2H), 6.85 - 6.78 (m, 3H), 6.71 (d, 3H, J = 7.9), 6.61 (d, 1 H, J = 10.0), 5.30 (dd, 2H, J1 = 13.9, J2 = 26.8), 2.91 (s, 6H), 2.73 - 2.54 (m, 4H), 2.03 (s, 3H). [00783] HPLC (gradient 5-95% ACN/H2O): > 95%. [00784] MS (ESI+) (+ 0.1% HCOOH): 458.5 [C28H28FN3O3+H]+ (m/z).
Example 49
Preparation of 4-r2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-6-methyl-2-(3- morpholin-4-yl-benzvl)-2H-pvridazin-3-one
Figure imgf000127_0001
[00785] a) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2-(3-morpholin-4-yl-benzyl)-2H-pyridazin-3-one
Figure imgf000127_0002
[00786] Utilizing the procedures described in Example 48b except substituting dimethylamine for morpholine, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2-(3-morpholin-4-yl-benzyl)-2H-pyridazin-3-one was obtained as a white solid (0.293 g, 95%).
[00787] MS (ESI+) (+ 0.1% HCOOH): 514.4 [C3iH32FN3O3+H]+ (m/z). [00788] b) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyI-2-(3-morpholin-4-yl-benzyl)-2H-pyridazin-3-one
Figure imgf000128_0001
[00789] Utilizing the procedures described in Example 48c except substituting 2- (2-dimethylamino-ethyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl- 2H-pyridazin-3-one of Example 48b for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy- phenyl)-6-methyl-2-(3-morpholin-4-yl-benzyl)-2H-pyridazin-3-one of Example 49a, 4- [2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3-morpholin-4-yl-benzyl)- 2H-pyridazin-3-one was obtained as a white solid (0.085 g, 38%).
[00790] 1H NMR (CH3OH-d4): δ 7.34 - 7.10 (m, 3H), 7.02 - 6.79 (m, 7H), 6.71 (d,
1H, J = 7.6), 6.62 (d, 1 H, J = 10.1), 5.31 (dd, 2H, J1 = 14.0, J2 = 20.6), 3.82 (t, 4H, J =
4.9), 3.13 (t, 4H, J = 4.9), 2.74 - 2.53 (m, 4H), 2.02 (s, 3H).
[00791] HPLC (gradient 5-95% ACN/H2O): > 95%.
[00792] MS (ESI+) (+ 0.1 % HCOOH): 500.3 [C3oH3oFN3θ3+H]+ (m/z).
Example 50 Preparation of 4-r2-(3-fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-6-methyl-2-(2- morpholin-4-yl-benzyl)-2H-pyridazin-3-one
Figure imgf000128_0002
[00793] a) Preparation of 2-(2-bromo-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000129_0001
[00794] Utilizing the procedures described in Example 39a except substituting 5- (2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 26b for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 1d, and 1-bromomethyl-3-methoxy-benzene for 2- bromobenzyl bromide, 2-(2-bromo-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (1.302 g, 87%).
[00795] 1H NMR (CDCl3): δ 7.54 (d, 2H, J = 7.8), 7.39 (t, 2H, J = 7.8), 7.24 (t, 2H, J = 8.2), 7.13 - 7.03 (m, 3H), 6.98 (t, 2H, J = 6.7), 6.83 - 6.78 (m, 2H), 6.74 (d, 1H, J = 7.7), 6.64 (d, 1H, J = 9.9), 5.48 (dd, 2H, J1 = 15.3, J2 = 46.4), 3.72 (s, 3H), 2.85 - 2.54 (m, 4H)1 1.95 (S1 3H).
[00796] b) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2-(2-morpholin-4-yl-benzyl)-2H-pyridazin-3-one
Figure imgf000129_0002
[00797] Utilizing the procedures described in Example 48b except substituting 2- (3-bromo-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 48a for 2-(2-bromo-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]- 5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 50a, and dimethylamine for morpholine, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2-(2-morpholin-4-yl-benzyl)-2H-pyridazin-3-one was obtained as a white solid (0.247 g, 55%).
[00798] 1H NMR (CDCI3): δ 7.41 (t, 1 H, J = 7.8), 7.31 - 6.97 (m, 7H), 6.84 - 6.77 (m, 2H), 6.74 (d, 1H, J = 6.6), 6.62 (d, 1H, J = 10.0), 5.56 (dd, 2H, J1 = 14.9, J2 = 31.1), 3.88 (t, 4H, J = 4.4), 3.75 (s, 3H), 3.00 (t, 4H, J = 3.8), 2.81 - 2.51 (m, 4H), 1.93 (s, 3H).
[00799] c) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2-(2-morpholin-4-yl-benzyl)-2H-pyridazin-3-one
Figure imgf000130_0001
[00800] Utilizing the procedures described in Example 48c except substituting 2- (2-dimethylamino-ethyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl- 2H-pyridazin-3-one of Example 48b for 4-[2-(3-fluoro-phenyI)-ethyl]-5-(2-methoxy- phenyl)-6-methyl-2-(2-rnorpholin-4-yl-benzyl)-2H-pyridazin-3-one of Example 50b, 4- [2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(2-morpholin-4-yl-benzyl)- 2H-pyridazin-3-one_was obtained as a white solid (0.176 g, 75%).
[00801] 1H NMR (DMSOd6): δ 7.30 - 7.18 (m, 4H), 7.06 (t, 1 H, J = 7.5), 6.98 - 6.88 (m, 5H), 6.72 (d, 1H, J = 7.6), 6.66 (d, 1 H, J = 10.0), 5.37 (dd, 2H, J1 = 15.2, J2 = 17.9), 3.74 (t, 4H, J = 4.1 ), 2.87 (t, 4H, J = 4.3), 2.68 - 2.38 (m, 4H), 1.88 (s, 3H). [00802] HPLC (gradient 5-95% ACN/H2O): > 99%. [00803] MS (ESI+) (+ 0.1 % HCOOH): 500.3 [C30H30FN3O3+H]+ (m/z).
Example 51
Preparation of 2-(3,5-dimethyl-isoxazol-4-ylmethyl)-4-f2-(3-fluoro-phenyl)-ethvN-5-(2- hvdroxy-phenyl)-6-methvl-2H-pyridazin-3-one
Figure imgf000130_0002
[00804] a) Preparation of 5-(2-benzyloxy-phenyl)-2-(3,5-dimethyl-isoxazol-4- ylmethyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000131_0001
[00805] Utilizing the procedures described in Example 41a except substituting 5- hydroxymethyl-benzo[1 ,3]dioxole for (3,5-dimethyl-4-isoxazolyl)methanol, 5-(2- benzyloxy-phenyl)-2-(3,5-dimethyl-isoxazol-4-ylmethyl)-4-[(E)-2-(3-fluoro-phenyl)- vinyl]-6-methyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.232 g, 64%).
[00806] 1H NMR (CDCI3): δ 8.19 (d, 1 H, J = 16.2), 7.42 (td, 1 H1 J1 = 2.2, J2 = 6.8),
7.21 - 7.17 (m, 6H), 7.11 - 7.01 (m, 4H), 6.93 - 6.87 (m, 2H), 6.58 (d, 1H, J = 16.2),
5.15 (dd, 2H, J1 = 14.3, J2 = 17.3), 5.07 (s, 2H), 2.54 (s, 3H), 2.39 (s, 3H), 2.02 (s,
3H).
[00807] MS (ESI+) (+ 0.1% HCOOH): 522.1 [C32H28FN3O3+H]+ (m/z).
[00808] b) Preparation of 2-(3,5-dimethyl-isoxazol-4-ylmethyl)-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000131_0002
[00809] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 26b for 5-(2-benzyloxy-phenyl)-2-(3,5-dimethyl-isoxazol-4-ylmethyl)-4-[(E)- 2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 51a, 2-(3,5- dimethyl-isoxazol-4-ylmethyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one_was obtained as a white solid (0.156 g, 80%).
[00810] 1H NMR (CDCI3): δ 7.31 (td, 1H, J1 = 1.7, J2 = 8.9), 7.10 - 6.94 (m, 3H), 6.82 - 6.75 (m, 2H), 6.66 (d, 1H, J = 7.5), 6.58 (s, 1 H), 6.56 (d, 1H, J = 10.1), 2.77 - 2.54 (m, 4H), 2.52 (s, 3H), 2.36 (s, 3H), 1.99 (s, 3H). [00811] HPLC (gradient 5-95% ACN/H2O): > 95%.
[00812] MS (ESI+) (+ 0.1 % HCOOH): 434.3 [C25H24FN3O3H-H]+ (m/z).
Example 52
Preparation of 4-[2-(3-fluoro-phenyl)-ethvn-5-(2-hvdroxy-phenvπ-6-methyl-2-(2- methyl-thiazol-4-ylmethyl)-2H-Pvridazin-3-one
Figure imgf000132_0001
[00813] a) Preparation of 4-[2-(3-fluoro-phenyl)-ethylj-5-(2-methoxy-phenyl)-6- methyl-2-(2-methyl-thiazol-4-ylmethyl)-2H-pyridazin-3-one
Figure imgf000132_0002
[00814] To a suspension of sodium hydride 60% (0.031 g, 0.77 mmol) in anhydrous dimethylformamide (3 ml_) was added 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 1d (0.237 g, 0.70 mmol). The reaction mixture was stirred at room temperature for 30 min before addition of 3- chloromethyl-5-methylisothiazole (0.139 g, 1.05 mmol) in anhydrous dimethylformamide (3 mL). The resulting reaction mixture was again stirred at room temperature for 2.5 h. Water (20 mL) was added followed by ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting crude product was purified by flash chromatography on silica gel, eluting with dichloromethane - ethyl acetate (95:5) to afford 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(2- methyl-thiazol-4-ylmethyl)-2H-pyridazin-3-one (0.225 g, 74%) as beige solid (0.206 g, 65%).
[00815] 1H NMR (CDCI3): δ 7.33 (t, 1H1 J = 8.0), 7.06 - 6.99 (m, 2H), 6.96 - 6.90 (m, 2H), 6.73 (d, 2H, J = 7.5), 6.65 (d, 1H, J = 7.7), 6.54 (d, 1H, J = 10.0), 5.38 (dd, 2H, J1 = 14.5, J2 = 46.3), 3.69 (s, 3H), 2.70 - 2.41 (m, 7H), 1.89 (s, 3H). [00816] b) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2-(2-methyl-thiazol-4-ylmethyl)-2H-pyridazin-3-one
Figure imgf000133_0001
[00817] Utilizing the procedures described in Example 1f except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 1e for 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2-(2- methyl-thiazol-4-ylmethyl)-2H-pyridazin-3-one of Example 52a, 4-[2-(3-fluoro-phenyl)- ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(2-methyl-thiazol-4-ylmethyl)-2H-pyridazin-3- one_was obtained as a white solid (0.122 g, 63%).
[00818] 1H NMR (CH3OH-d4): δ 7.32 (t, 1 H, J = 8.7), 7.18 (s, 1 H), 7.16 - 7.10 (m,
1 H), 6.98 - 6.92 (m, 2H), 6.87 - 6.79 (m, 2H), 6.72 (d, 2H, J = 7.6), 6.63 (d, 1H, J =
9.6), 5.41 (dd, 2H, J1 = 14.5, J2 = 37.3), 2.74 - 2.51 (m, 7H), 2.02 (s, 3H).
[00819] HPLC (gradient 5-95% ACN/H2O): > 99%.
[00820] MS (ESI+) (+ 0.1 % HCOOH): 436.3 [C24H22FN3O2S+H]+ (m/z)
Example 53
Preparation of 2-benzoH ,2,51oxadiazol-4-ylmethyl-4-r2-(3-fluoro-phenyl)-ethyll-5-(2- hydroxy-phenyl)-6-methvl-2H-pyridazin-3-one
Figure imgf000133_0002
[00821] a) Preparation of 2-benzo[1 ,2,5]oxadiazol-4-ylmethyl-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000134_0001
[00822] Utilizing the procedures described in Example 52a except substituting 3- chloromethyl-5-methylisothiazole for benzo[1 ,2,5]oxadiazol-4-yl-methanol, 2- benzo[1 ,2,5]oxadiazol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)- 6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.210 g, 63%).
[00823] 1H NMR (CDCI3): δ 7.76 (d, 1 H, J = 9.0), 7.41 (qd, 2H, J = 8.9), 7.21 (d,
1H, J = 6.6), 7.11 (qd, 1 H, J = 7.7), 7.05 - 6.98 (m, 2H), 6.83 - 6.77 (m, 2H), 6.73 (d,
1 H, J = 7.7), 6.60 (d, 1H, J = 10.0), 5.75 (dd, 2H, J1 = 15.5, J2 = 46.0), 3.77 (s, 3H),
2.78 - 2.50 (m, 4H), 1.95 (s, 3H).
[00824] HPLC (gradient 5-95% ACN/H2O): > 95%.
[00825] MS (ESI+) (+ 0.1 % HCOOH): 471.4 [C27H23FN4O3H-H]+ (m/z).
[00826] b) Preparation of 2-benzo[1 ,2,5]oxadiazol-4-ylmethyl-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000134_0002
[00827] Utilizing the procedures described in Example 1f except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 1d for 2-benzo[1 ,2,5]oxadiazol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5- (2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 53a, 2- benzo[1 ,2,5]oxadiazol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)- 6-methyl-2H-pyridazin-3-one_was obtained as a orange solid (0.051 g, 25%).
[00828] 1H NMR (CDCI3): δ 7.75 (d, 1 H, J = 9.0), 7.39 - 7.20 (m, 3H), 7.09 (qd, 1 H, J = 7.7), 6.97 (qd, 2H, J = 7.5), 6.83 - 6.76 (m, 2H), 6.69 (d, 1H1 J = 7.4), 6.58 (d, 1 H, J = 10.0), 5.75 (dd, 2H, J1 = 15.6, J2 = 31.4), 2.79 - 2.50 (m, 4H), 2.00 (s, 3H). [00829] HPLC (gradient 5-95% ACN/H2O): > 90%. [00830] MS (ESI+): 457.03 [C26H21FN4CVHj+ (m/z).
Example 54
Preparation of 4-f2-(3-fluoro-phenyl)-ethvn-5-(2-hvdroxy-phenyl)-6-methyl-2-piperidin-
3-vlmethvl-2H-pyridazin-3-one
Figure imgf000135_0001
[00831] a) 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2- pyridin-3-yimethyl-2H-pyridazin-3-one
Figure imgf000135_0002
[00832] Utilizing the procedures described in Example 41a except substituting 5- hydroxymethyl-benzo[1 ,3]dioxole for pyridin-3-yl-methanol, 5-(2-benzyloxy-phenyl)-4- [(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2-pyridin-3-ylmethyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.313 g, 89%).
[00833] 1H NMR (CDCI3): δ 8.80 (s, 1H), 8.56 (d, 1H, J = 4.7), 8.24 (d, 1H, J =
16.2), 7.86 (d, 1 H, J = 7.9), 7.44 - 7.38 (m, 1H), 7.31 - 6.85 (m, 13H), 6.57 (d, 1H, J =
16.2), 6.50 (broad s, 1H), 5.41 (dd, 2H, J1 = 13.9, J2 = 30.7), 5.07 (s, 2H), 2.04 (s,
3H).
[00834] MS (ESI+): 504.16 [C32H26FN3(V-H]+ (m/z).
[00835] b) 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-piperidin- 3-ylmethyl~2H-pyridazin-3-one
Figure imgf000136_0001
[00836] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2- pyridin-3-ylmethyl-2H-pyridazin-3-one of Example 54a, 4-[2-(3-fluoro-phenyl)-ethyl]-
5-(2-hydroxy-phenyl)-6-methyl-2-piperidin-3-ylmethyl-2H-pyridazin-3-one was obtained as a white solid (0.138 g, 53%).
[00837] 1H NMR (CDCI3): δ 9.47 and 9.21 (2 broad s, 1 H), 8.83 and 8.54 (2 broad s, 1 H), 7.29 (t, 1H1 J = 7.7), 7.13 - 7.04 (m, 2H), 6.91 (t, 1 H, J = 7.5), 6.79 (t, 1 H, J =
8.7), 6.70 (d, 1 H, J = 3.2), 6.63 (d, 1 H, J = 9.6), 4.49 - 4.46 (m, 1 H), 3.66 - 3.50 (m,
2H), 3.37 - 3.28 (broad s, 1 H), 2.77 - 2.42 (m, 7H), 1.99 (d, 3H1 J = 5.5), 1.91 - 1.79 ( m, 3H), 1.28 - 1.16 (m, 1 H).
[00838] HPLC (gradient 5-95% ACN/H2O): > 90%.
[00839] MS (ESI+) (+ 0.1% HCOOH): 422.3 [C25H28FN3O2+H]+ (m/z).
Example 55
Preparation of 4-[2-(3-fluoro-phenyl)-ethyl1-5-(2-hvdroxy-phenyl)-6-methyl-2-piperidin-
2-vlmethyl-2H-pvridazin-3-one
Figure imgf000136_0002
[00840] a) 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2- pyridin-2-ylmethyl-2H-pyridazin-3-one
Figure imgf000137_0001
[00841] Utilizing the procedures described in Example 41a except substituting 5- hydroxymethyl-benzo[1 ,3]dioxole for pyridin-2-yl-methanol, 5-(2-benzyloxy-phenyl)-4- [(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2-pyridin-2-ylmethyl-2H-pyridazin-3-one was obtained as a yellowish oil (0.299 g, 85%).
[00842] 1H NMR (CDCI3): δ 8.61 (d, 1H1 J = 4.9), 8.29 (d, 1H, J = 16.0), 7.64 (d, 1H, J = 7.9), 7.46 - 7.40 (m, 1H), 7.22 - 7.07 (m, 10H), 7.00 (d, 1H, J = 7.5), 6.91 - 6.85 (m, 2H), 6.60 (d, 1 H, J = 15.9), 5.58 (s, 2H), 5.08 (s, 2H), 2.07 (s, 3H). [00843] MS (ESI+): 504.12 [C32H26FN3O2H-H]+ (m/z).
[00844] b) 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-piperidin- 2-ylmethyl-2H-pyridazin-3-one
Figure imgf000137_0002
[00845] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)~4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2- pyridin-2-ylmethyl~2H-pyridazin-3-one of Example 55a, 4-[2-(3-fluoro-phenyl)-ethyl]-
5-(2-hydroxy-phenyl)-6-methyl-2-piperidin-2-ylmethyl-2H-pyridazin-3-one was obtained as a white solid (0.120 g, 49%).
[00846] 1H NMR (CDCI3): δ 7.30 (t, 1H, J = 6.6), 7.15 - 7.07 (m, 1 H), 7.02 - 6.88 (m, 2H), 6.84 - 6.70 (m, 3H), 6.64 (d, 1 H, J = 10.0), 4.96 and 4.54 (2 broad s, 1H), 4.06 and 3.78 (2 broad s, 1H), 3.63 - 3.55 (broad s, 1H), 3.35 - 3.27 (broad s, 1H), 2.80 - 2.45 (m, 5H), 2.01 (d, 3H, J = 4.9), 1.95 - 1.51 (m, 6H), 1.27 - 1.23 (m, 1H). [00847] HPLC (gradient 5-95% ACN/H2O): > 85%.
[00848] MS (ESI+) (+ 0.1% HCOOH): 422.3 [C25H28FN3O2+^* (m/z).
Example 56
Preparation of 4-f2-(3-Fluoro-phenylVethyll-5-(2-hvdroxy-phenyl)- 6-methyl-2- phenethyl-2H-pvridazin-3-one
Figure imgf000138_0001
[00849] a) Preparation of 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]- 6-methyl-2-phenethyl-2H-pyridazin-3-one
Figure imgf000138_0002
[00850] Utilizing the procedures described in Example 39a except substituting 1- bromomethyl-3-methoxy-benzene for (2-bromoethyl)benzene, 5-(2-benzyloxy- phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2-phenethyl-2H-pyridazin-3-one was obtained as a colorless solid (0.296 g, 95%).
[00851] 1H NMR (CDCI3): δ 8.31 (d, 1H, J = 16.0), 7.45 - 7.39 (m, 1H), 7.36 - 7.20 (m, 11 H), 7.12 - 7.02 (m, 4H), 6.93 - 6.87 (m, 2H), 6.61 (d, 2H, J = 16.0), 5.09 (s, 2H), 4.49 - 4.43 (m, 2H), 3.22 - 3.17 (m, 2H), 2.04 (s, 3H).
[00852] b) Preparation of 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)- 6- methyl-2-phenethyl-2H-pyridazin-3-one
Figure imgf000139_0001
[00853] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2- phenethyl-2H-pyridazin-3-one of Example 56a, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)- 6-methyl-2-phenethyl-2H-pyridazin-3-one was obtained as a white solid (0.296 g, 95%).
[00854] 1H NMR (CDCI3): δ 7.34 - 7.21 (m, 6H), 7.06 - 6.95 (m, 3H), 6.78 - 6.56
(m, 4H), 4.05 (t, 4H, J = 4.5), 4.49 - 4.35 (m, 2H), 3.13 (t, 2H, J = 8.1), 2.75 - 2.49 (m,
4H), 2.02 (s, 3H).
[00855] HPLC (gradient 5-95% ACN/H2O): > 95%.
[00856] MS (ESI+) (+ 0.1 % HCOOH): 429.3 [C27H25FN2O2+H]+ (m/z).
Example 57
Preparation of 2-(2,5-dimethyl-oxazol-4-ylmethyl)-4-f2-(3-fluoro-phenyl)-ethyll-5-(2- hvdroxy-phenyl)-6-methvl-2H-pyridazin-3-one
Figure imgf000139_0002
[00857] a) Preparation of 2-(2,5-dimethyl-oxazol-4-ylmethyl)-4-[(E)-2-(3-fluoro- phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-rnethyl-2H-pyridazin-3-one
Figure imgf000139_0003
[00858] Utilizing the procedures described in Example 52a except substituting 4- [2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 1d for 4-[(E)-2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 14b, and 3-chloromethyl-5-methylisoxazole for A- (chloromethyl)-2,5-dimethyl-1 ,3-oxazole, 2-(2,5-dimethyl-oxazol-4-ylmethyl)-4-[(E)-2- (3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a beige solid (0.238 g, 76%).
[00859] 1H NMR (CDCI3): δ 8.22 (d, 1 H, J = 16.1), 7.42 - 7.36 (m, 1 H), 7.12 (qd, 1 H, J = 7.5), 7.04 - 6.96 (m, 4H), 6.87 - 6.78 (m, 2H), 6.54 (d, 2H, J = 16.1), 5.17 (dd, 2H, J1 = 14.1 , J2 = 41.0), 3.70 (s, 3H), 2.38 (s, 3H), 2.33 (s, 3H), 1.98 (s, 3H).
[00860] b) Preparation of 2-(2,5-dimethyl-oxazol-4-ylmethyl)-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000140_0001
[00861] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 2-(2,5-dimethyl-oxazol-4-ylmethyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]- 5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 57a, 2-(2,5-dimethyl- oxazol-4-ylmethyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one_was obtained as a white solid (0.222 g, 94%).
[00862] 1H NMR (CDCI3): δ 7.34 (t, 1 H, J = 7.9), 7.03 (qd, 1H, J = 6.6), 6.96 - 6.90 (m, 2H), 6.75 - 6.66 (m, 2H), 6.64 (d, 1 H, J = 7.5), 6.53 (d, 1H, J = 10.0), 5.11 (dd, 2H, J1 = 14.2, J2 = 43.3), 3.67 (s, 3H), 2.69 - 2.41 (m, 4H), 2.35 (s, 6H), 1.91 (s, 3H).
[00863] c) Preparation of 2-(2,5-dimethyl-oxazol-4-ylmethyl)-4-[2-(3-fluoro-phenyl)- ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000141_0001
[00864] Utilizing the procedures described in Example 1f except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 1d for 2-(2,5-dimethyl-oxazol-4-ylmethyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5- (2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 57b, 2-(2,5-dimethyl- oxazol-4-ylmethyl)-4-t2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H- pyridazin-3-one_was obtained as a beige solid (0.097 g, 45%).
[00865] 1H NMR (CDCI3): δ 7.30 (t, 1 H1 J = 7.7), 7.07 (qd, 1 H, J = 7.7), 6.99 - 6.90 (m, 2H), 6.80 - 6.71 (m, 2H), 6.67 (d, 1 H, J = 7.6), 6.56 (d, 1 H, J = 9.9), 5.14 (dd, 2H, J1 = 14.3, J2 = 38.4), 2.78 - 2.45 (m, 4H), 2.39 (s, 3H), 2.32 (s, 3H), 1.97 (s, 3H). [00866] HPLC (gradient 5-95% ACN/H2O): > 90%. [00867] MS (ESI+) (+ 0.1% HCOOH): 434.4 [C25H24FN3O^H]+ (m/z).
Example 58
Preparation of 2-(2.5-dimethyl-2H-pyrazol-3-ylmethyl)-4-f2-(3-fluoro-phenyl)-ethyll-5- (2-hvdroxy-phenvD-6-methyl-2H-pyridazin-3-one
Figure imgf000141_0002
[00868] a) Preparation of 2-(2,5-dimethyI-2H-pyrazol-3-ylmethyl)-4-[(E)-2-(3- fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000141_0003
[00869] Utilizing the procedures described in Example 52a except substituting 4- [2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 1 d 4-[(E)-2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one of Example 14b, and 3-(chloromethyl)-5-methylisoxazole for 5- (chloromethyl)-i ,3-dimethyl-1 H-pyrazole, 2-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-4~ [(E)-2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one was obtained as a beige solid (0.255 g, 82%).
[00870] 1H NMR (CDCl3): δ 8.23 (d, 1 H, J = 16.1), 7.44 (t, 1 H, J = 6.9), 7.17 (qd, 1 H, J = 7.7), 7.08 - 7.00 (m, 4H), 6.90 - 6.83 (m, 2H), 6.55 (d, 1 H, J = 16.1), 6.20 (s, 1H), 5.35 (dd, 2H, J1 = 14.6, J2 = 30.8), 3.99 (s, 3H), 3.75 (s, 3H), 2.22 (s, 3H), 1.98 (s, 3H).
[00871] b) Preparation of 2-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-rnethyl-2H-pyridazin-3-one
Figure imgf000142_0001
[00872] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-[(E)-styryl]-2H-pyridazin-3-one of
Example 22e for 2-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-4-[(E)-2-(3-fluoro-phenyl)- vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 58a, 2-(2,5- dimethyl-2H-pyrazol-3-ylmethyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6- methyl-2H-pyridazin-3-one_was obtained as a white solid (0.224 g, 90%).
[00873] 1H NMR (CDCI3): δ 7.39 (t, 1 H1 J = 8.3), 7.08 (qd, 1 H, J = 7.7), 7.01 - 6.95 (m, 2H), 6.80 - 6.74 (m, 2H), 6.69 (d, 1H, J = 7.6), 6.58 (d, 1 H, J = 9.8), 6.18 (s, 1 H), 5.30 (dd, 2H, J1 = 14.5, J2 = 27.8), 3.97 (s, 3H), 3.72 (s, 3H), 2.72 - 2.43 (m, 4H), 2.22 (s, 3H), 1.91 (s, 3H). [00874] MS (ESI+) (+ 0.1 % HCOOH): 446.99 [C26H27FN4O2+H]+ (m/z)
[00875] c) Preparation of 2-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-4-[2-(3-fluoro- phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyI-2H-pyridazin-3-one
Figure imgf000143_0001
[00876] Utilizing the procedures described in Example 1f except substituting 4-[2- (3-fluoro-phenyl)-ethyl]-2-isobutyl-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 1e for 2-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-4-[2-(3-fluoro-phenyl)- ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of Example 58f, 2-(2,5- dimethyl-2H-pyrazol-3-ylmethyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one_was obtained as a beige solid (0.098 g, 45%).
[00877] 1H NMR (CDCI3): δ 7.30 - 7.28 (m, 1H), 7.09 - 7.02 (m, 2H), 6.93 (t, 1H, J
= 14.9), 6.79 - 6.69 (m, 2H), 6.68 (d, 1H, J = 7.2), 6.58 (d, 1H, J = 10.0), 6.17 (s, 1H),
5.27 (dd, 2H, J1 = 17.9, J2 = 31.2), 3.97 (s, 3H), 2.77 - 2.51 (m, 4H), 2.18 (s, 3H),
2.17 (s, 3H), 2.00 (s, 3H).
[00878] HPLC (gradient 5-95% ACN/H2O): > 95%.
[00879] MS (ESI+) (+ 0.1% HCOOH): 433.4 [C25H25FN4O2+H]+ (m/z).
Example 59
Preparation of 5-(2-Hydroxy-phenyl)-2-(1 H-imidazol-2-ylmethyl)-6-methyl-4 phenethyl-2H-pyridazin-3-one
Figure imgf000143_0002
[00880] a) 2-(1-Benzyl-1 H-imidazol-2-ylmethyl)-5-(2-benzyloxy-phenyl)-4-[2-(3- fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one
Figure imgf000144_0001
[00881] To a solution of 5-(2-benzyloxy-phenyl)-4-2-(3-fluoro-phenyl)-vinyl-6- methyl-2H-pyridazin-3-one of Example 26b (0.4 g, 0.96 mmol) and CsCO3 (0.95 g, 2.9 mmol) in anhydrous DMF (5.8 ml_), i-benzyl-2-chloromethyl-IH-imidazole hydrochloride (0.259 g, 1.06 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added to the reaction mixture followed by EtOAc (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuum. Column chromatography on silica gel (EtOAc - cyclohexane, 60:40) afforded 2-(1-Benzyl-1H-imidazol-2-ylmethyl)-5-(2-benzyloxy- phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one (0.46 g, 82%).
[00882] 1H NMR (DMSO): δ 8.10 (d, 1H1 J - 16Hz), 7.44 (m, 1H); 7.35-7.05 (m, 16H); 7.01-6.86 (m, 3H); 6.43 (d, 1 H, J = 16Hz); 5.51 (d, 1H, J = 15Hz); 5.38 (s, 2H); 5.25 (d, 1 H, J = 15Hz); 5.16 (s, 2H); 1.85 (s, 3H). [00883] MS (ESI+) (+0.1%HCOOH): 583.3 [C37H31 FN4O2+H]+ (m/z)
[00884] b) 5-(2-Hydroxy-phenyl)-2-(1 H-imidazol-2-ylmethyl)-6-methyl-4-phenethyl- 2H-pyridazin-3-one
Figure imgf000144_0002
[00885] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-styryl-2H-pyridazin-3-one of Example 22e for 2-(1-benzyl-1 H-imidazol-2-ylmethyl)-5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro- phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 59a, 5-(2-Hydroxy-phenyl)-2- (1H-imidazol-2-ylmethyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one was obtained as a white solid (0.1 g, 25%).
[00886] 1H NMR (DMSO): δ 11.92 (s broad, 1H), 9.81 (s, 1H), 7.32 - 7.17 (m, 2H),
7.05 - 6.83 (m, 6H), 6.76 - 6.61 (m, 2H), 5.24 (s, 2H), 2.72 - 2.58 (m, 2H), 2.46 - 2.33
(m, 2H), 1.91 (s, 3H).
[00887] LC/MS (gradient 5-80% ACN/H2O) : 97.83%.
[00888] MS (ESI+) (+0.1%HCOOH): 405.5 [C23H2IFN4CVH]+ (m/z).
[00889] IC50 greater than 50 μM.
Example 60
Preparation of 4-r2-(3-Fluoro-phenyl)-ethvπ-5-(2-hvdroxy-phenyl)-2-(2-methoxy- benzyl)-6-methvl-2H-pyridazin-3-one
Figure imgf000145_0001
[00890] a) 5-(2-Benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-(2-methoxy- benzyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000146_0001
[00891] Utilizing the procedures described in Example 14c except substituting A- [2-(3-fluoro-phenyl)-vinyl]-5-(2-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one of
Example 14b for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-(2-methoxy- benzyl)-6-methyl-2H-pyridazin-3-one of Example 26b, and 2-chlorobenzyl bromide and for 1-chloromethyl-2-methoxy-benzene, 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro- phenyl)-vinyl]-2-(2-methoxy-benzyl)-6-methyl-2H-pyridazin-3-one was obtained as a colorless oil (0.52 g, 80%).
[00892] 1H NMR (CDCI3): δ 8.35 (d, J = 16.01 , 1 H), 7.49 - 7.39 (m, 1 H), 7.28 - 7.07 (m, 10H), 7.04 - 6.83 (m, 6H), 6.63 (d, J = 16.01 , 1 H), 5.50 (dd, J1 = 33.91 , J2 = 15.25, 2H), 5.09 (dd, J1 = 12.81 , J2 = 12.63, 2H), 3.88 (s, 3H), 2.06 ( S, 3H)
[00893] b) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(2-methoxy- benzyl)-6-methyl-2H-pyridazin-3-one
Figure imgf000146_0002
[00894] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyI-2-phenethyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 22e for 5-(2-benzyloxy-phenyl)-4-[2-(3-fluoro-phenyl)-vinyl]-2-(2-methoxy- benzyl)-6-methyl-2H-pyridazin-3-one of Example of 60a, 4-[2-(3-fluoro-phenyl)-ethyl]- 5-(2-hydroxy-phenyl)-2-(2-methoxy-benzyl)-6-methyl-2H-pyridazin-3-one was obtained as a white solid (0.32 g, 85%).
[00895] 1H NMR (CDCI3): δ 9.79 (s. broad, 1H), 7.33 - 7.17 (m, 3H), 7.07 - 6.85
(m, 6H), 6.82 - 6.63 (m, 3H), 5.23 (dd, J1 = 26.29, J2 = 15.36, 2H), 3.83 (s, 3H), 2.73 -
2.37 (m, 4H), 1.90 (s, 3H)
[00896] LC/MS (gradient 5-80% ACN/H2O) :98.07%
[00897] MS (ESI+) (+0.1%HCOOH) : 445.1 [C27H25FN2C^H]+ (m/z)
Example 61 Preparation of 5-(2-Hvdroxy-phenyl)-6-metriyl-2-prιenethyl-4-(2-thiophen-3-yl-ethyl)-
2H-pyridazin-3-one
Figure imgf000147_0001
[00898] a) 4-Thiophen-3-yl-but-3-enoic acid s/ OH
Il
O
[00899] Utilizing the procedures described in Example 8a except substituting 3- fluorobenzaldehyde for thiophene-3-carbaldehyde, 4-thiophen-3-yl-but-3-enoic acid was obtained as a yellow solid (2.66 g, 71%).
[00900] 1H NMR (CDCI3): δ 7.25-7.12 (m, 3H); 6.52 (m, 1H); 6.15 (m, 1H); 3.25 (m, 2H).
[00901] b) 4-(2-Benzyloxy-phenyl)-5-hydroxy-5-methyl-3-(2-thiophen-3-yl-vinyl)- 5H-furan-2-one
Figure imgf000148_0001
[00902] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-phenyl)-2-bromo-propan-1-one, and trans- styrylacetic acid for 4-thiophen-3-yl-but-3-enoic acid of Example 61a, 4-(2-benzyloxy- phenyl)-5-hydroxy-5-methyl-3-(2-thiophen-3-yl-vinyl)-5H-furan-2-one was obtained as a brown gum. The crude product was used directly onto the next step without any further purification.
[00903] c) 5-(2-Benzyloxy-phenyl)-6-methyl-4-(2-thiophen-3-yl-vinyl)-2H-pyridazin- 3-one
Figure imgf000148_0002
[00904] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of
Example 8e for 4-(2-benzyloxy-phenyl)-5-hydroxy-5-methyl-3-(2-thiophen-3-yl-vinyl)-
5H-furan-2-one of Example 61b, the title compounds were obtained as a white solid
(0.9 g, 17% over two steps).
[00905] 1H NMR (DMSO): δ 12.85 (bs, 1 H); 8.29 (d, 1H, J = 15.5Hz); 7.61 -7.42
(m, 2H); 7.38-7.05 (m, 9H); 6.83 (m, 1H), 6.33 (d, 1H, J = 15.5Hz); 5.15 (s, 2H); 1.91
(s, 3H).
[00906] MS (ESI+) (+0.1%HCOOH): 401.1 [C24H20N2O2S+H]+ (m/z) [00907] d) 5-(2-Benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-3-yl-vinyl)- 2H-pyridazin-3-one
Figure imgf000149_0001
[00908] Utilizing the procedure described in Example 22e except substituting 5-(2- benzyloxy-phenyl)-6-methy!-4-((E)-styryl)-2H-pyridazin-3-one of Example 22d for 5- (2-benzyloxy-phenyl)-6-methyI-4-(2-thiophen-3-yl-vinyl)-2H-pyridazin-3-one of
Example 61 c, 5-(2-benzyloxy~phenyl)-6-methyl-2~phenethyl-4-(2-thiophen-3-yl-vinyl)~ 2H-pyridazin-3-one was obtained as yellow oil (0.47g, 98%).
[00909] 1H NMR (DMSO): δ 8.26 (d, 1H1 J = 15Hz); 7.58-7.42 (m, 3H); 7.22-7.10 (m, 13H); 6.84 (m, 1H); 6.35 (d, IH1 J = 15Hz); 5.17 (s, 2H); 4.34 (m, 2H); 3.09 (m, 2H); 1.94 (s, 3H). [00910] MS (ESI+) (+0.1 %HCOOH) : 504.9 [C32H28N2O2S+H]+ (m/z).
[00911] e) 5-(2-Benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-3-yl-ethyl)- 2 H -pyridazi n-3-one
Figure imgf000149_0002
[00912] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 9e for 5-(2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-3-yl- vinyl)-2H-pyridazin-3-one of Example 61 d, 5-(2-benzyloxy-phenyl)~6-methyl-2- phenethyl-4-(2-thiophen-3-yl-ethyl)-2H-pyridazin-3-one_was obtained as a yellow oil (0.2 g, 50%).
[00913] 1H NMR (CDCI3): δ 7.41-7.12 (m, 11 H); 7.13 (m, 1 H); 7.04 (m, 2H); 6.87 (m, 1 H); 6.73 (m, 1 H); 6.68 (m, 1 H); 5.07 (s, 2H); 4.42 (m, 2H); 3.17 (m, 2H); 2.76 (m, 3H); 2.55 (m, 1 H); 1.99 (s, 3H).
[00914] f) 5-(2-Hydroxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-3-yl-ethyl)- 2H-pyridazin-3-one
Figure imgf000150_0001
[00915] A solution of 5-(2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen- 3-yl-ethyl) 2H-pyridazin-3-one of Example 61 e (0.2 g, 0.4 mmol) in glacial acetic acid (6.4 ml.) and 37% hydrochloric acid (3.2 ml_) was heated at 80 0C for 6 h. Upon cooling, the reaction mixture was diluted with EtOAc (100 ml_) and neutralized with 5N NaOH aqueous solution. The aqueous phase was extracted with EtOAc (2 x 50 ml_). The organic layers were collected, dried over Na2SO4 and concentrated in vacuum to yield yellow oil which upon trituration with Et2O gave 5-(2-hydroxy-phenyl)- 6-methyl-2-phenethyl-4-(2-thiophen-3-yl-ethyl)-2H-pyridazin-3-one as a white solid (0.075 g, 18%).
[00916] 1H NMR (CDCI3): δ 7.41-7.22 (m, 6H); 7.13 (m, 1 H); 6.98 (m, 2H); 6.79
(m, 1 H); 6.67 (m, 2H); 5.70 (s, 1 H); 4.51-4.33 (m, 2H); 3.15 (m, 2H); 2.80-2.51 (m,
4H), 2.01 (s, 3H).
[00917] LC/MS (gradient 5-80% ACN/H2O + 0.1 %HCOOH): 92.53%.
[00918] MS (ESI+) (+0.1 %HCOOH): 417.2 [C25H24N2θ2S+H]+ (m/z). Example 62
Preparation of 5-(2-Hvdroxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-2-yl-ethyl)-
2H-pyridazin-3-one
Figure imgf000151_0001
[00919] 4-Thiophen-2-yl-but-3-enoic acid
Figure imgf000151_0002
[00920] Utilizing the procedures described in Example 8a except substituting thiophene-3-carbaldehyde for thiophene-2-carbaldehyde, 4-thiophen-2-yl-but-3-enoic acid was obtained as an orange solid (2.4 g, 80%).
[00921] 1H NMR (CDCI3): δ 7.15 (m, 1H); 6.94 (m, 2H); 6.45 (m, 2H); 6.11 (m, 1 H); 3.26 (m, 1H).
[00922] b) 4-(2-Benzyloxy-phenyl)-5-hydroxy-5-methyl-3-(2-thiophen-2-yl-vinyl)- 5H-furan-2-one
Figure imgf000151_0003
[00923] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-phenyl)-2-bromo-propan-1-one, and trans- styrylacetic acid for 4-thiophen-2-yl-but-3-enoic acid of Example 62a, 4-(2-benzyloxy- phenyl)-5-hydroxy-5-methyl-3-(2-thiophen-2-yl-vinyl)-5H-furan-2-one was obtained as a brown gum. The crude product was used directly onto the next step without any further purification.
[00924] c) 5-(2-Benzyloxy-phenyl)-6-methyl-4-(2-thiophen-2-yl-vinyl)-2H-pyridazin- 3-one
Figure imgf000152_0001
[00925] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-phenyl)-5-hydroxy-5-methyl-3-(2-thiophen-2-yl-vinyl)- 5H-furan-2-one of Example 62b, 5-(2-benzyloxy-phenyl)-6-methyl-4-(2-thiophen-2-yl- vinyl)-2H-pyridazin-3-one was obtained as yellow solid (0.32g, 6.5%).
[00926] 1H NMR (DMSO): δ 13.00 (s, 1 H); 8.49 (d, 1H, J = 15.6 Hz); 7.52-7.07 (m,
12H); 6.28 (d, 1 H, J = 15.6 Hz); 5.15 (s, 2H); 1.91 (s, 3H).
[00927] MS (ESI+) (+0.1% HCOOH): 401.1 [C24H20N2O2S+H]+ (m/z).
[00928] d) 5-(2-Benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2~thiophen-2-yl-vinyl)- 2H-pyridazin-3-one
Figure imgf000152_0002
[00929] Utilizing the procedure described in Example 22e except substituting 5-(2- benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 22d for 5- (2-benzyloxy-phenyl)-6-methyl-4-(2-thiophen-2-yl-vinyl)-2H-pyridazin-3-one of
Example 62c, 5-(2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-2-yl-vinyl)- 2H-pyridazin-3-one was obtained as a yellow oil (0.39 g, 91%).
[00930] 1H NMR (DMSO): δ 8.49 (d, 1 H, J = 15.9 Hz); 7.52-7.03 (m, 17H); 6.30 (d, 1 H, J = 15.9 Hz); 5.17 (s, 2H); 4.33 (m, 2H); 3.14-3.01 (m, 2H); 1.91 (s, 3H). [00931] MS (ESI+) (+0.1 %HCOOH): 504.9 [C32H28N2O2S+H]+ (m/z).
[00932] e) 5-(2-Benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-2-yl-ethyl)- 2H-pyridazin-3-one
Figure imgf000153_0001
[00933] Utilizing the procedures described in Example 9f except substituting 2- isopropyl-5-(2-methoxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of
Example 9e for 5-(2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-2-yl- vinyl)-2H-pyridazin-3-one of Example 62d, 5-(2-Benzyloxy-phenyl)-6-methyl-2- phenethyl-4-(2-thiophen-2-yl-ethyl)-2H-pyridazin-3-one was obtained as a yellow oil (0.89 g, 23%).
[00934] 1H NMR (CDCI3): δ 7.42-7.20 (m, 11 H); 7.03 (m, 3H); 6.84 (m, 2H); 6.60 (m, 1 H); 5.07 (s, 2H); 4.42 (m, 2H); 3.17 (m, 2H); 2.99 (m, 2H); 2.78 (m, 1 H); 2.63 (m, 1 H); 1.99 (s, 3H).
[00935] f) 5-(2-Hydroxy-phenyI)-6-methyl-2-phenethyl-4-(2-thiophen-2-yl-ethyl)- 2H-pyridazin-3-one
Figure imgf000154_0001
[00936] Utilizing the procedures described in Example 61f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-3-yl-ethyl)-2H-pyridazin-3- one of Example 61 e for 5-(2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen- 2-yl-ethyl)-2H-pyridazin-3-one of Example 62e, 5-(2-hydroxy-phenyl)-6-methyl-2~ phenethyl-4-(2-thiophen-2-yl-ethyl)-2H-pyridazin-3-one was obtained as a yellow oil (0.35g, 50%).
[00937] 1H NMR (CDCI3): δ 7.37-7.21 (m, 6H); 7.08-6.92 (m, 3H); 6.81 (m, 2H);
6.56 (m, 1 H); 5.09 (s, 1H); 4.40 (m, 2H); 3.16 (m, 2H); 3.03 (m, 2H); 2.82-2.63 (m,
2H); 2.01 (s, 3H).
[00938] LC/MS (gradient 5-80% ACN/H2O + 0.1 % HCOOH): 96.31 %.
[00939] MS (ESI+) (+0.1 %HCOOH): 417.22 [C25H24N2O2S+H]+ (m/z).
Example 63
Preparation of 4-f2-(3-Fluoro-phenyl)-ethyll-5-(2-hvdroxy-phenyl)-6-methyl-2-(3- phenyl-propvl)-2H-pyridazin-3-one
Figure imgf000154_0002
[00940] a) 5-(2-Benzyloxy-phenyl)-4-[(E)-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2-(3- phenyl-propyl)-2H-pyridazin-3-one
Figure imgf000155_0001
[00941] Utilizing the procedures described in Example 22e except substituting (2- bromo-ethyl)-benzene for 3-bromo-propyl-benzene, 5-(2-benzyloxy-phenyl)-4-[(E)-2- (3-fluoro-phenyl)-vinyl]-6-methyl-2-(3-phenyl-propyl)-2H-pyridazin-3-one was obtained as a yellow oil (0.26 g, 40%).
[00942] 1H NMR (DMSO): δ 8.18 (d, 1 H, J = 15.9Hz); 7.52-6.87 (m, 18H); 6.50 (d, 1H, J = 15.9Hz); 5.14 (s, 2H); 4.15 (m, 2H); 2.65 (m, 2H); 2.07 (m, 2H); 1.93 (s, 3H). [00943] MS (ESI+) (+0.1%HCOOH): 531.0 [C35H3iFN2O2+H]+ (m/z).
[00944] b) 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3- phenyl-propyl)-2H-pyridazin-3-one
[00945] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-styryl-2H-pyridazin-3-one of Example 22e for 5-(2-benzyloxy-phenyl)-4-[-2-(3-fluoro-phenyl)-vinyl]-6-methyl-2-(3-phenyl- propyl)-2H-pyridazin-3-one of Example 63a, 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2- hydroxy-phenyl)-6-methyl-2-(3-phenyl-propyl)-2H-pyridazin-3-one was obtained as a yellow oil (0.070 g, 32%).
[00946] 1H NMR (DMSO): δ 9.74 (bs, 1H); 7.42-7.15 (m, 7H); 7.02-6.85 (m, 4H); 6.76-6.61 (m, 2H); 4.13-3.98 (m, 2H); 2.78-2.33 (m, 6H); 2.03 (m, 2H); 1.90 (s, 3H). [00947] LC/MS (gradient 5-80% ACN/H2O + 0.1 %HCOOH): 95.9%. [00948] MS (ESI+) (+0.1 %HCOOH): 443.0 [C28H27FN2O2+H]+ (m/z).
Example 64
Preparation of 4-r2-(3,4-Difluoro-phenyl)-ethvn-5-(2-hvdroxy-phenyl)-6-methyl-2- phenethvl-2H-pyridazin-3-one
Figure imgf000156_0001
[00949] a) 4-(3,4-Difluoro-phenyl)-but-3-enoic acid
Figure imgf000156_0002
[00950] Utilizing the procedures described in Example 8a except substituting 3- fluorobenzaldehyde for 3,4-difluoro-benzaldehyde, 4-(3,4-difluoro-phenyl)-but-3-enoic acid was obtained as a yellow oil (1.36 g, 46%).
[00951] 1H NMR (CDCI3): δ 7.25-7.02 (m, 3H); 6.42 (m, 1 H); 6.20 (m, 1H); 3.29 (m, 2H).
[00952] b) 4-(2-Benzyloxy-phenyl)-3-[2-(3,4-difluoro-phenyl)-vinyl]-5-hydroxy-5- methyl-5H-furan-2-one
Figure imgf000157_0001
[00953] Utilizing the procedures described in Example 7a except substituting 2- bromopropiophenone for 1-(2-benzyloxy-phenyl)-2-bromo-propan-1-one, and trans styrylacetic acid for 4-(3,4-difluoro-phenyl)-but-3-enoic acid of Example 64a, 4-(2- benzyloxy-phenyl)-3-[2-(3,4-difluoro-phenyl)-vinyl]-5-hydroxy-5-methyl-5H-furan-2- one was obtained as a yellow oil. The crude product was used directly onto the next step without any further purification.
[00954] c) 5-(2-BenzyIoxy-phenyI)-4-[2-(3,4-difluoro-phenyl)-vinyl]-6-methyl-2H- pyridazin-3-one
Figure imgf000157_0002
[00955] Utilizing the procedures described in Example 8g except substituting 5- ethyl-3-[2-(3-fluoro-phenyl)-vinyl]-5-hydroxy-4-(2-methoxy-phenyl)-5H-furan-2-one of Example 8f for 4-(2-benzyloxy-phenyl)-3-[2-(3,4-difluoro-phenyl)-vinyl]-5-hydroxy-5- methyl-5H-furan-2-one of Example 64d, 5-(2-benzyloxy-phenyl)-4-[2-(3,4-difluoro- phenyl)-vinyI]-6-methyl-2H-pyridazin-3-one was obtained as a yellow foam (0.4 g,
'O J.
[00956] 1H NMR (DMSO): δ 13.04 (s, 1 H); 8.20 (d, 1 H, J = 15.9Hz); 7.52-7.01 (m, 12H); 6.40 (d, 1 H, J = 15.9Hz); 5.16 (s, 2H), 1.92 (s, 3H). [00957] MS (ESI+) (+0.1%HCOOH): 431.1 [C26H20F2N2O2 +H]+ (m/z).
[00958] d) 5-(2-Benzyloxy-phenyl)-4-[2-(3,4-difluoro-phenyl)-vinyl]-6-methyl-2- phenethyl-2H-pyridazin-3-one
Figure imgf000158_0001
[00959] Utilizing the procedure described in Example 22e except substituting 5-(2- benzyloxy-phenyl)-6-methyl-4-((E)-styryl)-2H-pyridazin-3-one of Example 22d for 5- (2-benzyloxy-phenyl)-4-[2-(3,4-difluoro-phenyl)-vinyl]-6-methyl-2H-pyridazin-3-one of Example 64c, 5-(2-Benzyloxy-phenyl)-4-[2-(3,4-difluoro-phenyl)-vinyl]-6-methyl-2- phenethyl-2H-pyridazin-3-one was obtained as yellow oil (0.32g, 66%).
[00960] 1H NMR (CDCI3): δ 8.30 (d, 1 H, J = 15.9Hz); 7.48-6.98 (m, 17H); 6.52 (d, 1H, J = 15.9Hz); 5.10 (s, 2H); 4.47 (m, 2H); 3.20 (m, 2H); 2.05 (s, 3H).
[00961] e) 4-[2-(3,4-Difluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2- phenethyl-2H-pyridazin-3-one
Figure imgf000158_0002
[00962] Utilizing the procedures described in Example 22f except substituting 5- (2-benzyloxy-phenyl)-6-methyl-2-phenethyl-4-styryl-2H-pyridazin-3-one of Example 22e for 5-(2-benzyloxy-phenyl)-4-[2-(3,4-difluoro-phenyl)-vinyl]-6-methyl-2-phenethyl- 2H pyridazin-3-one of Example 64d, 4-[2-(3,4-difluoro~phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2-phenethyl-2H-pyridazin-3-one was obtained as a white solid (0.18 g, 70%).
[00963] 1H NMR (CDCI3): δ 7.42-7.20 (m, 6H); 7.05-6.82 (m, 4H); 6.72-6.54 (m, 2H); 6.08 (s, 1H); 4.52-4.28 (m, 2H); 3.13 (m, 2H); 2.78-2.48 (m, 4H); 2.02 (s, 3H). [00964] LC/MS (gradient 5-80% ACN/H2O + 0.1%HCOOH): 96.1% [00965] MS (ESI+) (+0.1%HCOOH): 447.0 [C27H24F2N2O2 +H]+ (m/z).
[00966] The biological activity and pharmacokinetic parameters of the compounds of Formula (I) were demonstrated by the following tests:
[00967] Calcium Receptor Inhibitor Assay
[00968] Calcilytic activity was measured by determining the IC50 of the test compound for blocking increases of intracellular Ca2+ elicited by extracellular Ca2+ in hCaR HEK (7-2) cells stably expressing the human calcium receptor. hCaR HEK (7-2) cells were constructed as described by Rogers et a/., J. Bone Miner. Res. 10
(Sυppl. 1), S483, (1995) (incorporated herein by reference). Intracellular Ca2+ increases were elicited by increasing extracellular Ca2+ from 1.0 to 1.3 mM.
Intracellular Ca2+ was measured using fluo-3, a fluorescent calcium indicator (Biotium).
[00969] The procedure was as follows: Cells were maintained in DMEM with 10% FBS and 200 μg/ml hygromycin, under 5% CO2 at 37°C. At 24-hours prior to analysis, the cells were trypsinized and plated in the above medium at 120,000 cells/well in black sided, clear-bottom, collagen I coated, 96-well plates. Plates were centrifuged at 800 rpm for 2 minutes and incubated under 5% CO2 at 37°C overnight. The medium was then aspirated and 80 μL/well of 6 μM fluo-3 in assay buffer was added to the plate. Assay buffer contains 20 mM Na-Hepes, pH 7.4, 126 mM NaCI, 5 mM KCI, 1 mM MgCl2, 1 mM CaCl2, 1 mg/mL D-glucose and 1 mg/mL of bovine serum albumin (BSA; fraction V, ICN).
[00970] Cell-plates containing the fluo-3 solution were incubated in the dark, at room temperature, for 60 minutes. Following incubation plates were washed once, then refilled with 160 μL/well of assay buffer. Measurements of fluorescence were performed using the FLIPR system (Molecular Devices), with a laser setting of 0.8 W and a 0.4 second CCD camera shutter speed. A two-addition protocol was used with a 40-μL addition of buffer or test compound 95 seconds before the addition of extracellular Ca2+. The extracellular [Ca2+] is increased from 1.0 to 1.3 mM by adding 50 μL of 2.5 mM CaCl2 in assay buffer.
[00971] Calcilytic activity was determined by a compound's ability to block, in a concentration-dependent manner, increases in the concentration of intracellular
Ca2+ elicited by increases in extracellular Ca2+. Fluorescence signals were measured as the peak height of the response and normalized to the response elicited by extracellular Ca2+ in the absence of test compound. All compounds were tested at 8 concentrations in duplicate with the highest concentration being 100 μM. [00972] In general, those compounds having lower IC50 values in the Calcium
Receptor Inhibitor Assay are more preferred compounds. Compounds which are particularly useful in conjunction with the present disclosure have IC50 values below 50 μM. In some embodiments compounds have an IC50 of 30 μM or lower, while in other embodiments compounds have an IC50 of 10 μM or lower, and in yet other embodiments compounds have an IC50 of 3 μM or lower.
[00973] In vivo effect of calcilvtic compounds of Structure I.
[00974] Bolus Lv. injection in normal rats.
[00975] 4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isopropyl-6-methyl- 2H-pyridazin-3-one of Example 2b (10 μmol/kg) and its vehicle were administered by intravenous injection over about 15 seconds to normal conscious male Sprague- Dawley rats with chronic indwelling arterial and venous catheters. Arterial blood samples were collected at 30 min and immediately before, and at 1 , 5, 10, and 30 min after the start of the injection for measurement of the levels of parathyroid hormone (PTH) and ionized calcium (Ca2+) in plasma. PTH was measured using a specific rat PTH (1-84) ELISA (Immutopics, San Clemente, CA). Injection of compound of Example 2 induced a rapid, but transient dose-related increase in plasma PTH levels that were maximal at 1 min after the injection. Plasma PTH levels had returned to pre-dose levels by 10 min after the injection (Figure 1). Plasma levels of compound of Example 2 were maximal at 1 min after injection and declined rapidly during the next 10-30 min. There were no consistent changes in plasma Ca2+ levels during this experiment (not shown). [00976] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth.
[00977] Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the area can, using the preceding description, utilize the present disclosure to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention as claimed hereinafter. The embodiments disclosed, in which an exclusive property or privilege is claimed are defined as follows. [00978] It will be obvious to those having skill in the art that many changes may be made to the details of the above-described embodiments. The scope of the present invention should, therefore, be determined only by the following claims.

Claims

Claims
1. A compound having the chemical formula:
Structure I
Figure imgf000162_0001
wherein:
R1, R2, R3 and R4 are independently one of H, lower alkyl, cycloalk or a group of the formula CH(lower alkyl)(CH2)n-R5 or (CH2)n-R5 wherein n is 0, 1 , or 2, and R5 is a heterocycle or an aryl group which may have 0 to 4 substituents in the ring and each substituent is at least one of: halogen, CN, CF3, OCF3, lower alkyl, NO2, NH2, NH(lower alk), N(lower alk)2, NH[S(O)2lower alk], NH[S(O)2alkyI aryl], NH[S(O)2aryl], NH[S(O)2heterocycle], OS(O)2NH2, OS(O)2NH(lower alkyl), OS(0)2N(lower alkyl)2, lower alkoxy, OH, OC(O)-lower alk, OC(0)-lower alkyl-NH2, OC(O)-lower alkyl- NH(lower alk), OC(O)-lower alkyl-N(lower alk)2, OC(O)O-lower alk, OC(O)O-lower alkyl amino, OC(0)0-lower alkyl-NH(lower alk), OC(0)0-lower aIkyl-N(lower alk)2, OC(0)NH-lower alk, OC(O)N(lower alk)2, OC(O)heterocycle, 0-lower alkyl- P(O)(OH)2, 0-lower alkyl-P(0)OH(0-lower alkyl-OC(O)O-lower alkyl), O-lower alkyl- P(0)(0-lower alkyl-OC(O)O-lower alk)2, OP(O)(OH)2, OP(O)(O-lower alkyl-aryl)2, OP(0)(0-lower alk)2, OP(O)(O-lower alkyl-OC(O)O-lower alk)2 or OP(O)(O-metal)2; or pharmaceutically acceptable salts, hydrates, tautomers, solvates or complexes thereof.
2. The compound according to claim 1 , wherein R1 is one of lower alkyl, cycloalk, (CH2)n-R5or CH(lower alkyl)(CH2)n-R5.
3. The compound according to claim 2, wherein said lower alkyl of R1 is one of: isopropyl, isobutyl or isopentyl.
4. The compound according to claim 1 , wherein R1 is isopropyl or isobutyl.
5. The compound according to claim 1, wherein R1 is -(CH2)n- R5, n is 1 or 2, and R5 is phenyl.
6. The compound according to claim 1, wherein R2 is -(CH2)n- R5, n is 1 or 2, and R5 is phenyl optionally substituted with one or two halogens.
7. The compound according to claim 6, wherein n is 2 and said halogens are fluorine.
8. The compound according to claim 1 , wherein R3 is phenyl optionally substituted with either hydroxy or both hydroxy and fluorine.
9. The compound according to claim 1, wherein R4 is lower alkyl.
10. The compound according to claim 9, wherein said lower alkyl is one of: methyl, ethyl, or propyl.
11. The compound according to claim 1 , wherein R4 is methyl or ethyl.
12. The compound according to claim 1 , wherein R4 is methyl.
13. The compound according to claim 1, wherein the compound is at least one of: 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isobutyl-6-methyl-2H-pyridazin-3- one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isopropyl-6-methyl-2H-pyridazin- 3-one;
5-(2-hydroxy-phenyl)-6-methyl-2,4-diphenethyl-2H-pyridazin-3-one; 2-(3,5-dimethoxy-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl- 2H-pyridazin-3-one;
2-benzo[1 ,2,5]thiadiazol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2H-pyridazin-3-one;
5-(3-fluoro-2-hydroxy-phenyl)-6-methyl-2,4-diphenethyl-2H-pyridazin-3-one; 2-(3,5-dimethoxy-benzyl)-5-(2-hydroxy-phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3- one;
2-[2-(3,5-dimethoxy-phenyl)-ethyl]-5-(3-fluoro-2-hydroxy-phenyl)-6-methyl-4- phenethyl-2H-pyridazin-3-one; 2-(3,4-dimethoxy-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-
2H-pyridazin-3-one;
2-(3,5-dimethyl-isoxazol-4-ylmethyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2H-pyridazin-3-one;
2-benzo[1 ,3]dioxol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3-methyl-butyl)-2H- pyridazin-3-one;
2-cyclopentyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H- pyridazin-3-one;
2-benzyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H-pyridazin-3- one;
2-cyclopentylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H- pyridazin-3-one;
6-ethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-isopropyl-2H-pyridazin-3- one;
2-cyclopropylmethyl-5-(2-hydroxy-phenyl)-6-methyl-4-phenethyl-2H-pyridazin-3-one;
5-(2-hydroxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl-4-phenethyl-2H-pyridazin-3- one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(4-methoxy-benzyl)-6-methyl-2H- pyridazin-3-one;
4-[2-(4-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-phenethyl-2H-pyridazin-
3-one;
2-benzo[1 ,2,5]thiadiazol-4-ylmethyl-5-(3-fluoro-2-hydroxy-phenyl)-4-[2-(3-fluoro- phenyl)-ethyl]-6-methyl-2H-pyridazin-3-one;
2-(3,5-dimethoxy-benzyl)-5-(3-fluoro-2-hydroxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-
6-methyl-2H-pyridazin-3-one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3,4,5-trimethoxy- benzyl)-2H-pyridazin-3-one;
2-[3,5-bis-(2-methoxy-ethoxy)-benzyl]-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2H-pyridazin-3-one;
4-[2-(3-Fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)- 6-methyl-2-phenethyl-2H- pyridazin-3-one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(3-methoxy-benzyl)-6-methyl-2H- pyridazin-3-one; 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-piperidin-3-ylmethyl-2H- pyridazin-3-one;
2-benzo[1 ,2,5]oxadiazol-4-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy- phenyl)-6-methyl-2H-pyridazin-3-one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyI-2-(2-methyl-thiazol-4- ylmethyl)-2H-pyridazin-3-one;
5-(2-hydroxy-phenyl)-2-isopropyl-6-methyl-4-phenethyl-2H-pyridazin-3-one;
S-CS-fluoro^-hydroxy-phenyO^-p-CS-fluoro-phenyO-ethyll^-isopropyl-θ-methyl^H- pyridazin-3-one;
5-(2-fluoro-3-hydroxy-phenyl)-4-[2-(3-fluoro-phenyl)-ethyl]-2-isopropyl-6-methyl-2H- pyridazin-3-one;
5-(2-hydroxy-phenyl)-2-isopropyl-4-phenethyl-6-propyI-2H-pyridazin-3-one;
2-(2-chloro-benzyI)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2H- pyridazin-3-one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(2-methyI-benzyl)-2H- pyridazin-3-one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3-methyl-benzyl)-2H- pyridazin-3-one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(4-methyl-benzyl)-2H- pyridazin-3-one;
2-(3-chloro-benzyl)-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-methoxy-phenyl)-6-methyl-2H- pyridazin-3-one;
5-(2-hydroxy-phenyl)-6-methyl-4-phenethyl-2-(1-phenyl-ethyl)-2H-pyridazin-3-one;
4-[2-(3-fluoro-phenyl)-ethyI]-5-(2-hydroxy-phenyl)-6-methyl-2-(1-phenyl-ethyl)-2H- pyridazin-3-one;
2-[2-(3,5-dimethoxy-phenyl)-ethyl]-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-
6-methyl-2H-pyridazin-3-one;
2-benzo[1 ,3]dioxol-5-ylmethyl-4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6- methyl-2H-pyridazin-3-one;
.3-[4-(2-hydroxy-phenyl)-3-methyl-6-oxo-5-phenethyl-6H-pyridazin-1-ylmethyl]-N- methyl-benzamide;
3-{5-[2-(3-fluoro-phenyI)-ethyl]-4-(2-hydroxy-phenyl)-3-methyl-6-oxo-6H-pyridazin-1- ylmethyl}-N-methyl-benzamide;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-2-(2-methoxy-ethyl)-6-methyl-2H- pyridazin-3-one; 4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(2-morpholin-4-yl- benzyl)-2H-pyridazin-3-one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3-morpholin-4-yl- benzyl)-2H-pyridazin-3-one;
{5-[2-(3-fluoro-phenyI)-ethyl]-4-(2-hydroxy-phenyl)-3-methyl-6-oxo-6H-pyridazin-1-yl}- acetic acid methyl ester;
4-[2-(3-fluoro-phenyl)-ethyI]-5-(2-hydroxy-phenyl)-2-(2-methoxy-benzyl)-6-methyl-2H- pyridazin-3-one;
5-(2-hydroxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-3-yl-ethyl)-2H-pyridazin-3- one;
5-(2-hydroxy-phenyl)-6-methyl-2-phenethyl-4-(2-thiophen-2-yl-ethyl)-2H-pyridazin-3- one;
4-[2-(3-fluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-(3-phenyl-propyl)-2H- pyridazin-3-one; or
4-[2-(3,4-difluoro-phenyl)-ethyl]-5-(2-hydroxy-phenyl)-6-methyl-2-phenethyl-2H- pyridazin-3-one.
14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable diluent or excipient.
15. A method for preparing 1 ,3,5-substituted 2H-pyridazin-3-ones, comprising reacting 4-substituted 2-oxo-butyric acids with 1 -substituted alkan-2-ones and hydrazine hydrate.
16. A method for preparing 1,3,5-substituted 2H-pyridazin-3-ones, comprising reacting 3,4,5-substituted 5-hydroxy-5H-furan-2-ones with hydrazine hydrate.
17. A method of treating a disease or disorder characterized by abnormal bone or mineral homeostasis, comprising administering to a subject in need of treatment thereof an effective amount of a compound according to claim 1.
18. The method according to claim 17, wherein the disease or disorder is at least one of osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia malignancy, or osteoporosis.
19. The method according to claim 17, wherein the disease or disorder is osteoporosis.
20. A method of increasing serum parathyroid hormone levels in mammals, comprising administering to a subject in need of treatment thereof an effective amount of a compound according to claim 1.
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