US20080004312A1 - Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists - Google Patents

Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists Download PDF

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US20080004312A1
US20080004312A1 US11/807,047 US80704707A US2008004312A1 US 20080004312 A1 US20080004312 A1 US 20080004312A1 US 80704707 A US80704707 A US 80704707A US 2008004312 A1 US2008004312 A1 US 2008004312A1
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methylquinolin
ethyl
amine
ylamino
phenyl
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Eric Anderson
Brian Dupre
Daxin Gao
Raymond Kessler
Wen Li
Chengde Wu
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Encysive Pharmaceuticals Inc
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Encysive Pharmaceuticals Inc
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Publication of US20080004312A1 publication Critical patent/US20080004312A1/en
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
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Definitions

  • the present invention relates to urotensin II receptor antagonists, pharmaceutical compositions containing them and their use.
  • cardiovascular homeostasis The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
  • the principal mammalian vasoactive factors that comprise this neurohumoral axis are angiotensin-II, endothelin-1, and norepinephrine, all of which function via an interaction with specific G-protein coupled receptors (GPCR).
  • GPCR G-protein coupled receptors
  • this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
  • osmoregulation effects which include the modulation of transepithelial ion (Na + , Cl ⁇ ) transport.
  • human urotensin-II has been found to be an extremely potent and efficacious vasoconstrictor; exhibited sustained contractile activity that was extremely resistant to wash out; and had detrimental effects on cardiac performance (myocardial contractility).
  • Human urotensin-II was assessed for contractile activity in the rat-isolated aorta and was shown to be a very potent contractile agonist. Based on the in vitro pharmacology and in vivo hemodynamic profile of human urotensin-II, it plays a pathological role in cardiovascular diseases characterized by excessive or abnormal vasoconstriction and myocardial dysfunction. (Ames et al. Nature 1990, 401, 282.)
  • Compounds that antagonize the urotensin-II receptor may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, fibrosis (e.g. pulmonary fibrosis), restenosis, atherosclerosis, dyslipidemia, asthma, neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction.
  • Urotensin antagonists may provide end organ protection in hypersensitive cohorts in addition to lowering blood pressure.
  • urotensin-II and GPR 14 are both expressed within the mammalian CNS (Ames et al. Nature 1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, pain, migraine, neuromuscular function, Parkinsons, movement disorders, sleep-wake cycle, and incentive motivation.
  • urotensin-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications.
  • Urotensin may also be implicated in various metabolic diseases such as diabetes and in various gastrointestinal disorders, bone, cartilage, and joint disorders (e.g., arthritis and osteoporosis); and genito-urinary disorders. Therefore, these compounds may be useful for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence.
  • this invention provides for compounds and pharmaceutical compositions containing them.
  • this invention provides for the use of these compounds as antagonists of urotensin II, and as inhibitors of urotensin II.
  • this invention provides for the use of these compounds for treating conditions associated with urotensin II imbalance.
  • this invention provides for the use of these compounds for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhage stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint disease, arthritis and other inflammatory diseases, fibrosis (e.g.
  • pulmonary fibrosis sepsis atherosclerosis
  • dyslipidemia addiction
  • schizophrenia, cognitive disorders/Alzheimers disease impulsivity
  • anxiety anxiety
  • depression parkinsons
  • movement disorders sleep-wake cycle
  • incentive motivation pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
  • the urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-II receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ -adrenoceptor and 1 -adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • the present invention provides for compounds of Formula (I):
  • Preferred structures of Formula I are compounds of the formula:
  • the present invention is also directed to compounds of Formula (II):
  • A is CO 2 H, CONHSO 2 R 19 , SO 2 NHCOR 20 , tetrazole or other carboxylic isosteres where R 19 and R 20 have the same definition as R 16 , R 17 and R 18 .
  • cyclic and bicyclic ring systems include pyrrolidine, piperidine, azepane, azocane, piperazine, morpholine, diazepane, diazocane, imidazole, benzopyrolidine, benzopiperidine, benzopiperazine, benzoimidazole, benzoazepine and tetrahedrobenzoazepine derivatives.
  • Presently preferred compounds of the present invention are:
  • carbonyl or “CO” as used herein, alone or in combination, includes derivatives such as oximes, ketals and cyclic ketals.
  • alkyl refers to C 1 -C 6 straight or branched, substituted or unsubstituted saturated chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom, unless the term alkyl is preceded by a C x -C y designation.
  • Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl among others.
  • aryl refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group which is an aromatic ring containing at least one endocyclic N, O or S atom such as furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,
  • aralkyl refers to an aryl substituted alkyl radical, wherein the terms “alkyl” and aryl” are as defined above.
  • suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl and the like.
  • cycloalkyl refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl among others. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, diakylamino, hydroxyl, halo, mercapto, nitro, caroxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • Cycloalkyl includes cis or trans forms. Furthermore, the substituents may either be in endo or exo positions in the bridged bycyclic systems.
  • heteroaryl or “heteroarene” as used herein, alone or in combination, refers to a 3- to 10-membered ring containing at least one endocyclic N, O, or S atom.
  • the heterocycle may be optionally aryl-fused.
  • the heterocycle may also optionally be substituted with at least one substituent which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.
  • substituent is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.
  • optical isomers refers to compounds which differ only in the stereochemistry of at least one atom, including enantiomers, diastereomers and racemates.
  • substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylbeterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of
  • the linkers are typically short chains of 1-3 atoms containing any combination of —C—, —C(O)—, —N—H—, —S—, —S(O)—, —O—, —C(O)O— or —S(O)O—. Rings may be substituted multiple times.
  • Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, sulfonyl and aryl lower alkanoyl among others.
  • Electron donating groups include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide among others.
  • substituents may have electron donating or electron withdrawing properties under different chemical conditions.
  • present invention contemplates any combination of substituents selected from the above-identified groups.
  • the most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfanyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio, carboxy lower alkyl, arylalkoxy, alkanoylamino, alkanoyl (lower alkyl) amino, lower alkylsufonylamino, arylsulfonylamino, alkylsulfonyl(lower alkyl)amino,
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, a well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
  • mammals includes humans and other animals.
  • the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, dighiconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • therapeutically effective amount means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent.
  • the present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, among others.
  • compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or via a biodegradable polymer.
  • the compounds may also be complexed to ligands, such as antibodies, for targeted delivery.
  • compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
  • compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly-anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) hurnectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbent
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents. sweetening, flavoring and perfuming agents.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like.
  • the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
  • prodrugs of the compounds of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or iastereomers.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates.
  • solvated forms including hydrated forms, such as hemi-hydrates.
  • pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
  • Each dosage unit for oral administration contains suitably from 0.0001 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person.
  • a topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for parenteral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to 500 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • ischemic heart disease angina, myocardial ischemia
  • cardiac arrhythmia hypertension (essential and pulmonary)
  • renal disease acute and chronic renal failure/end stage renal disease
  • peripheral vascular disease male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease
  • ischemic/hemorrhagic stroke COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint disease, arthritis and other inflammatory diseases, fibrosis (e.g.
  • pulmonary fibrosis sepsis, atheroscloerosis, dyslipidemia, addiction, schizophrenia, cognitice disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
  • the urotension antagonists of the present invention may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-II receptor antagonists, phosphodieterase inhibitors, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ -adrenoceptor and ⁇ 1 -adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • Binding of human [ 125 ]-urotensin-II to human urotensin-II receptor was done using cell membranes from either TE-671 rhabdomyosarcoma cells or CHO cells stably expressing recombinant UTR, in a homogeneous Scintillation Proximity Assay (SPA).
  • SPA Scintillation Proximity Assay
  • the UTR cells membranes were pre-coupled overnight at 4° C. to WGA-PVT beads (Amersham RPNQ0001) at a ratio of 5-25 ⁇ g membrane to 0.5 mg beads/assay.
  • Assay was performed in 96-well microtiter Optiplates (Packard 6005290) by mixing coupled beads and 0.1 nM [ 125 U-II (2200 Ci/mmol, NEN NEX379), in a total volume of 100 ⁇ l 20 mM HEPES, 5 MM MgCl 2 , pH 7.4. Test compounds were diluted in DMSO and were put in the assay at a final concentration of 1% DMSO. IncLibation was done for 3 hours at 37° C.
  • Nonspecific binding was determined by adding 100 nM unlabeled human U-II (Phoenix Pharmaceuticals, 071-05) to the assay mixture. Analysis of the assay was performed using nonlinear least square fitting.
  • urotensin-II The function of urotensin-II was determined by measuring ligand-induced mobilization of intracellular Ca 2+ in a FlexStation scanning fluorometer (Molecular Devices). UTR cells were plated overnight at 50,000 cells/well in 96-well black/clear plates (Costar brand, Fisher 07-200-588). Cells were labeled with fluo-4AM dye (Molecular Probes, F-14201) in Hank's balanced salt solution (HBSS), 20 mM HEPES, 25 mM probenecid, pH 7.4, and then were washed with buffer. During the assay, cells were continuously monitored in the FlexStation and exposed to test compounds at a final concentration of 0.1% DMSO, followed by the addition of 1 nM human U-II.
  • Example 15 and 16 were synthesized in the same manner as for Example 2.
  • the compound of Example 17 was synthesized by methylating the compound of Example 3 using a standard method (NaH/DMF/MeI).
  • Example 33 The compound of Example 33 was synthesized in the same manner as the compound of Example 13 except that 3-nitro-5-trifluoromethylphenol was used instead of 13. 3-Nitro-5-trifluoromethylphenol was synthesized by demethylating 3-nitro-5-trifluoromethylanisole using a standard method (BBr 3 /CH 2 Cl 2 ).
  • the compound of Example 34 was synthesized by hydrolysis of the compound of Example 32 using a standard method (NaOH/MeOH/THF).
  • Example 58 The compound of Example 58 was synthesized in the same manner as the compound of Example 13 except that 4-chloro-2-tert-butylquinoline (C Wolf, R Lerebours: J Org Chem 2003, 68:7077-7084) was used instead of 4-chloro-2-methylquinoline.
  • 4-chloro-2-tert-butylquinoline C Wolf, R Lerebours: J Org Chem 2003, 68:7077-7084
  • Example 59 The compound of Example 59 was synthesized in the same manner as the compound of Example 13.
  • the compound of Example 60 was synthesized by acylating the compound of Example 21 using a standard method (NaH/DMF/AcCl).
  • Example 61 The compound of Example 61 was synthesized in the same manner as the compound of Example 13.
  • Example 62 The compound of Example 62 was synthesized in the same manner as the compound of Example 33.
  • Example 66 The compound of Example 66 was synthesized in the same manner as the compound of Example 13 and it was obtained as the dehydration product of the intended (1- ⁇ 2-[3-(2-methylquinolin-4-ylamino)phenoxy]ethyl ⁇ piperidin-4-yl)diphenylmethanol.
  • Example 67 The compound of Example 67 was synthesized in the same manner as the compound of Example 33.
  • Example 68 The compound of Example 68 was synthesized by the hydrolysis of the compound of Example 65 (NaOH/MeOH/THF/65° C./2 days).
  • Example 69 was synthesized by the hydrolysis of the compound of Example 36 (NaOH/MeOH/THF).
  • Example 74 The compound of Example 74 was synthesized in the same manner as the compound of Example 33.
  • Example 77 The compound of Example 77 was synthesized by benzylation of the compound of Example 2 using a standard method (NaH/BnBr/DMF).
  • the synthesis of Example 2 is the same as for Example 1 except that 3-nitrobenzoyl chloride was used instead of 3-nitrobenzenesulfonyl chloride.
  • the compound of Example 102 was synthesized by demethylation of the compound of Example 99 using a standard method (BBr 3 /CH 2 Cl 2 ).
  • Example 103 The compound of Example 103 was synthesized in the same manner as the compound of Example 2.
  • Example 104 The compound of Example 104 was synthesized in the same manner as the compound of Example 2 except that the last step was a standard coupling with 2,4-dimethoxybenzenesulfonyl chloride.
  • Example 105 The compound of Example 105 was synthesized in the same manner as the compound of Example 2.
  • Example 106 The compound of Example 106 was synthesized by demethylation of the compound of Example 103 using a standard method (BBr 3 /CH 2 Cl 2 ).
  • Example 107 The compound of Example 107 was synthesized in the same manner as the compound of Example 2 using 2,4,6-trimethyl-3-nitrobenzoyl chloride instead of 3-nitrobenzoyl chloride.
  • 2,4,6-Trimethyl-3-nitrobenzoyl chloride was synthesized by treatment of 2,4,6-trimethyl-3-nitrobenzoic acid (C Wu et al: J Med Chem 1999, 42:4485-4499) with POCl 3 .
  • Example 111 The compound of Example 111 was synthesized in the same manner as the compound of Example 79 except that 2,3,4,5-tetrahydro-1H-benzo[c]azepine (Al Meyers, R H Hutchings: Tetrahedron 1993, 49:1807-1820) was used instead of 1,2,3,4-tetrahydro-isoquinoline.
  • Example 112 The compound of Example 112 is shown.
  • Example 113 The compound of Example 113 was synthesized in the same manner as the compound of Example 110.
  • Example 114 The preparation of Example 114 is shown.
  • Example 115 The compound of Example 115 was synthesized in a 3-step sequence: coupling of 36 with 2-amino-5-nitrobenzoic acid (EDCI/HOBT/DIPEA/DMF), then steps 4 and 5 of Example 45.
  • EDCI/HOBT/DIPEA/DMF 2-amino-5-nitrobenzoic acid
  • Example 119 The compound of Example 119 was synthesized in the same manner as the compound of Example 79 except that 7-phenyl-1,2,3,4-tetrahydroisoquinoline was used instead of 1,2,3,4-tetrahydroisoquinoline.
  • 7-Phenyl-1,2,3,4-tetrahydroisoquinoline was synthesized by a standard Suzuki coupling between phenylboronic acid and 7-bromo-1,2,3,4-tetrahydroisoquinoline (G E Stokker: Tetrahedron Lett 1996:5453-5456).
  • Example 120 was synthesized in the same manner as the compound of Example 79 except that 7-fluoro-1,2,3,4-tetrahydroisoquinoline (G E Stokker: Tetrahedron Lett 1996:5453-5456) was used instead of 1,2,3,4-tetrahydroisoquinoline.
  • Example 123 The compound of Example 123 was synthesized in the same manner as the compound of Example 2.
  • Example 124 The compound of Example 124 was synthesized in the same manner as the compound of Example 120.
  • Example 125 was synthesized in the same manner as the compound of Example 79 except that the last step was a Buchwald coupling (Buchwald et al: Tetrahedron Len 1995 36:3609) with 5-bromo-m-xylene instead of the acid catalyzed coupling with 5.
  • Example 126 The compound of Example 126 was synthesized in the same manner as the compound of Example 2.
  • Examples 127 and 128 were synthesized in the same manner as the compound of Example 120.
  • Example 131 The compound of Example 131 was synthesized in the same manner as the compound of Example 120.
  • Example 136 The compound of Example 136 was synthesized in the same manner as the compound of Example 120.
  • Example 141 The compound of Example 141 was synthesized by a Buchwald coupling (Buchwald et al: Tetrahedron Lett 1995 36:3609) between 3-bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]benzamide and 4-amino-2-dimethylaminopyridine (Hnschberger A et al, Tetrahedron 2000, 56:1361-1367).
  • Example 142 The compound of Example 142 was synthesized in the same manner as the compound of Example 125.
  • Example 143 The compound of Example 143 was synthesized in the same manner as the compound of Example 2.
  • Example 144 The preparation of Example 144 is shown.
  • Example 147 The compound of Example 147 was synthesized in the same manner as the compound of Example 144.
  • Example 148 The compound of Example 148 was synthesized in the same manner as the compound of Example 2.
  • Example 149 The compound of Example 149 was synthesized in the same manner as the compound of Example 141.
  • Example 150 was synthesized in the same manner as the compound of Example 2.
  • Example 151 The compound of Example 151 was synthesized in the same manner as the compound of Example 144.
  • Example 152 The compound of Example 152 was synthesized by hydrolysis (1 eq NaOH/THF/MeOH/H 2 O) of methyl 4-( ⁇ 2-[3-(2-methyl quinolin-4-ylamino)benzoylamino]ethylamino ⁇ -methyl)benzoate which was synthesized in the same manner as for Example 144.
  • Example 153 The compound of Example 153 was synthesized in the same manner as the compound of Example 2.
  • Example 154 The compound of Example 154 was synthesized by hydrolysis (1 eq NaOH/THF/MeOH/H 2 O) of the compound of Example 151.
  • Example 155 The compound of Example 155 was synthesized in the same manner as the compound of Example 141.
  • Example 156 The compound of Example 156 was synthesized in the same manner as the compound of Example 2.
  • Example 157 The compound of Example 157 was synthesized in the same manner as the compound of Example 151 and during the reductive amination step the lactam ring was formed.
  • Example 158 The compound of Example 158 was synthesized in the same manner as the compound of Example 12 except that 2-bromo-2-methyl-N-(3-nitrobenzyl)propionamide and 40 were used instead of 3-nitrobenzyl bromide and dimethylamine, respectively.
  • 2-Bromo-2-methyl-N-(3-nitrobenzyl)propionamide was synthesized by a standard coupling (HOBt/EDCI/DIPEA/DMF) of 2-bromo-2-methylpropionic acid and 3-nitroaniline.
  • 57 was prepared from 56 by the procedure of Example 13 Step 2.
  • Example 174 The compound of Example 174 was synthesized in the same manner as the compound of Example 1.
  • Example 175 The compound of Example 175 was synthesized in the same manner as the compound of Example 177.
  • Example 178 The compound of Example 178 was synthesized in the same manner as the compound of Example 1.
  • Example 180 was synthesized in the same manner as the compound of Example 179.
  • Example 182 was synthesized in the same manner as the compound of Example 178 except that N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-nitrobenzenesulfonamide was methylated using a standard method (NaH/MeI/DMF) before carried on to the next step.
  • Example 185 The compound of Example 185 was synthesized in the same manner as the compound of Example 184.
  • Example 195 The compound of Example 195 was synthesized in the same manner as the compound of Example 190.
  • Example 196 The compound of Example 196 was synthesized in the same manner as the compound of Example 186.
  • Example 197 The compound of Example 197 was synthesized in the same manner as the compound of Example 191.
  • Example 199 The compound of Example 199 was synthesized in the same manner as the compound of Example 198.
  • Example 200 The compound, of Example 200 was synthesized in the same manner as the compound of Example 191.
  • Example 201 The compound of Example 201 was synthesized via reduction (see Example 112 step 3) of the compound of Example 134.
  • Example 204 The compound of Example 204 was synthesized in the same manner as the compound of Example 198.
  • Example 207 was synthesized via reduction (see Example 112 step 3) of the compound of Example 144.
  • Example 211 The compound of Example 211 was synthesized in the same manner as the compound of Example 210.
  • 71 is prepared from 70 by the procedure of Example 1 Step 3.
  • Step 6 ⁇ 3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)isoxazol-3-yl]phenyl ⁇ -(2-methyl-quinolin-4-yl)amine
  • Step 4 ⁇ 3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)propyl]phenyl ⁇ -(2-methylquinolin-4-yl)amine
  • 89 is prepared from 88 by the procedure of Example 110 Step 4.
  • Step 4 ⁇ 3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]phenyl ⁇ -(2-methylquinolin-4-yl)amine
  • Step 4 N 1 -[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-N 7 -(2-methylquinolin-4-yl)-1,2,3,4-tetrahydronaphthalene-1,7-diamine
  • Step 4 ⁇ 3-[2-(4-Benzylpiperidin-1-yl)ethanesulfonyl]phenyl ⁇ -(2-methylquinolin-4-yl)amine
  • Example 134 To a solution of Example 134 (0.62 g, 1.30 mmol) in THF (20 mL) was added LiAlH 4 (1 M in THF, 4.0 mL, 3.90 mmol) at 0° C. The mixture was warmed to room temperature and then heated at 80° C. for 16 hours. The reaction was allowed to cool to room temperature and quenched with Na 2 SO 4 .10H 2 O. The resulting slurry was filtered, rinsed with ethyl acetate, and the filtrate concentrated. The residue was chromatographed on silica gel (dichloromethane to 10:1 to 5:1 dichloromethane/methanol) to give the desired product as a yellow solid (170 mg, 28.3%).
  • Example 110 Step 4 was prepared from 110 by the procedure of Example 110 Step 4.
  • Example 209 A mixture of Example 209 (0.40 g, 0.86 mmol), ethoxyamine hydrochloric acid (0.22 g, 2.63 mmol,) and pyridine (0.19 g, 2.47 mmol) in anhydrous ethanol (3.0 mL) was heated under reflux overnight. The reaction was allowed to cool to room temperature and diluted with EtOAc (100 mL). Upon sequential washings with 1 N NaOH (2 ⁇ 100 mL) and brine (100 mL), the organic solution was dried over Na 2 SO 4 and evaporated to dryness. The resulting residue was purified via flash silica gel chromatography to give the desired product (100 mg, 24%) as a white foam.
  • Example 214 The compounds of Examples 214 and 221 were synthesized in the same manner and the synthesis for Example 214 is illustrated as follows:
  • Example 223 The compounds of Examples 223 and 224 were synthesized in the same manner as Example 214.
  • Example 222 To a solution of the product of Example 222 (81.3 mg, 0.16 mmol) in THF (2 ml) at 0° C. was added dropwise a solution of lithium aluminum hydride (0.8 ml of a 1 M solution in THF). The reaction was stirred for 3 hours while the bath temperature rose to ambient temperature. Powdered sodium sulfate decahydrate (300 mg) was added in portions at 0° C. and the resulting mixture was stirred for 2 hours before it was filtered through a pad of Celite®.
  • Example 226 and 227 were synthesized in the same manner as Example 214.
  • Example 230 The compound of Example 230 was synthesized in the same manner as Example 67.
  • Ex- ample physical # structure chemical Name description a [M + H] + 212 [3-(3-benzyl aminopropoxy)-5- trifluoro methylphenyl]- (2-methylquinolin-4- yl)amine white solid 466.20 213 ⁇ 3-(3-(1-methyl-1- phenylethylamino) propoxy]-5-trifluoro methylphenyl ⁇ - (2-methylquinolin-4- yl)amine yellow solid 494.07 214 (2-methylquinolin-4- yl)-(3- ⁇ 2-[(3- methylthiophen-2- ylmethyl) amino]ethoxy ⁇ phenyl) amine pale yellow solid 404.18 215 ⁇ 3-[2-(3- methoxybenzylamino) ethoxy]phenyl ⁇ (2-methyl quinolin-4-yl)amine pale yellow solid 414.25 216 (2-
  • Example 235 The compounds of Examples 235 and 236 were synthesized in the same manner and the synthesis is illustrated for Example 235 as follows:
  • Step 4 The title compound was synthesized via a sequence of coupling/reduction/coupling illustrated as for Example 67
  • step 1 was used.
  • Step 4 ⁇ 3-[2-(4-Acetyl-4-benzylpiperidin-1-yl)ethoxy]phenyl ⁇ (2-methylquinolin-4-yl)amine
  • the title compound was synthesized via a sequence of deprotection/coupling/reduction/coupling as illustrated for Example 67 (steps 3-5).
  • Example 240 was synthesized in the same manner as for Example 238.
  • Example 241 was synthesized in the same manner as for Example 67 (Steps 3-5).
  • Example 247 The compound of Example 247 was synthesized in the same manner as for Example 238.
  • Example 249 The compound of Example 249 was synthesized in the same manner as for Example 248.
  • Example 254 The compounds of Examples 254 and 255 were synthesized in the same manner as for Example 248.
  • Step 2 ⁇ 3-[2-(4-Phenylpiperidin-1-yl)ethoxyl-5-trifluoromethylphenyl ⁇ (2-isopropylquinolin-4-yl)amine
  • the titled compound was synthesized in the same manner as for Example 71 using 128.
  • Example 67 To a solution of Example 67 (0.19 g, 0.33 mmol) in THF (5 ml) was added lithium aluminum hydride (650 ml, 0.66 mmol) at 0° C. The mixture was stirred at room temperature overnight before it was quenched with Na 2 SO 4 .10H 2 O (pellets) until no more bubbles were observed.
  • Example 261 The compound of Example 261 was synthesized in the same manner as for Example 259.
  • the mixture was extracted with ether (75 mL, 50 mL) and washed with water (2 ⁇ 50 mL).
  • Example 269 was synthesized in the same manner as for Example 248, final step.
  • a [M + H] + 231 N-benzyl-4-benzyl-1- ⁇ 2-[3-(2-methyl quinolin-4- ylamino) phenoxy]ethyl ⁇ -N- methyl piperidine-4-carboxamide light yellow solid 599.29
  • b 523.22 233
  • Example 272 The compound of Example 272 was synthesized in the same manner as for Example 71.
  • Example 273 The compound of Example 273 was synthesized in the same manner as for Example 276 (vid infra).
  • Example 275 The compound of Example 275 was synthesized in the same manner as for Example 274.
  • Example 277 The compound of Example 277 was synthesized in the same manner as for Example 274.
  • Example 280 and 281 were synthesized in the same manner as for Example 274.
  • Example 284 The compound of Example 284 was synthesized in the same manner as for Example 274.
  • Example 285 The compound of Example 285 was synthesized in the same manner as for Example 276.
  • Example 286 The compound of Example 286 was synthesized in the same manner as for Example 67, Steps 3-5.
  • Examples 287 and 288 were synthesized in the same manner as for Example 274 using 3,5-difluorobenzyl bromide and 3-pyridiylmethyl bromide, respectively, instead of 3-trifluoromethylbenzyl bromide.
  • Example 289 The compound of Example 289 was synthesized in the same manner as for Example 276 except that tert-butyl[1,4]diazepane-1-carboxylate was used instead of tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.
  • Example 297 The compound of Example 297 was synthesized in the same manner as for Example 276.
  • Example 298 The compound of Example 298 was synthesized in the same manner as for Example 274.
  • Example 301 The compound of Example 301 was synthesized in the same manner as for Example 274 except that benzenesulfonyl chloride was used instead of 3-trifluoromethylbenzyl bromide.
  • Example 302 The compound of Example 302 was synthesized in the same manner as for Example 248, last step, except 1-(3-thienylmethyl)piperazine was used.
  • Example 303 The compound of Example 303 was synthesized in the same manner as for Example 274 except that 2-chloro-5-chloromethylpyridine was used instead of 3-trifluoromethylbenzyl bromide.
  • Step 4 ⁇ 3-[2-(4-Benzyl-3,5-dimethylpiperazin-1-yl)-ethoxy]-5-trifluoromethylphenyl ⁇ (2-methyl-quinolin-4-yl)amine
  • Example 305 The compound of Example 305 was synthesized in the same manner as for Example 274 except that 4-methylsulphonylbenzyl bromide was used instead of 3-trifluoromethylbenzyl bromide.
  • Example 306 The compound of Example 306 was synthesized in the same manner as for Example 276 except that benzenesulfonyl chloride was used instead of 2-chlorobenzyl chloride.
  • Example 307 was synthesized in the same manner as for Example 239 except that 3-chloro-5-(2-methylquinolin-4-ylamino)phenol and 2-benzyl-2,5-diazabicyclo[2.2.1]heptane were used instead of 3-(2-methylquinolin-4-ylamino)phenol and 4-(3-methylbenzyl)piperidin-4-ol, respectively.
  • Example 310 The compound of Example 310 was synthesized in the same manner as for Example 276 except that benzoyl chloride was used instead of 2-chlorobenzyl chloride.
  • Example 311 and 312 were synthesized in the same manner as for Example 214.
  • Example 313 and 314 were synthesized in the same manner as for Example 274 except that 1-bromo-3-methylbutane and cyclohexanemethyl bromide were used instead of 3-trifluoromethylbenzyl bromide.
  • Example 318 The compound of Example 318 was synthesized in the same manner as for Example 214.
  • Example 319 and 320 were synthesized in the same manner as for Example 276.
  • Example 321 The compound of Example 321 was synthesized in the same manner as for Example 67.
  • Example 325 The compound of Example 325 was synthesized in the same manner as for Example 67.
  • Example 326 The compound of Example 326 was synthesized in the same manner as for Example 248, last step.
  • Example 329 and 330 were synthesized in the same manner as for Example 328.
  • Example 331 The compound of Example 331 was synthesized in the same manner as for Example 67.
  • Examples 334 and 335 were synthesized in the same manner as for Example 67 using 129 instead of 31.
  • Example 339 The compound of Example 339 was synthesized in the same manner as for Example 214.
  • Example 343 The compound of Example 343 was synthesized in the same manner as for Example 342 using 1-amino-3-methylnaphthalene instead of 5-methoxyquinolin-8-ylamine.
  • 1-Amino-3-methylnaphthalene was synthesized from 1-amino-3-methylnaphthalene-2-carbonitrile (Kobayashi, K. et al. J. Org. Chem. 1997, 62, 664) using a literature procedure (Mirek, J., Sepiol, J. Ange. Chemie Int. Ed. Eng. 1973, 12, 837).
  • Example 209 To a solution of Example 209 (0.15 g, 0.32 mmol) in THF (5.0 ml) was added LAH (1.0 M in THF, 0.66 ml, 0.66 mmol) at 0° C. The mixture was stirred at room temperature overnight before it was quenched with Na 2 SO 4 .10H 2 O (pellets) until no further bubbles was observed.
  • the mixture was diluted with ethyl acetate and the solids filtered.
  • the filterate was washed with water (50 ml), brine (50 ml), dried over MgSO 4 and concentrated on a rotovap to give the desired alcohol as a yellow solid (0.04 g, 27%).
  • nitrile 161 (1.9 g, 7.29 mmol) in 1,2-dimethoxyethane (10 ml) was added 4 M NaOH (2 ml). The mixture was heated under reflux for 18 hours, then cooled and neutralized (to pH 7) by the addition of concentrated HCl. The solids were collected by filtration, and dried under vacuum to give product 162 as a white solid (1.4 g, 69%) which was used without further purification.
  • Carboxylic acid 162 (264 mg, 0.95 mmol) was dissolved in 1,2-dichloroethane (1 ml) and thionyl chloride (0.1 ml, 1.1 mmol) was added. The mixture was warmed at 60° C. for 10 min, then concentrated under reduced pressure. The residue was mixed with 1,2-dichloroethane (2 ml) then treated with a solution of N-2-aminoethyltetrahydroisoquinoline (36) (100 mg, 0.56 mmol) and N,N-diisopropyl-ethylamine (0.11 ml, 0.6 mmol) in 1,2-dichloroethane (1 ml).
  • Example 348 was synthesized in the same manner as for Example 191 using 1-benzylpiperazine instead of compound 36.
  • the ketone 165 obtained in the previous step was mixed with ethanol (1 ml), benzylamine (56 mg, 0.52 mmol) and 4 ⁇ molecular sieves (25 mg), and the mixture was heated under reflux overnight. The solution was then cooled to room temperature and sodium borohydride (40 mg, 1.06 mmol) was added, and the reaction was stirred at room temperature overnight before it was quenched by the addition of glacial acetic acid (0.5 ml). The mixture was concentrated under reduced pressure and the residue was partitioned between water (1.5 ml) and 7:3 methylene chloride/methanol (1.5 ml). The organic material was separated, concentrated and a portion was purified by reverse-phase HPLC (10-70% aq. acetonitrile) to give the desired product as a pale yellow solid (35 mg).
  • Example 355 The compound of Example 355 was synthesized in the same manner as for Example 350.
  • Example 356 The compound of Example 356 was synthesized in the same manner as for Example 354.
  • Example 357 The compound of Example 357 was synthesized in the same manner as for Example 350.
  • Ex- am- ple physical # structure chemical name description a [M + H] + 342 N-[2-(3,4-dihydro-1H- isoquinolin-2-yl) ethyl]-3-(5- methoxyquinolin-8- ylamino) benzamide orange solid b 453.18 343 N-[2-(3,4-dihydro-1H- isoquinolin- 2-yl) ethyl]-3-(3- methylnaphthalen-1- ylamino)benzamide orange solid b 436.20 344 N-[2-(4-benzylpiperidin- 1-yl) ethyl]- N-[3-(2-methylquinolin-4- ylamino)- phenyl]methanesulfonamide pale yellow solid b 529.21 345 3-(4-benzylpiperidin-1-yl)
  • Example 358 The compound of Example 358 was synthesized in the same manner as for Example 68.
  • Example 364 was synthesized in the same manner as for Example 68 using the product of Example 363.
  • Example 365 The compound of Example 365 was synthesized in the same manner as for Example 67.
  • Example 366 The compound of Example 366 was synthesized in the same manner as for Example 68.
  • Example 367 The compound of Example 367 was synthesized in the same manner as for Example 67.
  • Example 368 The compound of Example 368 was synthesized in the same manner as for Example 68.
  • Example 370 The compound of Example 370 was synthesized in the same manner as for Example 67.
  • Example 371 The compound of Example 371 was synthesized in the same manner as for Example 68.

Abstract

The present invention relates to urotensin II receptor antagonists, pharmaceutical compositions containing them and their use.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • The present application is a continuation-in-part of U.S. application Ser. No. 10/783,916, filed Feb. 20, 2004 which application claims the benefit of provisional application No. 60/451,089, filed Feb. 28, 2003.
    • FIELD OF THE INVENTION
  • The present invention relates to urotensin II receptor antagonists, pharmaceutical compositions containing them and their use.
    • BACKGROUND OF THE INVENTION
  • The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
  • The principal mammalian vasoactive factors that comprise this neurohumoral axis are angiotensin-II, endothelin-1, and norepinephrine, all of which function via an interaction with specific G-protein coupled receptors (GPCR). Urotensin-II, represents an important member of this neurohumoral axis.
  • In the fish, this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
  • both vascular and non-vascular (smooth muscle contraction) including smooth muscle preparations from the gastrointestinal tract and genitourinary tract. Both pressor and depressor activity has been described upon systemic administration of exogenous peptide.
  • osmoregulation effects which include the modulation of transepithelial ion (Na+, Cl−) transport.
  • Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR); urotensin-II influences prolactic secretion and exhibits a lipolytic effect in fish (activating triacylglycerol lipase resulting in the mobilization of non-esterified free fatty acids) (Person, et al. Proc. Natl. Acad. Sci. (U.S.A.) 1980, 77, 5021; Conlon, et al. J. Exp. Zool. 1996, 275, 226); human urotensin-II has been found to be an extremely potent and efficacious vasoconstrictor; exhibited sustained contractile activity that was extremely resistant to wash out; and had detrimental effects on cardiac performance (myocardial contractility). Human urotensin-II was assessed for contractile activity in the rat-isolated aorta and was shown to be a very potent contractile agonist. Based on the in vitro pharmacology and in vivo hemodynamic profile of human urotensin-II, it plays a pathological role in cardiovascular diseases characterized by excessive or abnormal vasoconstriction and myocardial dysfunction. (Ames et al. Nature 1990, 401, 282.)
  • Compounds that antagonize the urotensin-II receptor may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, fibrosis (e.g. pulmonary fibrosis), restenosis, atherosclerosis, dyslipidemia, asthma, neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction. Urotensin antagonists may provide end organ protection in hypersensitive cohorts in addition to lowering blood pressure.
  • Since urotensin-II and GPR 14 are both expressed within the mammalian CNS (Ames et al. Nature 1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, pain, migraine, neuromuscular function, Parkinsons, movement disorders, sleep-wake cycle, and incentive motivation.
  • Functional urotensin-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications. Urotensin may also be implicated in various metabolic diseases such as diabetes and in various gastrointestinal disorders, bone, cartilage, and joint disorders (e.g., arthritis and osteoporosis); and genito-urinary disorders. Therefore, these compounds may be useful for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence.
    • SUMMARY OF THE INVENTION
  • In one aspect this invention provides for compounds and pharmaceutical compositions containing them.
  • In a second aspect, this invention provides for the use of these compounds as antagonists of urotensin II, and as inhibitors of urotensin II.
  • In another aspect, this invention provides for the use of these compounds for treating conditions associated with urotensin II imbalance.
  • In yet another aspect, this invention provides for the use of these compounds for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhage stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint disease, arthritis and other inflammatory diseases, fibrosis (e.g. pulmonary fibrosis), sepsis atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, parkinsons, movement disorders, sleep-wake cycle, incentive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
  • The urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-II receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective β-adrenoceptor and 1-adrenoceptor antagonists.
  • Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention provides for compounds of Formula (I):
    Figure US20080004312A1-20080103-C00001
    • wherein Ar is selected from the group consisting of aryl, heteroaryl, benzoheteroaryl, pyridone, pyridazinone, and pyrimidone;
    • R1 and R2 are independently H, alkyl, cycloalkyl, bicyclic alkyl, adamantyl, aralkyl, aryl, R7CO, or R8OCO or R1 and R2 along with N can form a cyclic or bicyclic heterocyclic ring system or R1 and L1 or R1 and one carbon of (CH2)n can form a 5, 6, or 7 membered ring;
    • R3 is H, alkyl or aralkyl;
    • X and Y are independently C or N;
    • R4, R5, and R6 are independently selected from the group consisting of H, alkyl, aralkyl, aryl, heteroaryl, benzoheteroaryl, hydroxyl, halo, haloalkyl, alkoxy, aminocarbonyl and aminosulfonyl or R5 and R6 together can form a 5-6 membered aromatic ring or a 5-7 membered aliphatic ring;
    • L1 is selected from the group consisting of a single bond, O, NR9, CO, COO, OCO, SO2, NR10CO, NR11SO2, NR12CONR13, NR14SO2NR15, CH2CHOHCH2, arene heteroarene, pyridine, pyrimidone and pyridazinone;
    • L2 and L3 are independently selected from the group consisting of a single bond, CH2, NR16, CO and SO2;
    • L4 is (Z)n where each Z is independently CH2, CR17R18, CO, NR19, CONR20 or NR21CO, any two adjacent Zs may be replaced with a double or triple bond, R17, R18 or two R17s can form a 5-8 membered aliphatic ring or R17 and Ar can form a fused 5-8 membered aliphatic ring; n is an integer from 0 to 6;
    • R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20 and R21 are independently selected from the group consisting of H, alkyl, aryl and aralkyl, R16 is also alkylsulfonyl or alkylcarbonyl or R10 and CO and Ar can form pyridone, pyridazinone, and pyrimidone, and the pharmaceutically acceptable salts thereof.
  • Preferred structures of Formula I are compounds of the formula:
    Figure US20080004312A1-20080103-C00002
    • wherein each R15 is independently H, alkyl, aralkyl, haloalkyl, aryl, heteroaryl, benzoheteroaryl, alkoxy, aminocarbonyl or aminosulfonyl; two of them can form 5-6 membered aromatic rings or 5-7 membered aliphatic rings;
    • m is 0-3; and
    • R1, R2, R4, R5, R6, n, X and Y are as defined above, and the pharmaceutically acceptable salts is thereof
      Preferred structures of Formula I are also compounds of the formula:
      Figure US20080004312A1-20080103-C00003
    • R1, R2, R4, R5, R6, m, n and X are as defined above, and the pharmaceutically acceptable salts thereof
  • The present invention is also directed to compounds of Formula (II):
    Figure US20080004312A1-20080103-C00004
    • wherein A is a negatively ionizable group under physiological conditions;
    • X1—Y1-Z1 is C, C(R)qC or C(R)qN;
    • L4 is L5Ar′L6 or X2Y2Z2;
    • Ar′ and Ar″ are each independently aryl or heteroaryl;
    • L5 and L6 are each independently a bond, N, O, S, or X2Y2Z2 where
    • X2 and Z2 are each independently C, N or O and
    • Y2 is CO, SO, or SO2;
    • R is CR17R18;
    • m, n, p and q are independently an integer from (0 to 6) provided that m and n cannot both be 0; and
    • R16, R17 and R18 are each independently H, alkyl, arakyl, aryl, heteroaryl, hydroxyl, alkoxy, aryloxy, amino, aminocarbonyl, aminosulfonyl provided that when A is CO2H and X1—Y1-2 is C, then X2Y22 is not NCON; and the pharmaceutically acceptable salts thereof.
  • Preferably, A is CO2H, CONHSO2R19, SO2NHCOR20, tetrazole or other carboxylic isosteres where R19 and R20 have the same definition as R16, R17 and R18.
  • Presently preferred cyclic and bicyclic ring systems include pyrrolidine, piperidine, azepane, azocane, piperazine, morpholine, diazepane, diazocane, imidazole, benzopyrolidine, benzopiperidine, benzopiperazine, benzoimidazole, benzoazepine and tetrahedrobenzoazepine derivatives.
  • Presently preferred compounds of the present invention are:
  • {4-Chloro-3-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine.
    • {3-[2-(4-Benzyl-piperidin-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine.
    • {4-Chloro-3-(2-(4-phenylpiperidin-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine.
    • {3-[2-(4-Benzylpiperazin-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine.
    • {3-[2-(Benzylmethylamino)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine.
    • {3-[2-(4-Benzylpiperidin-1-yl)ethoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine.
    • {3-[3-(4-Benzylpiperidin-1-yl)propoxy]phenyl}-(2-methylquinolin-4-yl)amine.
    • {3-[2-(1-Methyl-1-phenylethylamino)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine.
    • {3-(2-Benzylaminoethoxy)phenyl]-(2-methylquinolin-4-yl)amine.
    • 1-(1-{2-[3-(2-Methylquinolin-4-ylamino)phenoxy]ethyl}-4-phenylpiperidin-4-yl)ethanone.
    • [3-(3-Benzylaminopropoxy)phenyl]-(2-methylquinolin-4-yl)amine.
    • {3-[2-(2-Benzylimidazol-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine.
    • (1-{2-[3-(2-Methylquinolin-4-ylamino)phenoxy]ethyl}piperidin-4-yl)diphenylmethanol.
    • 4-Benzyl-1-{2-[3-(2-tert-butylquinolin-4-ylamino)phenoxy]ethyl}piperidin-4-ol.
    • 4-Benzyl-1-{2-[3-(2-methylquinolin-4-ylamino)-S-trifluoromethylphenoxy]ethyl)piperidin-4-ol.
    • {3-[2-(4-Benzylpiperidin-1-yl)ethoxylphenyl}-(2,6-dimethylpyrimidin-4-yl)amine.
  • {3-[2-(5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy]phenyl}-(2-(2methylquinolin-4-yl)amine.
    • {3-[2-(4-Benzylpiperazin-1-yl)ethoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine.
    • (2-Methylquinolin-4-yl)-{3-[2-(4-phenylpiperidin-1-yl)ethoxy]-5-trifluoromethyl phenyl}amine.
    • {3-[3-(1-Methyl-1-phenylethylamino)propoxy]phenyl}-(2-methylquinolin-4-yl)amine.
    • {3-[2-(5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine.
    • N-(2-{1-[2-(3-Fluorophenyl)ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl)-3-(2-methylquinolin-4-ylamino)benzamide.
    • N-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-(2-methylquinolin-4-ylamino)benzamide.
    • N-[2-(1,3-Dihydroisoindol-2-yl)ethyl]-3-(2-methylquinolin-4-ylamino)benzamide.
    • N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2-methyl-5-(2-methylquinolin-4-ylamino)benzamide.
    • N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2-hydroxy-5-(2-methylquinolin-4-ylamino)benzamide.
    • N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-(2-trifluoromethylquinolin-4-ylamino)benzamide.
    • N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2,4,6-trimethyl-3-(2-methylquinolin-4-ylamino)benzamide.
    • 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl)-4-(2-methylquinolin-4-ylamino)-2,3-dihydroisoindol-1-one.
    • 3-(2-Methylquinolin-4-ylamino)-N-[2-(1,3,4,5-tetrahydrobenzo[c]azepin-2-yl)ethyl]benzamide.
    • N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2,5-bis(2-methylquinolin-4-ylamino)benzamide.
    • 3-(2-Methylquinolin-4-ylamino)-N-[2-(octahydro-cis-isoquinolin-2-yl)ethyl]benzamide.
    • N-(2-Azepan-1-ylethyl)-3-(2-methylquinolin-4-ylamino)benzamide.
    • N-(2-Benzylaminoethyl)-3-(2-methylquinolin-4-ylamino)benzamide.
    • 4-({2-[3-(2-Methylquinolin-4-ylamino)-benzoylamino]ethylamino}methyl)benzoic acid.
    • N-2-(2,2-Dimethylpropylamino)ethyl]-3-(2-methylquinolin-4-ylamino)benzamide.
    • N-[2-(4-Benzylpiperazin-1-yl)ethyl]-3-(2-methylquinolin-4-ylamino)benzenesulfonamide.
    • {3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)isoxazol-3-yl]phenyl -(2-methylquinolin-4-yl)amine.
    • {3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)propyl]-4-methylphenyl}-(2-methylquinolin-4yl)amine.
    • N1-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl)-N7-(2-methylquinolin-4-yl)-1,2,3,4-tetrahydronaphthalene-1,7-diamine.
    • {3′-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-yl]-(2-methylquinolin-4-yl)amine.
    • {3-[2-(4-Benzylpiperidin-1-yl)ethanesulfonyl]phenyl}-(2-methylquinolin-4-yl)amine.
    • N-[2-(4-Benzylpiperidin-1-yl)ethyl]-N′-(2-methylquinolin-4-yl)pyrimidine-4,6-diamine.
    • 3-(4-Benzylpiperidin-1-yl)-1-[3-(2-methylquinolin-4-ylamino)phenyl]propan-1-one oxime.
    • {3-[3-(1-Methyl-1-phenylethylamino)propoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine.
    • {3-[2-(4-(4-Fluorophenyl)piperidin-1-yl)ethoxyl-5-trifluoromethylphenyl}(2-methylquinolin-4-yl)amine.
    • (3-{2-[2S,4S-5-(2,4,5-Trifluorobenzyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}-5-trifluoromethylphenyl)(2-methyl quinolin-4-yl)amine.
    • {3-(3-Azepan-1-yl-propoxy)-5-trifluoromethyl-phenyl](2-methyl-quinolin-4-yl)amine.
    • {3-[3-(Adamantan-2-ylamino)-propoxy]-5-trifluoromethyl-phenyl}(2-methyl-quinolin-4-yl)amine.
    • {3-[3-(3,3-Dimethylpiperidin-1-yl)propoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine.
    • 4-phenyl-1-{2-[3-(2-Methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidine-4-carboxylic acid.
    • 1-{2-[3-Fluoro-5-(2-methylquinolin-4-ylamino)phenoxy)ethyl}-4-phenyl-piperidine-4-carboxylic acid.
  • The term “carbonyl” or “CO” as used herein, alone or in combination, includes derivatives such as oximes, ketals and cyclic ketals.
  • The term “alkyl” as used herein, alone or in combination, refers to C1-C6 straight or branched, substituted or unsubstituted saturated chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom, unless the term alkyl is preceded by a Cx-Cy designation. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl among others.
  • The term “aryl”, “arene” or “aromatic” as used herein alone or in combination, refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group which is an aromatic ring containing at least one endocyclic N, O or S atom such as furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-napthridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyazinyl, pyrazolo[1,5-c]triazinyl and the like. “Aralkyl” and “alkylaryl” employ the term “alkyl” as defined above. Rings may be multiply substituted.
  • The term “aralkyl” as used herein, alone or in combination, refers to an aryl substituted alkyl radical, wherein the terms “alkyl” and aryl” are as defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl and the like.
  • The term “cycloalkyl” as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl among others. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, diakylamino, hydroxyl, halo, mercapto, nitro, caroxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • “Cycloalkyl” includes cis or trans forms. Furthermore, the substituents may either be in endo or exo positions in the bridged bycyclic systems.
  • The term “heteroaryl” or “heteroarene” as used herein, alone or in combination, refers to a 3- to 10-membered ring containing at least one endocyclic N, O, or S atom. The heterocycle may be optionally aryl-fused. The heterocycle may also optionally be substituted with at least one substituent which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.
  • The term “optical isomers” as used herein refers to compounds which differ only in the stereochemistry of at least one atom, including enantiomers, diastereomers and racemates.
  • Use of the above terms is meant to encompass substituted and unsubstituted moieties. Substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylbeterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of —C—, —C(O)—, —N—H—, —S—, —S(O)—, —O—, —C(O)O— or —S(O)O—. Rings may be substituted multiple times.
  • The terms “electron-withdrawing” or “electron-donating” refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if hydrogen occupied the same position in the molecule. These terms are well-understood by one skilled in the art and are discussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18, incorporated herein by reference. Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, sulfonyl and aryl lower alkanoyl among others. Electron donating groups include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide among others. One skilled in the art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing properties under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above-identified groups.
  • The most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfanyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio, carboxy lower alkyl, arylalkoxy, alkanoylamino, alkanoyl (lower alkyl) amino, lower alkylsufonylamino, arylsulfonylamino, alkylsulfonyl(lower alkyl)amino, arysulfonyl(lower alkyl)amino, lower alkylcarboxamide, di(lower alkyl)carboxamide, sulfonamide, lower alkylsulfonamide, di(lower alkyl sulfonamide, lower alkylsulfonyl, arylsulfonyl and alkyldithio.
  • As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, a well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
  • As used herein, the term “mammals” includes humans and other animals.
  • The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase “pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, dighiconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase “therapeutically effective amount” of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • The present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term “parenterally,” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • In another aspect, the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent. The present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, among others.
  • The compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or via a biodegradable polymer. The compounds may also be complexed to ligands, such as antibodies, for targeted delivery.
  • Compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
  • These compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly-anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) hurnectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents. sweetening, flavoring and perfuming agents.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
  • Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • The term “pharmaceutically acceptable prodrugs” as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Prodrugs of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.
  • Compounds of the present invention that are formed by in vivo conversion of a different compound that was administered to a mammal are intended to be included within the scope of the present invention.
  • Compounds of the present invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or iastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
  • Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
  • Each dosage unit for oral administration contains suitably from 0.0001 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
  • The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to 500 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • These compounds may be used for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint disease, arthritis and other inflammatory diseases, fibrosis (e.g. pulmonary fibrosis), sepsis, atheroscloerosis, dyslipidemia, addiction, schizophrenia, cognitice disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
  • The urotension antagonists of the present invention may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-II receptor antagonists, phosphodieterase inhibitors, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective β-adrenoceptor and δ1-adrenoceptor antagonists.
  • The biological activity of the compounds of Formula (I) are demonstrated by the following tests:
  • 1) Inhibition of Human [125]-Urotensin-II Binding to Urotensin-II Receptor
  • Binding of human [125]-urotensin-II to human urotensin-II receptor (UTR) was done using cell membranes from either TE-671 rhabdomyosarcoma cells or CHO cells stably expressing recombinant UTR, in a homogeneous Scintillation Proximity Assay (SPA).
  • The UTR cells membranes were pre-coupled overnight at 4° C. to WGA-PVT beads (Amersham RPNQ0001) at a ratio of 5-25 μg membrane to 0.5 mg beads/assay. Assay was performed in 96-well microtiter Optiplates (Packard 6005290) by mixing coupled beads and 0.1 nM [125U-II (2200 Ci/mmol, NEN NEX379), in a total volume of 100 μl 20 mM HEPES, 5 MM MgCl2, pH 7.4. Test compounds were diluted in DMSO and were put in the assay at a final concentration of 1% DMSO. IncLibation was done for 3 hours at 37° C. followed by reading in a TopCount scintillation microplate reader. Nonspecific binding was determined by adding 100 nM unlabeled human U-II (Phoenix Pharmaceuticals, 071-05) to the assay mixture. Analysis of the assay was performed using nonlinear least square fitting.
  • I) Inhibition of Human Urotensin-II-Induced Ca2+ Mobilization in UTR Cells:
  • The function of urotensin-II was determined by measuring ligand-induced mobilization of intracellular Ca2+ in a FlexStation scanning fluorometer (Molecular Devices). UTR cells were plated overnight at 50,000 cells/well in 96-well black/clear plates (Costar brand, Fisher 07-200-588). Cells were labeled with fluo-4AM dye (Molecular Probes, F-14201) in Hank's balanced salt solution (HBSS), 20 mM HEPES, 25 mM probenecid, pH 7.4, and then were washed with buffer. During the assay, cells were continuously monitored in the FlexStation and exposed to test compounds at a final concentration of 0.1% DMSO, followed by the addition of 1 nM human U-II. Fluorescence was read every 2 seconds for 2 minutes. The excitation and emission wavelengths used were 485 nm and 525 nm. Inhibition of the urotensin-II-induced signal was calculated using a nonlinear least square fitting program. Compounds of the present invention are active in these assays and have an IC50 of <10 μM (Example 7 IC50=6.5 μM).
  • The following Examples are illustrative but not limiting of the present invention:
    • EXAMPLE 1 N-(2-Dimethylamino-ethyl)-3-(2-methyl-quinolin-4-ylamino)-benzenesulfonamide
  • Figure US20080004312A1-20080103-C00005
    • Step 1. N-(2-Dimethylamino-ethyl)-3-nitro-benzenesulfonamide (3)
  • To a solution of 3-nitrobenzenesulfonyl chloride (1, 1.0 g, 4.51 mmol) in anhydrous CH2Cl2 (9.0 mL) was added N,N-dimethyl-ethylenediamine (2, 0.5 mL, 4.55 mmol) dropwise. The resulting solution was stirred at room temperature overnight before it was diluted with EtOAc (80 mL). The organic mixture was washed with saturated NaHCO3 (90 mL), brine (90 mL), and dried over MgSO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 3 as a foam (0.8 g) which was used in the next step without further purification.
    • Step 2.3-Amino-N-(2-dimethylamino-ethyl)-benzenesulfonamide (4)
  • A solution of 3 (0.8 g) in ethanol (10 mL) was subjected to catalytic hydrogenation (10% Pd/C, Degussa, 0.8 g, 3 drops of AcOH, 1 atm.) overnight. To work up, the solids were filtered the filtrate was dried under vacuum to afford 4 as a solid (0.71 g) which was used in the next step without further purification.
    • Step 3. N-(2-Dimethylamino-ethyl)-3-(2-methyl-quinolin-4-ylamino)-benzenesulfonamide
  • To a solution of 4 (0.3 g, 1.23 mmol) and 4-chloroquinaldine (5, 0.26 mL, 1.29 mmol) in ethanol (10 mL) were added 2 drops of cone. HCl. The resulting mixture was heated under reflux overnight before ethanol was removed under reduced pressure. The residue was basified with saturated NaHCO3 (aq. 20 mL) and the basic solution was extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, the solids were filtered and the filtrate was concentrated on a rotavap. The residue was purified on Florisil® to give the title compound as an orange solid (15 mg).
    • EXAMPLE 2 N-(2-Dimethylamino-ethyl)-3-(2-methyl-quinolin-4-yl-amino)-benzamide
  • The title compound was synthesized in the same manner as for Example 1 except that 3-nitrobenzoyl chloride was used instead of 1 in Step 1. It was obtained as a pale yellow solid.
    • EXAMPLE 3 (3-(2-Dimethylamino-ethoxy)-4-methyl-phenyl)-(2-methyl-quinolin-4-yl)-amine
  • Figure US20080004312A1-20080103-C00006
    • Step 1. tert-Butyl (3-hydroxy-4-methyl-phenyl)-carbamate (7)
  • A solution of 5-amino-2-methylphenol (6, 1.0 g, 8.12 mmol) and di-tert-butyl dicarbonate (1.95 g, 8.93 mmol) in THF (25 mL) was heated under reflux overnight. After cooling to room temperature, the solution was diluted with EtOAc (75 mL) and the resulting mixture was washed with water (70 mL), 1N HCl (2×70 mL) and brine (70 mL). The organic layer was then dried over MgSO4, the solids were filtered, and the filtrate was concentrated under reduced pressure. The desired product 7 was obtained as an oil (2.16 g) and was carried on to the next step without further purification.
    • Step 2. tert-Butyl (3-(2-dimethylamino-ethoxy)-4-methyl-phenyl)-carbamate (8)
  • A mixture of 7 (2.16 g, 9.68 mmol), 2-(dimethylamino)-ethyl chloride hydrochloride (1.53 g, 10.6 mmol) and K2CO3 (5.35 g, 3.87 mmol) in DME (28 mL)/H2O (7 mL) was heated under reflux overnight. After cooling to room temperature, the solution was diluted with EtOAc (100 mL) and the resulting solution was washed with H2O (2×100 mL) and brine (100 mL). The organic layer was dried over MgSO4, the solids were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel to give 8 as an oil (1.15 g) which upon standing became a solid.
    • Step 3. 3-(2-Dimethylamino-ethoxy)-4-methylaniline (9)
  • A solution of 8 (1.15 g) in 6N HCl (10 mL) was heated at 60° C. for 4 hours. After cooling to room temperature, the solution was neutralized with 6N NaOH solution. The aqueous mixture was extracted with EtOAc (2×30 mL), the combined organic layers were washed with brine (1×50 mL) and dried over MgSO4. The solids were filtered, and the filtrate was concentrated under reduced pressure to give the desired product as an oil (0.68 g).
    • Step 4. (3-(2-Dimethylamino-ethoxy)-4-methyl-phenyl)-(2-methyl-quinolin-4-yl)-amine
  • To a solution of 9 (0.25 g, 1.29 mmol) and 5 (0.29 ml, 1.44 mmol) in EtOH (8 mL) were added 2 drops of conc. HCl. The mixture was heated under reflux overnight. After cooling to room temperature, EtOH was removed under reduced pressure. The residue was partitioned between sat. NaHCO3 (aq.) and EtOAc (100 mL each) and the aquous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, the solids were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on Florisil® (50% EtOAc/Hexanes to 15% MeOH/EtOAc) to yield the title compound as a light yellow solid (0.25 g).
  • The compounds of Examples 4-11 were synthesized in the same manner as Example 3.
    • EXAMPLE 12 (3-Dimethylaminomethyl-phenyl)-(2-methyl-quinolin-4-yl)-amine
  • Figure US20080004312A1-20080103-C00007
    • Step 1. Dimethyl-(3-nitrobenzyl)-amine (11)
  • A solution of 3-nitrobenzyl bromide (10, 1.67 g, 7.73 mmol) and N,N-dimethylamine (4.25 mL, 2M in THF) in anhydrous THF (30 mL) was heated at 40° C. overnight. The reaction mixture was diluted with 1N HCl (30 mL, aq.), the aqueous layer separated, and extracted with EtOAc (30 mL). The pH of the aqueous layer was then adjusted to 9 using saturated Na2CO3 (aq.) and the aqueous layer was extracted with EtOAc (50 mL). The organic layer was washed with water (40 mL), brine (40 mL), and dried over Na2SO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 11 (1.2 g).
    • Step 2. 3-Dimethylaminomethylaniline (12)
  • To a solution of 11 (1.2 g, 6.67 mmol) in methanol (100 mL) were sequentially added conc. HCl (10 mL) and SnCl2 (5 g, 26.67 mmol). The reaction mixture was stirred at room temperature overnight before it was partitioned between water and EtOAc (200 mL each). The organic layer was separated and washed with water (150 mL), brine (150 mL) and dried over Na2SO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 12 (500 mg).
    • Step 3. (3-Dimethylaminomethyl-phenyl)-(2-methyl-quinolin-4-yl)-amine
  • The title compound was synthesized in the same manner as shown in Step 3 of Example 1 and it was obtained as a yellowish solid (230 mg)
    • EXAMPLE 13 (4-Chloro-3-(2-(1-(2-(3,4-dimethoxy-phenyl)-ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy)-phenyl)-(2-methyl-quinolin-4-yl)-amine
  • Figure US20080004312A1-20080103-C00008
    Figure US20080004312A1-20080103-C00009
    • Step 1. 2-(2-Bromo-ethoxy)-1-chloro-4-nitrobenzene (15)
  • To a solution of 2-chloro-5-nitro-phenol (13, 0.87 g, 5 mmol) in acetone (10 mL) were sequentially added 1,2-dibromoethane (14, 0.85 ml, 10 mmol) and K2CO3 (1.45 g, 10.5 mmol). The mixture was heated under reflux over night. To work up, the solids were filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel) eluting with hexanes first, then EtOAc to yield 15 (600 mg).
    • Step 2. 2-(2-(2-Chloro-5-nitro-phenoxy)-ethyl)-1-(2-(3,4-dimethoxy-phenyl)-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (17)
  • To a solution of 15 (315 mg, 1.1 3 mmol) in anhydrous THF (3 mL) were sequentially added 1-(2-(3,4-dimethoxy-phenyl)-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (16, Morimoto et al, Heterocycles 1996 43:2557; Brossi et al, Helv Chim Acta 1960 43:1459; Meyers et al, Tetrahedron Lett 1981 22:5115; Meyers et al, J Am Chem Soc 1983 105:117) (404 mg, 1.13 mmol) and pyridine (0.3 mL). The reaction mixture was heated under reflux for 2 days before it was partitioned between EtOAc and water (20 mL each). The organic layer was separated, washed with water (15 mL), brine (15 mL), and dried over Na2SO4. The solids were filtered and the filtrate was purified by chromatography (silica gel) eluting with hexanes:EtOAc (1:1) to give 17 (205 mg)
    • Step 3. 4-Chloro-3-(1-(2-(3,4-dimethoxy-phenyl)-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-ethoxy)aniline (18)
  • To a solution of 17 (205 mg, 0.369 mmol) in methanol (10 mL) were sequentially added conc. HCl (0.5 mL) and SnCl2 (280 mg, 1.48 mmol). The mixture was stirred at room temperature for 8 hours before it was diluted with water (160 mL) and the pH was adjusted to 10 using 2N NaOH. The mixture was extracted with EtOAc (150 mL) and the organic layer was washed with water and brine (100 mL each) and then dried over Na2SO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 18 (170 mg).
    • Step 4. (4-Chloro-3-(2-(1-(2-(3,4-dimethoxy-phenyl)ethyl)-6,7-dimethoxy-3,4-dihydro
  • The title compound was synthesized in the same manner as shown in Example 1/Step 3 using 5 and 18. It was obtained as a yellow solid (79 mg).
    • EXAMPLE 14. 1-(4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl)-3-(2-methyl-quinolin-4-yl)-urea
  • To a solution containing 4-aminoquinaldine (74 mg, 0.46 mmol) in anhydrous THF (5.0 Ml) was added triethylamine (0.2 Ml, 1.4 mmol). The solution was cooled to 0° C. followed by the addition of triphosgene (45.0 mg, 0.18 mmol). The reaction mixture was stirred at 0° C. for 10 minutes before the addition of a solution of 4-chloro-3-(2-dimethylamino-ethoxy)aniline (100.0 mg, 0.46 mmol, for its synthesis see Steps 1-3 for Example 1) in THF (2 Ml). The ice bath was removed and the mixture was heated at 6 ° C. for 2 hours before it was poured into a mixture of CH2Cl2/MeOH (20 Ml, 7:1 ratio). The resulting mixture was washed with 10% sodium bicarbonate (aq. 15.0 Ml). The organic layer was dried over MgSO4 and concentrated. The oily residue was chromatographed over silica gel (eluent: 20% MeOH in EtOAc) to give the desired product as an off-white solid (82.0 mg, 45% yield).
  • The compounds of Example 15 and 16 were synthesized in the same manner as for Example 2.
    TABLE 1
    Physical
    Example Structure Name Description M + H
     1
    Figure US20080004312A1-20080103-C00010
         		N-(2-dimethylamino- ethyl)-3-(2-methyl- quinolin-4-ylamino)- benzenesulfonamide orange solid 385.27
     2
    Figure US20080004312A1-20080103-C00011
         		N-(2-dimethylamino- ethyl)-3-(2-methyl- quinolin-4-ylamino)-benzamide pale yellow solid 349.29
     3
    Figure US20080004312A1-20080103-C00012
         		(3-(2-dimethylamino- ethoxy)-4-methyl-phenyl)- (2-methyl-quinolin-4-yl)- amine light yellow solid 336.25
     4
    Figure US20080004312A1-20080103-C00013
         		(4-chloro-3-(2-dimethyl- amino-ethoxy)-phenyl)- (2-methyl-quinolin-4-yl)- amine yellow solid 355.19
     5
    Figure US20080004312A1-20080103-C00014
         		(4-chloro-4-(2-dimethyl- amino-ethoxy)-phenyl)- (2-methyl-quinolin-4-yl)- amine yellow solid 356.24
     6
    Figure US20080004312A1-20080103-C00015
         		(4-chloro-3-(2-dimethyl- amino-ethoxy)-phenyl)- (8-trifluoromethyl-quinolin-4-yl)-amine white solid 410.18
     7
    Figure US20080004312A1-20080103-C00016
         		(4-chloro-3-(2-dimethyl- amino-ethoxy)-phenyl)- (7-trifluoromethyl-quinolin-4-yl)-amine yellow solid 410.12
     8
    Figure US20080004312A1-20080103-C00017
         		(4-chloro-3-(2-dimethyl- amino-ethoxy)-phenyl)- (7-chloro-quinolin-4-yl)- amine yellow solid 376.22
     9
    Figure US20080004312A1-20080103-C00018
         		(4-chloro-3-(2-dimethyl- amino-ethoxy)-phenyl)- (2-methyl-quinolin-4-yl)- amine yellow oil 356.18
    10
    Figure US20080004312A1-20080103-C00019
         		(4-chloro-3-(2-dimethyl- amino-ethoxy)-phenyl)- (2-phenyl-quinazolin-4-yl)- amine yellow solid 419.24
    11
    Figure US20080004312A1-20080103-C00020
         		(4-chloro-3-(2-dimethyl- amino-ethoxy)-phenyl)- (3,5-dichloro-pyridin-4-yl)- amine oil 360.11
    12
    Figure US20080004312A1-20080103-C00021
         		(3-dimethyl- aminomethyl)-phenyl)- (2-methyl-quinolin-4-yl)- amine yellowish solid 291.27
    13
    Figure US20080004312A1-20080103-C00022
         		(4-chloro-3-(2-(1-(2-(3,4- dimethoxy-phenyl)-ethyl)- 6,7-dimethoxy-3,4- dihydro-1H-isoquinolin-2- yl)-ethoxy)-phenyl)- (2-methyl-quinolin-4-yl)- amine yellow solid 668.35
    14
    Figure US20080004312A1-20080103-C00023
         		1-(4-chloro-3-(2-dimethyl- amino-ethoxy)-phenyl)-3- (2-methyl-quinolin-4-yl)- urea off-white solid 399.23
    15
    Figure US20080004312A1-20080103-C00024
         		N-(2-(1-(2-(3,4-dimethoxy- phenyl)-ethyl)-6,7- dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl)-ethyl) 3-(2-methyl-quinolin-4- yl)amino-benzamide light yellow solid 661.39
    16
    Figure US20080004312A1-20080103-C00025
         		N-(2-(4-benzyl-piperazin- 1-yl)-ethyl)-3-(2-methyl- quinolin-4-yl)-amino- benzamide light yellow foam 480.37
  • The structures, chemical names, physical descriptions and M+H data for the compounds of Examples 17-76 are set forth in Table 2.
  • The compound of Example 17 was synthesized by methylating the compound of Example 3 using a standard method (NaH/DMF/MeI).
  • The compounds of Examples 18 and 19 were synthesized in the same manner as the compound of Example 3.
  • The compounds of Examples 20 to 32 were synthesized in the same manner as the compound of Example 13.
  • The compound of Example 33 was synthesized in the same manner as the compound of Example 13 except that 3-nitro-5-trifluoromethylphenol was used instead of 13. 3-Nitro-5-trifluoromethylphenol was synthesized by demethylating 3-nitro-5-trifluoromethylanisole using a standard method (BBr3/CH2Cl2).
  • The compound of Example 34 was synthesized by hydrolysis of the compound of Example 32 using a standard method (NaOH/MeOH/THF).
  • The compounds of Examples 35 to 44 were synthesized in the same manner as the compound of Example 13.
  • The preparation of the compound of Example 45 is shown.
  • The compounds of Examples 46 to 54 were synthesized in the same manner as the compound of Example 13.
  • The preparation of the compound of Example 55 is shown.
  • The compounds of Examples 56 and 57 were synthesized in the same manner as the compound of Example 13.
  • The compound of Example 58 was synthesized in the same manner as the compound of Example 13 except that 4-chloro-2-tert-butylquinoline (C Wolf, R Lerebours: J Org Chem 2003, 68:7077-7084) was used instead of 4-chloro-2-methylquinoline.
  • The compound of Example 59 was synthesized in the same manner as the compound of Example 13.
  • The compound of Example 60 was synthesized by acylating the compound of Example 21 using a standard method (NaH/DMF/AcCl).
  • The compound of Example 61 was synthesized in the same manner as the compound of Example 13.
  • The compound of Example 62 was synthesized in the same manner as the compound of Example 33.
  • The compounds of Examples 63 to 65 were synthesized in the same manner as the compound of Example 13.
  • The compound of Example 66 was synthesized in the same manner as the compound of Example 13 and it was obtained as the dehydration product of the intended (1-{2-[3-(2-methylquinolin-4-ylamino)phenoxy]ethyl}piperidin-4-yl)diphenylmethanol.
  • The compound of Example 67 was synthesized in the same manner as the compound of Example 33.
  • The compound of Example 68 was synthesized by the hydrolysis of the compound of Example 65 (NaOH/MeOH/THF/65° C./2 days).
  • The compound of Example 69 was synthesized by the hydrolysis of the compound of Example 36 (NaOH/MeOH/THF).
  • The compounds of Examples 70 and 71 were synthesized in the same manner as the compound of Example 33.
  • The compounds of Examples 72 and 73 were synthesized in the same manner as the compound of Example 13.
  • The compound of Example 74 was synthesized in the same manner as the compound of Example 33.
  • The compounds of Examples 75 and 76 were synthesized in the same manner as the compound of Example 13.
  • EXAMPLE 45
    • {3-[2-(4-Benzenesulfonylpiperazin-1-yl)ethoxy]phenyl)-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00026
    • Step 1. 3-(2-Methylquinolin-4-ylamino)phenol (20)
  • 20 is prepared by the procedure of Example 1 Step 3. 34
    • Step 2. [3-(2-Chloroethoxy)phenyl]-(2-methylquinolin-4-yl)amine (21)
  • To a heterogeneous mixture of 20 (2.16 g, 6.90 mmol) in acetone (22 mL) were sequentially added 1-bromo-2-chloroethane (7.2 mL, 86.50 mmol) and potassium carbonate (3.00 g, 21.71 mmol). The reaction was stirred and heated at 70° C. for 17 hours before it was allowed to cool to room temperature and was filtered. The solids were rinsed with a 3:1 mixture of dichloromethane/methanol (25 mL×3), and the filtrate was isolated and evaporated to give the crude product. Column chromatography on silica (dichloromethane to 20/1 to 15/1 to 5/1dichloromethane/methanol) gave 21 as a pale yellow solid (0.96 g, 35.5%).
    • Step 3.1-Benzenesulfonylpiperazine (22)
  • To a solution of benzenesulfonyl chloride (1 g, 5.66 mmol) in THF (20 mL) were sequentially is added triethylamine (1.97 mL, 14.15 mmol) and piperazine (2.92 g, 33.9 mmol). The reaction was stirred at room temperature for 1 hour before it was extracted with ethyl acetate and washed with water and brine. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatograpbed on silica gel (1:1 hexanes/ethyl acetate to 10/1 dichloromethane/methanol) to give 22 as a yellow oil.
    • Step 4. {3 [2-(4-Benzenesulfonylpiperazin-1-yl)ethoxy]phenyl}-(2-methylquinolin-yl)amine
  • To a solution of 21 (250 mg, 0.67 mmol) in DMF (5 mL) were sequentially added sodium carbonate (149 mg, 1.41 mmol) and 22 (183 mg, 0.808 mmol). The reaction was placed under a N2 atmosphere and heated at 90° C. for 16 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and washed with water and brine. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified via reversed phase HPLC to yield the title compound as a pale yellow solid (20 mg, 6%).
    • EXAMPLE 55 {3-[2-(2-Benzylimidazol-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00027
    • Step 1. 2-Benzyl-1H-imidazole (24)
  • A mixture of 23 (0.78 g, 4.8 mmol) and 10% PdiC (0.78 g) in toluene (25 mL) was heated at 120° C. for 48 hours. It was allowed to cool to room temperature and the solids were filtered off. The filtrate was concentrated in vaccuo and the residue was purified on silica gel column to give 24 (0.16 g, 21%).
    • Step 2. 2-Benzyl-1-[2-(3-nitrophenoxy)ethyl]-1H-imidazole (26)
  • 26 is prepared from 24 and 25 by the procedure of Example 45 Step 4.
    • Step 3. 3-[2-(2-Benzylimidazol-1-yl)ethoxy]phenylamine (27)
  • 27 is prepared from 26 by the procedure of Example 110 Step 4.
    • Step 4. (3-[2-(2-Benzylimidazol-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine
  • The title compound is prepared by the procedure of Example 1 Step 3.
    • EXAMPLE 67 Methyl 4-benzyl-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidine-4-carboxylate
  • Figure US20080004312A1-20080103-C00028
    Figure US20080004312A1-20080103-C00029
    • Step 1. 1-tert-Butyl 4-methyl piperidine-1,4-dicarboxylate (29)
  • To a solution of methyl isonipecotate (28) (2.84 g, 19.84 mmol) and DMAP (cat.) in anhydrous CH2Cl2 (25 mL) at 0° C. was added di-tert-butoxycarbonate (5.20 g, 23.82 mmol).
  • The mixture was heated under reflux for 5 hours before it was allowed to cool to room temperature and diluted with dichloromethane (100 mL). After washing with 1 N HCl (2×100 mL) and water (100 mL), the organic layer was dried over Na2SO4, and concentrated to provide 29 (4.64 g, 97%).
    • Step 2. 1-tert-Butyl 4-methyl 4-benzylpiperidine-1,4-dicarboxylate (30)
  • To a solution of 29 (4.64 g, 19.08 mmol) in anhydrous THF (20 mL) at −78° C. was added NaHMDS (1.0 M in THF, 22.90 mL, 22.90 mmol) slowly. It was stirred at −78° C. for 30 minutes before the addition of benzyl bromide (3.91 g, 22.87 mmol). The cold bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with EtOAc (150 mL) and washed with water (2×100 mL) and brine (100 mL). The organic layer was dried (Na2SO4), concentrated in vacuo, and the residue was purified by flash column chromatography to afford 30 (4.5 g, 71%).
    • Step 3. Methyl 4-benzylpiperidine-4-carboxylate
  • A solution of 30 (4.5 g, 13.5 mmol) in THF (25 mL) and CH2Cl2 (25 mL) was stirred at room temperature for 40 minutes. The mixture was concentrated and the residue diluted with EtOAc (100 mL). Upon sequential washings with 1 N NaOH (2×100 mL) and water (100 mL), the organic solution was dried (Na2SO4) and concentrated to dryness to afford the desired product as a yellow solid (2.9 g, 92%).
    • Step 4. Methyl 4-benzyl-1-[2-(3-nitro-5-trifluoromethylphenoxy)ethyl]piperidine-4-carboxylate (32)
  • 32 is prepared from 30 and 31 by the procedures of Example 45 Step 4.
    • Step 5. Methyl 1-[2-(3-amino-5-trifluoromethylphenoxy)ethyl]-4-benzylpiperidine-4-carboxylate (33)
  • 33 is prepared by the procedure of Example 110 Step 4.
    • Step 6. Methyl 4-benzyl-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl) piperidine-4-carboxylate
  • The title compound is prepared from 33 by the procedure of Example 1 Step 3.
    TABLE 2
    Ex-
    am- Physical
    ple Structure Chemical name descriptiona [M + H]+
    17
    Figure US20080004312A1-20080103-C00030
         		[4-Chloro-3-(2- dimethylamino- ethoxy)phenyl]- methyl-(2- methylquinolin-4-yl)amine yellow solidb 370.34
    18
    Figure US20080004312A1-20080103-C00031
         		[3-(2-Dimethylamino- ethoxy)-4- methylphenyl]quinolin- 4-ylamine pale yellow solid 322.24
    19
    Figure US20080004312A1-20080103-C00032
         		(6-Chloro2- methoxyacridin- 9-yl)- [3-(2-dimethylamino- ethoxy)- 4-methylphenyl]amine orange- yellow solidb 436.27
    20
    Figure US20080004312A1-20080103-C00033
         		{4-Chloro-3-[2-(3,4- dihydro-1H- isoquinolin-2- yl)ethoxy]phenyl)- (2-mthylquinolin-4- yl)amine yellowish solid 444.20
    21
    Figure US20080004312A1-20080103-C00034
         		{3-[2-(4-Benzyl- piperdin-1-yl) ethoxy]phenyl}-(2- methyl quinolin-4-yl)amine yellow solid 452.34
    22
    Figure US20080004312A1-20080103-C00035
         		{3-[2-(4-Benzyl- piperdine-1-yl) ethoxy]-4- chlorophenyl}- (2-methylquinolin-4- yl)amine off-white solid 486.30
    23
    Figure US20080004312A1-20080103-C00036
         		{4-Chloro-3-[2-(4- phenyl piperdin-1- yl)ethoxy)phenyl}- (2-methylquinolin-4- yl)amine white solidb 472.22
    24
    Figure US20080004312A1-20080103-C00037
         		(2-Methylquinolin-4- yl)- {3-[2-(4-phenyl- piperidin-1-yl) ethoxy]phenyl}amine brown solidb 438.26
    25
    Figure US20080004312A1-20080103-C00038
         		(2-Methylquinolin-4- yl)- (3-{2-[4-(3- trifluoromethyl- pheny)piperazin-1- yl)ethoxy}phenyl)amine brown solid 551.31c
    26
    Figure US20080004312A1-20080103-C00039
         		{3-[2-(4- Benzylpiperazin-1-yl) ethoxy]phenyl}- (2-methylquinolin-4- yl)amine yellow soledb 453.29
    27
    Figure US20080004312A1-20080103-C00040
         		(2-Methylquinolin-4- yl)- {3-[2-(4- phenylimidazol-1-yl) ethoxy]phenyl}amine yellow solid 420.32
    28
    Figure US20080004312A1-20080103-C00041
         		4-Benzyl-1-{2-[3-(2- methyl quinolin-4- ylamino)phenoxy]ethyl}piperidin-4-ol yellow solid 468.27
    29
    Figure US20080004312A1-20080103-C00042
         		1-{2-[3-(2- Methylquinolin-4-yl amino)phenoxy]ethyl}- 4- phenylpiperidin-4-ol yellow solid 454.23
    30
    Figure US20080004312A1-20080103-C00043
         		{3-[2- (Benzylmethylamino) ethoxy]phenyl}-(2- methyl quinolin-4-yl)amine yellow solid 398.24
    31
    Figure US20080004312A1-20080103-C00044
         		(2-Methylquinolin-4- yl)- [3-(2-piperidine-1-yl ethoxy)phenyl]amine yellow solid 362.23
    32
    Figure US20080004312A1-20080103-C00045
         		Methyl 2-{2-[3-(2- methyl quinolin-4- ylamino)phenoxy]ethyl}-1,2,3,4- tetrahydro isoquinoline-3- carboxylate white solidb 468.23
    33
    Figure US20080004312A1-20080103-C00046
         		{3-[2-(4- Benzylpiperidin-1-yl) ethoxy]-5- trifluoromethyl phenyl}-(2- methylquinolin-4-yl) amine yellow solid 520.25
    34
    Figure US20080004312A1-20080103-C00047
         		2-{2-[3-(2- Methylquinolin-4-yl amino)phenoxy]ethyl}- 1,2,3,4- tetrahydroisoquinoline- 3- carbvoxylic acid yellow solide 454.22
    35
    Figure US20080004312A1-20080103-C00048
         		{3-[2-(4- Benzylpiperidin-1-yl) ethoxy]-4- methylphenyl}-(2- methylquinolin-4- yl)amine yellow solid 466.31
    36
    Figure US20080004312A1-20080103-C00049
         		Methyl 1-{2-[3-(2- methyl quinolin-4- ylamino)phenoxy]ethyl}piperidne-4- carboxylate yellow solid 420.26
    37
    Figure US20080004312A1-20080103-C00050
         		(2-Methylquinolin-4- yl)- [3-(2- phenethylaminoethoxy) phenyl]amine yellow solidb 398.26
    38
    Figure US20080004312A1-20080103-C00051
         		(2-Methylquinolin-4- yl)- {3-[2-(4- phenethylpiperdin- 1-yl)- ethoxy]phenyl}amine yellow solidb 467.29
    39
    Figure US20080004312A1-20080103-C00052
         		{30[3-(4- Benzylpiperidin-1-yl) propoxy]phenyl}-(2- methyl quinolin-4-yl)amine yellow solid 466.37
    40
    Figure US20080004312A1-20080103-C00053
         		(2-Methylquinolin-4- yl)- [3-(3-phenethylamino propoxy)phenyl]amine yellow solid 412.33
    41
    Figure US20080004312A1-20080103-C00054
         		{3-[2-(1-Methyl-1- phenyl ethylamino)ethoxy]phenyl}- (2-methylquinolin-4- yl)amine yellow solid 412.20
    42
    Figure US20080004312A1-20080103-C00055
         		[3-(2- Benzylaminoethoxy) pheny]-(2-methyl quinolin-4-yl)amine pale yellow solid 384.25
    43
    Figure US20080004312A1-20080103-C00056
         		1-(1-{2-[3-(2- Methylquinolin- 4- ylamino)phenoxy]ethyl}piperidin-4-yl)-1,3- dihydro benzoimidazol-2-one pale yellow solid 498.28
    44
    Figure US20080004312A1-20080103-C00057
         		(2-Methylquinolin-4- yl)- {3-[2-(3- phenylpropylamino)-ethoxy]phenyl}amine yellow solidb 412.29
    45
    Figure US20080004312A1-20080103-C00058
         		{3-[2-(4- Benzenesulfonyl piperazin-1- yl)ethoxy]phenyl}- (2-methylquinolin-4- yl)amine yellow solidb 503.34
    46
    Figure US20080004312A1-20080103-C00059
         		1-{2-[3-(2- methylquinolin-4-yl amino)phenoxy]ethyl}- 4- phenylpiperidine-4- carbonitrile yellow solid 463.32
    47
    Figure US20080004312A1-20080103-C00060
         		1-(1-{2-[3-(2- Methylquinolin- 4- ylamino)phenoxy]ethyl}- 4- phenylpiperidin-4- yl)ethanone yellow solid 480.32
    48
    Figure US20080004312A1-20080103-C00061
         		{3-[2-(1,4-Dioxa-8-aza spiro[4.5]dec-8- yl)ethoxy]phenyl}-(2-methyl quinolin-4-yl)amine pale yellow solidb 420.26
    49
    Figure US20080004312A1-20080103-C00062
         		1-Benzoyl-4-{2-[3-(2- methyl quinolin-4- ylamino)phenoxy]ethyl}piperazine yellow solidb 467.33
    50
    Figure US20080004312A1-20080103-C00063
         		4-Benzyl-1-{2-[3-(2- methyl pyridin-4- ylamino)phenoxy]ethyl}piperidin-4-ol white solid 418.28
    51
    Figure US20080004312A1-20080103-C00064
         		[3-(3- Benzylaminopropoxy) phenyl]-(2-methyl quinolin-4-yl)amine yellow solid 398.26
    52
    Figure US20080004312A1-20080103-C00065
         		(2-Methylquinolin-4- yl)-[3-(2- phenylaminoethoxy) phenyl]amine yellow solid 370.26
    53
    Figure US20080004312A1-20080103-C00066
         		N-Methyl-N-(1-{2-[3- (2-methyl quinolin-4- quamino)phenoxy]ethyl}pyrrolidin-3-yl) benezenesulfonamide pale yellow solid 517.28
    54
    Figure US20080004312A1-20080103-C00067
         		{3-[2-(4- Methylpiperidin-1-yl) ethoxy]phenyl}-(2- methyl quinolin-4-yl)amine pale yellow solid 376.25
    55
    Figure US20080004312A1-20080103-C00068
         		{3-[2-(2- Benzylimidazol-1-yl) ethoxy]phenyl}-(2- methyl quinolin-4-yl)amine off-white foamb 435.29
    56
    Figure US20080004312A1-20080103-C00069
         		(1-{2-[3-(2- Methylquinolin-4-yl amino)phenoxy]ethyl}piperidin-4- yl)phenylmethanone off-white solidb 466.29
    57
    Figure US20080004312A1-20080103-C00070
         		(1-{2-[3-(2- Methylquinolin-4-yl amino)phenoxy]ethyl}piperidin-4- yl)diphenylmethanol yellow solid 544.30
    58
    Figure US20080004312A1-20080103-C00071
         		4-Benzyl-1-{2-[3-(2- tert-butyl quinolin-4- ylamino)phenxoy]ethyl}piperidin-4-ol yellow solid 510.39
    59
    Figure US20080004312A1-20080103-C00072
         		tert-Butyl (1-{2-[3-(2- methyl quinolin-4- ylamino)phenoxy]ethyl}piperidin yl)carbamate pale yellow solid 477.25
    60
    Figure US20080004312A1-20080103-C00073
         		N-{3-[2-(4- Benzylpiperidin-1-yl) ethoxy]phenyl}-N-(2- methyl quinolin-4-yl)acetamide pale yellow solidb 494.19
    61
    Figure US20080004312A1-20080103-C00074
         		{3-[2-(2-Benzybenzo imidazol-1- yl)ethoxy]phenyl}- (2-methylquinolin-4- yl)amine white solid 485.29
    62
    Figure US20080004312A1-20080103-C00075
         		4-Benzyl-1-{2-[3-(2- methyl quinolin-4-ylamino)-5- trifluoromethylphenoxy]ethyl}piperidin-4-ol yellow solid 536.28
    63
    Figure US20080004312A1-20080103-C00076
         		{3-[2-(4- Benzylpiperidin-1-yl) ethoxy]phenyl}-(2,6- dimethyl pyrimidin-4-yl)amine white solidb 417.29
    64
    Figure US20080004312A1-20080103-C00077
         		{30-8 2-(5-Benzyl-2,5- diaza bicyclo[2.2.1]hept-2-yl) ethoxy]phenyl}-(2- methyl quinolin-4-yl)amine white amorphous solidb 465.24
    65
    Figure US20080004312A1-20080103-C00078
         		Methyl 4-benzyl-1-(2- [3-(2- methylquinolin-4- ylamino) phenoxy]ethyl}piperidin-4- carboxylate yellow powder 510.25
    66
    Figure US20080004312A1-20080103-C00079
         		{3-[2-(4- Benzhydrylidene piperidine-1- yl)ethoxy]phenyl}- (2-tert-butylquinolin-4-yl)amine
    67
    Figure US20080004312A1-20080103-C00080
         		Methyl 4-benzyl-1-(2- [3-(2- methylquinolin-4- ylamino)-5-trifluoro- methylphenoxy]ethyl}piperidin-4- carboxylate pale yellow solid 578.24
    68
    Figure US20080004312A1-20080103-C00081
         		4-Benzyl-1-{2-[3-(2- methyl quinolin-4- ylamino)phenoxy]ethyl}piperidine-4- carboxylic acid yellow powder 496.25
    69
    Figure US20080004312A1-20080103-C00082
         		1-{2-[3-(2- Methylquinolin-4-yl amino)phenoxy]ethyl}piperidine-4-carboxylic acid yellow sokidc 406.13
    70
    Figure US20080004312A1-20080103-C00083
         		{3-[2-(4- Benzylpiperazin-1-yl) ethoxy]-5- trifluoromethyl phenyl}-(2-methyl quinolin-4-yl)amine yellow solid 521.23
    71
    Figure US20080004312A1-20080103-C00084
         		(2-Methylquinoline-4- yl)-{3-[2- (4-phenylpiperidin-1-yl) ethoxy]-5- trifluoromethyl phenyl}amine yellow solid 506.23
    72
    Figure US20080004312A1-20080103-C00085
         		(1-{2-[3-(2- Methylquinolin-4-yl amino)phenoxy]ethyl}piperidin-4-yl)phenyl acetonitrile yellow solid 477.30
    73
    Figure US20080004312A1-20080103-C00086
         		{3-[3-(1-Methyl-1- phenyl ethylamino)propoxy]phenyl}-(2-methyl- quinoline-4-yl)amine yellow solid 426.15
    74
    Figure US20080004312A1-20080103-C00087
         		{3-[2-(5-Benzyl-2,5- diaza bicyclo[2.2.1]hept-2-yl) ethoxy]-5- trifluoromethyl phenyl}-(2-methyl quinolin-4-yl)amine yellow solidf 533.26
    75
    Figure US20080004312A1-20080103-C00088
         		(2-Methylquinolin-4- yl)-{3-(3- (2-phenoxyethylamino) propoxy]phenyl}amine pale yellow solid 428.27
    76
    Figure US20080004312A1-20080103-C00089
         		{3-[2-(3- Methylbutylamino) ethoxy]phenyl}(2- methyl quinolin-4-yl)amine yellow oilb 364.23

    aDiHCl salt unless otherwise noted

    bParent compound

    c+CO2

    esodium salt

    fTriHCl salt
  • The compound of Example 77 was synthesized by benzylation of the compound of Example 2 using a standard method (NaH/BnBr/DMF). The synthesis of Example 2 is the same as for Example 1 except that 3-nitrobenzoyl chloride was used instead of 3-nitrobenzenesulfonyl chloride.
  • The compounds of Examples 78 to 101 were synthesized in the same manner as the compound of Example 2.
  • The compound of Example 102 was synthesized by demethylation of the compound of Example 99 using a standard method (BBr3/CH2Cl2).
  • The compound of Example 103 was synthesized in the same manner as the compound of Example 2.
  • The compound of Example 104 was synthesized in the same manner as the compound of Example 2 except that the last step was a standard coupling with 2,4-dimethoxybenzenesulfonyl chloride.
  • The compound of Example 105 was synthesized in the same manner as the compound of Example 2.
  • The structures, chemical names and physical descriptions for the compounds of Examples 77-173 are set forth in Table 3.
  • The compound of Example 106 was synthesized by demethylation of the compound of Example 103 using a standard method (BBr3/CH2Cl2).
  • The compound of Example 107 was synthesized in the same manner as the compound of Example 2 using 2,4,6-trimethyl-3-nitrobenzoyl chloride instead of 3-nitrobenzoyl chloride. 2,4,6-Trimethyl-3-nitrobenzoyl chloride was synthesized by treatment of 2,4,6-trimethyl-3-nitrobenzoic acid (C Wu et al: J Med Chem 1999, 42:4485-4499) with POCl3.
  • The compounds of Examples 108 and 109 were synthesized in the same manner as the compound of Example 2.
  • The preparation of the compound of Example 110 is shown.
  • The compound of Example 111 was synthesized in the same manner as the compound of Example 79 except that 2,3,4,5-tetrahydro-1H-benzo[c]azepine (Al Meyers, R H Hutchings: Tetrahedron 1993, 49:1807-1820) was used instead of 1,2,3,4-tetrahydro-isoquinoline.
  • The compound of Example 112 is shown.
  • The compound of Example 113 was synthesized in the same manner as the compound of Example 110.
  • The preparation of Example 114 is shown.
  • The compound of Example 115 was synthesized in a 3-step sequence: coupling of 36 with 2-amino-5-nitrobenzoic acid (EDCI/HOBT/DIPEA/DMF), then steps 4 and 5 of Example 45.
  • The compounds of Examples 116 to 118 were synthesized in the same manner as the compound of Example 2.
  • The compound of Example 119 was synthesized in the same manner as the compound of Example 79 except that 7-phenyl-1,2,3,4-tetrahydroisoquinoline was used instead of 1,2,3,4-tetrahydroisoquinoline. 7-Phenyl-1,2,3,4-tetrahydroisoquinoline was synthesized by a standard Suzuki coupling between phenylboronic acid and 7-bromo-1,2,3,4-tetrahydroisoquinoline (G E Stokker: Tetrahedron Lett 1996:5453-5456).
  • The compound of Example 120 was synthesized in the same manner as the compound of Example 79 except that 7-fluoro-1,2,3,4-tetrahydroisoquinoline (G E Stokker: Tetrahedron Lett 1996:5453-5456) was used instead of 1,2,3,4-tetrahydroisoquinoline.
  • The compounds of Examples 121 to 122 were synthesized in the same manner as the compound of Example 120.
  • The compound of Example 123 was synthesized in the same manner as the compound of Example 2.
  • The compound of Example 124 was synthesized in the same manner as the compound of Example 120.
  • The compound of Example 125 was synthesized in the same manner as the compound of Example 79 except that the last step was a Buchwald coupling (Buchwald et al: Tetrahedron Len 1995 36:3609) with 5-bromo-m-xylene instead of the acid catalyzed coupling with 5.
  • The compound of Example 126 was synthesized in the same manner as the compound of Example 2.
  • The compounds of Examples 127 and 128 were synthesized in the same manner as the compound of Example 120.
  • The compounds of Examples 129 and 130 were synthesized in the same manner as the compound of Example 2.
  • The compound of Example 131 was synthesized in the same manner as the compound of Example 120.
  • The compound of Examples 132 to 135 were synthesized in the same manner as the compound of Example 2.
  • The compound of Example 136 was synthesized in the same manner as the compound of Example 120.
  • The compounds of Examples 137 to 140 were synthesized in the same manner as the compounds of Example 2.
  • The compound of Example 141 was synthesized by a Buchwald coupling (Buchwald et al: Tetrahedron Lett 1995 36:3609) between 3-bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]benzamide and 4-amino-2-dimethylaminopyridine (Hnschberger A et al, Tetrahedron 2000, 56:1361-1367).
  • The compound of Example 142 was synthesized in the same manner as the compound of Example 125.
  • The compound of Example 143 was synthesized in the same manner as the compound of Example 2.
  • The preparation of Example 144 is shown.
  • The compounds of Examples 145 and 146 were synthesized in the same manner as the compound of Example 2.
  • The compound of Example 147 was synthesized in the same manner as the compound of Example 144.
  • The compound of Example 148 was synthesized in the same manner as the compound of Example 2.
  • The compound of Example 149 was synthesized in the same manner as the compound of Example 141.
  • The compound of Example 150 was synthesized in the same manner as the compound of Example 2.
  • The compound of Example 151 was synthesized in the same manner as the compound of Example 144.
  • The compound of Example 152 was synthesized by hydrolysis (1 eq NaOH/THF/MeOH/H2O) of methyl 4-({2-[3-(2-methyl quinolin-4-ylamino)benzoylamino]ethylamino}-methyl)benzoate which was synthesized in the same manner as for Example 144.
  • The compound of Example 153 was synthesized in the same manner as the compound of Example 2.
  • The compound of Example 154 was synthesized by hydrolysis (1 eq NaOH/THF/MeOH/H2O) of the compound of Example 151.
  • The compound of Example 155 was synthesized in the same manner as the compound of Example 141.
  • The compound of Example 156 was synthesized in the same manner as the compound of Example 2.
  • The compound of Example 157 was synthesized in the same manner as the compound of Example 151 and during the reductive amination step the lactam ring was formed.
  • The compound of Example 158 was synthesized in the same manner as the compound of Example 12 except that 2-bromo-2-methyl-N-(3-nitrobenzyl)propionamide and 40 were used instead of 3-nitrobenzyl bromide and dimethylamine, respectively. 2-Bromo-2-methyl-N-(3-nitrobenzyl)propionamide was synthesized by a standard coupling (HOBt/EDCI/DIPEA/DMF) of 2-bromo-2-methylpropionic acid and 3-nitroaniline.
  • The compounds of Examples 159 to 161 were synthesized in the same manner as the compound of Example 2.
  • The compounds of Examples 162 to 168 were synthesized in the same manner as the compound of Example 144.
  • The preparation of the compound of Example 169 is shown.
  • The compounds of Examples 170 to 173 were synthesized in the same manner as the compound of Example 144.
    • EXAMPLE 110 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-4-(2-methylquinolin-4-ylamino)-2,3-dihydroisoindol-1-one
  • Figure US20080004312A1-20080103-C00090
    • Step 1. Ethyl 2-methyl-3-nitrobenzoate
  • To a solution of 2-methyl-3-nitrobenzoic acid (34) (3.4 g, 18.8 mmol) in EtOH (60 mL) was added conc H2SO4 (1 mL) dropwise. The resulting solution was heated at 75° C. for 72 hours before the solvent was evaporated. The residue was basified with saturated aq. NaHCO3 and extracted with EtOAc, washed with water, brine. The organic layer was dried over MgSO4 and concentrated to give the desired ethyl ester (3.9 g, quantitative).
    • Step 2. Ethyl 2-bromomethyl-3-nitrobenzoate (35)
  • To a solution of ethyl 2-methyl-3-nitrobenzoate (3.9 g, 18.6 mmol) in CCl4 (56 mL) were sequentially added AlBN (0.61 g, 20% mol) and NBS (3.5 g, 19.5 mmol). The mixture was heated at 80° C. for 72 hours before it was allowed to cool to room temperature. The resulting precipitate was filtered through a plug of silica gel, washed with dichloromethane, and the filtrate was concentrated to give a 1:1 mixture of 35 (3.1 g, 58%) and the starting material.
    • Step 3. 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-4-nitro-2,3-dihydroisoindol-1-one (37)
  • To a solution of 2-(3,4-dihydro-1H-isoquinolin-2-yl)ethylamine (36) (0.36 g, 2.0 mmol) in dichloromethane (4 mL) was added the bromide 35 (0.75 g, 2.6 mmol) in dichloromethane (5 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 hours before it was poured into saturated NaHCO3 (aq. 50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (70 mL), brine (70 mL), dried over MgSO4, and concentrated on a rotavap. The residue was chromatographed on silica gel eluting with 3:1 to 1:1 hexanes/EtOAc to give 37 (0.39 g, 57%).
    • Step 4. 4-Amino-2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]2,3-dihydroisoindol-1-one (38)
  • To a solution of 37 (0.38 g, 1.1 mmol) in methanol (6 mL) was added a solution of ammonium chloride (0.13 g, 2.42 mmol) in water (1.5 mL). Zinc powder (0.49 g, 7.4 mmol) was then added portionwise and the resulting mixture was stirred for 2 hours. The solids were filtered and washed with methanol, the filtrate was basified with saturated sodium bicarbonate (aq.), and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 38 (0.31 g, 88%).
    • Step 5. 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-4-(2-methylquinolin-4-ylamino)-2,3-dihydroisoindol-1-one
  • The title compound was prepared from 38 by the procedure of Example 1 Step 3.
    • EXAMPLE 112 N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-1,1-dimethylethyl]-3-(2-methylquinolin-4-ylamino)benzamide
  • Figure US20080004312A1-20080103-C00091
    • Step 1. tert-Butyl [2-(3,4-dihydro-1H-isoquinolin-2-yl)-1,1-dimethyl-2-oxoethyl]carbamate (41)
  • To a solution of 39 (0.28 g, 1.38 mmol), 1,2,3,4-tetrahydroisoquinoline (40) (0.18 g, 1.38 mmol) and diisopropylethylamine (0.50 g, 3.85 mmol) in anhydrous DMF (5 mL) was added HBTU (0.72 g, 1.90 mmol). The mixture was heated at 65° C. overnight before it was allowed to cool to room temperature, and diluted with EtOAc (100 mL). The resulting solution was sequentially washed with 1N HCl (2×100 mL), 1N NaOH (2×100 mL) and brine (100 mL). The residue after drying (Na2SO4) and concentration of the organic layer was purified on silica gel column to give 41 (0.36 g, 82%).
    • Step 2. 2-Amino-1-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methylpropan-1-one (42)
  • A solution of 41 (0.36 g, 1.1 mmol) in TFA (5 mL) and CH2Cl2 (5 mL) was stirred at room temperature for 40 minutes. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). Upon sequential washings with 1N NaOH (2×50 mL) and brine (50 mL), the organic solution was dried (Na2SO4) and concentrated to afford 42 (0.20 g, 77%).
    • Step 3. 2-(3,4-Dihydro-1H-isoquinolin-2-yl)-1,1-dimethylethylamine (43)
  • To a solution of 42 (0.20 g, 0.91 mmol) in anhydrous THF (4 mL) at 0° C. was added LiAlH4 (1.0 M in THF, 3.0 mL, 3.0 mmol). The resulting mixture was heated under reflux overnight before it was allowed to cool to room temperature. Excess LiAlH4 was destroyed with slow addition of Na2SO4.10 H2O at 0° C. until gas evolution ceased. The solids were filtered off and the filtrate was concentrated to give 43 (0.14 g, 79%).
    • Step 4. N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-1,-dimethylethyl]-3-nitrobenzamide (44)
  • To a solution of 3-nitrobenzoylchloride (0.14 g, 0.75 mmol) and 43 (0.15 g, 0.76 mmol) in anhydrous CH2Cl2 (7 mL) was added DMAP (10 mg). The reaction was stirred at room temperature overnight before it was diluted with EtOAc (100 mL). Upon sequential washings with 1N NaOH (2×100 mL), water (200 mL), the organic mixture was dried (Na2SO4) and concentrated under reduced pressure to give 44 (0.31 g, ˜100%) as a thick dark oil.
    • Step 5. 3-Amino-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-1-dimethylethyl]benzamide (45)
  • 45 was prepared from 44 by the procedure of Example 110 Step 4.
    • Step 6. N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-1,1-dimethylethyl]-3-(2-methylquinolin-4-ylamino)benzamide
  • The title compound was prepared from 45 by the procedure of Example 1 Step 3.
    • EXAMPLE 114 N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-methylpropyl]-3-(2-methylquinolin
  • Figure US20080004312A1-20080103-C00092
    • Step 1. (3,4-Dihydro-1H-isoquinolin-2-yl)acetonitrile (46)
  • 46 was prepared from 40 by the procedure of Example 13 Step 2.
    • Step 2. 2-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-methylpropionitrile (47)
  • To a solution of 46 (1.27 g, 7.38 mmol) in anhydrous THF (20 mL) was slowly added LDA (2.0 M in THF, 8.1 mL, 16.2 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes before the addition of iodomethane (4.20 g, 29.6 mmol). The cold bath was removed and the reaction was allowed to warm up to room temperature and stirred overnight. To work up, the mixture was diluted with EtOAc (150 mL), the resulting solution washed with 1N NaOH (2×100 mL) and brine (100 mL). The organic layer was dried (Na2SO4), concentrated, and the residue purified on a silica gel column to afford 47 (0.38 g, 26%).
    • Step 3. 2-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-methylpropylamine (48)
  • 48 was prepared from 47 by the procedure of Example 112 Step 3.
    • Step 4. N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-methylpropyl]-3-(2-methylquinolin-4-ylamino)benzamide
  • 48 and 49 were reacted in the presence of AlMe3 and ClCH2CH2Cl at 80° by the procedure of Lipton, M F; Basha, A; Weinreb, M: Organic Syntheses, 1988, 6, 492-495.
    • EXAMPLE 144 N-(2-Benzylaminoethyl)-3-(2-methylquinolin-4-ylamino)benzamide
  • Figure US20080004312A1-20080103-C00093
    • Step 1. N-(2-Aminoethyl)-3-(2-methylquinolin-4-ylamino)benzamide (50)
  • A mixture of methyl ester 49 (2.0 g, 6.8 mmol) and ethylenediamine (30 mL) was heated at 110° C. for 2 hours before it was poured into ice water (300 mL). The precipitate was filtered and dried under high vaccum to give 50 (2.0 g, 91%) as an off-white solid, which was used without further purification.
    • Step 2. N-(2-Benzylaminoethyl)-3-(2-methylquinolin-4-ylamino)benzamide
  • A solution of amine 50 (0.22 g, 0.68 mmol) and benzyaldehyde (0.07 mL, 0.08 mmol) in EtOH (3.0 mL) was heated at reflux overnight before it was allowed to cool to room temperature. Sodium borohydride (0.04 g, 0.80 mmol) was added and the reaction was stirred at room temperature for 1 hour. The mixture was mixed with 2N NaOH (3.0 mL), brine (2.0 mL), and extracted with 7:3 CH2Cl2/MeOH (3×5.0 mL). The combined organic layers were dried (K2CO3) and concentrated under reduced pressure. The residue was purified by flash chromatrography (SiO2, gradient elution, 3:1 hexanes/EtOAc to 7:3 CH2Cl2/MeOH) to yield the desired product (0.15 g, 62%) as a pale yellow solid.
    • EXAMPLE 169 3-(2-Methylquinolin-4-ylamino)-N-[2-(4-phenyl-3,4-dihydro-1H-isoquinolin-2yl)ethyl]benzamide
  • Figure US20080004312A1-20080103-C00094
    Figure US20080004312A1-20080103-C00095
    • Step 1. Diphenylacetaldehyde Oxime (52)
  • To a solution of diphenylacetaldehyde (51) (4.0 g, 20.3 mmol) in EtOH (50 mL) were sequentially added hydroxylamine hydrochloride (1.41 g, 20.3 mmol) and 2 N NaOH (aq. 5 mL). The reaction was stirred at room temperature overnight followed by removal of EtOH under reduced pressure. The residue was washed with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 52 (4.0 g, 93%).
    • Step 2. 2,2-Diphenylethylamine (53)
  • To a solution of oxime 52 (4.0 g, 18.9 mmol) in THF (50 mL) was added LiAlH4 (1.0 M solution in THF, 28.3 mL, 28.3 mmol) at 0° C. and the mixture was stirred at room temperature for 4 hours. Sodium sulfate decahydrate was added and the reaction was stirred for an additional hour. The solids were filtered and the filtrate was concentrated under reduced pressure to give 53 (3.14 g, 84%) as a yellow oil.
    • Step 3. N-(2,2-Diphenylethyl)-2,2,2-trifluoroacetamide (54)
  • To neat TFAA (14.9 g, 63.6 mmol) at −5° C. was added amine 53 (3.14 g, 15.9 mmol) dropwise over a 10 minute period and the resulting mixture was stirred for 2 hours. The crude mixture was poured into ice water and extracted with ethyl acetate (3×60 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification by recrystallization (hexanes/ethyl acetate) provided 54 (1.5 g, 32%) as a yellow solid.
    • Step 4. 4-Pheny-1-trifluoroacetyl-3,4-dihydro-1H-isoquinoline (55)
  • Compound 54 (1.5 g, 5.11 mmol) and paraformaldehyde (1.2 g, 7.67 mmol) were added in small portions simultaneously to a solution of H2SO4 (4 mL) in HOAc (16 mL). The reaction mixture was stirred for 12 hours and then poured into ice water. The aqueous mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield 55 (1.0 g, 66%) a yellow solid.
    • Step 5. 4-Phenyl-1,2,3,4-tetrahydroisoquinoline (56)
  • To a solution of 55 (0.9 g, 2.94 mmol) in MeOH (10 mL) were added water (2 mL), KOH (0.33 g, 5.89 mmol), and the reaction was stirred at room temperature for 12 hours. The mixture was washed with a saturated sodium chloride solution and extracted with 7:3 CH2Cl2/MeOH (3×10 mL). The combined organic layers were dried (K2CO3) and concentrated under reduced pressure to give 56 (0.70 g. ˜100%) as a yellow oil.
    • Step 6. (4-Phenyl-3,4-dihydro-1H-isoquinolin-2-yl)acetonitrile (57)
  • 57 was prepared from 56 by the procedure of Example 13 Step 2.
    • Step 7. 2-(4-Phenyl-3,4-dihydro-1H-isoquinolin-2-yl)ethylamine (58)
  • 58 was prepared from 57 by the procedure of Example 112 Step 3.
    • Step 8. 3-(2-Methylquinolin-4-ylamino)-N-[2-(4-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]benzamide
  • The title compound was prepared by reacting 58 with 49 by the procedure of Lipton, M F; Basha, A; Weinreb, M: Organic Syntheses, 1988, 6, 492-495.
    TABLE 3
    Physical
    Ex- De-
    am- scrip- [M +
    ple Structure Chemical Name tiona H]+
     77
    Figure US20080004312A1-20080103-C00096
         		N-Benzyl-N-(2-dimethyl aminoethyl)-3-(2- methylquinolin-4-yl amino)-benzamide yellow solidb 439.28
     78
    Figure US20080004312A1-20080103-C00097
         		N-(2- Dimethylaminoethyl)-4- methyl-3-(2- methylquinolin-4-yl amino)benzamide Light yellow solidd 363.32
     79
    Figure US20080004312A1-20080103-C00098
         		N-[2-(3,4-Dihydro-1H-iso quinolin-2-yl)ethyl]-3-(2- methyl quinolin-4- ylamino)benzamide Light yellow solid 437.22
     80
    Figure US20080004312A1-20080103-C00099
         		N-(4- Dimethylaminobutyl)-3- (2-methylquinolin-4- ylamino) benzamide yellow- ish solidb 377.26
     81
    Figure US20080004312A1-20080103-C00100
         		N-(5- Dimethylaminopentyl)-3- (2- methylquinolin-4- ylamino) benzamide yellow oilb 391.28
     82
    Figure US20080004312A1-20080103-C00101
         		N-(2-{1-[2-(3,5- Difluorophenyl)ethyl]- 6,7-dimethoxy-3,4- dihydro-1H-iso quinolin-2-yl}ethyl)-3-(2- methyl quinolin-4- ylamino)benzamide off- white solidb 637.31
     83
    Figure US20080004312A1-20080103-C00102
         		N-(3- Dimethylaminopropyl)-3- (2-methylquinolin-4- ylamino) benzamide yellow solid 363.31
     84
    Figure US20080004312A1-20080103-C00103
         		N-(2-{1-[2-(3- Fluorophenyl)ethyl]- 6,7-dimethoxy-3,4- dihydro-1H- isoquinolin-2-yl}ethyl)-3-(2- methyl quinolin-4- ylamino)benzamide white solidd 619.38
     85
    Figure US20080004312A1-20080103-C00104
         		N-[2-(6,7-Dimethoxy-3,4- dihydro- 1H-isoquinolin-2- yl)ethyl]-3- (2-methylquinolin-4- ylamino) benzamide yellow foamb 497.34
     86
    Figure US20080004312A1-20080103-C00105
         		N-(2-{1-[2-(4- Fluorophenyl)ethyl]- 6,7-dimethoxy-3,4- dihydro-1H- isoquinolin-2-yl}ethyl)-3- (2-methyl quinolin-4- ylamino)benzamide yellow solidd 619.37
     87
    Figure US20080004312A1-20080103-C00106
         		3-(2-Methylquinolin-4- ylamino)-N- (2-piperidin-1-yl- ethyl)benzamide yellow- ish solid 389.32
     88
    Figure US20080004312A1-20080103-C00107
         		1-Methyl-4-[3-(2- methylquinolin-4-yl amino)benzoyl]piperazine yellow solid 361.32
     89
    Figure US20080004312A1-20080103-C00108
         		N-(1-Benzylpiperidine-4- yl)-3- (2-methylquinolin-4- ylamino) benzamide yellow solid 451.41
     90
    Figure US20080004312A1-20080103-C00109
         		N-[2-(1,3- Dihydroisoindol-2-yl) ethyl]-3-(2- methylquinolin-4-yl amino)benzamide off- white solid 423.35
     91
    Figure US20080004312A1-20080103-C00110
         		Ethyl 4-[3-(2- methylquinolin-4-yl amino)benzoylamino]piperidine-1-carboxylate yellow solod 433.40
     92
    Figure US20080004312A1-20080103-C00111
         		N-(2-{1-[2-(2,5- Difluorophenyl) ethyl]-6,7-dimethoxy-3,4- dihydro- 1H-isoquinolin-2- yl}ethyl)-3-(2- methylquinolin-4- ylamino) benzamide white solid 637.39
     93
    Figure US20080004312A1-20080103-C00112
         		N-(2-{1-[2-(3,4- Difluorophenyl) ethyl]-6,7-dimethoxy-3,4- dihydro- 1H-isoquinolin-2- yl}ethyl)-3-(2- methylquinolin-4- ylamino) benzamide yellow solid 637.33
     94
    Figure US20080004312A1-20080103-C00113
         		2-Chloro-N-8 2-(3,4- dihydro-1H- isoquinolin-2-yl)ethyl]-3- (2-methyl- quinolin-4- ylamino)benzamide white solid 471.29
     95
    Figure US20080004312A1-20080103-C00114
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-2-methyl-5-(2- methyl quinolin-4- ylamino)benzamide white solid 451.37
     96
    Figure US20080004312A1-20080103-C00115
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-4-methyl-3-(2- methyl quinolin-4- ylamino)benzamide off- white solid 451.34
     97
    Figure US20080004312A1-20080103-C00116
         		2-Chloro-N-8 2-(3,4- dihydro-1H- isoquinolin-2-yl)ethyl]-5- (2-methyl- quinolin-4- ylamino)benzamide yellow solid 471.38
     98
    Figure US20080004312A1-20080103-C00117
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-2-methyl-3-(2- methyl quinolin-4- ylamino)benzamide yellow- ish solid 451.25
     99
    Figure US20080004312A1-20080103-C00118
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-2-methoxy-5- (2-methyl quinolin-4- ylamino)benzamide yellow solid 467.33
    100
    Figure US20080004312A1-20080103-C00119
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-2-dimethyl- 3-(2-methyl quinolin-4- ylamino)benzamide white solid 465.37
    101
    Figure US20080004312A1-20080103-C00120
         		3-(2-Methylquinolin-4- ylamino)- N-(2-morpholin-4- ylethyl)benzamide yellow solidb 391.32
    102
    Figure US20080004312A1-20080103-C00121
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-2-hydroxy-5- (2-methyl quinolin-4- ylamino)benzamide yellow solid 453.29
    103
    Figure US20080004312A1-20080103-C00122
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-4-methoxy-3- (2-methyl quinolin-4- ylamino)benzamide yellow solid 467.34
    104
    Figure US20080004312A1-20080103-C00123
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-3-(3,4-dimethoxy benzenesulfonyl- amino)benzamide off- white solidb 496.26
    105
    Figure US20080004312A1-20080103-C00124
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-3-(2- trifluoromethyl quinolin-4- ylamino)benzamide yellow solid 491.22
    106
    Figure US20080004312A1-20080103-C00125
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-4-hydroxy-3- (2-methyl quinolin-4- ylamino)benzamide yellow solid 453.20
    107
    Figure US20080004312A1-20080103-C00126
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-2,4,6-trimethyl-3-(2- methylquinolin-4- ylamino)benzamide pink solid 479.27
    108
    Figure US20080004312A1-20080103-C00127
         		3-(8-Chloro-2- trifluoromethyl quinolin-4-ylamino)-N-[2- (3,4- dihydro-1H-isoquinolin-2- yl)ethyl]benzamide yellow solid 525.21
    109
    Figure US20080004312A1-20080103-C00128
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-2-fluoro-5-(2- methyl quinolin-4- ylamino)benzamide white solid
    110
    Figure US20080004312A1-20080103-C00129
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-4-(2- methylquinolin-4-yl amino))-2,3- dihydroisoindol-1-one off- white solid 449.21
    111
    Figure US20080004312A1-20080103-C00130
         		3-(2-Methylquinolin-4- ylamino)-N- [2-(1,3,4,5- tetrahydrobenzo[c]azepin-2- yl)ethyl]benzamide yellow solid 451.23
    112
    Figure US20080004312A1-20080103-C00131
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)-1,1-dimethylethyl]- 3-(2-methyl quinolin-4- ylamino)benzamide light yellow solid 465.25
    113
    Figure US20080004312A1-20080103-C00132
         		2-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-6-(2-methyl- quinolin-4-yl amino)-2,3- dihydroisoindol-1-one yellow solid 449.26
    114
    Figure US20080004312A1-20080103-C00133
         		N-[2-(3,4-Dihydro-1H- isoquinolin-2- yl)-2-methylpropyl]-3-(2- methyl quinolin-4- ylamino)benzamide light yellow solid 465.23
    115
    Figure US20080004312A1-20080103-C00134
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)-2-ethyl]-2,5-bis(2- methyl quinolin-4- ylamino)benzamide yellow- ish solid 452.18
    116
    Figure US20080004312A1-20080103-C00135
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-3-(2- methylquinolin-4-yl amino)-5-nl trifluoromethylbenzamide off- white solid 505.19
    117
    Figure US20080004312A1-20080103-C00136
         		N-[2-(7,8-Dihydro-5H- [1,3]dioxolo[4,5-g]isoquinolin- 6-yl)ethyl- 3-(2-methylquinolin-4- ylamino) benzamide pale yellow solid 481.20
    118
    Figure US20080004312A1-20080103-C00137
         		N-[2- (Benzylethylamino)ethyl]- 3- (2-methylquinolin-4- ylamino) benzamide pale yellow solid 439.18
    119
    Figure US20080004312A1-20080103-C00138
         		3-(2-Methylquinolin-4- ylamino)- N-[2-(7-phenyl-3,4- dihydro-1H- isoquinolin-2- yl)ethyl]benzamide yellow solid 513.29
    120
    Figure US20080004312A1-20080103-C00139
         		N-[2-(7-Fluoro-3,4- dihydro-1H-isoquinolin-2-yl)ethyl]-3- (2-methyl quinolin-4- ylamin)benzamide yellow solid 455.18
    121
    Figure US20080004312A1-20080103-C00140
         		N-[2-(7-Chloro-3,4- dihydro-1H- isoquinolin-2-yl)ethyl]-3- (2-methyl quinolin-4- ylamino)benzamide off- white solid 471.16
    122
    Figure US20080004312A1-20080103-C00141
         		N-[2-(7-Methyl-3,4- dihydro-1H- isoquinolin-2-yl)ethyl]-3- (2-methyl quinolin-4- ylamino)benzamide yellow solid 451.22
    123
    Figure US20080004312A1-20080103-C00142
         		N-[2-(3,4-Dihydor-2H- quinolin-1-yl) ethyl]-3-(2- methylquinolin-4-yl amino)benzamide yellow solid 437.25
    124
    Figure US20080004312A1-20080103-C00143
         		N-[2-(6-Chloro-3,4- dihydro-1H- isoquinolin-2-yl)ethyl]-3- (2-methyl quinolin-4- ylamino)benzamide off- white solid
    125
    Figure US20080004312A1-20080103-C00144
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-3-(3,5- dimethyl- phenylamino)benzamide white solidb 400.18
    126
    Figure US20080004312A1-20080103-C00145
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-3-(2- phenylquinolin-4-yl amino)benzamide yellow solid 499.24
    127
    Figure US20080004312A1-20080103-C00146
         		N-[2-(5,7-Dichloro-3,4- dihydro-1H- isoquinolin-2-yl)ethyl]-3- (2-methyl quinolin-4- ylamino)benzamide yellow solidb 505.08
    128
    Figure US20080004312A1-20080103-C00147
         		N-[2-(7-Floro-3,4- dihydro-1H- isoquinolin-2-yl)ethyl]-3- (2-methyl quinolin-4- ylamino)benzamide off- white solid 455.25
    129
    Figure US20080004312A1-20080103-C00148
         		N-[2-(1H,3H-Benzo[de]isoquinolin- 2-yl)ethyl]-3-(2- methylquinolin-4-yl amino)benzamide yellow solid 773.20
    130
    Figure US20080004312A1-20080103-C00149
         		3-(2-Methylquinolin-4- ylamino)- N-[2-(octahydro-cis- isoquinolin- 2-yl)ethyl]benzamide yellow solid 443.26
    131
    Figure US20080004312A1-20080103-C00150
         		N-[2-(5-Methyl-3,4- dihydro-1H- isoquinolin-2-yl)ethyl]-3- (2-methyl- quinolin-4- ylamino)benzamide yellow solid 451.24
    132
    Figure US20080004312A1-20080103-C00151
         		N-[2- (Benzylphenylamino)ethyl]- 3-(2-methylquinolin-4- ylamino) benzamide pale yellow solid 487.24
    133
    Figure US20080004312A1-20080103-C00152
         		N-[2- (Benzylmethylamino)ethyl]-3- (2-methylquinolin-4- ylamino) benzamide pale yellow solid 425.21
    134
    Figure US20080004312A1-20080103-C00153
         		N-[2-(4-Benzylpiperdin- 1-yl)ethyl]- 3-(2-methylquinolin-4- ylamino) benzamide yellow solid 479.24
    135
    Figure US20080004312A1-20080103-C00154
         		N-[2-(4-Benzyl-4-hydroxy piperidin-1-yl)ethyl]-3-(2- methyl quinolin-4- ylamino)benzamide yellow solid 495.20
    136
    Figure US20080004312A1-20080103-C00155
         		N-[2-(6,7-Dimethyl-3,4- dihydro-1H- isoquinolin-2-yl)ethyl]-3- (2-methyl quinolin-4- ylamino)benzamide yellow solid
    137
    Figure US20080004312A1-20080103-C00156
         		3-(2-Methylquinolin-4- ylamino)- N-[2-(octahydro-trans- isoquinolin- 2-yl)ethyl]benzamide brown solid 443.31
    138
    Figure US20080004312A1-20080103-C00157
         		N-(2-Azepan-1-ylethyl)-3- (2-methylquinolin-4- ylamino) benzamide yellow solid 403.23
    139
    Figure US20080004312A1-20080103-C00158
         		N-(2- Dibenzylaminoethyl)-3- (2-methylquinolin-4- ylamino) benzamide yellow solid 501.26
    140
    Figure US20080004312A1-20080103-C00159
         		N-(2-Diethylaminoethyl)- 3- (2-methylquinolin-4- ylamino) benzamide yellow solid 378.09
    141
    Figure US20080004312A1-20080103-C00160
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-3-(2- dimethylamino pyridin-4- ylamino)benzamide pale orange solid 416.26
    142
    Figure US20080004312A1-20080103-C00161
         		N-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-3-(naphthalen- 1-yl amino)benzamide brown solidd 422.23
    143
    Figure US20080004312A1-20080103-C00162
         		N-(2-Methylaminoethyl)- 3-(2-methyl quinolin-4- ylamino)benzamide pale yellow solidb 335.21
    144
    Figure US20080004312A1-20080103-C00163
         		N-(2-Benzylaminoethyl)- 3-(2-methyl quinolin-4- ylamino)benzamide yellow solid 411.24
    145
    Figure US20080004312A1-20080103-C00164
         		N-(1-Benzylpyrrolidin)-3- yl)-3- (2-methylquinolin-4- ylamino) benzamide yellow solid 437.28
    146
    Figure US20080004312A1-20080103-C00165
         		N-(2-Benzhydrylamino)ethyl)- 3-(2-methylquinolin-4- ylamino)benzamide off- white solid 487.18
    147
    Figure US20080004312A1-20080103-C00166
         		N-[2-(3- Methoxybenzylamino) ethyl]-3-(2- methylquinolin-4-yl amino)benzamide pale yellow solid 441.26
    148
    Figure US20080004312A1-20080103-C00167
         		N-{2-[(2- Hydroxybenzyl)methyl amino]ethyl}-3-(2-methyl quinolin-4- ylamino)benzamide pale yellow solidb 441.11
    149
    Figure US20080004312A1-20080103-C00168
         		N-[2-(4-Benzylpiperdin- 1-yl)ethyl]-3-(2- dimethylamino pyridin-4- ylamino)benzamide orange solid 458.26
    150
    Figure US20080004312A1-20080103-C00169
         		MethylN-[2-(3,4-dihydro- 1H-isoquinolin-2- yl)ethyl]-5-(2- methylquinolin-4- ylamino)isophthalamate off- white solid 495.23
    151
    Figure US20080004312A1-20080103-C00170
         		Methyl3-({2-[3-(2-methyl quinolin-4- ylamino)benzoylamino]ethylamino}- methyl)benzoate pale yellow solid 469.29
    152
    Figure US20080004312A1-20080103-C00171
         		4-({2-[3-(2- Methylquinolin-4-yl amino)-benzoylamino]ethylamino}methyl)benzoic acid pale yellow solide 455.30
    153
    Figure US20080004312A1-20080103-C00172
         		N-{2-[(3,5-Bis- trifluoromethyl benzyl)methylamino]ethyl}-3- (2-methylquinolin-4- ylamino)benzamide pale yellow solid 561.28
    154
    Figure US20080004312A1-20080103-C00173
         		3-({2-[3-(2-Methyl quinolin-4- ylamino)benzoylamino]ethylamino}- methyl)benzoic acid pale yellow solidc 455.27
    155
    Figure US20080004312A1-20080103-C00174
         		N-[2-(4-Benzyl-4-hydroxy piperidin-1-yl)ethyl]-3-(2- dimethyl aminopyridin-4- ylamino)benzamide pale yellow solid 474.28
    156
    Figure US20080004312A1-20080103-C00175
         		N-[2-(Methylnaphthalen- 2-ylmethyl amino)ethyl]-3-(2-methyl quinolin-4- ylamino)benzamide yellow solid 475.24
    157
    Figure US20080004312A1-20080103-C00176
         		3-(2-Methylquinolin-4- ylamino)- N-[2-(oxo-1,3-dihydro isoindol-2-yl)- ethyl]benzamide off- white solidd 437.24
    158
    Figure US20080004312A1-20080103-C00177
         		2-(3,4-Dihydro-1H- isoquinolin-2-yl)- N-[3-(2-methylquinolin-4- ylamino) benzyl]isobutyramide yellow solid 465.28
    159
    Figure US20080004312A1-20080103-C00178
         		3-(2-Methylquinolin-4- ylamino)- N-{2-[4-(3- trifluoromethylphenyl) piperazin-1-yl]- ethyl}benzamide light yellow solid 534.30
    160
    Figure US20080004312A1-20080103-C00179
         		N-[2- (Cyclohexylmethylamino) ethyl]-3-(2- methylquinolin-4-yl amino)benzamide pale yellow solid
    161
    Figure US20080004312A1-20080103-C00180
         		1-Benzyl-4-[3-(2- methylquinolin-4- ylamino)benzoyl]piperazine brown solid 437.30
    162
    Figure US20080004312A1-20080103-C00181
         		Ethyl{2-[3-(2- methylquinolin-4-yl amino)benzoylamino]ethyl-amino}phenylacetate pale yellow solid 483.25
    163
    Figure US20080004312A1-20080103-C00182
         		N-[2- (3- Methylbutylamino)ethyl]- 3-(2-methylquinolin-4- ylamino)benzamide pale yellow solid 391.23
    164
    Figure US20080004312A1-20080103-C00183
         		N-[2-(Cyclopropyl- methylamino)ethyl]-3-(2- methylquinolin-4-yl amino)benzamide pale yellow solid 374.27
    165
    Figure US20080004312A1-20080103-C00184
         		3-(2-Methylquinolin-4- ylamino)-N-[2-(2,4,6- trimethylbenzylamino) ethyl]benzamide pale yellow solid 453.25
    166
    Figure US20080004312A1-20080103-C00185
         		N-[2-(2,2- Dimethylpropylamino) ethyl]-3-(2- methylquinolin-4-yl amino)benzamide pale yellow solid 391.27
    167
    Figure US20080004312A1-20080103-C00186
         		N-{2-[(Biphenyl-4- ylmethyl)amino]ethyl}-3-(2- methylquinolin-4-yl amino)benzamide pale yellow solid 487.20
    168
    Figure US20080004312A1-20080103-C00187
         		3-(2-Methylquinolin-4- ylamino)- N-{2-[(3-methylthiophen- 2-yl methyl)amino]- ethyl}benzamide pale yellow solid 431.11
    169
    Figure US20080004312A1-20080103-C00188
         		3-(2-Methylquinolin-4- ylamino)- N-{2-(4-phenyl-3,4- dihydro-1H- isoquinolin-2- yl)ethyl]benzamide off- white solid
    170
    Figure US20080004312A1-20080103-C00189
         		Ethyl[4-({2-[3-(2- methylquinolin-4-yl amino)benzoylamino]ethyl-amino}methyl)phenoxy]acetate off- white solidb 513.15
    171
    Figure US20080004312A1-20080103-C00190
         		N-{2-[(Biphenyl-3- ylmethyl)amino]ethyl}-3-(2- methylquinolin-4-yl amino)benzamide off-white solidb 487.26
    172
    Figure US20080004312A1-20080103-C00191
         		Ethyl-{3-[((3-ethoxycarbonylmethyl benzyl)-{2-[3-(2- methylquinolin- 4-ylamino) benzoylamino]ethyl}amino)methyl]phenyl}acetate pale yellow solidb 673.34
    173
    Figure US20080004312A1-20080103-C00192
         		N-{2-[(2′- Methoxybiphenyl-3-yl methyl)amino]ethyl}-3- (2-methyl quinolin-4- ylamino)benzamide pale yellow solidb 517.29

    aDiHCl salt unless otherwise noted.

    bParent compound

    dHCl salt

    eNa salt
  • The compound of Example 174 was synthesized in the same manner as the compound of Example 1.
  • The compound of Example 175 was synthesized in the same manner as the compound of Example 177.
  • The preparation of the compounds of Examples 176 and 177 are shown.
  • The compound of Example 178 was synthesized in the same manner as the compound of Example 1.
  • The preparation of the compound of Example 179 is shown.
  • The compound of Example 180 was synthesized in the same manner as the compound of Example 179.
  • The preparation of the compound of Example 181 is shown.
  • The compound of Example 182 was synthesized in the same manner as the compound of Example 178 except that N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-nitrobenzenesulfonamide was methylated using a standard method (NaH/MeI/DMF) before carried on to the next step.
  • The preparation of the compounds of Examples 183 and 184 are shown.
  • The compound of Example 185 was synthesized in the same manner as the compound of Example 184.
  • The preparation of the compound of Example 186 is shown.
  • The compounds of Examples 187 and 188 were synthesized in the same manner as the compound of Example 184.
  • The preparation of the compounds of Examples 189 to 191 are shown.
  • The compounds of Examples 192 to 194 were synthesized in the same manner as the compound of Example 186.
  • The compound of Example 195 was synthesized in the same manner as the compound of Example 190.
  • The compound of Example 196 was synthesized in the same manner as the compound of Example 186.
  • The compound of Example 197 was synthesized in the same manner as the compound of Example 191.
  • The preparation of the compound of Example 198 is shown.
  • The compound of Example 199 was synthesized in the same manner as the compound of Example 198.
  • The compound, of Example 200 was synthesized in the same manner as the compound of Example 191.
  • The compound of Example 201 was synthesized via reduction (see Example 112 step 3) of the compound of Example 134.
  • The preparation of the compounds of Examples 202 and 203 are shown.
  • The compound of Example 204 was synthesized in the same manner as the compound of Example 198.
  • The compounds of Examples 205 and 206 were synthesized in the same manner as the compound of Example 2.
  • The compound of Example 207 was synthesized via reduction (see Example 112 step 3) of the compound of Example 144.
  • The preparation of the compounds of Examples 208 to 210 are shown.
  • The compound of Example 211 was synthesized in the same manner as the compound of Example 210.
  • The structures chemical names, physical descriptions and M+H data for the compounds of Examples 174-211 are set forth in Table 4.
    • EXAMPLE 176 N-(2-Dimethylaminoethyl)-N′-(2-methylquinolin-4-yl)phenylene-1,3-diamine
  • Figure US20080004312A1-20080103-C00193
    • Step 1. 2-Dimethylamino-N-(3-nitrophenyl)acetamide (62)
  • To a heterogeneous mixture of 61 (186 mg, 1.18 mmol) in dichloromethane (6 mL) were sequentially added imidazole (281 mg, 4.13 mmol) and a solution of 60 (214 mg, 1.55 mmol) in dichloromethane (6 mL). The reaction was stirred at room temperature for 16 hours before it was extracted with ethyl acetate (40 mL, 30 mL) and washed with water (30 mL). The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (1:1 hexanes/ethyl acetate to 10:1 dichloromethane/methanol) to give 62 as a yellow oil.
    • Step 2. N,N-Dimethyl-N′-(3-nitrophenyl)ethane-1,2-diamine (63)
  • To a solution of 62 (482 mg, 2.05 mmol) in THF (2.8 mL) under a N2 atmosphere was added BH3.THF (1.0 M solution in THF, 2.8 mL, 2.80 mmol). The reaction was heated at 70° C. for 1.5 hours before it was allowed to cool to room temperature.
  • The mixture was treated with 2 N HCl (aq. 3 mL) (moderate bubbling) and then the solvent was evaporated. The aqueous residue was extracted with chloroform (2×40 mL) and washed with sat. NaHCO3 (aq.), water, and brine (20 mL each). The chloroform extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on Florisil® (1:1 hexanes/ethyl acetate to 10:1 dichloromethane/methanol) to afford 63 as a yellow oil (124 mg, 28.9%).
    • Step 3. N-(2-Dimethylaminoethyl)benzene-1,3-diamine (64)
  • 64 is prepared from 63 by the procedure of Example 1 Step 2.
    • Step 4. N-(2-Dimethylaminoethyl)-N′-(2-methylquinolin-4-yl)phenylene-1,3-diamine
  • The title compound is prepared from 64 by the procedure of Example 1 Step 3.
    • EXAMPLE 177 [3-(3-Dimethylaminopropyl)phenyl]-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00194
    • Step 1. N,N-Dimethyl-3-(3-nitrophenyl)propionamide (67)
  • To a suspension of 65 (2.04 g, 10.45 mmol) in anhydrous dichloromethane (15 mL) under nitrogen were sequentially added anhydrous pyridine (2 drops) and oxalyl chloride (2 M in CH2Cl2, 11.5 mL, 23 mmol) dropwise. The resulting mixture was heated at 50° C. for 1.5 hours before it was concentrated. The residue was dissolved in anhydrous THF (20 mL) under nitrogen followed by the sequential addition of triethylamine (1.16 mL, 11.55 mmol) and dimethylamine (2 M in THF, 7.87 mL, 15.68 mmol). The reaction was stirred at room temperature overnight before it was diluted with EtOAc (150 mL), and washed with water (150 mL) and brine (150 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give 67 as a yellowish oil (977 mg, 43%).
    • Step 2. 3-(3-Aminophenyl)-N,N-dimethylpropionamide (68)
  • 68 was prepared from 67 by the procedure of Example 1 Step 2.
    • Step 3. 3-(3-Dimethylaminopropyl)phenylamine (69)
  • 69 was prepared from 68 by the procedure of Example 112 Step 3.
    • Step 4. [3-(3-Dimethylaminopropyl)phenyl]-(2-methylquinolin-4-yl)amine
  • The title compound is prepared from 69 by the procedure of Example 1 Step 3.
    • EXAMPLE 179 [3′-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-3-yl]-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00195
    • Step 1. (3-Bromophenyl)-(2-methylquinolin-4-yl)amine (71)
  • 71 is prepared from 70 by the procedure of Example 1 Step 3.
    • Step 2. 3′-(2-Methylquinolin-4-ylamino)biphenyl-3-carbaldehyde (73)
  • To a suspension of 71 (294 mg, 0.94 mmol) in toluene (9.6 mL) under N2 were sequentially added saturated NaHCO3 (aq. 3.8 mL), a solution of 72 (199 mg, 1.33 mmol) in EtOH (6.7 mL), and PdCl2(Ph3P)3 (32 mg, 0.046 mmol). The reaction was heated at 80° C. for 21 hours before it was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (15 mL), brine (15 mL). The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 73 as a yellow solid (219 mg, 68.9%).
    • Step 3. 3′-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-3-yl]-(2-methylquinolin-4-yl)amine
  • To a solution of 73 (102 mg, 0.301 mmol) in dichloroethane (3.0 mL) under N2 was added 40 (0.04 mL, 0.315 mmol). The reaction was stirred for 24 minutes before the sequential addition of NaBH(OAc)3 (94 mg, 0.444 mmol) and AcOH (0.02 mL, 0.349 mmol). The reaction was stirred for 19 hours and then extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were washed with 2 N NaOH (aq. 15 mL), brine (15 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane to 30:1 to 20:1 dichloromethane/methanol) to give the desired product as a yellow solid (75 mg, 55%).
    • EXAMPLE 181 2-Dimethylaminoethyl 3-(2-methylquinolin-4-ylamino)benzoate
  • Figure US20080004312A1-20080103-C00196
    • Step 1. 2-Dimethylaminoethyl 3-nitrobenzoate (76)
  • To a solution of 74 (835 mg, 4.50 mmol) in dichloromethane (50 mL) were sequentially added triethylamine (0.63 mL, 6.75 mmol), a solution of 75 (800 mg, 8.97 mmol) in dichloromethane (10 mL) and a catalytic amount of DMAP. The reaction was stirred for 16 hours before it was extracted with dichlormethane. The dichloromethane extracts were washed with water and brine, dried (MgSO4), and concentrated to give the crude product 76.
    • Step 2. 2-Dimethylaminoethyl 3-aminobenzoate (77)
  • 77 was prepared from 76 by the procedure of Example 110 Step 4.
    • Step 3. 2-Dimethylaminoethyl 3-(2-methylquinolin-4-ylamino)benzoate
  • The title compound was prepared from 77 by the procedure of Example 1 Step 3.
    • EXAMPLE 183 {3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)isoxazol-3-yl]phenyl}-(2-methyl-quinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00197
    • Step 1. 3-Nitrobenzaldehyde Oxime (79)
  • To a solution of 78 (6.04 g, 40 mmol) in ethanol (135 mL) were sequentially added hydroxylamine hydrochloride (2.92 g, 42 mmol) and triethylamine (4.6 g, 54 mmol). The mixture was heated at reflux overnight and concentrated under reduced pressure. The residue was mixed with ethyl acetate (100 mL) and washed with water (3×100 mL), brine (100 mL). The ethyl acetate solution was dried (MgSO4) and concentrated under reduced pressure to give 79 (5.67 g, ˜100%)
    • Step 2. 3-Nitrobenzonitrile oxide hydrogen chloride (80)
  • To a solution of 79 (1.66 g, 10 mmol) in chloroform (50 mL) was introduced chlorine gas at −5° C. over 15 minutes. The color of the reaction mixture changed from colorless to light blue, green, and finally yellow. After an additional 15 minutes, the reaction mixture was concentrated under reduced pressure to give 80 (2.0 g, 100%) as a yellow oil.
    • Step 3. 2-Propargyl-1,2,3,4-tetrahydroisoquinoline (81)
  • See Example 13 Step 2.
    • Step 4. 2-[3-(3-Nitrophenyl)isoxazol-5-ylmethyl]-1,2,3,4-tetrahydroisoquinoline (82)
  • A solution of 80 (0.2 g, 1.0 mmol) and 81 (0.2 g, 1.17 mmol) in toluene (5 mL) was heated a reflux for 4 hours. The reaction was cooled and mixed with 0.5 N NaOH (5 mL), then extracted with ethyl acetate (2×10 mL). The organic material was combined, dried (K2CO3) then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution, hexane to 3:1 hexane/ethyl acetate) to give 82 (228 mg, 68%) as a yellow oil.
    • Step 5. 3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)isoxazol-3-yl]phenylamine (83)
  • 83 was prepared from 82 by the procedure of Example 12 Step 2.
    • Step 6. {3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)isoxazol-3-yl]phenyl}-(2-methyl-quinolin-4-yl)amine
  • The title compound was prepared from 83 by the procedure of Example 1 Step 3.
    • EXAMPLE 184 {3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)propyl]phenyl}-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00198
    • Step 1. 2-Allyl-1,2,3,4-tetrahydroisoquinoline (84)
  • 84 was prepared from 40 by the procedure of Example 13 Step 2.
    • Step 2. 2-[3-(3-Nitrophenyl)propyl]-1,2,3,4-tetrahydroisoquinoline (85)
  • To a solution of 84 (488 mg, 2.82 mmol) in anhydrous THF (3 mL) was added 9-BBN (0.5 M in THF, 5.64 mL, 2.82 mmol) under N2. The mixture was stirred at room temperature for 3 hours to give mixture I.
  • To a solution of 1-bromo-3-nitrobenzene (518 mg, 2.56 mmol) in anhydrous THF (8 mL) were sequentially added PdCl2(dppf) (63 mg, 0.0077 mmol) and sodium methoxide (416 mg, 7.68 mmol) to mixture II.
  • To mixture II was added dropwise mixture I under N2 and the resulting mixture was heated at 75° C. for 17 hours. Upon cooling to room temperature, the reaction mixture was filtered, and the filtrate diluted with EtOAc (150 mL). The organic solution was washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified through column flash chromatography (silica gel) eluting with 8:1 hexanes/EtOAc to give 85 as an orange oil (226 mg, 27%).
    • Step 3. 3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)propyl]phenylamine (86)
  • 86 was prepared from 85 by the procedure of Example 110 Step 4.
    • Step 4. {3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)propyl]phenyl}-(2-methylquinolin-4-yl)amine
  • The title compound was prepared from 86 by the procedure of Example 1 Step 3.
    • EXAMPLE 186 1-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-[3-(2-methylquinolin-4-ylamino)phenyl]urea
  • Figure US20080004312A1-20080103-C00199
    • Step 1. 1-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-(3-nitrophenyl)urea (88)
  • To a solution of 36 (0.35 g, 2.0 mmol) in dichloromethane (10 mL) was added 3-nitrophenyl isocyanate (87) (0.35 g, 2.0 mmol). The mixture was stirred at room temperature overnight before it was partitioned between water (100 mL) and dichloromethane (100 mL). The organic layer was washed with 88 (0.56 g, 82%).
    • Step 2. 1-(3-Aminophenyl)-3-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]urea (89)
  • 89 is prepared from 88 by the procedure of Example 110 Step 4.
    • Step 3. 1-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-[3-(2-methylquinolin-4-ylamino)phenyl]urea
  • The title compound is prepared from 89 by the procedure of Example 1 Step 3.
    • EXAMPLE 189 {3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]phenyl}-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00200
    • Step 1. Ethyl (3,4-dihydro-1H-isoquinolin-2-yl)aceate (90)
  • To a solution of 40 (1.33 g, 10.0 mmol) in acetonitrile (50 mL) were sequentially added potassium carbonate (5.53 g, 40.0 mmol) and ethyl bromoacetate (1.67 g, 10.0 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 90 (2.1 g, 99%).
    • Step 2. (3,4-Dihydro-1H-isoquinolin-2-yl)acetic hydrazide (91)
  • A solution of 90 (2.0 g, 9.12 mmol) and hydrazine (5.1 g, 91 mmol) in ethanol (30 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure to give 91 (1.87 g ˜100%) which was used without further purification.
    • Step 3. 3-(2-Methylquinolin-4-ylamino)-N′-(2-3,4-dihydro-1H-isoquinolin-2-yl-acetyl)benzoic hydrazide (92)
  • To a solution of 91 (205 mg, 1.0 mmol) in xylene (5 mL) was added trimethyl aluminum (2 M solution in hexanes, 0.75 mL, 1.5 mmol). The mixture was stirred under nitrogen for 10 minutes before the addition of methyl 3-(2-methylquinolin-4-ylamino)benzoate (49) (150 mg, 0.5 mmol). The reaction was heated at reflux overnight, quenched with water (2 mL), basified to pH 9 (2 N NaOH), and extracted with 7:3 CH2Cl2/MeOH. The organic layer was dried (K2CO3) and concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, gradient elution) to give 92 as a pale yellow oil (147 mg, 63%).
    • Step 4. {3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]phenyl}-(2-methylquinolin-4-yl)amine
  • A mixture of 92 (195 mg, 0.42 mmol) in phosphorous oxychloride (0.5 mL) was heated overnight before mixing cautiously with ice water (2 mL). The mixture was extracted with 7:3 CH2Cl2/MeOH, and the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution) to give the desired product as a pale yellow solid (69 mg, 37%).
    • EXAMPLE 190 {3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)prop-1-ynyl]phenyl}-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00201
    • Step 1. 2-[3-(3-Nitrophenyl)prop-2-ynyl]-1,2,3,4-tetrahydroisoquinoline (93)
  • To a solution of 81 (2.06 g, 10.2 mmol) in anhydrous triethylamine (30 mL) were sequentially added 1-bromo-3-nitrobenzene (1.83 g, 10.67 mmol), CuI (0.39 g, 2.05 mmol) and Pd(PPh3)4 (1.17 g, 1.0 mmol). The mixture was heated at 90° C. for 1 hour before it was filtered through Celite® and the filtrate was diluted with EtOAc (150 mL). The resulting solution was washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified via flash silica gel chromatography to provide 93 (1.97 g, 66%).
    • Step 2. 3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)prop-1-ynyl]phenylamine (94)
  • 94 was prepared from 93 by the procedure of Example 110 Step 4.
    • Step 3. {3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)prop-1-ynyl]phenyl}-(2-methylquinolin-4-yl)amine
  • The title compound was prepared from 94 by the procedure of Example 1 Step 3.
  • EXAMPLE 191
    • N1-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-N7-(2-methylquinolin-4-yl)-1,2,3,4-tetrahydronaphthalene-1,7-amine
  • Figure US20080004312A1-20080103-C00202
    • Step 1. [2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-(7-nitro-3,4-dihydro-2H-naphthalen-1-ylidene)amine (96)
  • To a solution of 36 (964 mg, 5.48 mmol) and 7-nitro-3,4-dihydro-2H-naphthalen-1-one (95) (1.05 g, 5.48 mmol) in toluene (30 mL) was added a catalytic amount of TFA. The reaction was heated at 130° C. overnight before it was allowed to cool to room temperature and diluted with EtOAc (100 mL). The organic solution was sequentially washed with saturated NaHCO3 (aq. 100 mL), brine (100 mL), dried over Na2SO4, and concentrated to give 96 as a brown oil (1.8 g, 94%).
    • Step 2. [2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-(7-nitro-1,2,3,4-tetrahydro-naphthalen-1-yl)amine (97)
  • To a solution of 96 (1.42 g, 4.07 mmol) in anhydrous dichloroethane (10 mL) were sequentially added acetic acid (267 mg, 4.48 mmol) and NaBH(OAc)3 (1.12 g, 5.29 mmol) under N2. The reaction was stirred at room temperature for 2 hours before it was quenched by slow addition of water (100 mL). The mixture was extracted with dichloromethane (100 mL) and the organic layer was sequentially washed with water (100 mL), saturated aq. NaHCO3 (100 mL), and water (100 mL). The residue, from drying (Na2SO4) and concentrating the organic layer, was chromatographed on silica gel (EtOAc to 5:1 EtOAc/CH3OH) to yield 97 as a brown oil (755 mg, 53%).
    • Step 3. N1-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-1,2,3,4-tetrahydronaphthalene-1,7-diamine (98)
  • 98 was prepared from 97 by the procedure of Example 110 Step 4.
    • Step 4. N1-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-N7-(2-methylquinolin-4-yl)-1,2,3,4-tetrahydronaphthalene-1,7-diamine
  • The title compound was prepared from 98 by the procedure of Example 1 Step 3.
    • EXAMPLE 198 [2′-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-3-yl]-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00203
    • Step 1. 3′-(2-Methylquinolin-4-ylamino)biphenyl-2-carbaldehyde (100)
  • To a stirred suspension of 71 (411 mg, 1.31 mmol) in toluene (1 2.8 mL) under N2 were sequentially added saturated NaHCO3 (aq. 0.5 mL), a solution of 99 (303 mg, 2.02 mmol) in EtOH (8.9 mL), and PdCl2(Ph3P)3 (52 mg, 0.07 mmol). The reaction was heated at 80° C. for 41 hours before it was allowed to cool to room temperature and extracted with ethyl acetate (50 mL). The ethyl acetate extracts were washed with water (30 mL), brine (30 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 100 as a yellow solid (166 mg, 37.4%).
    • Step 2. [2′-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-3-yl]-(2-methylquinolin-4-yl)amine
  • To a solution of 100 (166 mg, 0.49 mmol) and 40 (0.06 mL, 0.473 mmol) in dichloroethane (4.9 mL) were sequentially added NaBH(OAc)3 (155 mg, 0.73 mmol) and HOAc (0.03 mL, 0.52 mmol). The reaction was stirred for 48 hours and then extracted with dichloromethane (2×30 mL). The dichloromethane extracts were washed with 2 N NaOH (aq. 15 mL), brine (15 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (ethyl acetate) to give desired product as a yellow solid (51 mg, 23.7%).
    • EXAMPLE 202 {3-[2-(4-Benzylpiperidin-1-yl)ethanesulfonyl]phenyl}-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00204
    • Step 1. 2-(3-Nitro-benzenesulfonyl)ethyl methanesulfonate (102)
  • To a solution of 2-(3-nitrobenzenesulfonyl)ethanol (101) (5.0 g, 21.6 mmol) in dichloromethane (31.5 mL) and pyridine (7 mL) was added methanesulfonyl chloride (4.9 g, 43 mmol). The mixture was stirred at room temperature overnight before it was partitioned between dichloromethane (200 mL) and 0.5 N HCl (200 mL). The organic layer was dried over MgSO4 and concentrated on a rotavap to give 102 (4.78 g, 71%).
    • Step 2. 4-Benzyl-1-[2-(3-nitrobenzenesulfonyl)ethyl]piperidine (104)
  • A mixture of 102 (1.0 g, 3.2 mmol), 4-benzylpiperidine (103) (0.62 g, 3.5 mmol), and potassium carbonate (1.1 g, 8.0 mmol) in acetonitrile (10 ml) was heated at 70° C. overnight. It was allowed to cool to room temperature and partitioned between EtOAc (150 mL) and water (150 mL). The organic layer was washed with water (100 ml), brine (100 ml), dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (8:1 to 4:1 to 2:1 hexanes/EtOAc) to give 104 (0.26 g, 21%).
    • Step 3. 3-[2-(4-Benzylpiperidin-1-yl)ethanesulfonyl]phenylamine (105)
  • See Example 110 Step 4.
    • Step 4. {3-[2-(4-Benzylpiperidin-1-yl)ethanesulfonyl]phenyl}-(2-methylquinolin-4-yl)amine
  • The title compound was prepared from 105 by the procedure of Example 1 Step 3.
    • EXAMPLE 203 (3-{[2-(4-Benzylpiperidin-1-yl)ethylamino]methyl}phenyl)-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00205
  • To a solution of Example 134 (0.62 g, 1.30 mmol) in THF (20 mL) was added LiAlH4 (1 M in THF, 4.0 mL, 3.90 mmol) at 0° C. The mixture was warmed to room temperature and then heated at 80° C. for 16 hours. The reaction was allowed to cool to room temperature and quenched with Na2SO4.10H2O. The resulting slurry was filtered, rinsed with ethyl acetate, and the filtrate concentrated. The residue was chromatographed on silica gel (dichloromethane to 10:1 to 5:1 dichloromethane/methanol) to give the desired product as a yellow solid (170 mg, 28.3%).
    • EXAMPLE 208 N-[2-(4-Benzylpiperidin-1-yl)ethyl]-N′-(2-methylquinolin-4-yl)pyrimidine-4,6-diamine
  • Figure US20080004312A1-20080103-C00206
    • Step 1. (6-Chloropyrimidin-4-yl)-(2-methylquinolin-4-yl)amine (108)
  • To a solution of 4-amino-2-methylquinoline (107) (1.0 g, 6.7 mmol) in anhydrous DMF (60 mL) was added NaH (60% in mineral oil, 0.32 g, 8.0 mmol). The mixture was stirred for 1 hour followed by the addition of 4,6-dichloropyrimidine (106) (1.0 g, 6.7 mmol). The reaction was heated at 90° C. overnight before it was poured into ice water (100 mL). The mixture was extracted with ether (3×100 mL) and the combined organic layers were dried (MgSO4), concentrated under reduced pressure. The residue was purified by flash chromatrography (SiO2, gradient elution. hexanes to 3:1 hexanes/ethyl acetate to 7:3 CH2Cl2/MeOH) to provide 108 (80 mg, 5%) as a white solid.
    • Step 2. N-[2-(4-Benzylpiperidin-1-yl)ethyl]-N′-(2-methylquinolin-4-yl)pyrimidine-4,6-diamine
  • To a solution of diamine 36 (0.05 g, 0.21 mmol) in n-BuOH (2 mL) were sequentially added 108 (0.05 g, 0.18 mmol) and diisopropylethylamine (37 mg, 0.27 mmol). The mixture was heated at 100° C. overnight before the volatiles were removed under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution, 3:1 hexanes/ethyl acetate to 7:3 CH2Cl2/MeOH) to yield the desired product (20 mg, 25%) as a yellow oil.
    • EXAMPLE 209 3-(4-Benzylpiperidin-1-yl)-1-[3-(2-methylquinolin-4-ylamino)phenyl]propan-1-one
  • Figure US20080004312A1-20080103-C00207
    • Step 1. 3-(4-Benzylpiperidin-1-yl)-1-(3-nitrophenyl)propan-1-one (110)
  • To a solution of 3-nitroacetophenone (109) (0.60 g, 3.63 mmol) and 4-benzylpiperidine (103) (0.64 g, 3.63 mmol) in absolute ethanol (5 mL) was added concentrated hydrochloric acid (0.30 mL, 3.60 mmol). The mixture was heated under reflux and paraformaldehyde (0.32 g, 10.96 mmol) was added in four portions over a period of 40 minutes. The resulting mixture was heated under reflux overnight before it was allowed to cool to room temperature and diluted with EtOAc (100 mL). Following sequential washings with 1 N NaOH (2×100 mL), water (100 mL), and brine (100 mL), the organic solution was dried (Na2SO4) and concentrated. The residue was purified via flash silica gel chromatography to provide 110 (0.26 g, 20%) as a dark syrup.
    • Step 2. 1-(3-Amino-phenyl)-3-(4-benzyl-piperidin-1-yl)-propan-1-one (111)
  • 111 was prepared from 110 by the procedure of Example 110 Step 4.
    • Step 3. 3-(4-Benzylpiperidin-1-yl)-1-[3-(2-methylquinolin-4-ylamino)phenyl]propan-1-one
  • The title compound was prepared from 111 by the procedure of Example 1 Step 3.
    • EXAMPLE 210 3-(4-Benzylpiperidin-1-yl)-1-[3-(2-methylquinolin-4-ylamino)phenyl]propan-1-one O-methyloxime
  • Figure US20080004312A1-20080103-C00208
  • A mixture of Example 209 (0.40 g, 0.86 mmol), ethoxyamine hydrochloric acid (0.22 g, 2.63 mmol,) and pyridine (0.19 g, 2.47 mmol) in anhydrous ethanol (3.0 mL) was heated under reflux overnight. The reaction was allowed to cool to room temperature and diluted with EtOAc (100 mL). Upon sequential washings with 1 N NaOH (2×100 mL) and brine (100 mL), the organic solution was dried over Na2SO4 and evaporated to dryness. The resulting residue was purified via flash silica gel chromatography to give the desired product (100 mg, 24%) as a white foam.
    TABLE 4
    Ex-
    ample Physical
    # Structure Chemical Name Descriptiona [M + H]+
    174
    Figure US20080004312A1-20080103-C00209
         		N-[2-(4- Benzylpiperazin-1-yl) ethyl]-3-(2-pale methylquinolin-4-yl amino)benzenesulfon- amide pale yellow solidb 516.39
    175
    Figure US20080004312A1-20080103-C00210
         		[3-(2- Dimethylaminoethyl) phenyl]-(2-methyl quinolin-4-yl)amine yellowish solidb 306.27
    176
    Figure US20080004312A1-20080103-C00211
         		N-(2- Dimethylaminoethyl)- N′- (2-methylquinolin-4- yl) phenylene-1,3-diamine yellow solidb 321.29
    177
    Figure US20080004312A1-20080103-C00212
         		[3-(3- Dimethylaminopropyl) phenyl]-(2-methyl quinolin-4-yl)amine yellow solid 320.35
    178
    Figure US20080004312A1-20080103-C00213
         		N-[2-(3,4-Dihydro- 1H-isoquinolin-2- yl)ethyl]-3- (2-methylquinolin-4- ylamino) benzenesulfonamide yellow solid 222.14
    179
    Figure US20080004312A1-20080103-C00214
         		[3′-(3,4-Dihydro-1H- isoquinolin- 2-ylmethyl)biphenyl-3- yl]- (2.methylquinolin-4- yl)amine yellow solid 456.18
    180
    Figure US20080004312A1-20080103-C00215
         		(3′- Dimethylaminomethyl biphenyl-3-yl)-(2- methylquinolin-4- yl)amine yellow solidb 368.00
    181
    Figure US20080004312A1-20080103-C00216
         		2-Dimethylaminoethyl 3-(2-methylquinolin-4- ylamino) benzoate yellow solid
    182
    Figure US20080004312A1-20080103-C00217
         		N-[2-(3,4-Dihydro- 1H-isoquinolin- 2-yl)-ethyl]-N- methyl-3-(2-methyl quinolin-4-ylamino) benzenesulfonamide yellow solid 487.21
    183
    Figure US20080004312A1-20080103-C00218
         		{3-[S-(3,4-Dihydro- 1H-isoquinolin- 2-ylmethyl)isoxazol- 3-yl]phenyl}- (2-methylquinolin-4- yl)amine pale yellow solidb 447.21
    184
    Figure US20080004312A1-20080103-C00219
         		{3-[3.(3,4-Dihydro- 1H-isoquinolin- 2-yl)propyl]phenyl}- (2-methyl quinolin-4-yl)amine yellow solid 408.29
    185
    Figure US20080004312A1-20080103-C00220
         		(3-[4-(3,4-Dihydro- 1H-isoquinolin- 2-yl)butyl]phenyl}-(2- methyl quinolin-4-yl)amine yellow solid 422.30
    186
    Figure US20080004312A1-20080103-C00221
         		1-[2-(3,4-Dihydro-1H- isoquinolin- 2-yl)ethyl]-3-[3-(2- methyl quinolin-4- ylamino)phenyl]urea yellow solid 452.08
    187
    Figure US20080004312A1-20080103-C00222
         		{3-[4-(3,4-Dihydro- 1H-isoquinolin- 2-yl)butyl]-4- methylphenyl) (2-methylquinolin-4- yl)amine yellow solid 436.31
    188
    Figure US20080004312A1-20080103-C00223
         		{3-[3-(3,4-Dihydro- 1H-isoquinolin- 2-yl)propyl]-4- methylphenyl}- (2-methylquinolin- 4-yl)amine yellow solid 422.30
    189
    Figure US20080004312A1-20080103-C00224
         		{3-[5-(3,4-Dihydro- 1H-isoquinolin- 2-ylmethyl)- [1,3,4]oxadiazol- 2-yl]phenyl}-(2- methylquinolin-4- yl)amine pale yellow solidb 448.20
    190
    Figure US20080004312A1-20080103-C00225
         		{3-[3-(3,4-Dihydro- 1H-isoquinolin- 2-yl)prop-1- ynyl]phenyl}- (2-methylquinolin-4- yl)amine off- white solid 401.19
    191
    Figure US20080004312A1-20080103-C00226
         		N1-[2-(3,4-Dihydro- 1H-isoquinolin- 2-yl)ethyl]-N7-(2- methylquinolin 4-yl)-1,2,3,4- tetrahydro naphthalene-1,7- diamine yellow solid 463.20
    192
    Figure US20080004312A1-20080103-C00227
         		1-[2-(4- Benzylpiperidin-1-yl) ethyl]-3-[3-(2- methylquinolin-4-yl amino)phenyl]urea green solid 494.14
    193
    Figure US20080004312A1-20080103-C00228
         		1-[2-(4-Benzyl-4- hydroxypiperidin 1-yl)ethyl]-3-[3-(2- methylquinolin- 4-ylamino)- phenyl]urea light brown solid 510.18
    194
    Figure US20080004312A1-20080103-C00229
         		1-(1-Benzylpyrrolidin- 3-yl)-3-[3- (2-methylquinolin-4- ylamino) phenyl)urea pale yellow solid 452.25
    195
    Figure US20080004312A1-20080103-C00230
         		(3-[4-(3,4-Dihydro- 1H-isoquinolin 2-yl)but-1- ynyl]phenyl}-(2- methylquinolin-4- yl)amine pale yellow solidb 418.31
    196
    Figure US20080004312A1-20080103-C00231
         		1-[3-(2- Methylquinolin-4- ylamino) phenyl)-3-{2-(4-(3- trifluoromethyl phenyl)piperazin-1- yl]ethyl}urea yellow solidf 549.15
    197
    Figure US20080004312A1-20080103-C00232
         		Benzylpiperidin-1-yl) ethyl]-N7-(2- methylquinolin-4-yl)- 1,2,3,4-tetrahydro naphthalene-1,7- diamine yellow solidb 505.24
    198
    Figure US20080004312A1-20080103-C00233
         		[2′-(3,4-Dihydro-1H- isoquinolin- 2-ylmethyl)biphenyl-3- yl]- (2-methylquinolin-4- yl)amine yellow solid 456.24
    199
    Figure US20080004312A1-20080103-C00234
         		[3′-(3,4-Dihydro-1H- isoquinolin- 2-ylmethyl)biphenyl- 4-yl]- (2-methylquinolin-4- yl)amine yellow solid 456.34
    200
    Figure US20080004312A1-20080103-C00235
         		N1-(2- Benzylamino ethyl)-N7- (2-methylquinolin-4- tetrahydro yl)-1,2,3,4- naphthalene-1,7- diamine brownish oilb 437.18
    201
    Figure US20080004312A1-20080103-C00236
         		(3-{[2-(3,4-Dihydro- 1H-isoquinolin-2- yl)ethylamino]methyl)phenyl)- (2-methyl-quinolin-4- yl)amine yellow solidb 423.29
    202
    Figure US20080004312A1-20080103-C00237
         		{3-[2-(4- Benzylpiperidin-1-yl) ethanesulfonyl]- phenyl}-(2- methylquinolin-4- yl)amine yellow solid 500.27
    203
    Figure US20080004312A1-20080103-C00238
         		(3-{[2-(4- Benzylpiperidin-1-yl) ethylamino]methyl}phenyl)- (2-methylquinolin-4- yl)amine yellow solid 465.28
    204
    Figure US20080004312A1-20080103-C00239
         		[3′-(4-Benzylpiperidin- 1-yl methyl)biphenyl-4-yl]- (2-methylquinolin-4- yl)amine pale yellow solid 498.37
    205
    Figure US20080004312A1-20080103-C00240
         		4-Benzyl-1-{[3-(2- methyl quinolin-4-ylamino) phenyl]acetyl}piperi- dine yellow solidb 450.35
    206
    Figure US20080004312A1-20080103-C00241
         		2-[3-(2- Methylquinolin-4-yl amino)phenyl]-N- phenethyl acetamide yellow solidb 396.30
    207
    Figure US20080004312A1-20080103-C00242
         		N-Benzyl-N′-[3-(2- methyl quinolin-4- ylamino)benzyl]ethane-1,2-diamine pale yellow solid 397.24
    208
    Figure US20080004312A1-20080103-C00243
         		N-[2-(4- Benzylpipendin-1-yl) ethyl]-N′-(2- methylquinolin-4- yl)pyridine-4,6- diamine off- white solidb 453.29
    209
    Figure US20080004312A1-20080103-C00244
         		3-(4-Benzylpiperidin- 1-yl)-1- [3-(2-methylquinolin- 4-ylamino) phenyl]propan-1-one yellow solid 464.26
    210
    Figure US20080004312A1-20080103-C00245
         		3-(4-Benzylpiperidin- 1-yl)-1- [3-(2-methylquinolin- 4-ylamino) phenyl]propan-1-one O-methyl oxime pale yellow solid 493.28
    211
    Figure US20080004312A1-20080103-C00246
         		3-(4-Benzylpiperidin- 1-yl)-1- [3-(2-methylquinolin- 4-ylamino) phenyl]propan-1-one oxime white solid 479.28

    aDiHCl salt unless otherwise noted.

    bParent compound

    fTriHCl salt
  • The compounds of Examples 212 and 213 were synthesized in the same manner as for Example 67.
  • The compounds of Examples 214 and 221 were synthesized in the same manner and the synthesis for Example 214 is illustrated as follows:
    • EXAMPLE 214 (2-Methylquinolin-4-yl)(3-{2-[(3-methylthiophen-2-ylmethyl)amino]ethoxy}phenyl)amine
  • Figure US20080004312A1-20080103-C00247
    • Step 1. tert-Butyl {2-[3-(2-methylquinolin-4-ylamino)phenoxy]ethyl}carbamate
  • To a solution of 20 (1.0 g, 3.9 mmol) in DMF (15 ml) were sequentially added potassium carbonate (0.6 g, 4.7 mmol) and tert-butyl (2-bromoethyl)carbamate (0.9 g, 3.9 mmol). The reaction mixture was stirred at 80° C. overnight before it was mixed with water (20 ml), saturated NaCl solution (5.0 ml), and extracted with 7:3 CH2Cl2/MeOH (3×20 ml). The organic layers were combined, dried (K2CO3), and then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution, 9:1 to 8:2 A/B, A: 3:1 hexanes/ethyl acetate, B: 7/3 CH2Cl2/MeOH) to yield the desired product 112 as a colorless oil (0.18 g, 12%).
    • Step 2. [3-(2-Aminoethoxy)phenyl](2-methylquinolin-4-yl)amine
  • To a solution of 112 (0.18 g, 0.45 mmol) in CH2Cl2 (5.0 ml) was added trifluoroacetic acid (0.35 ml, 4.5 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was mixed with water (5.0 ml), saturated NaCl solution (3.0 ml), made basic with 2N NaOH (3.0 ml), and extracted with 7:3 CH2Cl2/MeOH (3×5.0 ml). The organic materials were combined, dried (K2CO3), and then concentrated under reduced pressure to give amine 113 as a white solid (0.11 g, 85%).
    • Step 3. (2-Methylquinolin-4-yl)(3-{2-[(3-methylthiophen-2-ylmethyl)amino]ethoxy}phenyl)amine
  • Amine 113 (0.10 g, 0.34 mmol) and 3-methyl-thiophene-2-carboxaldehyde (0.03 ml, 0.34 mmol) were mixed and heated under vacuum with a heat gun for 5 minutes or until bubbling stops. The reaction mixture was allowed to cool to room temperature under vacuum. To a solution of this mixture in EtOH (4 ml) was added sodium borohydride (0.03 g, 0.85 mmol) in portions, and the resulting mixture was stirred at room temperature for 1 hour. The reaction was treated with water (4 ml), saturated NaCl solution (3.0 ml), made basic with 2N NaOH (2.0 ml), and extracted with 7:3 CH2Cl2/MeOH (3×5.0 ml). The organic layers were combined, dried (K2CO3), and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10-50% aqueous acetonitrile) to yield the desired product as an off-white solid (0.01 g, 4%).
    • EXAMPLE 222 2-{3-[3-(2-Methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]propyl}isoindole-1,3-dione
  • Figure US20080004312A1-20080103-C00248
    • Step 1. 3-Methoxy-5-trifluoromethylphenylamine
  • To a solution of 1-methoxy-3-nitro-5-trifluoromethylbenzene (10.0 g, 45.22 mmol) in methanol (100 mL) were sequentially added sat. aq. NH4Cl (100 ml) and zinc (19.31 g, 295.35 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours before the reaction was filtered through Celite®, rinsed with methanol (2×100 mL), and the filtrate was evaporated. The residue was extracted with ethyl acetate (200 mL), washed with water (50 mL), and brine (50 mL). The organic layer was dried over MgSO4 and concentrated on a rotavap to give the desired product 114 as a yellow solid (7.63 g, 88% yield).
    • Step 2. (3-Methoxy-5-trifluoromethylphenyl)(2-methylquinolin-4-yl)amine
  • To a solution of 114 (7.61 g, 39.81 mmol) in EtOH (80 ml) were sequentially added 4-chloroquinaldine (5) (7.07 g, 39.83 mmol) and conc. HCl (0.25 ml) at room temperature. The resulting mixture was heated at 80° C. for 1 hour before the reaction was allowed to cool to room temperature and filtered. The solids were rinsed with diethyl ether (6×50 mL) and air-dried under house vacuum to afford the desired product 115 as a pale purple solid (12.73 g, 87%).
    • Step 3. 3-(2-Methylquinolin-4-ylamino)-5-trifluoromethylphenol
  • To a suspension of 115 (12.70 g, 38.22 mmol) in dichloromethane (109 ml) was added BBr3 (50 g, 199.57 mmol) over 3 min. at 0° C. The resulting mixture was stirred at 0 ° C. for 3 hours before the reaction was quenched with methanol (40 ml) over 3 minutes. The mixture was stirred an additional 5 minutes and filtered. The solids were rinsed with MeOH (3×50 ml) and air-dried under house vacuum to afford the desired product 116 as a pale yellow solid (9.76 g, 71% yield).
    • Step 4. 2-{3-[3-(2-Methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]propyl}isoindole-1,3-dione
  • To a solution of 116 (3.0 g, 8.46 mmol) and N-3-bromopropylphthalimide (2.27 g, 8.46 mmol) in acetone (50 ml) was added potassium carbonate (2.57 g, 18.6 mmol). The mixture was heated under reflux for 2 days before the solvent was removed under reduced pressure.
  • The residue was partitioned between water (75 ml) and 7:3 methylene chloride/methanol (50 ml), and the organic layer was separated, dried (MgSO4), and concentrated. The residue was recrystallized from hot ethyl acetate to give the desired product as white crystals (3.01 g, 72%).
  • The compounds of Examples 223 and 224 were synthesized in the same manner as Example 214.
    • EXAMPLE 225 {3-[3-(1,3-Dihydroisoindol-2-yl)propoxy]-5-trifluoromethylphenyl}(2-methylquinolin-4-yl)amine
  • To a solution of the product of Example 222 (81.3 mg, 0.16 mmol) in THF (2 ml) at 0° C. was added dropwise a solution of lithium aluminum hydride (0.8 ml of a 1 M solution in THF). The reaction was stirred for 3 hours while the bath temperature rose to ambient temperature. Powdered sodium sulfate decahydrate (300 mg) was added in portions at 0° C. and the resulting mixture was stirred for 2 hours before it was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the residue purified by flash chromatography (SiO2, gradient 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) to give the desired product as a yellow solid (55 mg, 72%). It was converted to the diHCl salt (X) by the sequential addition of acetonitrile (1 mL), 0.1N HCl (2.3 mL) and followed by lyopholization.
  • The compounds of Examples 226 and 227 were synthesized in the same manner as Example 214.
  • The compounds of Examples 228 and 229 were synthesized in the same manner as Example 45.
  • The compound of Example 230 was synthesized in the same manner as Example 67.
    Ex-
    ample physical
    # structure chemical Name descriptiona [M + H]+
    212
    Figure US20080004312A1-20080103-C00249
         		[3-(3-benzyl aminopropoxy)-5- trifluoro methylphenyl]- (2-methylquinolin-4- yl)amine white solid 466.20
    213
    Figure US20080004312A1-20080103-C00250
         		{3-(3-(1-methyl-1- phenylethylamino) propoxy]-5-trifluoro methylphenyl}- (2-methylquinolin-4- yl)amine yellow solid 494.07
    214
    Figure US20080004312A1-20080103-C00251
         		(2-methylquinolin-4- yl)-(3-{2-[(3- methylthiophen-2- ylmethyl) amino]ethoxy}phenyl) amine pale yellow solid 404.18
    215
    Figure US20080004312A1-20080103-C00252
         		{3-[2-(3- methoxybenzylamino) ethoxy]phenyl}(2-methyl quinolin-4-yl)amine pale yellow solid 414.25
    216
    Figure US20080004312A1-20080103-C00253
         		(2-methylquinolin- 4-yl) {3-[3-(3- trifluoromethylbenzyl amino) propoxy]phenyl}amine pale yellow solid 466.29
    217
    Figure US20080004312A1-20080103-C00254
         		{3-[3-(3- methoxybenzylamino) propoxy]phenyl}(2- methyl quinolin-4-yl)amine white solid 428.29
    218
    Figure US20080004312A1-20080103-C00255
         		(2-methyl quinolin-4-yl){3-[3- (2,4,6- trimethylbenzyl amino)solid propoxy]phenyl}amine pale yellow solid 440.22
    219
    Figure US20080004312A1-20080103-C00256
         		{3-[3-(2-chloro-4- fluorobenzylamino) propoxy]phenyl}(2- methyl quinolin-4-yl)amine pale yellow solid 450.18
    220
    Figure US20080004312A1-20080103-C00257
         		(2-methyl quinolin-4-yl) (3-{3- [(naphthanlen-2-yl methyl)amino]propoxy}phenyl)amine off- white solid 448.27
    221
    Figure US20080004312A1-20080103-C00258
         		(3-{3 -[(2′- methoxybiphenyl- 3ylmethyl)amino]propoxy}phenyl)(2-methyl quinolin-4yl)amine pale yellow solidb 504.29
    222
    Figure US20080004312A1-20080103-C00259
         		2-{3-[3-(2- methylquinolin- 4-ylamino)-5- trifluoromethyl phenoxy]propyl}isoindole-1,3-dione white solidb 506.30
    223
    Figure US20080004312A1-20080103-C00260
         		(2-methyl quinolin-4-yl){3- trifluoromethyl- 5-[3-(2,4,6-trimethyl benzylamino) propoxy]phenyl}amine white solid 508.36
    224
    Figure US20080004312A1-20080103-C00261
         		(2-methyl quinolin-4-yl){3- trifluoromethyl- 5-[3-(3-trifluoromethyl benzylamino) propoxy]phenyl}amine white solid 534.30
    225
    Figure US20080004312A1-20080103-C00262
         		{3-[3-(1,3- dihydroisoindol-2- yl)propoxy]-5-trifluoro methylphenyl}(2- methylquinolin-4- amine green solid 478.37
    226
    Figure US20080004312A1-20080103-C00263
         		(2-methylquinolin- 4-yl) {3-[3- (3-methylthien-2- yl) methylamino) propoxy]- 5- trifluoro methylphenyl) amine white solid 486.35
    227
    Figure US20080004312A1-20080103-C00264
         		{3-[3-(3- methoxybenzyl amino)propoxy]-5- trifluoromethylphenyl}(2-methylquinolin-4- yl)amine white solidb 496.39
    228
    Figure US20080004312A1-20080103-C00265
         		{3-[3- (benzylethylamino) propoxy]-5- trifluoromethyl phenyl}(2-methyl- quinolin-4-yl)amine pale yellow solidb 494.23
    229
    Figure US20080004312A1-20080103-C00266
         		{3-[3- (benzylcyclo hexylamino) propoxy]-5- trifluoromethyl phenyl}(2-methyl- quinolin-4-yl)amine pale yellow solidb 548.44
    230
    Figure US20080004312A1-20080103-C00267
         		{3-[3-(benzyl- tert-butyl amino)propoxy]-5- fluoro methylphenyl}(2-methyl- quinolin-4-yl)amine pale yellow solid 466.39

    adiHCl salt unless otherwise noted

    bparent compound

    csodium salt

    dtriHCl salt
  • The compounds of Examples 231 to 234 were synthesized in the same manner as for Example 238.
  • The compounds of Examples 235 and 236 were synthesized in the same manner and the synthesis is illustrated for Example 235 as follows:
    • EXAMPLE 235 {3-[2-(4-Benzyl-4-methoxypiperidin-1-yl)ethoxy]phenyl}(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00268
    • Step 1. Benzyl 4-benzyl-4-hydroxy-piperidine-1-carboxylate
  • To a solution of 4-benzyl-piperidin-4-ol (1.39 g, 7.28 mmol) in dry THF (10 ml) were sequentially added Et3N (1.2 ml, 8.0 mmol) and benzyl chloroformate (0.95 g, 7.28 mmol).
  • The resulting solution was stirred at room temperature overnight under N2 before it was partitioned between water (50 ml) and EtOAc (50 ml). The organic layer was washed with brine and dried over MgSO4 and concentrated on a rotavap. The residue was chromatographed on silica gel (hexanes/EtOAc 10:1 to 3:1) to give the desired compound 117 as a colorless oil (0.98 g, 41% yield).
    • Step 2. Benzyl 4-benzyl-4-methoxy-piperidine-1-carboxylate
  • To a solution of 117 (685 mg, 2.1 mmol)) in dry DMF (5 ml) was added NaH (60% in mineral oil, 1.26 mg, 3.16 mmol) at 0° C. It was stirred for 15 minutes before the addition of iodomethane (299 mg, 2.1 mmol). The reaction was stirred overnight and quenched with methanol (1 ml). The mixture was partitioned between water (30 ml) and EtOAc (30 ml) and the organic layer was washed with brine, dried over MgSO4, and concentrated on a rotavap.
  • The residue was chromatographed on silica gel (hexanes/EtOAc 4:1) to give the desired compound 118 as a colorless oil (0.75 g, ˜100% yield)
    • Step 3. 4-Benzyl-4-methoxypiperidine
  • To a solution of 118 (321 mg, 0.95 mmol)) in EtOH (10 ml) was added Pd (10% on carbon, 160 mg) and the mixture was stirred overnight under H2. The solids were filtrated off and the filtrate was concentrated to give the desired compound 119 as a colorless oil (180 mg, 93%).
    • Step 4. The title compound was synthesized via a sequence of coupling/reduction/coupling illustrated as for Example 67 EXAMPLE 237 {3-[2-(4-Acetyl-4-benzylpiperidin-1-yl)ethoxy]phenyl}(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00269
    • Step 1. 4-Benzyl-1-tert-butoxycarbonylpiperidine-4-carboxylic acid
  • To the solution of 30 (2.42 g, 7.26 mmol) in THF (22 ml) was added 2 N NaOH (11 ml) at room temperature. MeOH (˜5 ml) was added dropwise to this mixture until the mixture became homogeneous. The reaction was stirred overnight before the addition of NaOH pellets (2.03 g, 50.75 mmol). The resulting mixture was heated at 55° C. for 3 days, allowed to cool to room temperature, diluted with water (100 ml), washed with Et2O (50 ml×2), and cidified with 2N HCl. The desired product 120 was collected on a filter paper as a white solid (2.0 g, 86%).
    • Step 2. 4-Benzyl-1-tert-butoxycarbonyl-4-(methoxymethylcarbamoyl)piperidine
  • The same procedure as shown for Example 112, step 1 was used.
    • Step 3. 4-Acetyl-4-benzyl-1-tert-butoxycarbonylpiperidine
  • To the solution of 121 (0.15 g, 0.42 mmol) in anhydrous THF (2 ml) was added CH3MgBr (3.0 M in Et2O, 0.63 ml, 1.89 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 1 hour and at 500° C. for 3 hours before the reaction was quenched with sat. NH4Cl.
  • The mixture was extracted with EtOAc (3×50 ml) and the combined organic layers were washed with brine (50 ml), dried over Na2SO4 and concentrated on a rotavap. The residue was chromatographed on silica gel to afford the desired product 122 as a colorless oil. (75 mg, 56%).
    • Step 4. {3-[2-(4-Acetyl-4-benzylpiperidin-1-yl)ethoxy]phenyl}(2-methylquinolin-4-yl)amine
  • The title compound was synthesized via a sequence of deprotection/coupling/reduction/coupling as illustrated for Example 67 (steps 3-5).
    • EXAMPLE 238 {3-[2-(4-Benzyl-4-(morpholin-4-ylcarbonyl))piperidin-1-yl)ethoxy]phenyl}(2-methylquinolin-4-yl)amine
  • The title compound was synthesized from the product of Example 68 using the same procedure as shown for Example 112, step 1.
    • EXAMPLE 239 4-(3-Methylbenzyl)-1-{2-[3-(2-methylquinolin-4-ylamino)phenoxy]ethyl}piperidin-4-ol
  • Figure US20080004312A1-20080103-C00270
    • Step 1. 1-Benzyl-4-(3-methylbenzyl)piperidin-4-ol
  • To a solution of 3-methylbenzyl bromide (2.343 g, 12.66 mmol) in ether (53 mL) in a flame-dried flask was added magnesium (789 mg, 10.63 mmol) at room temperature. The resulting mixture was stirred for 35 minutes, and then to the mixture was added 1-benzylpiperidin-4-one (2.012 g, 10.63 mmol). The resulting mixture was stirred at room temperature for 1 hour before it was quenched with sat. NH4Cl (aq) (40 mL). The mixture was extracted with ether (30 mL, 50 mL) and washed with sat. NH4Cl (aq) (40 mL), brine (40 mL). The organic layer was dried over MgSO4, concentrated on a rotavap, and the residue chromatographed on silica gel (1:1 to >1:3 hexanes/ethyl acetate) to afford the desired product 123 as a pale yellow oil (969 mg, 31%).
    • Step 2. 4-(3-Methylbenzyl)piperidin-4-ol
  • To a solution of 123 (958 mg, 3.243 mmol) in methanol (16.3 mL) was added 10% palladium on carbon (884 mg, 0.831 mmol) at room temperature. The resulting mixture was placed under a H2 atmosphere and stirred at room temperature for 90 hours before the reaction was filtered through Celite®. The Celite® was rinsed with methanol (5×10 mL), and the filtrate was concentrated on a rotavap to give desired product 124 as a pale yellow oil (700 mg, quantitative yield).
    • Step 3. 4-(3-Methylbenzyl)-1-{2-[3-(2-methylquinolin-4-ylamino)phenoxy]ethyl}piperidin-4-ol
  • To a solution of 124 (253 mg, 0.809 mmol) in DMF (5.3 mL) were sequentially added 21 (161 mg, 0.784 mmol) and Na2CO3 (217 mg, 2.047 mmol) at room temperature. The resulting solution was heated at 100° C. for 17 hours before the reaction was diluted with EtOAc (40 mL). The mixture was extracted with ethyl acetate (2×40 mL) and washed with water (2×30 mL). The organic layer was dried over MgSO4, concentrated on a rotavap, and the residue was chromatographed on silica gel (10:1 ethyl acetate/methanol to >8:1 dichloromethane/methanol) to afford the desired product as a yellow solid (89 mg, 24%). The compound of Example 240 was synthesized in the same manner as for Example 238.
  • The compound of Example 241 was synthesized in the same manner as for Example 67 (Steps 3-5).
  • The compounds of Examples 242 and 243 were synthesized in the same manner as for Example 71.
    • EXAMPLE 244 4-(4-Methylbenzyl)-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidin-4-ol Step 1. 4-(4-Methyl-benzyl)-piperidin-4-ol
  • See Example 239, Steps 2-3.
    • Step 2. 4-(4-Methylbenzyl)-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidin-4-ol
  • See Example 67, Steps 3-5.
  • The compounds of Examples 245 and 246 were synthesized in the same manner as for Example 71.
  • The compound of Example 247 was synthesized in the same manner as for Example 238.
  • The compound of Example 248. 4-(2-Chlorobenzyl)-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidin-4-ol.
    Figure US20080004312A1-20080103-C00271
  • Step 1. [3-(2-Chloroethoxy)-5-trifluoromethylphenyl](2-methylquinolin-4-yl)amine (127)
  • The same procedure as Step 1 of Example 239 was used except that compound 116 was used instead of 20.
    • Step 2. Ethyl 4-(2-chlorobenzyl)-4-hydroxypiperidine-1-carboxylate
  • The same procedure as Step 2 for Example 239 was used except that ethyl carbamate was is utilized as the protecting group instead of a benzyl group.
    • Step 3. 4-(2-Chlorobenzyl)piperidin-4-ol
  • To a solution of 125 (1.28 g, 4.30 mmol) in ethanol (22 mL) was added aq. 5 N NaOH (8.60 mL) at room temperature. The resulting mixture was heated at 80° C. for 94 hours before the reaction was diluted with ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (2×50 mL), and washed with water (20 mL). The organic layer was dried over MgSO4 and concentrated on a rotavap to afford the desired product 126 as a yellow solid (730 mg, 75%).
    • Step 4. 4-(2-Chlorobenzyl)-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidin-4-ol
  • See Step 4 of Example 239.
  • The compound of Example 249 was synthesized in the same manner as for Example 248.
  • The compounds of Examples 250 to 253 were synthesized in the same manner as for Example 71.
  • The compounds of Examples 254 and 255 were synthesized in the same manner as for Example 248.
    • EXAMPLE 256 {3-[2-(4-Phenylpiperidin-1-yl)ethoxy)-5-trifluoromethylphenyl}(2-isopropylquinolin-4-yl)amine Step 1. 4-Chloro-2-isopropylquinoline
  • Figure US20080004312A1-20080103-C00272
  • To a solution of 4-chloroquinoline (1.06 mg, 6.48 mmol) in dry THF (35 ml) was added dropwise sec-BuLi (11.6 ml, 0.7 M in pentane, 8.1 mmol) at −78° C. over 10 minutes. The resulting solution was stirred for 4 hours at −78° C. before it was quenched with sat. aq. NH4Cl (5 ml). The mixture was extracted with EtOAc (100 ml), washed with water (100 ml), and brine (100 ml). The organic layer was dried over MgSO4 and concentrated on a rotavap to give crude product (3.3 g) as a brown oil. To a solution of the brown oil (3.3 g) in acetone (7 ml) was added a solution of CAN (7 g) in water (30 ml). The resulting mixture was stirred for 1 hour before it was extracted with DCM (100 ml) and washed with water (100 ml). The organic layer was dried over MgSO4 and concentrated on a rotavap. The residue was chromatographed on silica gel (hexanes/EtOAc 3:1) to give the desired compound 128 as a brown oil (670 mg, 50%).
    • Step 2. {3-[2-(4-Phenylpiperidin-1-yl)ethoxyl-5-trifluoromethylphenyl}(2-isopropylquinolin-4-yl)amine
  • The titled compound was synthesized in the same manner as for Example 71 using 128.
  • The compounds of Examples 257 and 258 were synthesized in the same manner as for Example 248.
  • The compound of Example 259. (4-Benzyl-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidin-4-yl)methanol.
  • To a solution of Example 67 (0.19 g, 0.33 mmol) in THF (5 ml) was added lithium aluminum hydride (650 ml, 0.66 mmol) at 0° C. The mixture was stirred at room temperature overnight before it was quenched with Na2SO4.10H2O (pellets) until no more bubbles were observed.
  • The mixture was then diluted with ethyl acetate, the solids filtered, and the filtrate washed with water (50 ml), brine (50 ml). The organic layer was dried over MgSO4 and concentrated on a rotovap to give the desired product as a yellow solid (0.1 g, 67%).
    • EXAMPLE 260 (2-Methylquinolin-4-yl)-{3-[3-(4-phenylpiperidin-1-yl)propoxy]-5-trifluoromethylphenyl}amine Step 1. 1-(3-Bromopropoxy)-3-nitro-5-trifluoromethylbenzene
  • Figure US20080004312A1-20080103-C00273
  • To a solution of 3-nitro-5-trifluoromethylphenol (6.2 g, 29.94 mmol) in toluene (100 ml) were sequentially added a solution of sodium hydroxide (2.4 g, 59.87 mmol) in water (60 ml), 1,3-dibromopropane (9.1 ml, 89.81 mmol), and tetrabutylammonium hydrogensulfate (1.0 g, 3.0 mmol). The resulting mixture was heated at 90° C. overnight before it was partitioned between water and toluene. The aqueous layer was extracted with ethyl acetate (2×50 ml).
  • The combined organic layers were washed with water (200 ml), brine (150 ml), dried over MgSO4 and concentrated on a rotavap. The residue was chromatographed on silica gel with hexanes/ethyl acetate (100:1 to 50:1 to 20:1) to afford the desired product 129 as yellow oil (8.80 g, 90% yield).
    • Step 2. (2-Methylquinolin-4-yl)-{3-[3-(4-phenylpiperidin-1-yl)propoxy]-5-trifluoromethylphenyl}amine
  • The title compound was synthesized in the same manner as for Example 71 using 129.
  • The compound of Example 261 was synthesized in the same manner as for Example 259.
    • EXAMPLE 262 {3-[2-(4,4-Diphenylpiperidin-1-yl)ethoxy]-5-trifluoromethylphenyl) (2-methylquinolin-4-yl)amine Step 1. 4,4-Diphenylpiperidine
  • Figure US20080004312A1-20080103-C00274
  • To a solution of piperidone (0.5 g, 5.04 mmol) in dry benzene (5 ml) was added trifluoromethanesulfonic acid (5 ml). The resulting solution was stirred at room temperature overnight before it was poured into ice, basified with 2N NaOH (30 ml), extracted with ethyl acetate (3×30 ml), and washed with water (100 ml), brine (50 ml). The organic layer was dried over MgSO4 and concentrated on a rotavap to give the desired product 130 (0.80 g, 67% yield).
    • Step 2. {3-[2-(4,4-Diphenylpiperidin-1-yl)ethoxy]-5-trifluoromethylphenyl}(2-methylquinolin-4-yl)amine
  • The title compound was synthesized in the same manner as for Example 71 using 130.
  • The compounds of Examples 263 to 265 were synthesized in the same manner as for Example 71.
    • EXAMPLE 266 4-Benzyl-1-{2-[5-(2-methylquinolin-4-ylamino)biphenyl-3-yloxy]ethyl}piperidin-4-ol
  • Figure US20080004312A1-20080103-C00275
    • Step 1. 1-Bromo-3,5-dinitrobenzene
  • To a solution of 1,3-dinitrobenzene (14.98 g, 88.93 mmol) in trifluoroacetic acid (50 mL) were sequentially added H2SO4 (20 mL) and N-bromosuccinimide (23.85 g, 134.00 mmol) at room temperature. The resulting mixture was heated at 45° C. for 65 hours before the reaction was poured into iced water (300 mL). The mixture was extracted with dichloromethane (2×100 mL). The organic layer was dried over MgSO4, concentrated on a rotavap, the residue was recrystallized, and the mother liquor was concentrated to give impure desired product.
  • The product was then chromatographed on silica gel (20:1 hexanes/ethyl acetate) to afford the desired 131 as a pale orange-yellow solid (1.28 g, 6%).
    • Step 2. 1-Benzyloxy-3-bromo-5-nitrobenzene
  • To a solution of 131 (1.26 g, 5.09 mmol) in 1,1,3,3-tetramethylurea (12.7 mL) were sequentially added benzyl alcohol (606 mg, 5.61 mmol), KOH (409 mg, 7.289 mmol), and tetrabutylammonium iodide (184 mg, 0.50 mmol) at room temperature. The resulting mixture was heated at 80° C. for 23 hours before the reaction was diluted with ether (50 mL).
  • The mixture was extracted with ether (75 mL, 50 mL) and washed with water (2×50 mL).
  • The organic layer was dried over MgSO4, concentrated on a rotavap, and the residue chromatographed on silica gel (20:1 hexanes/ethyl acetate) to afford the desired product 132 as a yellow oil (993 mg, 63%).
    • Step 3. 5-Benzyloxy-3-nitrobiphenyl
  • See Example 179, Step 2.
    • Step 4. 5-Aminobiphenyl-3-ol
  • To a solution of 133 (982 mg, 3.19 mmol) in toluene (21 mL) were added sequentially a solution of phenylboronic acid (519 mg, 3.82 mmol) in ethanol (13 mL), sat. aq. NaHCO3 (8.4 mL), and dichlorobis(triphenylphosphine)palladium(II) (110 mg, 0.16 mmol). The resulting mixture was placed under a nitrogen atmosphere and heated at 80° C. for 18 hours before the reaction was diluted with ethyl acetate (50 mL). The mixture was extracted with ethyl acetate (50 mL) and washed with water (2×30 mL). The organic layer was dried over MgSO4, concentrated on a rotavap, and the residue was chromatographed on silica gel (20:1 hexanes/ethyl acetate) to afford the desired product 134 as a yellow solid (523 mg, 54%).
    • Step 5. 5-(2-Methylquinolin-4-ylamino)biphenyl-3-ol
  • See Example 1, Step 3.
    • Step 6. [5-(2-Chloroethoxy)biphenyl-3-yl](2-methylquinolin-4-yl)amine
  • See Example 239, Step 1.
    • Step 7. 4-Benzyl-1-{2-[5-(2-methylquinolin-4-ylamino)biphenyl-3-yloxy]ethyl}piperidin-4-ol
  • See Example 239, Step 4.
    • EXAMPLE 267 1-{2-[3-(2-Methylquinolin-4-ylamino)-trifluoromethylphenoxy]ethyl}-N-phenylpiperidine-4-carboxamide
  • Figure US20080004312A1-20080103-C00276
    • Step 1. Methyl 1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidine-4-carboxylate
  • Compound 135 was synthesized in the same manner as for Example 71.
    • Step 2. 1-{2-[3-(2-Methylquinolin-4-ylamino)-trifluoromethylphenoxy]ethyl}-N-phenylpiperidine-4-carboxamide
  • A mixture of aniline (0.041 g, 0.44 mmol) and AlMe3 (2.0 M in heaxanes, 0.2 ml, 0.40 mmol) in anhydrous dichloroethane (5 ml) was stirred at 0° C. for 20 minutes before the addition of 135 (0.10 g, 0.21 mmol). The resulting mixture was heated at 80° C. overnight before it was partitioned between water (30 ml) and EtOAc (80 ml). The organic layer was washed with 0.5 N NaOH (2×50 ml), water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated on a rotavap. The residue was chromatographed on silica gel to afford the desired product as yellow solid (0.092 g, 82%).
    • EXAMPLE 268 4-Benzyl-1-{2-[3-chloro-5-(2-methylquinolin-4-ylamino)phenoxy]ethyl}piperidin-4-ol
  • Figure US20080004312A1-20080103-C00277
    • Step 1. 2-Methoxy-6-nitrophenylamine
  • To a solution of 2-amino-3-nitrophenol (5 g, 32.4 mmol) in DMF (165 ml) were sequentially added potassium carbonate (9.0 g, 65 mmol) and methyl iodide (2.2 ml, 35 mmol). The mixture was heated at 50° C. overnight before it was cooled to room temperature, mixed with water (300 ml), and extracted with ethyl acetate (3×50 ml). The extracts were combined, washed with water (150 ml), brine (80 ml), and dried (MgSO4). Removal of the solvent under reduced pressure gave a dark orange solid that was triturated with 1:1 hexane/ether.
  • The solids were collected by filtration to give product 136 as orange needles (4.1 g, 76%).
    • Step 2. 4-Chloro-2-methoxy-6-nitrophenylamine
  • Aniline 136 from the previous step (3.74 g, 22.2 mmol) was dissolved in acetonitrile (100 ml) and N-chlorosuccinimide (3.07 g, 23 mmol) was added. The mixture was heated under reflux overnight then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give product 137 as orange needles 3.05 g (69%).
    • Step 3. 1-chloro-3-methoxy-5-nitrobenzene
  • 4-Chloro-2-methoxy-6-nitroaniline (137) (14 g, 69 mmol) was dissolved in glacial acetic acid (115 ml) and treated with concentrated sulfuric acid (110 ml). The solution was cooled in an ice bath and a cold solution of sodium nitrite (5.03 g, 73 mmol) in water (20 ml) was added slowly to keep the reaction temperature below 5° C. After the addition was complete, the reaction was stirred for an additional 15 minutes before the addition of hypophosphorous acid (70 ml of a 50% solution in water, 0.9 M). The mixture was stirred at room temperature overnight and recooled with an ice bath. The solids were collected by filtration, washed with water, then dried under vacuum to give 3-chloro-5-nitro anisole (138) as a light salmon-colored solid 7.43 g, 57%).
    • Step 4. 4-Benzyl-1-{2-[3-chloro-5-(2-methylquinolin-4-ylamino)phenoxy]ethyl}piperidin-4-ol
  • The title compound was synthesized in the same manner as for Example 239.
  • Example 269 was synthesized in the same manner as for Example 248, final step.
    Ex-
    ample physical
    # structure chemical Name descriptiona [M + H]+
    231
    Figure US20080004312A1-20080103-C00278
         		N-benzyl-4-benzyl-1- {2-[3-(2-methyl quinolin-4- ylamino) phenoxy]ethyl}-N- methyl piperidine-4-carboxamide light yellow solid 599.29
    232
    Figure US20080004312A1-20080103-C00279
         		4-benzyl-1- {2-[3-(2-methylquinolin- 4-amino) phenoxy]ethyl}-N,N- dimethyl piperidine-4-carboxamide yellow foamb 523.22
    233
    Figure US20080004312A1-20080103-C00280
         		4-benzyl-1- {2-[3-(2-methyl quinolin-4- ylamino) phenoxy]ethyl)-N-methyl pipendine-4-carboxamide yellow solid 509.32
    234
    Figure US20080004312A1-20080103-C00281
         		4-benzyl-1- {2-[3-(2- methylquinolin-4- ylamino) phenoxy]ethyl}piperidine-4-carboxamide light yellow solid 495.30
    235
    Figure US20080004312A1-20080103-C00282
         		{3-(2-(4- benzyl-4-methoxy piperidin-1- yl)ethoxy]phenyl}(2-methylquinolin-4- yl)amine yellow solid 482.29
    236
    Figure US20080004312A1-20080103-C00283
         		{3-[2-(4-benzyl-4- methoxypiperidin-1- yl)ethoxy]-5- trifluoromethylphenyl-2- methylquinolin-4- yl)amine yellowish solid 275.60e
    237
    Figure US20080004312A1-20080103-C00284
         		{3-[2-(4-acetyl-4- benzylpiperidin-1- yl)ethoxy]phenyl}(2-methyl quinolin-4-yl)amine yellow solid 494.35
    238
    Figure US20080004312A1-20080103-C00285
         		{3-[2-(4-benzyl-4- (morpholin-4- ylcarbonyl))piperidin-1- yl)ethoxy]phenyl}(2-methyl quinolin-4-yl)amine yellow solid 565.57
    239
    Figure US20080004312A1-20080103-C00286
         		4-(3-methylbenzyl)- 1-{2-[3- (2-methylquinolin-4- ylamino) phenoxy]ethyl}piperidin-4-ol yellow solid 482.48
    240
    Figure US20080004312A1-20080103-C00287
         		{3-[2-(4-benzyl-4- (piperidin-1- ylcarbonyl))piperidin-1- yl)ethoxy]phenyl}(2- methyl quinolin-4-yl)amine yellow solid 563.59
    241
    Figure US20080004312A1-20080103-C00288
         		4-(3-methylbenzyl)- 1-{2-[3- (2-methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]ethyl)piperidin- 4-ol pale yellow solid 550.24
    242
    Figure US20080004312A1-20080103-C00289
         		{3-[2-(4-(4- fluorophenyl)piperidin-1- yl)ethoxy]-5-trifluoro- methyl phenyl}(2-methyl quinolin-4-yl)amine pale yellow solid 524.35
    243
    Figure US20080004312A1-20080103-C00290
         		{3-[2-(4-(4- chlorophenyl)pipendin-1- yl)ethoxy-5- trifluoromethyl phenyl}(2- methylquinolin-4-yl) amine light yellow solid 540.16
    244
    Figure US20080004312A1-20080103-C00291
         		4-(4-methylbenzyl)-1- {2-[3- (2-methylquinolin-4- ylamino-5- trifluommethyl phenoxy]ethyl}piperidin- 4-ol pale yellow solidb 550.46
    245
    Figure US20080004312A1-20080103-C00292
         		{3-[2-(4-(4- ethylphenyl)piperidin-1- yl)ethoxy]-5- trifluommethyl phenyl}(2- methylquinolin-4- yl)amine yellow solid 520.20
    246
    Figure US20080004312A1-20080103-C00293
         		{3-trifluoromethyl-5- [2-(4-(4- trifluoromethylphenyl) pipendin-1-yl) ethoxy]phenyl}(2- methyl quinolin-4-yl)amine yellow solid 574.15
    247
    Figure US20080004312A1-20080103-C00294
         		{3-[2-(4-benzyl-4- (pipendin-1- ylcarbonyl))piperidin-1- yl)ethoxy]-5- trifluoromethyl phenyl}(2- methyl quinolin-4-yl)amine light yellow solid 631.56
    248
    Figure US20080004312A1-20080103-C00295
         		4-(2-chlorobenzyl)-1- {2-[3- (2-methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]ethyl)piperidin- 4-ol pale yellow solid 570.18
    249
    Figure US20080004312A1-20080103-C00296
         		4-(3-chlorobenzyl)-1- {2-[3- (2-methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]ethyl}pipendin- 4-ol pale yellow solidb 570.41
    250
    Figure US20080004312A1-20080103-C00297
         		{3-[2-(4-(3- methoxyphenyl) piperidin- 1-yl)ethoxy]-5- trifluoro methylphenyl}(2- methylquinolin- 4-yl)amine light yellow solid 536.45
    251
    Figure US20080004312A1-20080103-C00298
         		{3-[2-(4-(3- chlorophenyl) piperidin- 1-yl)ethoxy]-5- trifluoromethyl phenyl}(2- methylquinolin-4- yl)amine pale yellow solid
    252
    Figure US20080004312A1-20080103-C00299
         		{3-[2-(4-(3- methylphenyl)piperidin- 1-yl)ethoxy]-5- trifluoromethyl phenyl}(2- methylquinolin-4- yl)amine pale yellow solid
    253
    Figure US20080004312A1-20080103-C00300
         		{3-[2-(4-(3- methoxyphenyl) piperidin- 1-yl)ethoxy]-5- trifluoromethyl phenyl}(2- methylquinolin-4- yl)amine light yellow solid 536.38
    254
    Figure US20080004312A1-20080103-C00301
         		4-(3,5-difluorobenzyl)-1- {2-[3- (2-methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]ethyl}pipendin- 4-ol pale yellow solidb 572.42
    255
    Figure US20080004312A1-20080103-C00302
         		4-(2,6-difluorobenzyl)-1- {2-[3- (2-methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]ethyl}pipendin- 4-ol pale yellow solidb 604.38
    256
    Figure US20080004312A1-20080103-C00303
         		{3-[2-(4-phenylpiperidin- 1-yl)ethoxy]-5- trifluoro methylphenyl}(2- isopropylquinolin-4- yl)amine off- white solid 534.45
    257
    Figure US20080004312A1-20080103-C00304
         		4-(2-chloro-6- fluorobenzyl)-1- {2-[3- (2-methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]ethyl}pipendin- 4-ol yellow solid 586.23
    258
    Figure US20080004312A1-20080103-C00305
         		4-(2-chloro-4- fluorobenzyl)-1- {2-[3- (2-methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]ethyl}pipendin- 4-ol pale yellow solidb 588.18
    259
    Figure US20080004312A1-20080103-C00306
         		4-benzyl)-1- {2-[3- (2-methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]ethyl}pipendin- 4-yl)methanol white solid 550.23
    260
    Figure US20080004312A1-20080103-C00307
         		(2-methylquinolin-4-yl)- {3- 3-(4-phenylpiperidin- 1-yl)propoxy]-5- trifluoromethyl phenyl}amino off- white solid 520.21
    261
    Figure US20080004312A1-20080103-C00308
         		(1-{2-[3-(2-methyl quinolin- 4-ylamino)-5- trifluoromethyl phenoxy]ethyl}-4- phenyl piperidin-4-yl)methanol yellow powder 536.23
    262
    Figure US20080004312A1-20080103-C00309
         		{3-[2-(4,4- diphenyl)piperidin- 1-yl)ethoxy]-5- trifluoro methylphenyl}(2- methylquinolin-4- yl)amine off- white solid 582.24
    263
    Figure US20080004312A1-20080103-C00310
         		8-{2-[3-(2-methyl quinolin-4-yl amino)-5- trifluoro methylphenoxy]ethyl}-2-phenyl-2,8- diazaspiro[4.5]decan-1- one white solid 575.23
    264
    Figure US20080004312A1-20080103-C00311
         		2-benzyl-8-{2-[3-(2- methyl quinolin-4-ylamino)-5- trifluoro methylphenoxy]ethyl}-2,8- diazaspiro[4.5]decan-1- one white solid 589.58
    265
    Figure US20080004312A1-20080103-C00312
         		(2-methylquinolin-4- yl){3- [2-(4-spiro indanepiperidin- 1-yl)ethoxy]-5- trifluoromethylphenyl}amine pale yellow solid 532.16
    266
    Figure US20080004312A1-20080103-C00313
         		4-benzyl-1-{2-[5- (2-methyl quinolin-4- ylamino)biphenyl-3- yloxy]ethyl}piperidin-4-ol pale yellow solidb 544.28
    267
    Figure US20080004312A1-20080103-C00314
         		1-{2-[3-(2-methyl quinolin- 4-ylamino)- trifluoromethyl phenoxy]ethyl}-N- phenyl piperidin-4-carboxamide light yellow solid 549.21
    268
    Figure US20080004312A1-20080103-C00315
         		4-benzyl-1-{2-[3- chloro-5- (2-methylquinolin-4- ylamino) phenoxy]ethyl}piperidin-4-ol pale yellow solid 502.33
    269
    Figure US20080004312A1-20080103-C00316
         		1-{2-[3-(2-methyl quinolin- 4-ylamino)-5- trifluoromethyl phenoxy]ethyl}-4- phenylpiperidin-4- carbonitrile pale yellow solidb 531.34

    adiHCl salt unless otherwise noted

    bparent compound

    csodium salt

    dtriHCl salt

    e(M + 2H)2+/2
  • The compounds of Examples 270 and 271 were synthesized in the same manner as for Example 45.
  • The compound of Example 272 was synthesized in the same manner as for Example 71.
  • The compound of Example 273 was synthesized in the same manner as for Example 276 (vid infra).
  • The compound of Example 274. (2-Methylquinolin-4-yl)(3-{2-[4-(3-trifluoromethylbenzyl)piperazin-]-yl]ethoxy}phenyl)amine.
    Figure US20080004312A1-20080103-C00317
    • Step 1. tert-Butyl 4-(3-trifluoromethylbenzyl)piperazine-1-carboxylate
  • To a solution of tert-butyl-1-piperzinecarboxylate (0.8 g, 4.2 mmol) in DMF (15 ml) were sequentially added K2CO3 (1.2 g, 8.5 mmol) and 3-trifluoromethylbenzylbromide (0.68 g, 4.2 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with water (20 ml), brine (5.0 ml), and extracted with EtOAc (3×20 ml).
  • The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give product 139 as an off-white solid (1.47 g, 99%).
    • Step 2. 1-(3-Trifluoromethylbenzyl)piperazine
  • To a solution of 139 (1.4 g, 4.2 mmol) in CH2Cl2 (15 ml) was added TFA (1.3 ml, 17 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction was mixed with water (10 ml), brine (3.0 ml), made basic with 2N NaOH (2.0 ml), and extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give product 140 as an off-white solid (0.5 g, 50%).
    • Step 3. (2-Methylquinolin-4-yl)(3-{2-[4-(3-trifluoromethylbenzyl)piperazin-1-yl]ethoxy}phenyl)amine
  • The title compound was synthesized in the same procedure of Example 248, last step.
  • The compound of Example 275 was synthesized in the same manner as for Example 274.
    • EXAMPLE 276 (3-{2-[2S,4S-5-(3-Chlorobenzyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}-5-trifluoromethylphenyl)(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00318
    • Step 1. tert-Butyl 5-[2-(3-nitro-5-trifluoromethylphenoxy)ethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • The title compound was synthesized in the same manner as for Example 67, Step 3, ii).
    • Step 2. 2-(2-Chlorobenzyl)-5-[2-(3-nitro-5-trifluoromethylphenoxy)ethyl]-2,5-diazabicyclo[2.2.1]heptane
  • A mixture of 2-chlorobenzyl chloride (82 mg, 0.51 mmol), 20 (168 mg,0.51 mmol), and K2CO3 (84 mg, 0.615 mmol) in dry DMF (3 ml) was heated at 90° C. overnight. The mixture was partitioned between H2O (50 ml) and EtOAc (50 ml). The organic layer was washed with brine, dried over MgSO4, and concentrated on a rotavap to give the desired crude compound 143 as a brown oil (256 mg, ˜100%).
    • Step 3. (3-{2-[2S,4S-5-(3-Chlorobenzyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}-5-trifluoromethylphenyl)(2-methylquinolin-4-yl)amine
  • The title compound was synthesized using a sequence of reduction/coupling as illustrated by Steps 4-5 for Example 67.
  • The compound of Example 277 was synthesized in the same manner as for Example 274.
  • The compounds of Examples 278 and 279 were synthesized in the same manner as for Example 276.
  • The compounds of Examples 280 and 281 were synthesized in the same manner as for Example 274.
  • The compounds of Examples 282 and 283 were synthesized in the same manner as for Example 276.
  • The compound of Example 284 was synthesized in the same manner as for Example 274.
  • The compound of Example 285 was synthesized in the same manner as for Example 276.
  • The compound of Example 286 was synthesized in the same manner as for Example 67, Steps 3-5.
  • The compounds of Examples 287 and 288 were synthesized in the same manner as for Example 274 using 3,5-difluorobenzyl bromide and 3-pyridiylmethyl bromide, respectively, instead of 3-trifluoromethylbenzyl bromide.
  • The compound of Example 289 was synthesized in the same manner as for Example 276 except that tert-butyl[1,4]diazepane-1-carboxylate was used instead of tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.
  • The compounds of Examples 290 and 291 were synthesized in the same manner as for Example 274.
  • The compounds of Examples 292 and 293 were synthesized in the same manner as for Example 276.
  • The compounds of Examples 294 and 295 were synthesized in the same manner as for Example 67, Steps 3-5.
    • EXAMPLE 296 1-Benzyl-4-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperazin-2-one
  • Figure US20080004312A1-20080103-C00319
    • Step 1. 4-[2-(3-Nitro-5-trifluoromethylphenoxy)ethyl]piperazin-2-one
  • See Example 67, Step 3, ii).
    • Step 2. 1-Benzyl-4-[2-(3-nitro-5-trifluoromethylphenoxy)ethyl]piperazin-2-one
  • To a solution of A (0.10 g, 0.31 mmol) in anhydrous DMF (5 ml) was added NaH (60% disperse in mineral oil, 0.02 g, 0.46 mmol) at room temperature. After 10 minutes stirring at room temperature, benzyl bromide (0.06 g, 0.34 mmol) was added. The resulting mixture was stirred at room temperature overnight before the reaction was quenched with water and brought into EtOAc (60 ml). The organic layer was washed with water (50 ml), brine (50 ml), and dried over Na2SO4. The organic layer was concentrated on a rotavap and the residue was chromatographed on silica gel to give product 145 as a yellow oil (46 mg, 35%).
    • Step 3. 1-Benzyl-4-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperazin-2-one
  • The title compound was synthesized in the same manner as for Example 67, last 3 steps.
  • The compound of Example 297 was synthesized in the same manner as for Example 276.
  • The compound of Example 298 was synthesized in the same manner as for Example 274.
  • The compounds of Examples 299 and 300 were synthesized in the same manner as for Example 288.
  • The compound of Example 301 was synthesized in the same manner as for Example 274 except that benzenesulfonyl chloride was used instead of 3-trifluoromethylbenzyl bromide.
  • The compound of Example 302 was synthesized in the same manner as for Example 248, last step, except 1-(3-thienylmethyl)piperazine was used.
  • The compound of Example 303 was synthesized in the same manner as for Example 274 except that 2-chloro-5-chloromethylpyridine was used instead of 3-trifluoromethylbenzyl bromide.
    • EXAMPLE 304 {3-[2-(4-Benzyl-3,5-dimethylpiperazin-1-yl)-ethoxy]-5-trifluoromethylphenyl}(2-methyl-quinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00320
    • Step 1. tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
  • To a solution of 2,6-cis-dimethylpiperazine (2.0 g, 17 mmol) in CH2Cl2 (60 ml) were sequentially added di-tert-butyl dicarbonate (3.8 g, 17 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred at room temperature overnight before it was washed with water (50 ml), brine (10 ml), and extracted with CH2Cl2 (3×30 ml). The extracts were dried (MgSO4) and concentrated under reduced pressure to give product 146 as colorless oil (3.95, ˜100%).
    • Step 2. tert-Butyl 4-benzyl-3,5-dimethylpiperazine-1-carboxylate
  • To a solution of amine 146 (0.8 g, 3.7 mmol) in DMF (15 ml) were added K2CO3 (1.0 g, 7.4 mmol), benzyl bromide (0.45 ml, 3.7 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15 ml), brine (5.0 ml), and extracted with EtOAc (3×20 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give product 147 as colorless oil (1.0 g, 88%).
    • Step 3. 1-Benzyl-2,6-dimethylpiperazine
  • To a solution of 147 (1.0 g, 3.3 mmol) in CH2Cl2 (15 ml) was added TFA (2.2 ml, 19 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water (15 ml), saturated NaCl solution (5.0 ml), made basic with 2N NaOH (2.0 ml), and extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give product 148 as a white solid (0.86 g, 95%).
    • Step 4. {3-[2-(4-Benzyl-3,5-dimethylpiperazin-1-yl)-ethoxy]-5-trifluoromethylphenyl}(2-methyl-quinolin-4-yl)amine
  • The title compound was synthesized in the same manner as for Example 248, last step.
  • The compound of Example 305 was synthesized in the same manner as for Example 274 except that 4-methylsulphonylbenzyl bromide was used instead of 3-trifluoromethylbenzyl bromide.
  • The compound of Example 306 was synthesized in the same manner as for Example 276 except that benzenesulfonyl chloride was used instead of 2-chlorobenzyl chloride.
  • The compound of Example 307 was synthesized in the same manner as for Example 239 except that 3-chloro-5-(2-methylquinolin-4-ylamino)phenol and 2-benzyl-2,5-diazabicyclo[2.2.1]heptane were used instead of 3-(2-methylquinolin-4-ylamino)phenol and 4-(3-methylbenzyl)piperidin-4-ol, respectively.
  • The compounds of Examples 308 and 309 were synthesized in the same manner as for Example 276.
  • The compound of Example 310 was synthesized in the same manner as for Example 276 except that benzoyl chloride was used instead of 2-chlorobenzyl chloride.
    Ex-
    ample physical
    # structure chemical Name descriptiona [M + H]+
    270
    Figure US20080004312A1-20080103-C00321
         		{3-[2-(4-benzhydryl piperidin- 1-yl)ethoxy](2-methyl quinolin-4-yl)amine yellow solid 529.17
    271
    Figure US20080004312A1-20080103-C00322
         		[3-(2-{4-(bis(4- fluorophenyl) methyl]piperazin-1-yl) ethoxy)phenyl](2-methylquinolin- 4-yl)amine yellow solid 565.22
    272
    Figure US20080004312A1-20080103-C00323
         		{3-[2-(2R,5R-5- benzyl-2,5- diazabicyclo [2.2.1]hept-2- yl)ethoxy]-5- trifluoromethyl phenyl}(2-methylquinolin- 4-yl)amine yellowish solidd 533.44
    273
    Figure US20080004312A1-20080103-C00324
         		(3-{2-[2S,4S-5- (3-chlorobenzyl)- 2,5-diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoro methylphenyl) (2-methylquinolin- 4-yl) amine yellowish solidd 567.19
    274
    Figure US20080004312A1-20080103-C00325
         		(2-methylquinolin- 4-yl) (3-{2-[4- (3-trifluoro methylbenzyl) piperazin- 1-yl]ethoxy}phenyl)amine pale yellow solidd 531.23
    275
    Figure US20080004312A1-20080103-C00326
         		(2-methylquinolin- 4-yl) (3-{2-[4- (3-methylbenzyl) piperazin-1- yl]ethoxy) phenyl)amine pale yellow solidd 467.30
    276
    Figure US20080004312A1-20080103-C00327
         		(3-{2-[2S,4S-5- (2-chlorobenzyl)- 2,5-diazablcyclo [2.2.1]hept-2- trifluoromethylphenyl) (2-methylquinolin- 4-yl)amine yellow solidd 467.48
    277
    Figure US20080004312A1-20080103-C00328
         		(2-methylquinolin- 4-yl)- {3-[2-(4- naphthalen-2- ylmethyl piperazin- 1-yl)ethoxyl]phenyl}amine off- white solidd 503.44
    278
    Figure US20080004312A1-20080103-C00329
         		(3-{2-[2S,4S-5- (4-chlorobenzyl)- 2,5-diazablcyclo [2.2.1]hept.2- yl]ethoxy}-5- trifluoromethylphenyl) (2-methylquinolin- 4-yl)amine yellow solidd 567.16
    279
    Figure US20080004312A1-20080103-C00330
         		(3-{2-[2S,4S-5- (3,5- dimethylbenzyl)- 2,5- diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoromethylphenyl) (2-methylquinolin-4- yl)amine yellow solidd 561.26
    280
    Figure US20080004312A1-20080103-C00331
         		(2-methylquinolin-4- yl)(3-trifluoro methyl-5-{2-[4- (3-trifluoromethyl benzyl)piperazin- 1-yl]ethoxy}phenyl) amine pale yellow solidd 589.41
    281
    Figure US20080004312A1-20080103-C00332
         		(2-methylquinolin- 4-yl) (3-{2-[4- (3-methyl benzyl) piperazin-1-yl]- ethoxy}-5- trifluoro methylphenyl)amine pale yellow solidd 535.59
    282
    Figure US20080004312A1-20080103-C00333
         		(3-{2-[2S,4S-5- (2,4- dichlorobenzyl)- 2,5-diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoromethylphenyl) (2-methylquinolin-4- yl)amine yellow solidd 601.40
    283
    Figure US20080004312A1-20080103-C00334
         		(3-{2-[2S,4S-5- (2,4,6- trimethylbenzyl)- 2,5-diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoromethylphenyl) (2-methylquinolin-4- yl)amine yellow solidd 575.51
    284
    Figure US20080004312A1-20080103-C00335
         		(2-methylquinolin- 4-yl) (3-{2-[4- (3-methoxy benzyl) piperazin-1-yl]- ethoxy}-5- trifluoro methylphenyl)amine pale yellow solidd 551.40
    285
    Figure US20080004312A1-20080103-C00336
         		(3-{2-[2S,4S-5- (4-methylbenzyl)- 2,5-diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoromethylphenyl) (2-methylquinolin-4- yl)amine yellow solidd 547.46
    286
    Figure US20080004312A1-20080103-C00337
         		{3-[2-(4-benzhydryl piperazin-1-yl) ethoxy]-5-trifluoro methylphenyl}(2-methylquinolin-4- yl)amine yellow solidd 597.45
    287
    Figure US20080004312A1-20080103-C00338
         		(2-methylquinolin- 4-yl) (3-{2-[4- (3,5-difluorobenzyl) piperazin-1-yl]- ethoxy}-5- trifluoro methylphenyl) amine yellow solidd 557.38
    288
    Figure US20080004312A1-20080103-C00339
         		(2-methylquinolin- 4-yl) (3-{2-[4- (pyridin-3-yl) piperazin-1-yl]- ethoxy}-5- trifluoro methylphenyl) amine off- white solidb 522.41
    289
    Figure US20080004312A1-20080103-C00340
         		{3-(2-(4-benzyl [1,4]diazepan-1- ethoxy]-5- trifluoromethyl phenyl}(2-methyl quinolin-4-yl)amine yellow solidd 535.47
    290
    Figure US20080004312A1-20080103-C00341
         		(3-{2-[4-(2-chloro- 5-fluoro benzyl)piperazin-1-yl]- ethoxy}-5-trifluoro methylphenyl) (2-methyl quinolin-4- yl)amine yellow solidb 573.33
    291
    Figure US20080004312A1-20080103-C00342
         		(2-methylquinolin- 4-yl) (3-trifluoromethyl-5- {2-[4(2,4-6 trimethylbenzyl) piperazin-1-yl]ethoxy}phenyl)amine yellow solidb 563.45
    292
    Figure US20080004312A1-20080103-C00343
         		(3-{2-[2S,4S-5-(4- methoxybenzyl)-2,5- diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoro methylphenyl) (2-methylquinolin-4- yl)amine yellow solidd 563.44
    293
    Figure US20080004312A1-20080103-C00344
         		(3-{2-[2S,4S-5-(4- fluorobenzyl)-2,5- diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoro methylphenyl) (2-methylquinolin-4- yl)amine yellow solidd 551.45
    294
    Figure US20080004312A1-20080103-C00345
         		(3-{2-[2S,4S-5-(4- chlorobenzyl)-2,5- diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoro methylphenyl) (2-methylquinolin-4- yl)amine off- white solidd 553.37
    295
    Figure US20080004312A1-20080103-C00346
         		{3-[2-(4- methanesulfonyl [1,4]diazepan-1-yl) ethoxy]-5- trifluoromethyl phenyl}(2-methyl quinolin-4-yl)amine yellow solid 523.34
    296
    Figure US20080004312A1-20080103-C00347
         		1-benzyl-4-{2- [3-(2-methyl quinolin-4-ylamino)-5- trifluoromethyl phenoxy]ethyl) piperazin-2-one light yellow solid 535.41
    297
    Figure US20080004312A1-20080103-C00348
         		(3-{2-[2S,4S-5-(3,4- dimethylbenzyl)-2,5- diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoro methylphenyl) (2-methylquinolin-4- yl)amine yellow solidd 561.43
    298
    Figure US20080004312A1-20080103-C00349
         		{3-[2-(4- phenylpipeazin-1-yl]- ethoxy)-5- trifluoromethyl phenyl}(2-methyl quinolin-4-yl)amine pale yellow solidb 507.39
    299
    Figure US20080004312A1-20080103-C00350
         		(3-{2-[4-pyridin-2- ylpiperazin-1- yl]- ethoxy}- 5-trifluoro methylphenyl) (2-methyl quinolin-4- yl)amine pale yellow solidb 522.40
    300
    Figure US20080004312A1-20080103-C00351
         		(3-{2-[4-pyridin- 4-ylplperazin-1- yl]- ethoxy}- 5-trifluoro methylphenyl) (2-methyl quinolin-4- yl)amine pale yellow solidb 522.39
    301
    Figure US20080004312A1-20080103-C00352
         		{3-[2-(4- benzenesulfonyl piperazin-1- yl)ethoxy]-5- trifluoromethyl phenyl-2- methylquinolin- 4-yl)amine off- white solidb 571.32
    302
    Figure US20080004312A1-20080103-C00353
         		(2-methyqinolin-4- yl)-{3-[2- (4-thiophen-3- ylmethyl piperazin-1-yl) ethoxy]-5- trifluoromethyl phenyl}amine off- white solidb 527.18
    303
    Figure US20080004312A1-20080103-C00354
         		(3-{2-[4- (6-chloropyridin-3- ylmethyl) piperazin-1-yl]ethoxy}-5- trifiuoromethyl phenyl)-(2- methylquinolin-4- yl)amine pale yellow solidb 556.18
    304
    Figure US20080004312A1-20080103-C00355
         		{3-(2-(4-benzyl- 3,5-dimethyl piperazin-1-yl)- ethoxy]-5- trifluoromethyl phenyl}- (2-methyl-quinolin- 4-yl)amine pale yellow solidd 549.19
    305
    Figure US20080004312A1-20080103-C00356
         		(3-{2-[4-(4- methanesulfonyl benzyl)piperazin- 1-yl]ethoxy}-5- trifluoromethyl phenyl)(2-methyl quinolin-4-yl)amine pale yellow solidd 599.24
    306
    Figure US20080004312A1-20080103-C00357
         		(3-[2-(5- benzene sulfonyl-1S,4S- 2,5-diazabicyclo [2.2.1.]hept-2- yl)ethoxyl-5- trifluoromethyl- henyl}(2-methyl quinolin-4- yl)amine yellow solid 583.23
    307
    Figure US20080004312A1-20080103-C00358
         		{3-(2-(1S,4S-5- benzyl-2,5- diazabicyclo[2.2.1]hept-2-yl)ethoxy]-5- chlorophenyl}(2- methyl quinolin-4-yl)amine pale yellow solid 499.33
    308
    Figure US20080004312A1-20080103-C00359
         		(3-{2-[2S,4S-5-(2,6- difluorobenzyl)-2,5- diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoro methylphenyl) (2-methylquinolin-4- yl)amine yellow solid 569.26
    309
    Figure US20080004312A1-20080103-C00360
         		(3-{2-[2S,4S-5-(2,4,5- trifluorobenzyl)-2,5- diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoro methylphenyl) (2-methylquinolin-4- yl)amine yellow solid 587.24
    310
    Figure US20080004312A1-20080103-C00361
         		(3-{2- [2S,4S-5-acetyl-2,5- diazabicyclo [2.2.1]hept-2- yl]ethoxy}-5- trifluoro methylphenyl) (2-methylquinolin-4- yl)amine yellow solid 547.35

    adiHCl salt unless otherwise noted

    bparent compound

    csodium salt

    dtriHCl salt
  • The compounds of Examples 311 and 312 were synthesized in the same manner as for Example 214.
  • The compounds of Examples 313 and 314 were synthesized in the same manner as for Example 274 except that 1-bromo-3-methylbutane and cyclohexanemethyl bromide were used instead of 3-trifluoromethylbenzyl bromide.
  • The compounds of Examples 315 and 317 were synthesized in the same manner as for Example 67.
  • The compound of Example 318 was synthesized in the same manner as for Example 214.
  • The compounds of Examples 319 and 320 were synthesized in the same manner as for Example 276.
  • The compound of Example 321 was synthesized in the same manner as for Example 67.
  • The compounds of Examples 322 to 324 were synthesized in the same manner as for Example 248, last step.
  • The compound of Example 325 was synthesized in the same manner as for Example 67.
  • The compound of Example 326 was synthesized in the same manner as for Example 248, last step.
    • EXAMPLE 327 [3-Chloro-5-(3-piperidin-1-ylpropoxy)phenyl](2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00362
    • Step 1. [3-Chloro-5-(3-chloropropoxy)phenyl](2-methylquinolin-4-yl)amine
  • Compound 149 was synthesized in the same manner as for 116 from 138 (see Example 222).
  • To a solution of the 149 (1.14 g, 4 mmol) in DMF (20 ml) were sequentially added 1-bromo-3-chloropropane (1.36 g, 15 mmol), potassium carbonate (2.1 g, 15 mmol), and the mixture was heated at 100° C. for 4 hours. The reaction was mixed with water (80 ml) then extracted with methylene chloride (3×20 ml). The extracts were combined, washed with water (50 ml), brine (50 ml), then dried (MgSO4) and concentrated. The residue was purified by flash chromatography (SiO2, gradient 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) to give the desired product 150 as an off-white solid (350 mg, 20%).
    • Step 2. [3-Chloro-5-(3-piperidin-1-ylpropoxy)phenyl](2-methylquinolin-4-yl)amine
  • The title compound was synthesized in the same manner as for Example 248, last step using 149 and piperidine.
    • EXAMPLE 328 4-Methyl-1-{3-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]propyl}piperidin-4-ol
  • Figure US20080004312A1-20080103-C00363
    • Step 1. [3-(3-Chloropropoxy)-5-trifluoromethylphenyl](2-methylquinolin-4-yl)amine
  • See Example 327, Step 1.
    • Step 2. 4-Methyl-1-{3-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]propyl}piperidin-4-ol
  • The title compound was synthesized in the same manner as for Example 248, last step using 151 and 4-methylpiperidin-4-ol.
  • The compounds of Examples 329 and 330 were synthesized in the same manner as for Example 328.
  • The compound of Example 331 was synthesized in the same manner as for Example 67.
    • EXAMPLE 332 (3-{3-[4-3-Methylbutyl)piperazin-1-yl]propoxy}-5-trifluoromethylphenyl)-(2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00364
    • Step 1. tert-Butyl 4-(3-methylbutyl)piperazine-1-carboxylate
  • To a solution of tert-butyl-1-piperzinecarboxylate (0.8 g, 4.2 mmol) in DMF (20 ml) were sequentially added K2CO3 (1.8 g, 12 mmol), 1-bromo-3-methylbutane (0.8 ml, 4.2 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 ml), brine (4 ml), and extracted with EtOAc (3×20 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give product 152 as a white solid (0.82 g, 60%).
    • Step 2.1-(3-Methylbutyl)piperazine
  • To a solution of 152 (0.82 g, 3.1 mmol) in CH2Cl2 (12 ml) was added TFA (1.4 ml, 19 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with water (10 ml), brine (3 ml), made basic with 2N NaOH (3.0 ml), and extracted with 7:3 CH2Cl2/MeOH (3×5.0 ml). The organic layers were combined, dried (K2CO3), and then concentrated under reduced pressure to give 153 as an off-white solid (0.41 g, 82%).
    • Step 3. (3-{3-[4-(3-Methylbutyl)piperazin-1-yl]propoxy}-5-trifluoromethylphenyl)-(2-methylquinolin-4-yl)amine
  • The title compound was synthesized in the same manner as for Example 248, last step using amine 153 and chloride 151.
    • EXAMPLE 333
  • {3-[3-(8-Azabicyclo[3.2.1]oct-8-yl)propoxy]-5-trifluoromethylphenyl}(2-methylquinolin-4-yl)amine
    Figure US20080004312A1-20080103-C00365
    • Step 1. 2,2,2-Trichloroethyl 8-azabicyclo[3.2.1]octane-8-carboxylate
  • To a solution of tropane (0.50 g, 3.99 mmol) in anhydrous toluene (10 ml) was added trichloroethane chloroformate (0.93 g, 4.38 mmol) at room temperature. The resulting solution was heated at 80° C. for 2 hours before it was partitioned between Et2O (80 ml) and water (50 ml). The organic layer was washed subsequently with 1N NaOH (2×50 ml), brine (50 ml), dried over Na2SO4 and concentrated on a rotavap to give the desired carbamate 154 as white solid (0.94 g, 82%).
    • Step 2. 8-Azabicyclo[3.2.1]octane
  • To a solution of carbamate 154 (0.94 g, 3.28 mmol) in HOAc (10 ml) was added zinc (0.64 g, 9.84 mmol). The resulting mixture was stirred at room temperature overnight before excess zinc was removed by filtration. The filtrate was brought into EtOAc (80 ml) which was then washed with dilute NaOH (2×50 ml) and brine. The organic layer was dried over Na2SO4 and concentrated on a rotavap to give the desired product 155 as an orange oil (0.06 g, 16%).
    • Step 3. (3-[3-(8-Azabicyclo[3.2.1]oct-8-yl)propoxy]-5-trifluoromethylphenyl}(2-methylquinolin-4-yl)amine
  • The title compound was synthesized in the same manner as for Example 67 using the amine 155 and 1-(3-bromopropoxy)-3-nitro-5-trifluoromethyl-benzene (129).
  • Examples 334 and 335 were synthesized in the same manner as for Example 67 using 129 instead of 31.
  • The compounds of Examples 336 to 338 were synthesized in the same manner as for Example 248.
  • The compound of Example 339 was synthesized in the same manner as for Example 214.
  • The compounds of Examples 340 and 341 were synthesized in the same manner as for Example 67 using 129 instead of 31.
    Ex-
    ample physical
    # structure chemical Name descriptiona [M + H]+
    311
    Figure US20080004312A1-20080103-C00366
         		{3-[3-(3-methylbutylamino) propoxy]phenyl](2-methyl quinolin-4-yl)amine pale yellow solid 378.24
    312
    Figure US20080004312A1-20080103-C00367
         		{3-[3-(cyclohexylmethylamino) propoxy]phenyl}(2-methyl quinolin-4-yl)amine pale yellow solid 404.32
    313
    Figure US20080004312A1-20080103-C00368
         		(3-{2-[4-(3-methylbutyl) piperazin-1-yl]ethoxy}-5- trifluoromethylphenyl) (2-methylquinolin-4-yl)amine pale yellow solidd 501.39
    314
    Figure US20080004312A1-20080103-C00369
         		(3-{2-[4-cyclohexylmethyl piperazin-1-yl]ethoxy}-5- trifluoromethylphenyl) (2-methylquinolin-4-yl)amine pale yellow solidd 527.33
    315
    Figure US20080004312A1-20080103-C00370
         		(2-methylquinolin-4-yl)[3-(2- morpholin-4-ylethoxy)-5- trifluoromethylphenyl]amine yellow solid 432.24
    316
    Figure US20080004312A1-20080103-C00371
         		(2-methylquinolin-4-yl)[3-(2- piperidin-1-ylethoxy)-5- trifluoromethylphenyl]amine yellow solid 430.30
    317
    Figure US20080004312A1-20080103-C00372
         		(2-methylquinolin-4-yl)[3-(2- (4-propylpiperidin-1- yl)ethoxy)-5- trifluoromethylphenyl]amine yellow solid 472.30
    318
    Figure US20080004312A1-20080103-C00373
         		{3-[3-(cyclohexylmethylamino) propoxy]-5-trifluoromethyl phenyl}(2-methyl quinolin-4-yl)amine white solid 472.23
    319
    Figure US20080004312A1-20080103-C00374
         		{3-[2-(5-cyclohexylmethyl- 2,5-diazabicyclo [2.2.1]hept-2- yl)ethoxy]-5- trifluoro methylphenyl}(2-isopropylquinolin-4- yl)amine brown solidd 567.35
    320
    Figure US20080004312A1-20080103-C00375
         		{3-[2-(5-cyclohexylmethyl- 2,5-diazabicyclo [2.2.1]hept-2- yl)ethoxy]-5- trifluoro methylphenyl}(2-methylquinolin-4- yl)amine yellow solidd 539.28
    321
    Figure US20080004312A1-20080103-C00376
         		(2-methylquinolin-4-yl)-[3-(3- piperidin-1-ylpropoxy)-5- trifluoromethylphenyl]amine yellow solid 444.21
    322
    Figure US20080004312A1-20080103-C00377
         		(3-{2-(4- methylpiperazin-1-yl]ethoxy}-5- trifluoromethyl phenyl)-(2-methyl quinolin-4-yl)amine yellow solidd 445.18
    323
    Figure US20080004312A1-20080103-C00378
         		4-methyl-1-{2- (3-(2- methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]- ethyl}piperidin-4-ol pale yellow solid 460.21
    324
    Figure US20080004312A1-20080103-C00379
         		4-ethyl-1-{2-[3- (2-methylquinolin- 4-ylamino)-5- trifluoro methylphenoxy]- ethyl) piperidin-4-ol pale yellow solidb 473.29
    325
    Figure US20080004312A1-20080103-C00380
         		[3-(3-azepan-1- yl-propoxy)-5- trifluoromethyl- phenyl]-(2-methyl- quinolin-4- yl)-amine pale yellow solid 458.27
    326
    Figure US20080004312A1-20080103-C00381
         		{3-[3-(1,4- dioxa-8-azaspiro [4.5]dec-8- yl)propoxy]-5- trifluoromethyl phenyl}(2- methylquinolin- 4-yl)amine pale yellow solid 502.39
    327
    Figure US20080004312A1-20080103-C00382
         		[3-chloro-5- (3-pipendin-1- ylpropoxy)phenyl]- (2-methylquinolin- 4-yl)amine pale yellow solid 410.31
    328
    Figure US20080004312A1-20080103-C00383
         		4-methyl-1-{3- [3-(2-methyl quinolin-4- ylamino)-5- trifluoromethyl phenoxy]propyl}piperidin- 4-ol pale yellow solidb 474.32
    329
    Figure US20080004312A1-20080103-C00384
         		4-ethyl-1-{3- [3-(2-methyl quinolin-4- ylamino)-5- trifluoromethyl phenoxy]propyl}piperidin- 4-ol pale yellow solid 486.26
    330
    Figure US20080004312A1-20080103-C00385
         		(2-methylquinolin-4-yl)[3-(4- piperidin-1-yl-butoxy)-5- trifluoromethylphenyl]amine yellow solidb 458.39
    331
    Figure US20080004312A1-20080103-C00386
         		{3-[3-(2R- 2-methylpiperidin-1- propoxy]-5- trifluoromethyl phenyl}- (2-methyl quinolin-4- yl)amine pale yellow solid 458.53
    332
    Figure US20080004312A1-20080103-C00387
         		(3-{3-[4-(3-methylbutyl) piperazin-1-yl]propoxy}-5- trifluoromethylphenyl) (2-methylquinolin-4-yl)amine pale yellow solidd 515.40
    333
    Figure US20080004312A1-20080103-C00388
         		{3-[3-(8- azabicyclo[3.2.1]oct-8-yl) propoxy]-5- trifluoromethyl phenyl}(2- methylquinolin- 4-yl)amine off- white solid 470.40
    334
    Figure US20080004312A1-20080103-C00389
         		(1-{3-[3- (2-methylquinolin-4- ylamino)-5- trifluoromethyl phenoxy]propyl}piperidin-2- yl)methanol pale yellow solid 474.23
    335
    Figure US20080004312A1-20080103-C00390
         		{3-[3-(3- methylpiperidin-1- yl)propoxy]-5- trifluoromethyl phenyl}(2- methylquinolin- 4-yl)amine pale yellow solid 458.39
    336
    Figure US20080004312A1-20080103-C00391
         		{3-[3- (bicyclo[3.3.1]non-9-ylamino) propoxy]-5- trifluoromethyl phenyl}(2- methylquinolin- 4-yl)amine off- white solid 498.29
    337
    Figure US20080004312A1-20080103-C00392
         		{3-[3-(3- azabicyclo[3.2.2]non-3-yl) propoxy]-5- trifluoromethyl phenyl}(2- methylquinolin- 4-yl)amine pale yellow solid 484.26
    338
    Figure US20080004312A1-20080103-C00393
         		{3-(3-[4- methylpiperidin-1- yl]propoxy}-5- trifluoromethyl phenyl)-(2- methylquinolin- 4-yl)amine pale yellow solidb 459.22
    339
    Figure US20080004312A1-20080103-C00394
         		{3-[3-(adamantan- 2-ylamino)- propoxy]-5- trifluoromethyl- phenyl}-(2- methyl-quinolin-4yl)- amine pale yellow solid 510.40
    340
    Figure US20080004312A1-20080103-C00395
         		{3-[3-(cis-3,5- dimethylpiperidin- 1-yl)propoxy]-5- trifluoromethyl phenyl}-(2-methyl quinolin-4-yl)amine pale yellow solid 472.30
    341
    Figure US20080004312A1-20080103-C00396
         		{3-[3-(3,3- methylpiperidin-1- yl)propoxy]-5- trifluoromethyl phenyl}-(2- methylquinolin- 4-yl)amine pale yellow solid 472.25

    adiHCl salt unless otherwise noted

    bparent compound

    csodium salt

    dtriHCl salt
    • EXAMPLE 342 N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-(5-methoxyquinolin-8-ylamino)benzamide
  • Figure US20080004312A1-20080103-C00397
    • Step 1. 3-Bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]benzamide
  • To a solution of N-2-aminoethyl tetrahydroisoquinoline (0.53 g, 3 mmol) in DMF (12 ml) were sequentially added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide HCl (0.58 g, 3 mmol), 1-hydroxybenzotriazole hydrate (0.41 g, 3 mmol), diisopropylethyl amine (1.1 ml, 6.1 mmol) then 3-bromobenzoic acid (0.6 g, 3 mmol). The mixture was stirred at room temperature for 24 hours, then water (100 ml) was added, and the mixture was extracted with ethyl acetate (3×10 ml). The organic materials were combined, dried (MgSO4) then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, gradient 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) to give amide 157 as an orange oil (0.91 g, 85%).
    • Step 2. N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-(5-methoxyquinolin-8-ylamino)benzamide
  • To a solution of the amide 157 (300 mg, 0.835 mmol) and 8-amino-5-methoxyquinoline (204 mg, 1.17 mmol) in toluene (8 ml), were sequentially added BINAP (78 mg, 15 mol %), potassium tert-butoxide (141 mg, 1.25 mmol), and tris(dibenzylidene acetone)dipalladium (0) (38 mg). The mixture was purged with nitrogen and heated under reflux for 14 hours, then mixed with water (10 ml) and extracted with ethyl acetate (3×5 ml). The organic materials were combined, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (5-70% aq acetonitrile) to give the desired product as an orange solid (217 mg, 58%).
  • The compound of Example 343 was synthesized in the same manner as for Example 342 using 1-amino-3-methylnaphthalene instead of 5-methoxyquinolin-8-ylamine. 1-Amino-3-methylnaphthalene was synthesized from 1-amino-3-methylnaphthalene-2-carbonitrile (Kobayashi, K. et al. J. Org. Chem. 1997, 62, 664) using a literature procedure (Mirek, J., Sepiol, J. Ange. Chemie Int. Ed. Eng. 1973, 12, 837).
    • EXAMPLE 344 N-[2-(4-benzylpiperidin-1-yl)ethyl]-N-[3-(2-methylquinolin-4-ylamino)phenyl]methanesulfonamide
  • Figure US20080004312A1-20080103-C00398
    • Step 1. N-(3-Nitrophenyl)methanesulfonamide
  • To a solution of 3-nitroaniline (3.00 g, 21.72 mmol) in THF (75 mL) were sequentially added pyridine (4.29 g, 54.30 mmol) and methanesulfonyl chloride (6.20 g, 54.14 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours before the reaction was quenched with water (50 mL). The mixture was extracted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried over MgSO4 and concentrated on a rotavap to afford the desired 158 as a yellow solid (3.94 g, 84% yield).
    • Step 2. N-(2-Chloroethyl)-N-(3-nitrophenyl)methanesulfonamide
  • To a solution of 158 (1.023 g, 4.73 mmol) in DMF (19 mL) were sequentially added NaH (60% dispersion in mineral oil, 290 mg, 7.25 mmol) and 1-bromo-2-chloroethane (1.361 g, 9.49 mmol) at room temperature. The resulting mixture was stirred at room temperature for 89 hours before the reaction was quenched with water (40 mL). The mixture was acidified with conc. HCl (1 mL), extracted with ethyl acetate (50 mL), and washed with water (2×40 mL). The organic layer was dried over MgSO4 and concentrated on a rotavap to give a 1:1 mixture of product 158 and the desired product 159 as a mixture (805 mg, 30% yield).
    • Step 3. N-[2-(4-Benzylpiperidin-1-yl)ethyl]-N-(3-nitrophenyl)methanesulfonamide
  • To a solution of the 1:1 mixture of 158 and 159 (805 mg) in DMF (5.1 mL) were sequentially added Na2CO3 (218 mg, 2.06 mmol) and 4-benzylpiperidine (197 mg, 1.12 mmol) at room temperature. The resulting mixture was heated at 100° C. for 53 hours before the reaction was diluted with EtOAc (50 mL). The mixture was extracted with ethyl acetate (2×50 mL) and washed with water (2×40 mL). The organic layer was dried over MgSO4, concentrated on a rotavap, and the residue chromatographed on silica gel (1:1 to >1:6 hexanes/ethyl acetate) to afford the desired product 160 as a yellow oil (238 mg, 51%).
    • Step 4. N-[2-(4-benzylpiperidin-1-yl)ethyl]-N-[3-(2-methylquinolin-4-ylamino)phenyl]methanesulfonamide
  • The title compound was synthesized in the same manner as for Example 67, Steps 4 and 5 using 160.
    • EXAMPLE 345 3-(4-Benzylpiperidin-1-yl)-1-[3-(2-methylquinolin-4-ylamino)phenyl]propan-1-ol
  • To a solution of Example 209 (0.15 g, 0.32 mmol) in THF (5.0 ml) was added LAH (1.0 M in THF, 0.66 ml, 0.66 mmol) at 0° C. The mixture was stirred at room temperature overnight before it was quenched with Na2SO4.10H2O (pellets) until no further bubbles was observed.
  • The mixture was diluted with ethyl acetate and the solids filtered. The filterate was washed with water (50 ml), brine (50 ml), dried over MgSO4 and concentrated on a rotovap to give the desired alcohol as a yellow solid (0.04 g, 27%).
    • EXAMPLE 346 N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-(2-methylquinolin-4-yloxy)benzamide
  • Figure US20080004312A1-20080103-C00399
    • Step 1. 4-(3-Isocyanophenoxy)-2-methylquinoline
  • To a solution of 4-chloroquinolidine (5) (1.18 g, 10 mmol) and 3-cyanophenol (1.19 g, 10 mmol) in DMF (50 ml) was added potassium tert-butoxide (1.23 g, 11 mmol). The mixture was heated under reflux for 18 hours, then mixed with water (200 ml). The mixture was extracted with methylene chloride (3×15 ml), and the extracts were combined, washed with water (50 ml), brine (50 ml), and dried (MgSO4). The solution was concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, gradient hexane to 2:1 hexane/ethyl acetate) to give product 161 as a pale yellow oil (1.9 g, 73%).
    • Step 2. 3-(2-Methylquinolin-4-yloxy)benzoic acid
  • To a solution of nitrile 161 (1.9 g, 7.29 mmol) in 1,2-dimethoxyethane (10 ml) was added 4 M NaOH (2 ml). The mixture was heated under reflux for 18 hours, then cooled and neutralized (to pH 7) by the addition of concentrated HCl. The solids were collected by filtration, and dried under vacuum to give product 162 as a white solid (1.4 g, 69%) which was used without further purification.
    • Step 3. N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-(2-methylquinolin-4-yloxy)benzamide
  • Carboxylic acid 162 (264 mg, 0.95 mmol) was dissolved in 1,2-dichloroethane (1 ml) and thionyl chloride (0.1 ml, 1.1 mmol) was added. The mixture was warmed at 60° C. for 10 min, then concentrated under reduced pressure. The residue was mixed with 1,2-dichloroethane (2 ml) then treated with a solution of N-2-aminoethyltetrahydroisoquinoline (36) (100 mg, 0.56 mmol) and N,N-diisopropyl-ethylamine (0.11 ml, 0.6 mmol) in 1,2-dichloroethane (1 ml). The mixture was stirred at room temperature overnight, then washed with water (10 ml), then saturated sodium chloride solution (10 ml) and dried (MgSO4). The solution was concentrated under reduced pressure, and a portion of the residue was purified by reverse-phase HPLC (5-70% aq acetonitrile) to provide 18 mg of the title compound as an orange solid.
    • EXAMPLE 347 (3-{2-[2-(4-Benzylpiperidin-1-yl)ethyl][1,3]dioxan-2-yl}phenyl)(2-methylquinolin-4-yl)amine
  • To the mixture of the compound of Example 209 (0.31 g, 0.67 mmol) in toluene/propane-1,3-diol (7 ml/7 ml) was added p-TsOH (0.32 g, 1.68 mmol) at room temperature. The resulting mixture was heated under reflux in a Dean-Stark setup overnight before the reaction was diluted with EtOAc (80 ml). The mixture was washed with 1 N NaOH (2×50 ml) and brine (50 ml). The organic layer was dried over Na2SO4 and concentrated on a rotavap to dryness.
  • The residue was purified by reverse phase HPLC to afford the desired product as an off-white solid (74 mg, 42% with 50% starting material recovered).
  • The compound of Example 348 was synthesized in the same manner as for Example 191 using 1-benzylpiperazine instead of compound 36.
    • EXAMPLE 349 trans-[3-(4-Benzylaminocyclohexyloxy)phenyl](2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00400
    • Step 1. 1,4-Dioxa-spiro[4.5]dec-8-yl methanesulfonate
  • To a solution of 1,4-cyclohexandione monoethylene ketal (1.0 g, 6.4 mmol) in ethanol (30 ml) was added sodium borohydride (0.4 g, 10 mmol) in small portions at 0° C. and the mixture was stirred at room temperature overnight. The reaction was then quenched by the cautious addition of glacial acetic acid (˜2 ml) and the mixture was stirred an additional 30 minutes, then concentrated under reduced pressure. The residue was mixed with ethyl acetate (20 ml) and brine (20 ml), then the organic materials were separated, dried (MgSO4) and concentrated under reduced pressure. To a solution of the residue in methylene chloride (30 ml) were sequentially added triethylamine (1.67 ml, 12 mmol) and methane sulfonyl chloride (0.74 g, 6.5 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and mixed with water (30 ml). The organic layer was separated, dried (MgSO4) then concentrated under reduced pressure to give product 163 as a clear oil (1.33 g, 89%).
    • Step 2. [3-(1,4-Dioxaspiro[4.5]dec-8-yloxy)phenyl](2-methylquinolin-4-yl)amine
  • To a solution of 3-(2-methylquinolin-4-ylamino)phenol (20) (0.5 g, 2 mmol) in DMF (8 ml) were sequentially added K2CO3 (0.55 g, 4 mmol) and a solution of 1,4-dioxaspiro[4,5]dec-8-yl methanesulfonate (163, 0.47 g, 2 mmol) in DMF (2 ml). The mixture was heated at 80° C. under nitrogen for 24 hours, then cooled and diluted with water (30 ml). The mixture was extracted with ethyl acetate (3×5 ml) and the organic materials were combined, dried (MgSO4) then concentrated under reduced pressure to give product 164 as a pale yellow oil (0.75 g, 98%).
    • Step 3. 4-[3-(2-Methylquinolin-4-ylamino)phenoxy]cyclohexanone
  • Compound 164 was dissolved in THF (10 ml) and acetone (3 ml), then 2 N aqueous HCl (5 ml) was added and the mixture was stirred at 50° C. overnight. The reaction was cooled to room temperature and neutralized (pH 7) with 2 N NaOH, then extracted with 7:3 methylene chloride/methanol (3×8 ml). The extracts were combined, washed with saturated sodium bicarbonate (15 ml) then dried (K2CO3) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) to give 165 170 mg (25%).
    • Step 4. trans-[3-(4-Benzylaminocyclohexyloxy)phenyl](2-methylquinolin-4-yl)amine
  • The ketone 165 obtained in the previous step was mixed with ethanol (1 ml), benzylamine (56 mg, 0.52 mmol) and 4 Å molecular sieves (25 mg), and the mixture was heated under reflux overnight. The solution was then cooled to room temperature and sodium borohydride (40 mg, 1.06 mmol) was added, and the reaction was stirred at room temperature overnight before it was quenched by the addition of glacial acetic acid (0.5 ml). The mixture was concentrated under reduced pressure and the residue was partitioned between water (1.5 ml) and 7:3 methylene chloride/methanol (1.5 ml). The organic material was separated, concentrated and a portion was purified by reverse-phase HPLC (10-70% aq. acetonitrile) to give the desired product as a pale yellow solid (35 mg).
    • EXAMPLE 350 1-Benzylamino-3-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]-2S-propan-2-ol
  • Figure US20080004312A1-20080103-C00401
    • Step 1. (2-Methylquinolin-4-yl)(3-oxiranylmethoxy-5-trifluoromethylphenyl)amine
  • To a solution of 116 (467 mg, 1.47 mmol) in DMF (9.7 mL) were sequentially added K2CO3 (509 mg, 3.68 mmol) and (2S)-(+)-glycidyl tosylate (497 mg, 2.18 mmol) at room temperature. The resulting mixture was stirred at 60° C. for 7 hours before the reaction was diluted with ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (2×50 mL) and washed with water (2×30 mL). The organic layer was dried over MgSO4 and concentrated on a rotavap to give the desired 166 as a pale yellow solid (124 mg, 23%).
    • Step 2. 1-Benzylamino-3-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]-2S-propan-2-ol
  • To a solution of 166 (114 mg, 0.305 mmol) in methanol (3.1 mL) was added benzylamine (39 mg, 0.366 mmol) at room temperature. The resulting mixture was heated at 70° C. for 17 hours before the solvent was evaporated. The residue was chromatographed on silica gel (1:4 hexanes/ethyl acetate to >4/1 dichloromethane/methanol), then further purified on reversed-phase HPLC (20% to >50% 95:5 acetonitrile:water) to afford the desired produect as a colorless film (5.5 mg, 4%).
  • The compounds of Examples 351 to 353 were synthesized in the same manner as for Example 350.
    • EXAMPLE 354 [3-(1-Benzylpyrrolidin-3R-3-yloxy)-5-trifluoromethylphenyl](2-methylquinolin-4-yl)amine
  • Figure US20080004312A1-20080103-C00402
    • Step 1. 1-Benzylpyrrolidin-3-ol
  • To a solution of (R)-pyrrolidine-3-ol (0.24 g, 2.75 mmol) and benzyl bromide (0.56 g, 3.28 mmol) in DMF (10 ml) was added K2CO3 (0.49 g, 3.54 mmol, 1.3 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight before it was diluted with EtOAc (80 ml). The organic layer was washed with water (3×50 ml), brine (50 ml), dried over Na2SO4 and concentrated on a rotavap to give the desired product 167 as a yellow oil 0.15 g, 32%).
    • Step 2.1-Benzyl-3R-3-(3-nitro-5-trifluoromethylphenoxy)pyrrolidine
  • To a solution of 167 (0.15 g, 0.85 mmol) and 1,3-dinitro-5-trifluoromethylbenzene (0.19 g, 0.85 mmol) in DMF (5 ml) was added K2CO3 (0.23 g, 1.70 mmol) at room temperature. The resulting mixture was heated at 80° C. overnight before the reaction was diluted with EtOAc (60 ml). The organic layer was washed with water (30 ml), brine (30 ml), dried over Na2SO4 and concentrated on a rotavap. The residue was chromatographed on silica gel to give the desired product 168 as a yellow oil (0.11 g, 37%).
    • Step 3. [3-(1-Benzylpyrrolidin-3 R-3-yloxy)-5-trifluoromethylphenyl](2-methylquinolin-4-yl)amine
  • The title compound was synthesized in the same manner as for Example 67, last 3 steps using 168.
  • The compound of Example 355 was synthesized in the same manner as for Example 350.
  • The compound of Example 356 was synthesized in the same manner as for Example 354.
  • The compound of Example 357 was synthesized in the same manner as for Example 350.
    Ex-
    am-
    ple physical
    # structure chemical name descriptiona [M + H]+
    342
    Figure US20080004312A1-20080103-C00403
         		N-[2-(3,4-dihydro-1H- isoquinolin-2-yl) ethyl]-3-(5- methoxyquinolin-8- ylamino) benzamide orange solidb 453.18
    343
    Figure US20080004312A1-20080103-C00404
         		N-[2-(3,4-dihydro-1H- isoquinolin- 2-yl) ethyl]-3-(3- methylnaphthalen-1- ylamino)benzamide orange solidb 436.20
    344
    Figure US20080004312A1-20080103-C00405
         		N-[2-(4-benzylpiperidin- 1-yl) ethyl]- N-[3-(2-methylquinolin-4- ylamino)- phenyl]methanesulfonamide pale yellow solidb 529.21
    345
    Figure US20080004312A1-20080103-C00406
         		3-(4-benzylpiperidin-1-yl)- 1-[3-(2-methylquinolin-4-yl amino)phenyl]propan-1-ol pale yellow solid 466.27
    346
    Figure US20080004312A1-20080103-C00407
         		N-[2-(3,4-dihydro-1H- isoquinolin- 2-yl) ethyl]-3-(2-methylquinolin- 4-yl oxy)benzamide orange solidb 438.15
    347
    Figure US20080004312A1-20080103-C00408
         		(3-{2-[2-(4-benzylpiperidin- 1-yl) ethyl][1,3]dioxan-2- yl}phenyl) (2-methylquinolin-4- yl)amine light yellow solid 522.18
    348
    Figure US20080004312A1-20080103-C00409
         		[8-(4-benzylpiperazin-1-yl)- 5,6,7,8- tetrahydronaphthalen-2- yl](2-methylquinolin- 4-yl)amine yellow solidd 463.21
    349
    Figure US20080004312A1-20080103-C00410
         		trans-[3-(4- benzylaminocyclohexyloxy) phenyl](2-methylquinolin- 4-yl)amine pale yellow solidb 438.44
    350
    Figure US20080004312A1-20080103-C00411
         		1-benzylamino-3-[3- (2-methyl quinolin-4-ylamino)-5- trifluoromethylphenoxy]-2S- propan-2-ol pale yellow solid 482.30
    351
    Figure US20080004312A1-20080103-C00412
         		1-benzylamino-3-[3- (2-methyl quinolin-4-ylamino)-5- trifluoromethylphenoxy]-2R- propan-2-ol pale yellow solidb 482.17
    352
    Figure US20080004312A1-20080103-C00413
         		1-[3-(2-methylquinolin-4- ylamino)-5- trifluoromethyl- phenoxy]-3-(4- phenylpiperidin-1-yl)- 2S-propan-2-ol white solidb
    353
    Figure US20080004312A1-20080103-C00414
         		1-(Benzyl-methyl-amino)-3- [3-(2-methyl-quinolin-4-yl- amino)-5-trifluoromethyl- phenoxy]-2S-propan-2-ol yellow solidb 496.15
    354
    Figure US20080004312A1-20080103-C00415
         		[3-(1-benzylpyrrolidin-3R-3- yloxy)-5- trifluoromethylphenyl](2- methyl quinolin-4-yl)amine light yellow solid 478.08
    355
    Figure US20080004312A1-20080103-C00416
         		4-benzyl-1-{2S-2-hydroxy- 3-[3-(2- methylquinolin-4- ylamino)-5- trifluoromethylphenoxy]propyl}piperidin-4-ol pale yellow solidb 566.26
    356
    Figure US20080004312A1-20080103-C00417
         		[3-(1-benzhydrylpyrrolidin- 3R-3-yloxy)-5- trifluoromethylphenyl](2- methyl quinolin-4-yl)amine light yellow solid 554.18
    357
    Figure US20080004312A1-20080103-C00418
         		1-[3-(2-methylquinolin-4-yl amino)-5-trifluoromethyl phenoxy]-3-piperidin-1-yl- 2S-propan-2-ol pale yellow solidb

    adiHCl salt unless otherwise noted

    bparent compound

    csodium salt

    dtriHCl salt
  • The compound of Example 358 was synthesized in the same manner as for Example 68.
  • The compounds of Examples 359 to 362 were synthesized in the same manner as for Example 67.
    • EXAMPLE 363 Ethyl 4-phenyl-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidine-4-carboxylate
  • Figure US20080004312A1-20080103-C00419
    • Step 1. Ethyl 4-phenylpiperidine-4-carboxylate
  • To a solution of 4-phenylpiperidine-4-carboxylic acid p-toluenesulfonate (0.94 g, 2.49 mmol) in EtOH (10 ml) was added conc. H2SO4 (5 drops). The resulting solution was heated under reflux overnight before the solvent was removed on a rotavap. The residue was brought into EtOAc (80 ml) which was washed with 1N NaOH (3×60 ml) and brine (50 ml). The organic layer was dried over Na2SO4 and concentrated on a rotavap to give the desired product 169 as coloreless oil (0.40 g, 69%).
    • Step 2. Ethyl 4-phenyl-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidine-4-carboxylate
  • The title compound was synthesized in the same manner as for Example 67, see last 3 steps using 169.
  • The compound of Example 364 was synthesized in the same manner as for Example 68 using the product of Example 363.
  • The compound of Example 365 was synthesized in the same manner as for Example 67.
  • The compound of Example 366 was synthesized in the same manner as for Example 68.
  • The compound of Example 367 was synthesized in the same manner as for Example 67.
  • The compound of Example 368 was synthesized in the same manner as for Example 68.
    • EXAMPLE 369 1-{2-[3-Chloro-5-(2-methylquinolin-4-ylamino)phenoxy]ethyl}-4-phenylpiperidine-4-carboxylic acid Step 1. Ethyl 1-{2-[3-chloro-5-(2-methylquinolin-4-ylamino)phenoxy]ethyl}-4-phenylpiperidine-4-carboxylic acid
  • See Step 4 in Example 268.
    • Step 2.-{2-[3-Chloro-5-(2-methylquinolin-4-ylamino)phenoxy]ethyl}-4-phenylpiperidine-4-carboxylic acid
  • The title compound was synthesized in the same manner as for Example 68.
  • The compound of Example 370 was synthesized in the same manner as for Example 67.
  • The compound of Example 371 was synthesized in the same manner as for Example 68.
    • EXAMPLE 372 1-{2-[3-Fluoro-5-(2-methylquinolin-4-ylamino)phenoxy]ethyl}-4-phenyl-piperidine-4-carboxylic acid
  • Figure US20080004312A1-20080103-C00420
    • Step 1. 1-Fluoro-3-methoxy-5-nitrobenzene
  • In a 100 ml flask, boron trifluoride etherate (1.63 ml, 12.93 mmol) was cooled in an ice bath and a solution of 3-methoxy-5-nitrophenylamine (1.45 g, 8.62 mmol) in DME (25 ml) was added slowly. The mixture was stirred for 5 minutes then a solution of i-amyl nitrite (1.4 ml, 10.3 mmol) in DME (20 ml) was added slowly while the temperature was maintained below 5° C. The thick slurry was stirred for an additional hour before the solids were collected by filtration and washed with cold DME (10 ml) and dried under vacuum. The resulting diazonium tetrafluoroborate salt was pyrolyzed under a slight stream of nitrogen which gave 3-fluoro-5-nitroanisole (170) as a dark solid (0.9 g, 61%).
    • Step 2. 3-Fluoro-5-methoxyphenylamine
  • Compound 170 was dissolved in methanol (25 ml) and was treated with zinc powder (1.96 g, 30 mmol) then saturated ammonium chloride solution (20 ml) in small portions. The mixture was stirred vigorously for 5 hours then filtered through a pad of Celite® and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (25 ml) and brine (20 ml). The organic material was separated, dried (MgSO4) then concentrated under reduced pressure. The residue was flushed through a pad of silica gel with 3:1 hexane/ethyl acetate to give 3-fluoro-5-methoxyaniline (171) as a yellow solid (0.404 g, 54%).
    • Step 3. 1-{2-[3-Fluoro-5-(2-methylquinolin-4-ylamino)phenoxy]ethyl}-4-phenyl-piperidine-4-carboxylic acid
  • The title compound was synthesized in the same manner as for Example 369 using 3-fluoro-5-methoxyphenylamine (171) instead of 3-chloro-5-methoxyphenylamine.
    Ex-
    am-
    ple physical
    # structure chemical name descriptiona [M + H]+
    358
    Figure US20080004312A1-20080103-C00421
         		4-benzyl-1-{2-[3-(2-methyl quinolin-4-ylamino)-5- trifluoromethyl phenoxy]ethyl}piperidine- 4-carboxylic acid yellow solid 464.42
    359
    Figure US20080004312A1-20080103-C00422
         		methyl 4-(4-chlorobenzyl)- 1-{2-[3-(2-methyl-quinolin- 4-ylamino)phenoxy]ethyl}piperidine-4-carboxylate pale yellow solid 544.22
    360
    Figure US20080004312A1-20080103-C00423
         		methyl 4-(2-chlorobenzyl)- 1-{2-[3-(2-methyl-quinolin- 4-ylamino)phenoxy]ethyl}piperidine-4-carboxylate pale yellow solid 544.20
    361
    Figure US20080004312A1-20080103-C00424
         		ethyl 4-benzyl-1- {2-[3-(2-methyl-quinolin- 4-ylamino)phenoxy]ethyl}piperidine-4-carboxylate pale yellow solid 524.27
    362
    Figure US20080004312A1-20080103-C00425
         		methyl 4-(2-methylbenzyl)- 1-{2-[3-(2-methylquinolin- 4-ylamino)-5-trifluoromethyl phenoxy]ethyl}piperidine- 4-carboxylate off-white solid 592.40
    363
    Figure US20080004312A1-20080103-C00426
         		ethyl 4-phenyl-1- {2-[3-(2-methylquinolin- 4-ylamino)-5-trifluoromethyl phenoxy]ethyl}piperidine- 4-carboxylate off-white solid 578.27
    364
    Figure US20080004312A1-20080103-C00427
         		4-phenyl-1-{2-[3-(2-methyl- quinolin-4-ylamino)-5- trifluoromethyl phenoxy]ethyl}piperidine- 4-carboxylic acid off-white solid 550.25
    365
    Figure US20080004312A1-20080103-C00428
         		methyl 4-(3,5- dimethylphenyl)-1-{2-[3- (2-methylquinolin-4- ylamino)-5-trifluoromethyl phenoxy]ethyl}piperidine- 4-carboxylate white foamb 592.16
    366
    Figure US20080004312A1-20080103-C00429
         		4-(3,5-dimethylphenyl)- 1-{2-[3-(2-methylquinolin- 4-ylamino)-5- trifluoromethyl phenoxy]ethyl}piperidine- 4-carboxylic acid off-white solid 578.27
    367
    Figure US20080004312A1-20080103-C00430
         		methyl 1-{2-[3-(2-methyl quinolin-4-ylamino)-5- trifluoromethylphenoxy]- ethyl}-4-(3- trifluoromethylphenyl)- piperidine-4-carboxylate yellowish solidb 632.27
    368
    Figure US20080004312A1-20080103-C00431
         		1-{2-[3-(2-methyl quinolin-4-ylamino)-5- trifluoromethylphenoxy]- ethyl}-4-(3- trifluoromethylphenyl)- piperidine-4-carboxylic acid yellowish solid 618.18
    369
    Figure US20080004312A1-20080103-C00432
         		1-{2-[3-chloro-5-(2-methyl quinolin-4-ylamino)phenoxy]ethyl}-4-phenyl piperidine-4-carboxylic acid pale yellow solid 516.36
    370
    Figure US20080004312A1-20080103-C00433
         		methyl 1-{2-[3-(2-methyl quinolin-4-ylamino)-5- trifluoromethylphenoxy]- ethyl}-4-(4- trifluoromethylphenyl)- piperidine-4-carboxylate yellowish solidb 632.31
    371
    Figure US20080004312A1-20080103-C00434
         		1-{2-[3-(2-methyl quinolin-4-ylamino)-5- trifluoromethylphenoxy]- ethyl}-4-(4- trifluoromethylphenyl)- piperidine-4-carboxylic acid yellow solid 618.31
    372
    Figure US20080004312A1-20080103-C00435
         		1-{2-[3-fluoro-5-(2-methyl quinolin-4-ylamino) phenoxy]ethyl}-4-phenyl- piperidine-4-carboxylic acid pale yellow solid 500.23

    adiHCl salt unless otherwise noted

    bparent compound

    csodium salt

    dtriHCl salt
  • Representative additional analogs of compounds of the present invention include:
    Figure US20080004312A1-20080103-C00436
    Figure US20080004312A1-20080103-C00437
    Figure US20080004312A1-20080103-C00438
    Figure US20080004312A1-20080103-C00439

Claims (12)

1. A compound of the formula
Figure US20080004312A1-20080103-C00440
wherein Ar is selected from the group consisting of aryl, heteroaryl, benzoheteroaryl, pyridone, pyridazinone, and pyrimidone;
R1 and R2 are independently H, alkyl, cycloalkyl, bicyclic alkyl, adamantyl, aralkyl, aryl, R7CO, or R8OCO or R1 and R2 along with N can form a cyclic or bicyclic heterocyclic ring system or R1 and L1 or R1 and one carbon of (CH2)n can form a 5, 6, or 7 membered ring;
R3 is H, alkyl or aralkyl;
X and Y are independently C or N;
R4, R5, and R6 are independently selected from the group consisting of H, alkyl, aralkyl, aryl, heteroaryl, benzoheteroaryl, hydroxyl, halo, haloalkyl, alkoxy, aminocarbonyl and aminosulfonyl or R5 and R6 together can form a 5-6 membered aromatic ring or a 5-7 membered aliphatic ring;
L1 is selected from the group consisting of a single bond, O, NR9, CO, COO, OCO, SO2, NR10CO, NR11SO2, NR12CONR13, NR14SO2NR15, CH2CHOHCH2, arene heteroarene, pyridine, pyrimidone and pyridazinone;
L2 and L3 are independently selected from the group consisting of a single bond, CH2, NR16, CO and SO2;
L4 is (Z)n where each Z is independently CH2, CR17R18, CO, NR19, CONR20 or NR21CO, any two adjacent Zs may be replaced with a double or triple bond or R17, R18 or two R17s can form a 5-8 membered aliphatic ring or R17 and Ar can form a fused 5-8 membered aliphatic ring; n is an integer from 0 to 6; and
R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20 and R21 are independently selected from the group consisting of H, alkyl, aryl and aralkyl, R16 is also alkylsulfonyl or alkylcarbonyl or R10 and CO and Ar can form pyridone, pyridazinone, and pyrimidone, and the pharmaceutically acceptable salts thereof.
2. A compound of claim 1 of the formula
Figure US20080004312A1-20080103-C00441
wherein each R15 is independently H, alkyl, aralkyl, haloalkyl, aryl, heteroaryl, benzoheteroaryl, alkoxy, aminocarbonyl or aminosulfonyl and two of R15 can form a 5-6 membered aromatic ring or a 5-7 membered aliphatic ring;
m is 0-3; and
R1, R2, R4, R5, R6, n, X and Y are as defined in claim 1, and the pharmaceutically acceptable salts thereof.
3. A compound of claim 1 of the formula:
Figure US20080004312A1-20080103-C00442
wherein each R15 is independently H, alkyl, aralkyl, haloalkyl, aryl, heteroaryl, benzoheteroaryl, alkoxy, aminocarbonyl or aminosulfonyl and two of R15 can form a 5-6 membered aromatic ring or a 5-7 member aliphatic ring;
M is 0-3; and
R1, R2, R4, R5, R6, n and X are as defined in claim 1, and the pharmaceutically acceptable salts thereof.
4. A compound of claim 1 selected from the group consisting of:
{4-Chloro-3-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;
{3-[2-(4-Benzyl-piperidin-1-yl)ethoxy]phenyl)-(2-methylquinolin-4-yl)amine;
{4-Chloro-3-[2-(4-phenylpiperidin-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;
{3-[2-(4-Benzylpiperazin-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;
{3-[2-(Benzylmethylamino)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;
{3-[2-(4-Benzylpiperidin-1-yl)ethoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine;
{3-[3-(4-Benzylpiperidin-1-yl)propoxy]phenyl}-(2-methylquinolin-4-yl)amine;
{3-[2-(1-Methyl-1-phenylethylamino)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;
[3-(2-Benzylaminoethoxy)phenyl]-(2-methylquinolin-4-yl)amine;
1-(1-{2-[3-(2-Methylquinolin-4-ylamino)phenoxy]ethyl}-4-phenylpiperidin-4-yl)ethanone;
[3-(3-Benzylaminopropoxy)phenyl]-(2-methylquinolin-4-yl)amine;
{3-[2-(2-Benzylimidazol-1-yl)ethoxy]phenyl)-(2-methylquinolin-4-yl)amine;
1-{2-[3-(2-Methylquinolin-4-ylamino)phenoxy]ethyl}piperidin-4-yl)diphenylmethanol;
4-Benzyl-1-{2-[3-(2-tert-butylquinolin-4-ylamino)phenoxy]ethyl)piperidin-4-ol;
4-Benzyl-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidin-4-ol;
{3-[2-(4-Benzylpiperidin-1-yl)ethoxy]phenyl}-(2,6-dimethylpyrimidin-4-yl)amine;
{3-[2-(5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;
{3-[2-(4-Benzylpiperazin-1-yl)ethoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine;
(2-Methylquinolin-4-yl)-{3-[2-(4-phenylpiperidin-1-yl)ethoxy]-5-trifluoromethyl phenyl}amine;
{3-[3-(1-Methyl-1-phenylethylamino)propoxy]phenyl}-(2-methylquinolin-4-yl)amine.
{3-[2-(5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine;
N-(2-{1-[2-(3-Fluorophenyl)ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}ethyl)-3-(2-methylquinolin-4-ylamino)benzamide;
N-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-(2-methylquinolin-4-ylamino)benzamide;
N-[2-(1,3-Dihydroisoindol-2-yl)ethyl]-3-(2-methylquinolin-4-ylamino)benzamide;
N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2-methyl-5-(2-methylquinolin-4-ylamino)benzamide;
N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2-hydroxy-5-(2-methylquinolin-4-ylamino)benzamide;
N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-(2-trifluoromethylquinolin-4-ylamino)benzamide;
N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2,4,6-trimethyl-3-(2-methylquinolin-4-ylamino)benzamide;
2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-4-(2-methylquinolin-4-ylamino)-2,3-dihydroisoindol-1-one;
3-(2-Methylquinolin-4-ylamino)-N-[2-(1,3,4,5-tetrahydrobenzo[c]azepin-2-yl)ethyl]benzamide;
N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2,5-bis(2-methylquinolin-4-ylamino)benzamide;
3-(2-Methylquinolin-4-ylamino)-N-[2-(octahydro-cis-isoquinolin-2-yl)ethyl]benzamide;
N-(2-Azepan-1-ylethyl)-3-(2-methylquinolin-4-ylamino)benzamide;
N-(2-Benzylaminoethyl)-3-(2-methylquinolin-4-ylamino)benzamide;
4-({2-[3-(2-Methylquinolin-4-ylamino)-benzoylamino]ethylamino}methyl)benzoic acid;
N-[2-(2,2-Dimethylpropylamino)ethyl]-3-(2-methylquinolin-4-ylamino)benzamide;
N-[2-(4-Benzylpiperazin-1-yl)ethyl]-3-(2-methylquinolin-4-ylamino)benzenesulfonamide;
(3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)isoxazol-3-yl]phenyl}-(2-methylquinolin-4-yl)amine;
{3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)propyl]-4-methylphenyl}-(2-methylquinolin-4yl)amine;
N1-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-N7-(2-methylquinolin-4-yl)-1,2,3,4-tetrahydronaphthalene-1,7-diamine;
[3′-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-yl]-(2-methylquinolin-4-yl)amine;
{3-[2-(4-Benzylpiperidin-1-yl)ethanesulfonyl]phenyl}-(2-methylquinolin-4-yl)amine;
N-[2-(4-Benzylpiperidin-1-yl)ethyl]-N′-(2-methylquinolin-4-yl)pyrimidine-4,6-diamine; and
3-(4-Benzylpiperidin-1-yl)-1-[3-(2-methylquinolin-4-ylamino)phenyl]propan-1-one oxime.
5. A compound of the formula
Figure US20080004312A1-20080103-C00443
wherein A is a negatively ionizable group under physiological conditions;
X1—Y1-Z1 is C, C(R)qC or C(R)qN;
L4 is L5Ar′L6 or X2Y2Z2;
Ar′ and Ar″ are each independently aryl or heteroaryl;
L5 and L6 are each independently a bond, N, O, S, or X2Y2Z2 where
X2 and Z2 are each independently C, N or O and
Y2 is CO, SO, or SO2;
R is CR17R18;
m, n, p and q are independently an integer from (0 to 6) provided that m and n cannot both be 0; and
R16, R17 and R18 are each independently H, alkyl, arakyl, aryl, heteroaryl, hydroxyl, alkoxy, aryloxy, amino, aminocarbonyl, aminosulfonyl provided that when A is CO2H and X1—Y1-2 is C, then X2Y22 is not NCON; and the pharmaceutically acceptable salts thereof.
6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
7. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier or excipient.
8. A method of treating conditions associated with urotensin-II imbalance by antagonizing the urotensin-II receptor which comprises administering to a patient in need thereof, a compound of claim 5.
9. A method of treating conditions associated with urotensin-II imbalance by antagonizing the urotensin-II receptor which comprises administering to a patient in need thereof, a compound of claim 1.
10. A method of treating conditions associated with urotensin-II imbalance by antagonizing the urotensin-II receptor which comprises administering to a patient in need thereof, a compound of claim 5.
11. A method according to claim 9 wherein the condition is selected from the group consisting of congestive heart failure, stroke, ischemic heart disease, angina, myocardial ischemia, cardiac arrhythmia, essential and pulmonary hypertension, renal disease, acute and chronic renal failure, end stage renal disease, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease, ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis, pulmonary fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders, Alzheimers disease, impulsivity, anxiety, stress, depression, Parkinsons, movement disorders, sleep-wake cycle, inventive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
12. A method according to claim 10 wherein the condition is selected from the group consisting of congestive heart failure, stroke, ischemic heart disease, angina, myocardial ischemia, cardiac arrhythmia, essential and pulmonary hypertension, renal disease, acute and chronic renal failure, end stage renal disease, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease, ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis, pulmonary fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders, Alzheimers disease, impulsivity, anxiety, stress, depression, Parkinsons, movement disorders, sleep-wake cycle, inventive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
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