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WO2011119693A1 - Trpv4 antagonists - Google Patents

Trpv4 antagonists Download PDF

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Publication number
WO2011119693A1
WO2011119693A1 PCT/US2011/029570 US2011029570W WO2011119693A1 WO 2011119693 A1 WO2011119693 A1 WO 2011119693A1 US 2011029570 W US2011029570 W US 2011029570W WO 2011119693 A1 WO2011119693 A1 WO 2011119693A1
Authority
WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
phenyl
quinolinecarboxamide
phenylethyl
bipiperidin
Prior art date
Application number
PCT/US2011/029570
Other languages
French (fr)
Inventor
Carl A. Brooks
Mui Cheung
Ryan M. Fox
Krista B. Goodman
Mark A. Hilfiker
Guosen Ye
Original Assignee
Glaxosmithkline Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Llc filed Critical Glaxosmithkline Llc
Publication of WO2011119693A1 publication Critical patent/WO2011119693A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings

Definitions

  • the present invention relates to quinoline analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.
  • TRPV4 is a member of the Transient Receptor Potential (TRP) superfamily of cation channels and is activated by heat, demonstrating spontaneous activity at physiological temperatures (Guler et al., 2002. J Neurosci 22. 6408-6414). Consistent with its polymodal activation property TRPV4 is also activated by hypotonicity and physical cell stress/pressure (Strotmann et al., 2000. Nat Cell Biol 2: 695-702), through a mechanism involving phospholipase A2 activation, arachidonic acid and epoxyeicosatrienoic acid generation (Vriens et al., 2004.
  • TRP Transient Receptor Potential
  • tyrosine kinase activity may also regulate TRPV4 (Wegierski et al., 2009. J Biol Chem. 284: 2923-33).
  • Heart failure results in the decreased ability of the left ventricle to pump blood into the peripheral circulation as indicated by a reduced ejection fraction and/or left ventricular dialation. This increases the left ventricular end diastolic pressure resulting in enhanced pulmonary blood pressures. This places the septal barrier, which separates the circulatory aqueous environment and the alveolar airspaces of the lung, at risk. Increased pulmonary pressure results in the flow of fluid from the pulmonary circulation into the alveolar space resulting in lung edema/congestion, as is observed in patients with congestive heart failure.
  • TRPV4 is expressed in the lung (Delany et al., 2001. Physiol. Genomics 4: 165- 174) and has been shown to mediate Ca 2+ entry in isolated endothelial cells and in intact lungs (Jian et al., 2009 Am J Respir Cell Mol Biol 38: 386-92). Endothelial cells are responsible for forming the capillary vessels that mediate oxygen/carbon dioxide exchange and contribute to the septal barrier in the lung.
  • TRPV4 channels Activation of TRPV4 channels results in contraction of endothelial cells in culture and cardiovascular collapse in vivo (Willette et al., 2008 J Pharmacol Exp Ther 325: 466-74), at least partially due to the enhanced filtration at the septal barrier evoking lung edema and hemorrage (Alvarez et al., 2006. Circ Res 99: 988-95). Indeed filtration at the septal barrier is increased in response to increased vascular and/or airway pressures and this response is dependent on the activity of TRPV4 channels (Jian et al., 2008 Am J Respir Cell Mol Biol 38: 386-92). Overall this suggests a clinical benefit of inhibiting TRPV4 function in the treatment of heart failure associated lung congestion.
  • TRPV4 function in pulmonary-based pathologies presenting with symptoms including lung edema/congestion, infection, inflammation, pulmonary remodeling and/or altered airway reactivity.
  • a genetic link between TRPV4 and chronic obstructive pulmonary disorder (COPD) has recently been identified (Zhu et al., 2009. Hum Mol Genetics, 18: 2053-62) suggesting potential efficacy for TRPV4 modulation in treatment of COPD with or without coincident emphysema.
  • Enhanced TRPV4 activity is also a key driver in ventilator-induced lung injury (Hamanaka et al., 2007.
  • TRPV4 activation may underlie pathologies involved in acute respiratory distress syndrome (ARDS), pulmonary fibrosis and asthma (Liedtke & Simon, 2004. Am J Physiol 287: 269-71 ).
  • ARDS acute respiratory distress syndrome
  • pulmonary fibrosis fibrosis
  • asthma pulmonary fibrosis
  • Am J Physiol 287: 269-71 A potential clinical benefit for TRPV4 blockers in the treatment of sinusitis, as well as allergic and non-allergic rhinitis is also supported (Bhargave et al., 2008. Am J Rhinol 22:7-12).
  • TRPV4 channels have recently been implicated in urinary bladder function (Thorneloe et al., 2008. J Pharmacol Exp Ther 326 : 432-42) and are likely to provide therapeutic benefit for conditions of bladder overactivity, characterized by an increased urge to urinate and an enhancement of micturition frequency. These data suggest a clinically beneficial effect of inhibiting TRPV4, located on multiple cell types, on urinary bladder function that is likely to be effective in bladder disorders such as overactive bladder, interstitial cystitis and painful bladder syndrome.
  • TRPV4 has in recent years been implicated in a number of other physiological/pathophysiological processes in which TRPV4 antagonists are likely to provide significant clinical benefit. These include various aspects of pain (Todaka et al., 2004. J Biol Chem 279: 35133-35138; Grant et al., 2007. J Physiol 578: 715-733;
  • this invention provides for quinoline analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them.
  • this invention provides for the use of the compounds of the invention as TRPV4 antagonists.
  • this invention provides for the use of the compounds of the invention for treating and preventing conditions associated with TRPV4 imbalance.
  • this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, osteoarthritis Crohn's disease, colitis, diarrhea, intestinal irregularity
  • hyporeactivity/hyporeactivity fecal incontinence
  • IBS irritable bowel syndrome
  • the TRPV4 antagonist may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal antiinflammatory drugs, bronchodilators, anti-histamines, leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective ⁇ -adrenoceptor and a-
  • agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (
  • the present invention provides for compounds selected from the group consisting of: 6-amino-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-[(methylsulfonyl)amino]-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-[(ethylsulfonyl)amino]-3- ⁇ [4-(4-morpholinyl)-1-piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-tri
  • the compounds of the invention may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts of the compounds of the invention may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately treating the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • compounds of the invention may contain an acidic functional group and are, therefore, capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base.
  • bases include a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc; and b) primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
  • compounds of the invention may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
  • suitable acids include pharmaceutically acceptable inorganic acids and organic acids.
  • Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.
  • the compounds of the invention may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • polymorphism i.e. the capacity to occur in different crystalline structures. These different crystalline forms are typically known as "polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H, 1 1 C, 13C, 14C, 15N, 170, 180, 31 P, 32P, 35S, 18F, 36CI, 1231 and 1251.
  • Isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 1 1 C and 18F isotopes are particularly useful in PET
  • Isotopically labelled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds according to Formula I are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, osteoarthritis, Crohn's disease, colitis, diarrhea, intestinal irregularity
  • the biological activity of the compounds according to Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a TRPV4 antagonist, as well as tissue and in vivo models.
  • TRP channel activation/opening results in an influx of divalent and monovalent cations including calcium.
  • the resulting changes in intracellular calcium are monitored using a calcium selective fluorescent dye Fluo4 (MDS Analytical Technologies).
  • Dye loaded cells are initially exposed to test compound to verify a lack of agonist activity. Cells are subsequently activated by addition of an agonist and inhibition of the agonist-induced activation is recorded.
  • Human embryonic kidney 293 cells stably expressing the macrophage scavenger receptor class II (HEK-293-MSR-II) and transduced with 1 % BacMam (J. P. Condreay, S.M. Witherspoon, W.C. Clay and T.A.
  • virus expressing the human TRPV4 gene are plated at 15000 cells/well in a volume of 50 uL in a 384 well poly-D lysine coated plate. Cells are incubated for 24 hours at 37 degrees and 5% C0 2 . Media is then aspirated using a Tecan Plate- washer and replaced with 20 uL of dye loading buffer: HBSS, 500 uM Brilliant Black (MDS Analytical Technologies), 2 uM Fluo-4. Dye loaded plates are then incubated in the dark at room temperature for 1 -1 .5 hours.
  • BHK/AC9_DMEM/F12 conditioned (Baby Hamster Kidney) cells are transduced with 2% BacMam virus expressing the human TRPV4 gene and are plated at 10K cells per well in a volume of 50 uL in 384 well poly-D-lysine coated plates. Cells are incubated for 18-24 hours at 37 degrees and 5% C0 2. The following day, the media is aspirated using a Tecan Plate-washer and replaced with 20uL of dye loading buffer: HBSS buffer, 2.5 mM Probenecid, 500 uM Brilliant Black, 2 uM Fluo-4. The dye loaded cells are incubated for 1-1 .5 hours at room temperature in the dark.
  • the compounds of the invention are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction and osteoarthritis. Accordingly, in another aspect the invention is directed to methods of treating such conditions.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound of the invention or a pharmaceutically-acceptable salt thereof to a patient in need thereof.
  • treat in reference to a condition means: (1 ) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention of a condition includes prevention of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound will vary with the particular compound chosen (e.g.
  • patient refers to a human or other animal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Typical daily dosages may vary depending upon the particular route of
  • Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a
  • each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in
  • compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chel
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
  • the compounds 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, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal antiinflammatory drugs, bronchodilators, anti-histamines, leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective ⁇ -adrenoceptor and a-
  • ACE angiotensin converting enzyme
  • J are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).
  • the naming program used is ACD Name Pro 6.02.
  • Methyl 3-methyl-6-nitro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.7 g, 14.60 mmol) was suspended in carbon tetrachloride (60 mL) and /V-bromosuccinimide (2.86 g, 16.06 mmol) and benzoyl peroxide (0.354 g, 1 .460 mmol) were added. The mixture was heated to 100°C overnight. The solvent was removed in vacuo to afford a brown oil, which was dissolved in acetonitrile (60 mL).
  • the resultant black suspension was heated to 70°C for 2 h.
  • the reaction mixture was cooled to room temperature, filtered through Celite ® , washed with methanol, and concentrated to a volume of 80 mL of methanol.
  • Fresh ammonium formate (3.59 g, 57.0 mmol) and 10% Pt/C (1.140 mmol) were added and the reaction heated back to reflux for 1 h and then at 4°C overnight.
  • the reaction mixture was filtered through Celite ® , washed with methanol, and concentrated in vacuo. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate.
  • Methanesulfonyl chloride (0.139 ml_, 1 .787 mmol) was added to a stirred solution of 6-amino-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3-(trifluoromethyl)phenyl]-/ ⁇ /-[(1 R)- 2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (1 g, 1 .489 mmol) in pyridine (10 ml_). The mixture was heated to 100 °C for 3 h. Additional mesyl chloride (0.139 ml_, 1.787 mmol) was added and the mixture was heated to 100 °C for an hour.
  • A/JV-diisopropylethylamine (6.09 mL, 34.8 mmol) was added and the mixture was stirred overnight at room temperature and then allowed to stand at room temperature for 1 week. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and 10% sodium carbonate solution. The phases were separated and the organic phase was washed twice more with a 10% sodium carbonate solution. The organic phase was then extracted with 2N HCI (3 times). The combined aqueous extracts were cooled in a ice bath and the pH was adjusted to -12 with 6N NaOH. The resulting emulsion was extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried, and concentrated in vacuo.
  • Ethanesulfonyl chloride (0.081 ml_, 0.851 mmol) was added to a stirred yellow solution of methyl 6-amino-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (300 mg, 0.568 mmol) in pyridine (3 ml.) in two portions. The mixture was stirred for 30 min. The reaction mixture was concentrated and azeotroped with methanol twice to give a brown oil.
  • Acetyl chloride (0.021 g, 0.267 mmol) was added to a stirred solution of 6-amino-3- ⁇ [4-(4-morpholinyl)-1-piperidinyl]methyl ⁇ -2-[3-(trifluoromethyl)phenyl]-/ ⁇ /-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (150 mg, 0.223 mmol, Example 2) and /V,/V-diisopropylethylamine (0.1 17 mL, 0.670 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 30 min. Additional acetyl chloride was added (0.017 g,
  • Example 8 and analogous sulfonamides may also be prepared using the procedure described below:
  • Methyl 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (72g, 170 mmol) was added to a 1 L flask and azeotroped (3 times) with benzene to remove any residual water.
  • NBS (36.3 g, 204 mmol) and diphenylperoxyanhydride (4.1 1 g, 16.97 mmol) were added followed by carbon tetrachloride (800 mLI). The solution was heated to reflux fori .5 h, cooled to room temperature, and concentrated to a minimal volume (-200 ml.) to afford a light yellow slurry.
  • Acetonitrile 700 ml. was added to the slurry followed by 4-(4-piperidinyl)morpholine (30.3 g, 178 mmol) and DIEA (35.6 ml_, 204 mmol). The solution was stirred for one hour at room temperature, and the solution was concentrated to a volume of -200 ml. Water (1 L) and dichloromethane (500 ml.) were added. The two layers were separated, and the aqueous phase was extracted with dichloromethane (2 x 300 ml_). The combined dichloromethane extracts were concentrated, and the residue was dissolved in 2N HCI (1.75L).
  • the HCI solution was transferred to a separatory funnel and washed with dichloromethane (2 x 500 mLI).
  • the dichloromethane extracts were washed with 200 ml 2N HCI.
  • the combined HCI solutions were made basic with 6N
  • the thick slurry was filtered, and the filter cake was washed with 250 ml. iPrOH.
  • the solid was dried under reduced pressure and azeotroped with toluene to afford 41 g (48%) of the title compound as a white solid.
  • the yellow filtrate was concentrated under reduced pressure and azeotroped with toluene.
  • iPrOH 250 ml. was added to the residue, the mixture was heated until the solid was dissolved, and the resulting solution was allowed to cool with stirring.
  • the thick slurry was stirred at room temperature overnight, and the solid was collected by filtration to afford 32 g (37%) as an off white solid.
  • Methanesulfonyl chloride (0.035 mL, 0.448 mmol) was added to a stirred solution of 6-amino-3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-[3-(trifluoromethyl)phenyl]-/ ⁇ /-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.200 g, 0.299 mmol, Example 10) in pyridine (2 mL). The reaction mixture was heated in the microwave at 140°C for 20 min. The solvent was removed under reduced pressure.
  • 6-Bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (16 g, 39.0 mmol) was suspended in toluene (160 ml.) and methanol (40 ml_). The brown suspension was cooled to 0 °C. 2N TMS-diazomethane in diethyl ether (19.50 ml_, 39.0 mmol) was added portionwise over 10 min. The resulting mixture was stirred for 1 h. The solvents were removed in vacuo and the resultant solid was again suspended in toluene (160 ml.) and methanol (40 ml_).
  • Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (2.1 g, 3.56 mmol) was suspended in methanol (20 ml.) and water (10 ml_). Potassium hydroxide (1.596 g, 28.5 mmol) was added in one portion and the reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The suspension became a solution. The reaction mixture was cooled, the methanol was removed in vacuo, and the residue was diluted with dichloromethane.
  • Phenylboronic acid (0.124 g, 1.061 mmol)
  • methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6- bromo-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.500 g, 0.847 mmol)
  • PdCI 2 dppf PdCI 2 dppf
  • 2N Na 2 C0 3 in dioxane were heated to 160 °C in the microwave for 10 min.
  • the reaction mixture was diluted with water and methylene chloride and filtered through Celite ® .
  • the phases were separated, and the aqueous phase was extracted twice with methylene chloride.
  • Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate 200 mg, 0.339 mmol
  • 4-methoxypiperidine 46.8 mg, 0.406 mmol
  • palladium(ll) acetate 7.60 mg, 0.034 mmol
  • cesium carbonate 221 mg, 0.677 mmol
  • di-t-butylbiphenylphosphine (20.19 mg, 0.068 mmol) were weighed into a microwave vial and suspended in dioxane.
  • Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[4-(methyloxy)-1 -piperidinyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (61.5 mg, 0.0984 mmol) was dissolved in 2 ml. of 1 N HCI and 1 ml. of THF. The solution was heated to 100°C in the microwave for 15 minutes. The reaction mixture was diluted with dichloromethane and sat. aqueous NaHC0 3 . The layers were shaken and separated. The organic phase was dried over MgS0 4 , filtered, and concentrated to afford 60 mg of crude acid. The residue was dissolved in 1 ml.
  • the aqueous phase was acidified to pH 7 and washed with ethyl acetate.
  • the aqueous phase was acidified to pH 3 and washed with ethyl acetate.
  • the organic phases were combined, dried over MgS0 4 , filtered, and concentrated to give 6- (ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.16 g, >99% yield) as a light orange solid.
  • Methyl-3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (0.934 g, 1 .681 mmol) was dissolved in methanol (9.04 ml_), tetrahydrofuran (3.01 ml_), and water (3.01 ml_). Potassium hydroxide (0.472 g, 8.40 mmol) was added and the reaction mixture was heated to 70°C. After 3 days the reaction was cooled to room temperature and concentrated. The crude product was suspended in ethyl acetate and water.
  • the reaction mixture was allowed to stir at 0°C for 2 h before it was quenched with water and stirred for 30 min. The phases were separated, and the organic phase was concentrated to crude yellow product.
  • the crude product was purified via HPLC (Waters, Sunfire 30 x 100 mm, 15-70% CH 3 CN/H 2 0 with 0.1 % TFA). The product fractions were concentrated and dissolved in methylene chloride.
  • Potassium hydroxide (1 .527 g, 27.2 mmol) was added to a solution of methyl 3- (1 ,4'-bipiperidin-1 '-ylmethyl)-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (3.1 g, 5.44 mmol) in methanol (30 mL) and water (10 mL). The mixture was heated to reflux for 5 hours. The solvent was removed under reduced pressure, and the residue was adjusted to pH ⁇ 5-6 with 2N HCI and extracted with methylene chloride (3 times).
  • the residue was dissolved in methanol and purified via HPLC (Gilson, Sunfire Prep C18 OBD, 30 x 150 mm, 10-100% CH 3 CN/H 2 0 with 0.1 % TFA). The residue was diluted with water (3 mL), neutralized with Na 2 C0 3 , and extracted with ethyl acetate.
  • Example 37 was prepared as described for Example 37, using the quinoline synthesis conditions in Example 15 in place of the first step above. As is appreciated by those skilled in the art, this analogous example may involve variations in general reaction conditions.
  • Oxalyl chloride (29.0 g, 228 mmol) was added to a suspension of 7-hydroxy-3- methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (20.5 g, 54.3 mmol) in methylene chloride (150 mL) at 0°C. DMF (5 drops) was added, and the reaction mixture was stirred for 6 h. Methanol was added, and the reaction mixture was warmed to room temperature and stirred for 2.5 d.
  • Triethylamine (6.70 mL, 48.1 mmol) was added slowly, and the mixture was stirred overnight. The solvent was removed under reduced pressure. The residue was diluted with saturated aqueous NaHC0 3 and extracted with ethyl acetate. The phases were separated, and the organic phase was washed with brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo. The crude material was purified via column
  • the reaction mixture was cooled and concentrated in vacuo to give a cream oily solid, which was partitioned between water (-100 mL) and CH 2 CI 2 (200 mL). The phases were separated the aqueous phase was extracted three more times with CH 2 CI 2 . The combined organic extracts were washed with brine (twice), dried, and concentrated in vacuo to afford the title compound as a light brown solid (4.3g, 10.1 1 mmol, 29.7 % yield).
  • the aqueous phase was washed once with CH 2 CI 2 and cooled in an ice bath, and the pH was adjusted to ⁇ 1 1 with 6N NaOH.
  • the basic aqueous phase was extracted with CH 2 CI 2 (three times) and the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford a yellow solid:
  • the solid was purified by ISCO silica gel chromatography (40g) eluting with 0 ⁇ 20% CH 2 CI 2 /MeOH to afford: the title compound as a yellow solid (930 mg, 1.428 mmol, 34.0 % yield). MS (m/z) 619.2 (M+H + ).
  • the reaction was quenched with a small amount of water, concentrated in vacuo, dissolved in MeOH and purified by Waters reverse phase HPLC (20% to 60% MeCN, 0.1 %TFA, 16mins, 50ml/min, Sunfire column). The purified fractions were combined and diluted with dichloromethane and 10% sodium carbonate solution. The phases were separated, and the aqueous phase was extracted once more with
  • the reaction mixture was concentrated, the resulting yellow oil was dissolved in acetonitrile (20 mL), 4-(4- piperidinyl)morpholine (0.813 g, 4.77 mmol) was added in one portion, and the solution was stirred for 3 hours.
  • the reaction mixture was concentrated in vacuo, the residue was partitioned between CH 2 CI 2 ( ⁇ 75 ml) and 10% aqueous sodium carbonate solution, and the layers were separated.
  • the organic phase was washed twice more with carbonate solution.
  • the organic phase was extracted three times with 30 ml aqueous 2N HCI, and the combined acidic aqueous extracts were washed once with CH 2 CI 2 .
  • T3P (0.245 mL, 0.386 mmol) was added in one portion and the resultant mixture was stirred for one hour.
  • the reaction mixture was concentrated in vacuo, and the residue was dissolved in methanol and purified by Waters reverse phase HPLC (20% to 60% MeCN, 0.1 %TFA, 16mins,
  • Methyl 6-[(dimethylamino)sulfonyl]-3- ⁇ [4-(4-morpholinyl)-1-piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (900 mg, 1.450 mmol, contaminated with -30% methyl 6-[(methylamino)sulfonyl]-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate, synthesis described in Example 45) was dissolved in methanol (10 ml.) to give a yellow solution.
  • Tetrahydrofuran (2 mL) (2 mL) was added DIPEA (0.613 mL, 3.51 mmol). The mixture was stirred at 50°C overnight. The reaction mixture was concentrated to remove THF, and the residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire,
  • Example 48 The following example was prepared using a procedure analogous to that described in Example 48, substituting 3-isopropoxyaniline for 3-[(2-methylpropyl)oxy]aniline in the first step. As is appreciated by those skilled in the art, this analogous example may involve variations in general reaction conditions.
  • the reaction mixture was cooled to room temperature, combined with an identical reaction run on 0.088 mmol scale, and concentrated to dryness.
  • the residue was dissolved in ethyl acetate, and the solution was washed once with water, twice with 1 N NaOH, once with water, and once with brine.
  • the organic phase was dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by preparative HPLC (60-90% CH 3 CN/H 2 0 + 0.1 % TFA over 21 min, 15 mL/min, VYA 2515 305 column). Fractions containing the product were made basic with saturated NaHC0 3 , concentrated to remove acetonitrile, and extracted three times with dichloromethane.

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Abstract

The present invention relates to indole or benzothiophene analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.

Description

TRPV4 ANTAGONISTS
FIELD OF THE INVENTION
The present invention relates to quinoline analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.
BACKGROUND OF THE INVENTION
TRPV4 is a member of the Transient Receptor Potential (TRP) superfamily of cation channels and is activated by heat, demonstrating spontaneous activity at physiological temperatures (Guler et al., 2002. J Neurosci 22. 6408-6414). Consistent with its polymodal activation property TRPV4 is also activated by hypotonicity and physical cell stress/pressure (Strotmann et al., 2000. Nat Cell Biol 2: 695-702), through a mechanism involving phospholipase A2 activation, arachidonic acid and epoxyeicosatrienoic acid generation (Vriens et al., 2004. Proc Natl Acad Sci U S A 101 : 396-401 ), In addition, amongst other mechanisms proposed, tyrosine kinase activity may also regulate TRPV4 (Wegierski et al., 2009. J Biol Chem. 284: 2923-33).
Heart failure results in the decreased ability of the left ventricle to pump blood into the peripheral circulation as indicated by a reduced ejection fraction and/or left ventricular dialation. This increases the left ventricular end diastolic pressure resulting in enhanced pulmonary blood pressures. This places the septal barrier, which separates the circulatory aqueous environment and the alveolar airspaces of the lung, at risk. Increased pulmonary pressure results in the flow of fluid from the pulmonary circulation into the alveolar space resulting in lung edema/congestion, as is observed in patients with congestive heart failure.
TRPV4 is expressed in the lung (Delany et al., 2001. Physiol. Genomics 4: 165- 174) and has been shown to mediate Ca2+ entry in isolated endothelial cells and in intact lungs (Jian et al., 2009 Am J Respir Cell Mol Biol 38: 386-92). Endothelial cells are responsible for forming the capillary vessels that mediate oxygen/carbon dioxide exchange and contribute to the septal barrier in the lung. Activation of TRPV4 channels results in contraction of endothelial cells in culture and cardiovascular collapse in vivo (Willette et al., 2008 J Pharmacol Exp Ther 325: 466-74), at least partially due to the enhanced filtration at the septal barrier evoking lung edema and hemorrage (Alvarez et al., 2006. Circ Res 99: 988-95). Indeed filtration at the septal barrier is increased in response to increased vascular and/or airway pressures and this response is dependent on the activity of TRPV4 channels (Jian et al., 2008 Am J Respir Cell Mol Biol 38: 386-92). Overall this suggests a clinical benefit of inhibiting TRPV4 function in the treatment of heart failure associated lung congestion.
Additional benefit is suggested in inhibiting TRPV4 function in pulmonary-based pathologies presenting with symptoms including lung edema/congestion, infection, inflammation, pulmonary remodeling and/or altered airway reactivity. A genetic link between TRPV4 and chronic obstructive pulmonary disorder (COPD) has recently been identified (Zhu et al., 2009. Hum Mol Genetics, 18: 2053-62) suggesting potential efficacy for TRPV4 modulation in treatment of COPD with or without coincident emphysema. Enhanced TRPV4 activity is also a key driver in ventilator-induced lung injury (Hamanaka et al., 2007. Am J Physiol 293: L923-32) and it is suggested that TRPV4 activation may underlie pathologies involved in acute respiratory distress syndrome (ARDS), pulmonary fibrosis and asthma (Liedtke & Simon, 2004. Am J Physiol 287: 269-71 ). A potential clinical benefit for TRPV4 blockers in the treatment of sinusitis, as well as allergic and non-allergic rhinitis is also supported (Bhargave et al., 2008. Am J Rhinol 22:7-12).
In addition, TRPV4 channels have recently been implicated in urinary bladder function (Thorneloe et al., 2008. J Pharmacol Exp Ther 326 : 432-42) and are likely to provide therapeutic benefit for conditions of bladder overactivity, characterized by an increased urge to urinate and an enhancement of micturition frequency. These data suggest a clinically beneficial effect of inhibiting TRPV4, located on multiple cell types, on urinary bladder function that is likely to be effective in bladder disorders such as overactive bladder, interstitial cystitis and painful bladder syndrome.
Furthermore TRPV4 has in recent years been implicated in a number of other physiological/pathophysiological processes in which TRPV4 antagonists are likely to provide significant clinical benefit. These include various aspects of pain (Todaka et al., 2004. J Biol Chem 279: 35133-35138; Grant et al., 2007. J Physiol 578: 715-733;
Alessandri-Haber et al., 2006. J Neurosci 26: 3864-3874), genetic motor neuron disorders (Auer-Grumbach et al., 2009. Nat Genet. PMID: 20037588; Deng et al., 2009. Nat Genet PMID: 20037587; Landoure et al., 2009. Nat Genet PMID: 20037586), cardiovascular disease (Earley et al., 2005. Circ Res 97: 1270-9; Yang et al., 2006. Am. J Physiol.
290:L1267-L1276), and bone related disorders; including osteoarthritis (Muramatsu et al., 2007. J. Biol. Chem. 282: 32158-67), genetic gain-of function mutations (Krakow et al., 2009. Am J Hum Genet 84: 307-15; Rock et al., 2008 Nat Genet 40: 999-1003) and osteoclast differentiation (Masuyama et al. 2008. Cell Metab 8: 257-65). SUMMARY OF THE INVENTION
In one aspect this invention provides for quinoline analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them.
In a second aspect, this invention provides for the use of the compounds of the invention as TRPV4 antagonists.
In another aspect, this invention provides for the use of the compounds of the invention for treating and preventing conditions associated with TRPV4 imbalance.
In yet another aspect, this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, osteoarthritis Crohn's disease, colitis, diarrhea, intestinal irregularity
(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowel syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance, and flatulence.
The TRPV4 antagonist may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal antiinflammatory drugs, bronchodilators, anti-histamines, leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective β-adrenoceptor and a-| -adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin inhibitors.
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 selected from the group consisting of: 6-amino-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-[(methylsulfonyl)amino]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-[(ethylsulfonyl)amino]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-(acetylamino)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-[(2-methylpropanoyl)amino]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-6-[(trifluoroacetyl)amino]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-6-[(propylsulfonyl)amino]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-[(cyclopropylsulfonyl)amino]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-{[(2-methylpropyl)sulfonyl]amino}-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-amino-3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(methylsulfonyl)amino]-2-[3-(trifluoromethyl)ph N-[(1 R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(ethylsulfonyl)amino]-2-[3-(trifluoromethyl)phenyl]-N
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(cyclopropylsulfonyl)amino]-2-[3-
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-{[(dimethylamino)sulfonyl]amino}-3-{[4-(4-^
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-N-[(1 S)-1 -phenylethyl]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-methyl-1 H-pyrazol-5-yl)-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(3,5-dimethyl-4-isoxazolyl)-2-[3-
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1 H-pyrazol-3-yl)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-
2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(3-pyridinyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-
2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[2-(methyloxy)-3-pyridinyl]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-methyl-1 H-pyrazol-4-yl)-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-phenyl-N-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-phenyl-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide ;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[4-(methyloxy)-1 -piperidinyl]-2-[3- (trifluoromethyl)phenyl]-N-(2,2,2-trifluoro-1 -phenylethyl)-4-quinolinecarboxamide trifluoroacetate;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-pyrrolidinylcarbonyl)-2-[3-(trifluoromethyl)phenyl]- N-[(1 R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(4-morpholinylcarbonyl)-2-[3-(trifluoromethyl)pheny ^ N-[(1 R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-piperidinylcarbonyl)-2-[3-(trifluoromethyl)pheny ^
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-N6,N6-dimethyl-2-[3-(trifluoromethyl)phen
2,2,2-trifluoro-1 -phenylethyl]-4,6-quinolinedicarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-N-[(1 S)-1 -phenylethyl]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(1 -methylethyl)oxy]-N-[(1 S)-1-phenylethy
(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(1 -methylethyl)oxy]-2-[3-(trifluoromethyl)phenyl]-N-
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-8-chloro-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-[(1 -methylethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-N-[(1 S)-1 -phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-8-chloro-N-[(1 S)-1 -phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide trifluoroacetate;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(cyanomethyl)oxy]-N-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-{[2-(methyloxy)ethyl]oxy}-N-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-7-[(2,2,2-trifluoroethyl)oxy]-2-[3-
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-{[2-(methyloxy)ethyl]oxy}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-[(2-methylpropyl)oxy]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-N-
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(dimethylamino)sulfonyl]-2-[3-(trifluoromethyl)phen
N-[(1 R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide;
6-[(dimethylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
6-[(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3-
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
6-[(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-N-[(1 S)-1 - phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(2-methylpropyl)oxy]-2-[3-(trifluoromethyl)phenyl]-N-
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(1 -methylethyl)oxy]-2-[3-(trifluoromethyl)phenyl]-N-
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-6-(methyloxy)-N-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-N-
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(trifluoromethyl)oxy]-2-[3-(trifluoromethyl)phen
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-N-[(1 S)-1-phenylethyl]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxamide; 3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-N-[(1 S)-1 -phenylethyl]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(1-methylethy^
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarb
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-cyano-7-[(1 -methylethyl)oxy]-N-[(1 S)-1 -phenylethyl]-2-
[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-methyl-7-[(1 -methylethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarbo and
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-N-[(1 S)-1 -phenylethyl]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
or a pharmaceutically acceptable salt thereof.
With regard to stereoisomers, the compounds of the invention may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.
As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The skilled artisan will appreciate that pharmaceutically acceptable salts of the compounds of the invention may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately treating the purified compound in its free acid or free base form with a suitable base or acid, respectively.
In certain embodiments, compounds of the invention may contain an acidic functional group and are, therefore, capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base. Examples of such bases include a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc; and b) primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
In certain embodiments, compounds of the invention may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and organic acids. Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.
The compounds of the invention may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit
polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H, 1 1 C, 13C, 14C, 15N, 170, 180, 31 P, 32P, 35S, 18F, 36CI, 1231 and 1251.
Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 1 1 C and 18F isotopes are particularly useful in PET
(positron emission tomography), and 1251 isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
Biological Activity
As stated above, the compounds according to Formula I are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, osteoarthritis, Crohn's disease, colitis, diarrhea, intestinal irregularity
(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowel syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance, and flatulence. The biological activity of the compounds according to Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a TRPV4 antagonist, as well as tissue and in vivo models.
The biological activity of the compounds of Formula (I) are demonstrated by the following tests.
Liqand-qated assay:
TRP channel activation/opening results in an influx of divalent and monovalent cations including calcium. The resulting changes in intracellular calcium are monitored using a calcium selective fluorescent dye Fluo4 (MDS Analytical Technologies). Dye loaded cells are initially exposed to test compound to verify a lack of agonist activity. Cells are subsequently activated by addition of an agonist and inhibition of the agonist-induced activation is recorded. Human embryonic kidney 293 cells stably expressing the macrophage scavenger receptor class II (HEK-293-MSR-II) and transduced with 1 % BacMam (J. P. Condreay, S.M. Witherspoon, W.C. Clay and T.A. Kost, Proc Natl Acad Sci 96 (1999), pp. 127-132) virus expressing the human TRPV4 gene are plated at 15000 cells/well in a volume of 50 uL in a 384 well poly-D lysine coated plate. Cells are incubated for 24 hours at 37 degrees and 5% C02. Media is then aspirated using a Tecan Plate- washer and replaced with 20 uL of dye loading buffer: HBSS, 500 uM Brilliant Black (MDS Analytical Technologies), 2 uM Fluo-4. Dye loaded plates are then incubated in the dark at room temperature for 1 -1 .5 hours. 10 uL of test compound diluted in HBSS + 0.01 % Chaps is added to the plate, incubated for 10 min at room temperature in the dark and then 10 uL of agonist is added at a final cone, equal to the agonist EC80. Calcium release is measured using the FLIPRtetra (MDS Analytical Technologies).
All examples described herein possessed TRPV4 biological activity with IC50s ranges from 1 nM - 10 uM.
Hypotonicity assay (BHK cells):
BHK/AC9_DMEM/F12 conditioned (Baby Hamster Kidney) cells are transduced with 2% BacMam virus expressing the human TRPV4 gene and are plated at 10K cells per well in a volume of 50 uL in 384 well poly-D-lysine coated plates. Cells are incubated for 18-24 hours at 37 degrees and 5% C02. The following day, the media is aspirated using a Tecan Plate-washer and replaced with 20uL of dye loading buffer: HBSS buffer, 2.5 mM Probenecid, 500 uM Brilliant Black, 2 uM Fluo-4. The dye loaded cells are incubated for 1-1 .5 hours at room temperature in the dark. 10 uL of test compound diluted in HBSS/H20 (-1 :2.3) + 0.01 % Chaps is added to the plate, incubated for 10 min at room temperature in the dark, and then 10 uL of hypotonic buffer (H20 + 1.5mM CaCI2 + ~68 mM NaCI; 140 mOsm stock/260mOsm FAC) is used to test the inhibition of the hypotonicity-induced activation. Reaction is measured on a heated stage (37 degrees) using the FLIPRtetra.
Methods of Use
The compounds of the invention are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction and osteoarthritis. Accordingly, in another aspect the invention is directed to methods of treating such conditions.
The methods of treatment of the invention comprise administering a safe and effective amount of a compound of the invention or a pharmaceutically-acceptable salt thereof to a patient in need thereof.
As used herein, "treat" in reference to a condition means: (1 ) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
As indicated above, "treatment" of a condition includes prevention of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
As used herein, "safe and effective amount" in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound chosen (e.g.
consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
As used herein, "patient" refers to a human or other animal.
The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
Typical daily dosages may vary depending upon the particular route of
administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose.
Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
Compositions
The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.
The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
As used herein, "pharmaceutically-acceptable excipient" means a
pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in
pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing
Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
The compounds 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, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal antiinflammatory drugs, bronchodilators, anti-histamines, leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective β-adrenoceptor and a-| -adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin inhibitors.
EXAMPLES
The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
In the Examples:
Chemical shifts are expressed in parts per million (ppm) units. Coupling constants
(J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).
Flash column chromatography was performed on silica gel.
The naming program used is ACD Name Pro 6.02.
The following abbreviations and terms had the indicated meanings throughout:
AcOH acetic acid
Aq Aqueous
BBr3 boron tribromide
Brine saturated aqueous NaCl
CC14 carbon tetrachloride
CH2C12 methylene chloride
CH3CN or MeCN Acetonitrile
(COCl)2 oxalyl chloride
Cs2C03 cesium carbonate
d Day
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DCE Dichloroethane
DMAP 4-dimethylaminopyridine
DMF NN-dimethylformamide
DMSO Dimethylsulfoxide
EDC 1 - [3 -(dimethylamino)propyl] -3 -ethylcarbodiimide hydrochloride
Equiv Equivalents
Et Ethyl
Et-I ethyl iodide
Et3N Triethylamine
EtOH Ethanol
Et20 diethyl ether
EtOAc ethyl acetate
h, hr Hour
(2-(7-aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium
HATU
hexafluorophosphate)
HC1 hydrochloric acid
HOBt 1 -hydroxybenzotriazole
z-PrOH Isopropanol
z-Pr2NEt N',N'-diisopropylethylamine K2CO3 potassium carbonate
Kl potassium iodide
KOH potassium hydroxide
LCMS liquid chromatography-mass spectroscopy
Me Methyl
MeOH or CH3OH Methanol
MgS04 magnesium sulfate
Min Minute
Mo(CO)6 molybdenum hexacarbonyl
MS mass spectrum
μΛν Microwave
Na2C03 sodium carbonate
NaH sodium hydride
NaHCC>3 sodium bicarbonate
NaOH sodium hydroxide
Na2S04 sodium sulfate
NBS N-bromosuccinimide
NH4CI ammonium chloride
NH4HCO2 ammonium formate
NH4OH ammonium hydroxide
Pd/C palladium on carbon
Pd(dppf)Cl2 [1,1 '-Bis(diphenylphosphino)ferrocene] dichloropalladium(II)
Ph Phenyl
Pt/C platinum on carbon
pyr Pyridine
rt room temperature
satd Saturated
SCX strong cation exchange
SOCI2 thionyl chloride
SPE solid phase extraction
T3P propylphosphonic anhydride
TFA trifluoroacetic acid
TMSCHN2 Trimethylsilyldiazomethane
THF Tetrahydrofuran
?R retention time INTERMEDIATE 1
3-(propyloxy)aniline
1 -nitro-3-(propyloxy)benzene
A mixture of 3-nitrophenol (13.91 g, 100 mmol), 1-bromopropane (10.90 mL, 120 mmol) and potassium carbonate (20.73 g, 150 mmol) in acetonitrile (200 mL) was heated to reflux overnight. The mixture was filtered through a plug of silica plug (100 g), washed with ethyl acetate, and the filtrate was concentrated to give 1-nitro-3-(propyloxy)benzene (17.2 g, 95% yield). 1H N MR (400 MHz, DMSO-d6) δ 7.81 (dd, J = 1 .38, 8.16 Hz, 1 H), 7.70 (t, J = 2.38 Hz, 1 H), 7.58 (t, J = 8.28 Hz, 1 H), 7.42 (dd, J = 2.13, 7.91 Hz, 1 H), 4.06 (t, J = 6.53 Hz, 2H), 1 .71 - 1 .82 (m, 2H), 1 .00 (t, J = 7 AO Hz, 3H).
3-(propyloxy)aniline
Palladium on carbon (2.53 g, 2.373 mmol) was added to a solution of 1 -nitro-3- (propyloxy)benzene (17.2 g, 95 mmol) in ethanol (200 mL) and ethyl acetate (200 mL) under nitrogen. The reaction mixture was placed under an atmosphere of hydrogen and stirred overnight at room temperature. The mixture was filtered through Celite®, washed with ethyl acetate, and concentrated under reduced pressure to afford 3-(propyloxy)aniline (14.2 g, >99% yield). 1 H NMR (400 MHz, DMSO-d6) 6.88 (t, J = 8.28 Hz, 1 H), 6.12 - 6.17 (m, 2H), 6.07 (dd, J = 1 .51 , 7.03 Hz, 1 H), 5.01 (s, 2H), 3.80 (t, J = 6.53 Hz, 2H), 1.69 (sxt, J = 7.08 Hz, 2H), 0.96 (t, J = 7.40 Hz, 3H).
INTERMEDIATE 2
3-[(2-methylpropyl)oxy]aniline
3-Aminophenol (10.91 g, 100 mmol), 1-bromo-2-methylpropane (10.87 mL, 100 mmol) and potassium carbonate (20.73 g, 150 mmol) were combined in acetonitrile (200 mL) and heated to reflux overnight. The solution was filtered, the filter cake was washed with EtOAc, and the filtrate was concentrated. The residue was purified via ISCO chromatography (330 g, 0%-40% EtOAc/Hexanes) to provide 5.8 g (35%) of the title compound. MS (m/z) 166.1 (M+H).
INTERMEDIATE 3
3-[(2-methylethyl)oxy]aniline
A mixture of 3-aminophenol (2.183 g, 20 mmol), 2-bromopropane (4.92 g, 40.0 mmol) and potassium carbonate (5.53 g, 40.0 mmol) in acetonitrile (50 mL) was heated to reflux for 3 days. The reaction mixture was filtered, the solid was washed with EtOAc, and the filtrate was concentrated. The residue was purified via ISCO chromatography (0%- 40% EtOAc/Hexanes) to afford 2.1 g of the title compound MS (m/z) 152.1 (M+H). INTERMEDIATE 4
{4-bromo-3-[(1-methylethyl)oxy]phenyl}amine
5-amino-2-bromophenol
(JW210467-038-A2)1 -Bromo-2-(methyloxy)-4-nitrobenzene (20.0 g, 86.2 mmol) was treated with 48% aqueous HBr (450 mL). The reaction mixture was stirred at 130 °C for 16 hours. The mixture was cooled to room temperature, poured onto ice, and filtered to collect the solid. The residue was dissolved in EtOAc (100 mL), dried over Na2S04, filtered and concentrated to afford 16.7g (88.9%) of the title compound as a yellow solid. 1 H NMR (400 MHz, MeOD-d4) ppm 7.57 - 7.63 (m, 1 H) 7.66 - 7.75 (m, 2 H).
1-bromo-2-r(1-methylethyl)oxyl-4-nitrobenzene To a solution of 5-amino-2- bromophenol (17 g, 78.34 mmol) in acetonitrile (300 mL) was added potassium carbonate (21.6 g, 156.68 mmol) and isopropyl iodide (20g, 1 12.5 mmol). The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, and
concentrated to dryness. The residue was dissolved in ethyl acetate, and the resulting solution was washed twice with water, dried over sodium sulfate, filtered, and
concentrated. The title compound was isolated as a brown solid (20.1 g) and was used directly in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.38 - 1.50 (m, 6 H) 4.68 - 4.74 (m, 1 H) 7.68 - 7.71 (m, 8 H) 7.71 - 7.74 (m, 4 H).
{4-bromo-3-r(1-methylethyl)oxylphenyl}amine
To a solution of 1-bromo-2-[(1-methylethyl)oxy]-4-nitrobenzene (20 g, 76.9 mmol) in MeOH (20 mL) was added NiCI2*6H20 (27.42 g, 1 15.35 mmol). The mixture was stirred at 0°C for five minutes. NaBH4 (8.73g, 230.69 mmol) was added slowly portionwise. The mixture was stirred for 10 minutes, quenched with satd. aqueous NH4CI, and extracted three times with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the title compound as a brown oil (16.7g) which was used directly in subsequent reactions without further purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1 .28 (d, J=6.09 Hz, 6 H) 3.56 (br. s., 2 H) 4.34 - 4.46 (m, 1 H) 6.1 1 (dd, J=8.41 , 2.57 Hz, 1 H) 6.20 (d, J=2.57 Hz, 1 H) 7.17 (d, J=8.47 Hz, 1 H). EXAMPLE 1
6-amino-3-{[4-(4-morpholinyl)-1-piperidinyllmethyl}-2-[3-(trifluorom R)- 2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide 3-methyl-6-nitro-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxyN acid
A stirred suspension of 5-nitro-1 H-indole-2,3-dione (16 g, 83 mmol) and 1-[3-
(trifluoromethyl)phenyl]-1 -propanone (17.68 g, 87 mmol) in ethanol (150 mL) and water (60 mL) was cooled in an ice bath, and potassium hydroxide (28.0 g, 500 mmol) was added in one portion. The reaction mixture was warmed to room temperature and stirred for 3 d. Additional water (60 mL) was added, and the suspension was cooled in an ice bath. The pH was adjusted to 1 with concentrated HCI, and the resulting solid was collected by filtration, washed with water, and dried in the vacuum oven at 30°C overnight. The wet orange solid was suspended in methylene chloride (400 mL) and stirred vigorously. The solid was collected by filtration, washed with further methylene chloride, and dried to afford 3-methyl-6-nitro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (19.7 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) 8.71 (d, J = 2.27 Hz, 1 H), 8.51 (dd, J = 2.52, 9.06 Hz, 1 H), 8.32 (d, J = 9.06 Hz, 1 H), 8.00 - 8.07 (m, 2H), 7.93 (d, J = 8.06 Hz, 1 H), 7.80 (t, J = 7.81 Hz, 1 H), 2.46 (s, 3H); MS (m/z) 377.0 (M+H+). methyl 3-methyl-6-nitro-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
3-Methyl-6-nitro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (19.7 g,
52.4 mmol) was suspended in dichloromethane (200 mL) and was cooled to 0°C in an ice bath. A few drops of DMF were added, followed by the careful portionwise addition of oxalyl chloride (5.50 mL, 62.8 mmol). The reaction mixture was stirred for 2 h. Methanol (100 mL) was added and the mixture was stirred overnight at 50°C. The reaction mixture was concentrated and the resulting solid was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The phases were separated, and the aqueous phase was extracted twice more with methylene chloride. The combined organic extracts were washed with additional saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, and concentrated in vacuo to afford methyl 3-methyl-6-nitro-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (15.7 g, 77% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) 8.66 (d, J = 2.26 Hz, 1 H), 8.52 (dd, J = 2.38, 9.16 Hz, 1 H), 8.34 (d, J = 9.29 Hz, 1 H), 8.07 (s, 1 H), 8.03 (d, J = 7.78 Hz, 1 H), 7.93 (d, J = 8.03 Hz, 1 H), 7.77 - 7.84 (m, 1 H), 4.14 (s, 3H), 2.43 (s, 3H); MS (m/z) 391 .0 (M+H+). methyl 3-{[4-(4-morpholinyl)-1 -piperidinyllmethyl}-6-nitro-2-[3-(trifluoromethv
quinolinecarboxylate
Methyl 3-methyl-6-nitro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.7 g, 14.60 mmol) was suspended in carbon tetrachloride (60 mL) and /V-bromosuccinimide (2.86 g, 16.06 mmol) and benzoyl peroxide (0.354 g, 1 .460 mmol) were added. The mixture was heated to 100°C overnight. The solvent was removed in vacuo to afford a brown oil, which was dissolved in acetonitrile (60 mL). Sodium iodide (0.219 g, 1 .460 mmol), 4-(4-piperidinyl)morpholine (4.26 g, 17.52 mmol) and /V,/V-diisopropylethylamine (7.65 mL, 43.8 mmol) were added and the suspension was stirred for 3 d. The acetonitrile was removed in vacuo. The residue was partitioned between methylene chloride and 2N NaOH. The phases were separated, and the methylene chloride was washed once more with 2N NaOH. The organic layer was then extracted with 2N HCI (3 x 150 mL). The combined acidic aqueous extracts were cooled in an ice bath, and solution was adjusted to pH 12 with 6N NaOH. The precipitated product was extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to afford methyl 3-{[4-(4-morpholinyl)-1 - piperidinyl]methyl}-6-nitro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.2 g, 57% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) 8.75 (d, J = 2.26 Hz, 1 H), 8.55 (dd, J = 2.51 , 9.29 Hz, 1 H), 8.35 (d, J = 9.03 Hz, 1 H), 8.02 (s, 1 H), 7.93 (d, J = 8.28 Hz, 2H), 7.77 - 7.83 (m, 1 H), 4.06 (s, 3H), 3.67 (s, 2H), 3.50 - 3.56 (m, 4H), 2.63 (d, J = 1 1.29 Hz, 2H), 2.34 - 2.41 (m, 4H), 1.95 - 2.05 (m, 1 H), 1.83 (t, J = 10.92 Hz, 2H), 1.62 (d, J = 1 1 .29 Hz, 2H), 1 .18 - 1.32 (m, 2H); MS (m/z) 559.2 (M+H+).
3-{r4-(4-morpholinyl)-1 -piperidinyllmethyl}-6-nitro-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
Potassium hydroxide (4.18 g, 74.5 mmol) was added to a stirred suspension of methyl 3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-6-nitro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (5.2 g, 9.31 mmol) in methanol (50 mL) and water (25.00 mL). The reaction mixture was heated to 90°C overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was partitioned between methylene chloride and water. The pH was adjusted to 5 with 2N HCI and the phases were separated. The aqueous phase was extracted twice more with methylene chloride. The combined organic extracts were washed with brine, dried, and concentrated to afford 3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-6-nitro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (5.8 g). This material was used in the next reaction without further purification. MS (m/z) 545.2 (M+H+). 3-{[4-(4-morpholinyl)-1 -piperidinyllmethyl}-6-nitro-2-[3-(trifluoromethyl)phenyll-/\/-[( 1 R)- 2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
T3P in ethyl acetate (8.13 mL of a 50% solution, 12.78 mmol) was added to a stirred solution of 3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-6-nitro-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (5.8 g, 10.65 mmol), (1 /?)-2,2,2-trifluoro- 1-phenylethanamine (2.70 g, 12.78 mmol) and A/JV-diisopropylethylamine (5.58 mL, 32.0 mmol) in dichloromethane (30 mL). The mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with methylene chloride and 2N NaOH and the phases were separated. The aqueous phase was extracted with methylene chloride (2 times). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to afford 3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-6- nitro-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2-trifluoro-1-phenylethyl]-4- quinolinecarboxamide (8.4 g). 1H NMR (400 MHz, DMSO-d6) 10.10 (br. s., 1 H), 8.82 (br. s., 1 H), 8.54 (br. s., 1 H), 8.33 (d, J = 9.04 Hz, 1 H), 8.00 (br. s., 1 H), 7.88 (d, J = 7.53 Hz, 2H), 7.72 - 7.80 (m, 1 H), 7.67 (d, J = 3.76 Hz, 2H), 7.46 (br. s., 3H), 6.21 - 6.37 (m, 1 H), 4.03 - 4.17 (m, 1 H), 3.43 - 3.60 (m, 5H), 3.28 (br. s., 1 H), 2.37 (br. s., 2H), 2.23 (br. s., 3H), 2.08 (br. s., 1 H), 1 .74 (br. s., 1 H), 1.41 - 1.59 (m, 1 H), 1 .22 (br. s., 2H), 0.88 - 1.03 (m, 1 H), 0.84 (br. s., 1 H); MS (m/z) 702.2 (M+H+). 6-amino-3-{[4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-[3-(trifluoromethyl)phenyll-N- [(1 R)-2,2,2-trifluoro-1 -phenylethvH-4-quinolinecarboxamide 3-{[4-(4-morpholinyl)-1- piperidinyl]methyl}-6-nitro-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 - phenylethyl]-4-quinolinecarboxamide (8g, 1 1 .40 mmol) was dissolved in methanol (80 mL) and ammonium formate (3.59 g, 57.0 mmol) was added followed by 10% Pt/C (1.140 mmol). The resultant black suspension was heated to 70°C for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite®, washed with methanol, and concentrated to a volume of 80 mL of methanol. Fresh ammonium formate (3.59 g, 57.0 mmol) and 10% Pt/C (1.140 mmol) were added and the reaction heated back to reflux for 1 h and then at 4°C overnight. The reaction mixture was filtered through Celite®, washed with methanol, and concentrated in vacuo. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with saturated aqueous sodium bicarbonate, brine, dried over Na2S04, filtered, and concentrated in vacuo, to afford 6-amino-3-{[4-(4-morpholinyl)-1 - piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4- quinolinecarboxamide (8.4 g, 99 % yield) as a light orange solid. 350 mg of this material was further purified by reverse phase HLPC (10% to 50% MeCN, 0.1 %TFA, 16min, 50ml/min, Sunfire column). The fractions containing the product were passed over an SCX column eluting with 2N ammonia in methanol to provide the title compound as a light orange solid (186 mg). MS (m/z) 672 (M+H).
EXAMPLE 2
6-r(methylsulfonyl)aminol-3-{r4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-r3-
(trifluoromethyl)phenyll-/\/-r(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide 6-r(methylsulfonyl)aminol-3-{r4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-r3- (trifluoromethyl)phenyll-/\/-r(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
Methanesulfonyl chloride (0.139 ml_, 1 .787 mmol) was added to a stirred solution of 6-amino-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)- 2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (1 g, 1 .489 mmol) in pyridine (10 ml_). The mixture was heated to 100 °C for 3 h. Additional mesyl chloride (0.139 ml_, 1.787 mmol) was added and the mixture was heated to 100 °C for an hour. The reaction mixture was concentrated in vacuo and the crude residue was dissolved in methanol and purified by reverse phase HPLC (Waters, Sunfire column, 10-50% MeCN/H20 with 0.1 % TFA). The purified fractions passed through an SCX column to afford 6- [(methylsulfonyl)amino]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-/\/-[(1 /?)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.515 g, 44% yield). LCMS (m/z) 750.2 (M+H+).
EXAMPLE 3
6-r(ethylsulfonyl)aminol-3-{r4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-r3- (trifluoromethyl)phenyll-/\/-r(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide 3-methyl-6-nitro-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
A stirred suspension of 5-nitro-1 H-indole-2,3-dione (5 g, 26.0 mmol) and 1 -[3- (trifluoromethyl)phenyl]-1 -propanone (5.52 g, 27.3 mmol) in a mixture of ethanol (50 ml.) and water (20 ml.) was cooled in a ice bath. Potassium hydroxide (8.76 g, 156 mmol) was added in one portion and the mixture was allowed to warm to room temperature and was stirred overnight. Additional water (20 m) was added and the suspension became a solution and was cooled in an ice bath. The pH was adjusted to 1 with concentrated HCI. The resulting solid was collected by filtration, washed with water, and dried in the vacuum oven at 50°C overnight to afford 3-methyl-6-nitro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (6.4 g, 59% yield). 1H NMR (400 MHz, DMSO-d6) 8.71 (d, J = 2.27 Hz, 1 H), 8.51 (dd, J = 2.52, 9.06 Hz, 1 H), 8.32 (d, J = 9.06 Hz, 1 H), 8.00 - 8.07 (m, 2H), 7.93 (d, J = 8.06 Hz, 1 H), 7.80 (t, J = 7.81 Hz, 1 H), 2.46 (s, 3H); MS (m/z) 377.0 (M+H+). methyl 3-methyl-6-nitro-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
3-Methyl-6-nitro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (6.4 g, 17.01 mmol) was suspended in dichloromethane (100 mL) and was cooled to 0°C in an ice bath. A few drops of DMF were added followed by oxalyl chloride (2.233 mL, 25.5 mmol). The reaction mixture was stirred for 2 h. Methanol (50 mL) was added and the mixture was heated to reflux for 3 h, before it was cooled to room temperature and concentrated in vacuo. The resulting solid was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted twice more with methylene chloride. The combined organic extracts were washed with additional saturated aqueous sodium bicarbonate, brine, dried over sodium sulphate, and concentrated in vacuo to afford methyl 3-methyl-6-nitro-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (6.8 g, >99 % yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) 8.65 (d, J = 2.52 Hz, 1 H), 8.51 (dd, J = 2.52, 9.32 Hz, 1 H), 8.33 (d, J = 9.06 Hz, 1 H), 8.00 - 8.09 (m, 2H), 7.93 (d, J = 7.81 Hz, 1 H), 7.80 (t, J = 7.81 Hz, 1 H), 4.13 (s, 3H), 2.42 (s, 3H); MS (m/z) 391 .0 (M+H+). methyl 3-{[4-(4-morpholinyl)-1 -piperidinyllmethyl}-6-nitro-2-[3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
A stirred yellow suspension of methyl 3-methyl-6-nitro-2-[3-(trifluoromethyl)phenyl]-
4-quinolinecarboxylate (6.8 g, 17.42 mmol), /V-bromosuccinimide (3.72 g, 20.91 mmol) and benzoyl peroxide (0.422 g, 1.742 mmol) in carbon tetrachloride (60 mL) was heated to reflux 100°C for 20 h. The reaction mixture was cooled and concentrated in vacuo. The residue suspended in acetonitrile (60 mL) and 4-(4-piperidinyl)morpholine hydrochloride (3.26 g, 19.16 mmol) was added in one portion. The reaction mixture was stirred overnight at room temperature. A/JV-diisopropylethylamine (6.09 mL, 34.8 mmol) was added and the mixture was stirred overnight at room temperature and then allowed to stand at room temperature for 1 week. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and 10% sodium carbonate solution. The phases were separated and the organic phase was washed twice more with a 10% sodium carbonate solution. The organic phase was then extracted with 2N HCI (3 times). The combined aqueous extracts were cooled in a ice bath and the pH was adjusted to -12 with 6N NaOH. The resulting emulsion was extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 120 g, 0-10% methanol/methylene chloride) to afford methyl 3-{[4-(4-morpholinyl)-1- piperidinyl]methyl}-6-nitro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1 .6 g, 16 % yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) 8.74 (d, J = 2.52 Hz, 1 H), 8.54 (dd, J = 2.39, 9.19 Hz, 1 H), 8.35 (d, J = 9.32 Hz, 1 H), 8.01 (s, 1 H), 7.93 (d, J = 7.81 Hz, 2H), 7.77 - 7.83 (m, 1 H), 4.06 (s, 3H), 3.67 (s, 2H), 3.50 - 3.56 (m, 4H), 2.63 (d, J = 1 1 .33 Hz, 2H), 2.37 (br. s., 4H), 1 .96 - 2.05 (m, 1 H), 1 .84 (t, J = 10.95 Hz, 2H), 1 .61 (d, J = 10.58 Hz, 2H), 1 .18 - 1 .31 (m, 2H); MS (m/z) 559.2 (M+H+). methyl 6-amino-3-{r4-(4-morpholinyl)-1-piperidi^
quinolinecarboxylate
Platinum on carbon (10%, 0.286 g, 0.269 mmol) was added to a solution of methyl 3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-6-nitro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (1 .5 g, 2.69 mmol) and ammonium formate (2.54 g, 40.3 mmol) in ethanol. The reaction mixture was heated at reflux for 4 h, cooled to room temperature, filtered through Celite®, and concentrated in vacuo. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The phases were separated and the aqueous phase was extracted once more with methylene chloride. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, dried over Na2S04, filtered, and concentrated in vacuo to afford methyl 6-amino-3-{[4-(4- morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1 .2 g, 80% yield) as a yellow solid. MS (m/z) 529.2 (M+H+).
6-[(ethylsulfonyl)aminol-3-{[4-(4-morpholinyl)-1-piperidinyllmethyl}-2-[3- (trifluoromethyl)phenyll-4-quinolinecarboxylic acid
Ethanesulfonyl chloride (0.081 ml_, 0.851 mmol) was added to a stirred yellow solution of methyl 6-amino-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (300 mg, 0.568 mmol) in pyridine (3 ml.) in two portions. The mixture was stirred for 30 min. The reaction mixture was concentrated and azeotroped with methanol twice to give a brown oil. The crude ester was dissolved in methanol (5 ml.) and water (2 ml.) and potassium hydroxide (0.318 g, 5.68 mmol) was added. The mixture was heated to reflux for two days before the reaction mixture was concentrated in vacuo. The residue was dissolved in 2N HCI and loaded onto an Oasis cartridge (6 g) and removed with methanol to 6-[(ethylsulfonyl)amino]-3-{[4-(4- morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.350 g). This material was used in the next step without further purification. MS (m/z) 607.2 (M+H+). 6-[(ethylsulfonyl)amino1-3-{[4-(4-moro^
(trifluoromethyl)phenyll-/V-[(1 /?)-2,2,2-trifluoro-1 -phenylethyll-4-quin
/V-diisopropylethylamine (0.345 mL, 1 .978 mmol) and [(1 R)-2,2,2-trifluoro-1 - phenylethyl]amine (0.209 g, 0.989 mmol) were added to a stirred suspension of 6- [(ethylsulfonyl)amino]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.300 g, 0.495 mmol) in
dichloromethane (5 mL). The solution was stirred for 5 minutes and then 50% T3P in ethyl acetate (0.378 mL, 0.593 mmol) was added in one portion. The mixture was stirred for 3 h before it was concentrated in vacuo and the residue was dissolved in methanol (4 mL). The crude material was purified by reverse phase HPLC (Waters, 30-70%
MeCN/H20 with 0.1 % NH4OH). The pure fractions were loaded onto a 10 g SCX SPE and the product eluted off with 2N ammonia in methanol to afford 6-[(ethylsulfonyl)amino]-3- {[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.040 g, 10% yield). MS (m/z) 764.2 (M+H+).
EXAMPLE 4
6-(acetylamino)-3-{[4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-[3-(trifluoromethyl)phenyll-/\/- [(1 /?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
Acetyl chloride (0.021 g, 0.267 mmol) was added to a stirred solution of 6-amino-3- {[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (150 mg, 0.223 mmol, Example 2) and /V,/V-diisopropylethylamine (0.1 17 mL, 0.670 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 30 min. Additional acetyl chloride was added (0.017 g,
0.223 mmol) and the mixture was stirred for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in methanol and purified via HPLC (Waters, 10-60% CH3CN/H20 with 0.1 % TFA). The collected fractions were partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase was removed and was washed with brine, and passed through a phase separator to afford 6-
(acetylamino)-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-/\/- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.040 g, 24% yield) as a cream solid. 1H N MR (400 MHz, DMSO-d6) 10.23 - 10.42 (m, 1 H), 9.91 (d, J = 9.29 Hz, 1 H), 8.36 (br. s., 1 H), 8.02 (d, J = 9.03 Hz, 1 H), 7.89 - 7.95 (m, 2H), 7.82 (d, J = 7.53 Hz, 2H), 7.63 - 7.75 (m, 3H), 7.41 - 7.49 (m, 3H), 6.08 - 6.21 (m, 1 H), 3.50 (br. s., 4H), 3.09 - 3.20 (m, 2H), 2.19 - 2.38 (m, 5H), 2.13 (br. s., 2H), 2.07 - 2.10 (m, 1 H), 1.99 - 2.07 (m, 1 H), 1 .65 (br. s., 1 H), 1 .51 (br. s., 1 H), 1.38 (br. s., 1 H), 1.27 (d, J = 7.28 Hz, 2H), 1.09 - 1.21 (m, 1 H), 0.84 - 1 .01 (m, 1 H), 0.69 - 0.84 (m, 1 H); MS (m/z) 714.2 (M+H+).
The following compounds were prepared using procedures analogous to those described in Example 4 using an appropriate acid chloride or anhydride in place of acetyl chloride. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.
Figure imgf000028_0001
EXAMPLE 7
3-{[4-(4-morpholinyl)-1 -piperidinyllmethyl}-6-[(propylsulfonyl)aminol-2-[3- (trifluoromethyl)phenyll-/\/-r(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
3-{r4-(4-morpholinyl)-1 -piperidinyllmethyl}-6-r(propylsulfonyl)aminol-2-r3-
(trifluoromethyl)phenyll-/\/-r(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
1-Propanesulfonyl chloride (0.032 g, 0.223 mmol) was added to a stirred solution of 6-amino-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 /?)- 2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.100 g, 0.149 mmol, Example 1 ) and DMAP (1 .819 mg, 0.015 mmol) in pyridine (2 ml_). The reaction mixture was heated in the microwave for 20 min at 140 °C. The solvent was removed under reduced pressure. The residue was dissolved in methanol and purified via HPLC (Sunfire column, 20-60% MeCN/H20 with 0.1 % TFA). The collected fractions were passed through an SCX column (10 g, methanol, then 2N ammonia in methanol) to afford 3-{[4-(4-morpholinyl)-1- piperidinyl]methyl}-6-[(propylsulfonyl)amino]-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 /?)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.057 g, 47% yield). MS (m/z) 778.2 (M+H+).
EXAMPLE 8
6-r(cvclopropylsulfonyl)aminol-3-{r4-(4-morpholinyl)-1-piperidinyllmethyl}-2-r3- (trifluoromethyl)phenyll-/\/-r(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
Cyclopropanesulfonyl chloride (0.031 g, 0.223 mmol) was added to a stirred solution of 6-amino-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-/\/-[(1 /?)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.100 g, 0.149 mmol, Example 1 ) and DMAP (1 .819 mg, 0.015 mmol) in pyridine (2 ml_). The reaction mixture was heated in the microwave for 20 min at 140°C. The solvent was removed under reduced pressure. The residue was dissolved in methanol and purified via HPLC (Sunfire column, 20-60% MeCN/H20 with 0.1 % TFA). The collected fractions were passed through an SCX column (10 g, methanol, then 2N ammonia in methanol) to afford 6-[(cyclopropylsulfonyl)amino]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.012 g, 10% yield). MS (m/z) 778.2 (M+H+).
Example 8 and analogous sulfonamides may also be prepared using the procedure described below:
Figure imgf000030_0001
methyl 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (67.5g,
165 mmol), dimethyl sulfoxide (DMSO) (1316 mL), cesium carbonate (59.0 g, 181 mmol) and Mel (20.58 mL, 329 mmol) were combined in a 2L flask. The mixture was stirred at room temperature overnight. Water (500 mL) was added to the resulting slurry, and the mixture became warm and was cooled with an ice/water bath. Stirring was continued an additional 30 minutes, and the reaction mixture was filtered and washed with 2 additional liters of water. The filter cake was dissolved in dichloromethane, the solution was filtered to remove a dark residue, and the filtrate was concentrated. The resulting residue was azeotroped three times with toluene, dissolved in dichloromethane/Hexanes, and heated to reflux. When the solution became cloudy, it was allowed to cool to room temperature. The precipitate was collected by filtration to afford a tan solid. The resulting solid was dried under reduced pressure to give 61.7 g of the title compound. The filtrate was concentrated to afford 3 g material (92.3% combined yield). Both solids were combined with an additional 16 g material from a separate reaction and dissolved in
dichloromethane. Hexanes was added to the solution, and the resulting mixture was heated to reflux until the solution became cloudy. The mixture was cooled to room temperature overnight without stirring. The suspension was filtered to collect the solids, which were dissolved in dichloromethane and passed over a plug of silica gel (eluting with dichloromethane) to afford an off-white solid (72 g, 89% recovery). MS (m/z) 426 (M+H). 6-bromo-3-{r4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
Methyl 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (72g, 170 mmol) was added to a 1 L flask and azeotroped (3 times) with benzene to remove any residual water. NBS (36.3 g, 204 mmol) and diphenylperoxyanhydride (4.1 1 g, 16.97 mmol) were added followed by carbon tetrachloride (800 mLI). The solution was heated to reflux fori .5 h, cooled to room temperature, and concentrated to a minimal volume (-200 ml.) to afford a light yellow slurry. Acetonitrile (700 ml.) was added to the slurry followed by 4-(4-piperidinyl)morpholine (30.3 g, 178 mmol) and DIEA (35.6 ml_, 204 mmol). The solution was stirred for one hour at room temperature, and the solution was concentrated to a volume of -200 ml. Water (1 L) and dichloromethane (500 ml.) were added. The two layers were separated, and the aqueous phase was extracted with dichloromethane (2 x 300 ml_). The combined dichloromethane extracts were concentrated, and the residue was dissolved in 2N HCI (1.75L). The HCI solution was transferred to a separatory funnel and washed with dichloromethane (2 x 500 mLI). The dichloromethane extracts were washed with 200 ml 2N HCI. The combined HCI solutions were made basic with 6N
NaOH and extracted with dichloromethane (4 x 500ml). The combined dichloromethane extracts were concentrated to afford a dark residue.
Methanol (1500 mLI) and a solution of KOH (95 g, 1697 mmol) in water (500 mL) were added, and the mixture was heated to reflux. The mixture was refluxed overnight, MeOH was removed under reduced pressure, additional water was added, and the mixture was stirred at room temperature for two hours. The solution was filtered to collect the desired product as an off white solid (75.48g, 69.6%). MS (m/z) 580.1 (M+H). 6-bromo-3-{[4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-[3-(trifluorometh
2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
6-Bromo-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl^ quinolinecarboxylic acid (72.48 g, 1 17 mmol), dichloromethane (1 174 ml_l), DIEA (24.60 ml_, 141 mmol), and ([(1 R)-2,2,2-trifluoro-1-phenylethyl]amine (27.3 g, 129 mmol) were combined in a 2 L flask. The mixture was cooled to 0°C and T3P (140 ml_, 235 mmol) (50% in EtOAc) was added dropwise. The mixture was stirred at 0 °C for 2h, warmed to room temperature, and stirred overnight. The next day water (250 ml.) and saturated NaHC03 (250 ml.) were added and the mixture was stirred for 10 minutes. The solution was transferred to a separatory funnel and diluted with dichloromethane and saturated aqueous NaHC03. The phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined dichloromethane extracts were washed with brine, dried over Na2S04, filtered and concentrated to afford the crude product. iPrOH (1 L) was added to the residue, and the mixture was concentrated to a volume of about 500 ml_. The thick slurry was filtered, and the filter cake was washed with 250 ml. iPrOH. The solid was dried under reduced pressure and azeotroped with toluene to afford 41 g (48%) of the title compound as a white solid. The yellow filtrate was concentrated under reduced pressure and azeotroped with toluene. iPrOH (250 ml.) was added to the residue, the mixture was heated until the solid was dissolved, and the resulting solution was allowed to cool with stirring. The thick slurry was stirred at room temperature overnight, and the solid was collected by filtration to afford 32 g (37%) as an off white solid. The resulting liquor was concentrated and the resulting residue was purified by reverse phase chromatography (Biotage 65i column, 0.1 % TFA, 2 column volumes Water, then 0-100% ACN/Water over 15 column volumes). The fractions containing product were transferred to a separatory funnel and diluted with dichloromethane and NaHC03. The phases were separated and the organic phase was dried over Na2S04, filtered and concentrated to the title compound as an off white solid (10 g, 12%). MS (m/z) 735.2 (M+H). 6-r(cvclopropylsulfonyl)aminol-3-{r4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-r3-
(trifluoromethyl)phenyll-N-r(1 R)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
To a 2-neck 250 ml flask was added copper(l) iodide (5.18 g, 27.2 mmol), cyclopropanesulfonamide (3.38 g, 27.9 mmol), A/JV-dimethylglycine (2.94 g, 28.5 mmol) and potassium phosphate tribasic (17.32 g, 82 mmol). The flask was flushed with N2 3 times, and 6-bromo-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3-
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (10 g, 13.60 mmol) was added followed by dimethyl sulfoxide (DMSO) (27.2 ml_). The flask was purged with N2 3 times. The mixture was stirred under N2 at 100 °C overnight. The mixture was diluted with dichloromethane and water, and stirred for 10 min. The resulting solution was transferred to a separatory funnel, and the phases were separated. The aqueous phase was extracted three times with dichloromethane. The combined organic extracts were passed over a phase separator, concentrated, and loaded onto silica gel. The material was purified by silica gel chromatography (330 g column, 0-3%
MeOH/dichloromethane over 20 min→ 3% MeOH/dichloromethane over 10 min→ 3-10% MeOH over 30 min). Fractions containing the product were concentrated to afford a light red solid (6g). The solid was dissolved in iPrOH and heated to reflux. The solution was cooled with stirring to room temperature and subsequently to 0°C. White crystals formed and were collected by filtration. The solid was dried and azeotroped with EtOH to give 3.7 g of a light yellow solid. The filtrate was concentrated to give 2.3 g of an orange solid, which was re-purified as described above using a 120 g column. The fractions containing product were concentrated to afford a yellow solid (2.1 g) which was combined with the solid isolated previously to afford a total of 5.8g (55%) of the title compound. MS (m/z) 776.2 (M+H).
EXAMPLE 9
6-{[(2-methylpropyl)sulfonyllamino}-3-{[4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-[3- (trifluoromethyl)phenyll-/\/-[(1 /?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
Ssobuianesu!iony! chloride (0.035 g, 0.223 mmol) was added to a stirred solution of 6-amino-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)- 2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.100 g, 0.149 mmol, Example 2) and DMAP (1 .819 mg, 0.015 mmol) in pyridine (2 ml_). The reaction mixture was heated in the microwave for 20 min at 140°C. The solvent was removed under reduced pressure. The residue was dissolved in methanol and purified via HPLC (Sunfire column, 20-60% MeCN/H20 with 0.1 % TFA). The collected fractions were passed through an SCX column (10 g, methanol, then 2N ammonia in methanol) to afford 6-{[(2- methylpropyl)sulfonyl]amino}-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-
(trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.014 g, 1 1 % yield). MS (m/z) 792.3 (M+H+). EXAMPLE 10
6-amino-3-( 1 ,4'-bipiperidin-1 lmethyl V2-r3-(trifluoromethyl)phenyl1-A/-r( 1 /?)-2,2,2-trifluoro-
1-phenylethyll-4-quinolinecarboxamide methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-nitro-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
Methyl 3-methyl-6-nitro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.2 g, 5.64 mmol) was suspended in carbon tetrachloride (50 mL) and /V-bromosuccinimide (1 .104 g, 6.20 mmol) and benzoyl peroxide (0.137 g, 0.564 mmol) were added. The reaction mixture was heated to reflux for 3 d before it was cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in acetonitrile (50 mL). 1 ,4'-Bipiperidine (1.043 g, 6.20 mmol) and /V,/V-diisopropylethylamine (2.95 mL, 16.91 mmol) were added and the reaction mixture was stirred for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and 2N NaOH. The phases were separated and the aqueous phase was extracted with methylene chloride. The combined organic extracts were washed once more with 2N NaOH and were extracted with 2N HCI (3 times). The combined aqueous extracts were cooled and adjusted to pH 12 with 6N NaOH. This solution was extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 10% methanol/methylene chloride) to afford methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-nitro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (2.5 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) 8.74 (d, J = 2.27 Hz, 1 H), 8.54 (dd, J = 2.39, 9.19 Hz, 1 H), 8.35 (d, J = 9.32 Hz, 1 H), 8.01 (s, 1 H), 7.93 (d, J = 8.06 Hz, 2H), 7.76 - 7.82 (m, 1 H), 4.05 (s, 3H), 3.66 (s, 2H), 2.62 (d, J = 1 1 .08 Hz, 2H), 2.36 (br. S.. 4H), 1.98 - 2.1 1 (m, 1 H), 1.82 (t, J = 10.95 Hz, 2H), 1.53 (d, J = 10.83 Hz, 2H), 1.39 - 1.48 (m, 4H), 1 .15 - 1 .39 (m, 4H); MS (m/z) 557.2 (M+H+)
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-nitro-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
A stirred suspension of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-nitro-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.700 g, 1 .258 mmol) and potassium hydroxide (0.423 g, 7.55 mmol) in methanol (2 mL) and water (1 mL) was heated to reflux overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and methylene chloride. The pH was adjusted to 5 carefully with 2N HCI and the phases were separated. The aqueous phase was extracted twice more and the combined organic extracts were washed with brine, dried, and concentrated to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-nitro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (0.630 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) 9.01 (d, J = 2.51 Hz, 1 H), 8.43 (dd, J = 2.64, 9.16 Hz, 1 H), 8.14 - 8.21 (m, 2H), 8.02 (d, J = 7.53 Hz, 1 H), 7.89 (d, J = 7.78 Hz, 1 H), 7.75 (t, J = 7.65 Hz, 2H), 3.59 (br. s., 2H), 2.98 - 3.10 (m, 2H), 2.75 (d, J = 10.79 Hz, 2H), 2.04 (t, J = 10.92 Hz, 3H), 1.92 (d, J = 6.27 Hz, 4H), 1.84 (d, J = 10.04 Hz, 3H), 1 .64 - 1 .77 (m, 2H), 1 .37 - 1.54 (m, 3H); MS (m/z) 543.2 (M+H+).
Figure imgf000035_0001
phenylethyll-4-quinolinecarboxamide
T3P in ethyl acetate (0.887 mL of a 50% solution, 1.393 mmol) was added to a stirred solution of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-nitro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (0.630 g, 1 .161 mmol), (1 R)-2,2,2-trifluoro-1 -phenylethanamine (0.295 g, 1.393 mmol) and /V,/V-diisopropylethylamine (0.608 mL, 3.48 mmol) in dichloromethane (15 mL). The reaction mixture was stirred for 10 min before it was diluted with methylene chloride and 2N NaOH. The phases were separated and the aqueous phase was extracted twice more with methylene chloride. The combined organic extracts were washed with brine, dried, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g column, 10% methanol/methylene chloride) to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-nitro-2-[3-(trifluoromethyl)phenyl]-A/- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.900 g). MS (m/z) 700.2 (M+H+).
6-amino-3-(1 ,4'-bipiperidin-1 '-ylmethvn-2-r3-(trifluoromethvnphenyll-/\/-r(1 /?V2,2,2-trifluoro- 1-phenylethyll-4-quinolinecarboxamide
Platinum on carbon (10%, 0.090 g, 1 .286 mmol) was added to a stirred suspension of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-nitro-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.900 g, 1 .286 mmol) and ammonium formate (0.406 g, 6.43 mmol) in methanol (10 mL). The mixture was heated to reflux for 3 h. The reaction was filtered through Celite®, washed with methanol, and concentrated. The residue was diluted with methanol (10 mL) and 10% platinum on carbon (0.090 g, 1.286 mmol) and ammonium formate (0.406 g, 6.43 mmol) were added. The reaction mixture was heated to reflux for 10 min before it was filtered through Celite®, washed with methanol and concentrated. The residue was partitioned between methylene chloride and water. The phases were separated and the organic phase was washed with brine, dried, and concentrated in vacuo. A portion of the residue (100 mg) was purified via HPLC (Waters, 10-50% CH3CN/H20 with 0.1 % TFA). The collected fractions were neutralized with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic phase was washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to afford 6-amino-3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-[3-(trifluoromethyl)phenyl]-/\/- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.037 g, 4.08% yield). 1H NMR (400 MHz, DMSO-d6) 9.86 (d, J = 9.29 Hz, 1 H), 7.87 - 8.03 (m, 1 H), 7.76 (t, J = 8.53 Hz, 3H), 7.63 - 7.71 (m, 3H), 7.45 (br. s., 3H), 7.12 - 7.29 (m, 1 H), 6.73 (br. s., 1 H), 6.07 - 6.21 (m, 1 H), 5.86 (br. s., 1 H), 5.69 (br. s., 1 H), 3.44 (br. s., 1 H), 3.1 1 (br. s., 1 H), 2.17 - 2.42 (m, 4H), 2.09 (br. s., 1 H), 1.71 (br. s., 2H), 1.28 - 1.53 (m, 8H), 1.08 - 1.28 (m, 2H), 0.77 - 1.08 (m, 2H); MS (m/z) 670.3 (M+H+).
EXAMPLE 11
3-(1 ,4'-bipiperidin-1 lmethyl)-6-r(methylsulfonyl)aminol-2-r3-(trifluoromethyl)phenyll-/\/- Γ(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
Methanesulfonyl chloride (0.035 mL, 0.448 mmol) was added to a stirred solution of 6-amino-3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.200 g, 0.299 mmol, Example 10) in pyridine (2 mL). The reaction mixture was heated in the microwave at 140°C for 20 min. The solvent was removed under reduced pressure. The residue was dissolved in methanol and purified via HPLC (Waters, 20-60% CH3CN/H20 with 0.1 % TFA). The collected fractions were loaded onto an SCX column and eluted with ammonia in methanol to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(methylsulfonyl)amino]-2-[3- (trifluoromethyl)phenyl]-/\/-[(1 /?)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.034 g, 14% yield). MS (m/z) 748.2 (M+H+).
The following examples were prepared using procedures analogous to that described in Example 1 1 , substituting an appropriate sulfonyl or sulfamoyi chloride for methanesulfonyl chloride. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.
Figure imgf000036_0001
Figure imgf000037_0001
EXAMPLE 15
3-(1 ,4'-bipiperidin-1 lmethyl)-6-(1-methyl-1 H-pyrazol-5-yl)-2-r3-(trifluoromethyl)p
r(1 /?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
Potassium hydroxide (39.7 g, 708 mmol) was added to 5-bromoisatin (20 g, 88 mmol) and 3-trifluoropropiophenone (19.68 g, 97 mmol) in ethanol (150 ml.) and water (37.5 ml.) portionwise over 5 minutes. The dark brown solution was heated to 100°C and stirred for 2 h. The mixture was cooled to room temperature and was stirred overnight. The solvent was removed under reduced pressure and the residue was diluted with water and cooled in an ice bath. The pH was adjusted to 1 with concentrated HCI. The solid precipitate was collected via filtration, washed with water, and dried to afford 6-bromo-3- methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (37 g, 91 % yield). 1H NMR (400 MHz, DMSO-d6) 14.52 (br. s., 1 H), 8.05 (d, J = 8.81 Hz, 1 H), 7.92 - 8.01 (m, 4H), 7.89 (d, J = 7.81 Hz, 1 H), 7.74 - 7.81 (m, 1 H), 2.41 (s, 3H); MS (m/z) 41 1 .8 (M+H+). methyl 6-bromo-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
6-Bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (16 g, 39.0 mmol) was suspended in toluene (160 ml.) and methanol (40 ml_). The brown suspension was cooled to 0 °C. 2N TMS-diazomethane in diethyl ether (19.50 ml_, 39.0 mmol) was added portionwise over 10 min. The resulting mixture was stirred for 1 h. The solvents were removed in vacuo and the resultant solid was again suspended in toluene (160 ml.) and methanol (40 ml_). 2N TMS-diazomethane in diethyl ether (19.50 ml. was added and the mixture was stirred for 3 d. The solvents were removed under reduced pressure and the solid was purified via column chromatography (ISCO, 40 g silica, 50% ethyl acetate/methylene chloride) to afford methyl 6-bromo-3-methyl-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (1 1 .9 g, 65% yield) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) 8.02 (d, J = 8.81 Hz, 1 H), 7.93 (d, J = 2.01 Hz, 1 H), 7.87 (s, 1 H), 7.82 (dd, J = 2.01 , 8.81 Hz, 1 H), 7.74 - 7.80 (m, 2H), 7.63 - 7.70 (m, 1 H), 4.14 (s, 3H), 2.43 (s, 3H); MS (m/z) 425.8 (M+H+). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
A solution of methyl 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (10.5 g, 24.75 mmol) was dissolved in carbon tetrachloride (200 ml.) and /V-bromosuccinimide (5.73 g, 32.2 mmol) and benzoyl peroxide (0.300 g, 1 .238 mmol) were added. The reaction mixture was heated to reflux overnight before it was cooled to room temperature and concentrated in vacuo. The residue was suspended in acetonitrile (150 ml.) and piperidinepiperidine (5.00 g, 29.7 mmol) was added. The suspension was stirred overnight. The crude material was filtered and the solvent was removed under reduced pressure. The residue was purified via column chromatography (ISCO, 120 g, 0- 10% methanol/methylene chloride). The isolated material was dissolved in ethyl acetate (400 ml.) and washed with 10% Na2C03 (3 x 100 ml_), brine, dried over Na2S04, filtered, and concentrated in vacuo to afford methyl 3-(1 ,4'-bipiperidin-1 '- yield) as a yellow solid.
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (2.1 g, 3.56 mmol) was suspended in methanol (20 ml.) and water (10 ml_). Potassium hydroxide (1.596 g, 28.5 mmol) was added in one portion and the reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The suspension became a solution. The reaction mixture was cooled, the methanol was removed in vacuo, and the residue was diluted with dichloromethane. The pH was adjusted to 5/6 with 2N HCI(aq) and the layers were separated. The aq was extracted twice more with dichloromethane and the combined organics were washed with brine, dried and concentrated to afford a brown solid. (1.2 g, 2.082 mmol, 58.5 % yield) Additional material was still present in the aqueous phase (pH~3-4). The pH was adjusted back to 5-6 with 2N NaOH, and the aqueous phase was extracted three times with dichloromethane. The combined organics were washed with brine, dried and combined with the previously isolated material to afford the title compound (2.2g, 3.82 mmol, 107 % yield) MS (m/z) 576 (M+H) 1 H NMR (400 MHz, CHLOROFORM-d) 8.35 (d, J = 2.01 Hz, 1 H), 8.04 - 8.14 (m, 1 H), 7.97 (d, J = 8.81 Hz, 1 H), 7.70 - 7.82 (m, 3H), 7.60 - 7.67 (m, 1 H), 3.74 (br. s., 2H), 3.52 (br. s., 1 H), 3.07 - 3.20 (m, 2H), 2.94 - 3.07 (m, 3H), 2.74 (br. s., 2H), 2.16 (t, J = 1 1 .46 Hz, 4H), 2.04 (d, J = 10.83 Hz, 4H), 1.85 (br. s., 3H); MS (m/z) 576.1 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethvn-6-bromo-2-r3-(trifluoromethvnphenyll-/\/-r(1 /?V2,2,2- trifluoro-1 -phenylethyll-4-quinolinecarboxamide
T3P in ethyl acetate (2.153 ml. of a 50% solution, 3.38 mmol) was added to 3-
(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1 .5 g, 2.60 mmol), [(1 R)-2,2,2-trifluoro-1-phenylethyl]amine (0.684 ml_, 3.12 mmol) and /V,/V-diisopropylethylamine (0.591 ml_, 3.38 mmol) in dichloromethane (10 ml_). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with methylene chloride and water and the phases were separated. The aqueous phase was extracted twice more with methylene chloride. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, brine, dried, filtered, and
concentrated in vacuo to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-[3- (trifluoromethyl)phenyl]-/\/-[(1 /?)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (2.1 g, >100% yield). MS (m/z) 733 (M+H).
EXAMPLE 16
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-methyl-1 /-/-pyrazol-5-yl)-2-r3-(trifluoromethyl)phenyll-/\/- r(1 /?)-2,2,2-trifluoro-1-phenylethyll-4-quinolinecarboxamide
3-(1 ,4'-Bipiperidin-1 '-ylmethyl)-6-bromo-2-[3-(trifluoromethyl)phenyl]-A -[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.200 g, 0.273 mmol) and (1 -methyl-1 H- pyrazol-5-yl)boronic acid (0.016 g, 0.354 mmol) were suspended in 1 ,4-dioxane (1 .5 ml_). 10% Sodium carbonate (0.454 ml_, 0.818 mmol) was added followed by
PdCI2(dppf)'CH2CI2 (0.022 g, 0.027 mmol). The reaction mixture was heated in the microwave at 160 °C for 10 min. The crude material was diluted with methanol (0.5 ml_), filtered, and purified via HPLC (20-60% MeCN/H20 with 0.1 % TFA). The collected fractions were then passed through a carbonate cartridge to afford 3-(1 ,4'-bipiperidin-1 '- ylmethyl)-6-(1-methyl-1 H-pyrazol-5-yl)-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2-trifluoro- 1-phenylethyl]-4-quinolinecarboxamide (0.081 g, 38% yield). MS (m/z) 734.3 (M+H+). The following examples were prepared using procedures analogous to that described in Example 16, substituting an appropriate boronic acid or boronic ester for (1 -methyl-1 H- pyrazol-5-yl)boronic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.
Figure imgf000040_0001
EXAMPLE 22
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-phenyl-A -r(1 S)-1-phenylethyl1-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide methyl 3-{r4-(dipropylamino)-1 -piperidinyllmethyl}-6-phenyl-2-r3-(trifluorometh
quinolinecarboxylate
Phenylboronic acid (0.124 g, 1.061 mmol), methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6- bromo-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.500 g, 0.847 mmol), PdCI2dppf, and 2N Na2C03 in dioxane were heated to 160 °C in the microwave for 10 min. The reaction mixture was diluted with water and methylene chloride and filtered through Celite®. The phases were separated, and the aqueous phase was extracted twice with methylene chloride. The combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g, 0-20% methanol/methylene chloride) to afford methyl 3- (1 ,4'-bipiperidin-1 '-ylmethyl)-6-phenyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.380 g, 76 % yield).
3- (1 ,4'-bipiperidin-1 '-ylmethyl)-6-phenyl-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
Potassium hydroxide (0.290 g, 5.17 mmol) was added to a stirred brown suspension of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-phenyl-2-[3-(trifluoromethyl)phenyl]-
4- quinolinecarboxylate (0.380 g, 0.647 mmol) in methanol (10 ml.) and water (4 ml.) was heated to 90°C and stirred overnight. After 18 h, additional potassium hydroxide (0.072 g, 1.29 mmol ) was added along with additional water (4 ml_). The mixture was heated at 1 10°C for 8 h. The reaction mixture was concentrated in vacuo, the residue was partitioned between water and methylene chloride, was cooled in an ice bath, and was adjusted to pH 6 with 2N HCI. The phases were separated and the aqueous phase was extracted twice more with methylene chloride. The combined organic extracts were washed with brine, dried, and concentrated in vacuo to afford methyl 3-(1 ,4'-bipiperidin-1 '- ylmethyl)-6-phenyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.360 g, 82 % yield). MS (m/z) 574.2 (M+H+)
3-(1.4'-bipiperidin-1 '-ylmethvn-6-phenyl-A -r(1 S)-1-phenylethyl1-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
T3P in ethyl acetate (0.240 ml. of a 50% solution, 0.377 mmol) was added to a solution of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-phenyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (0.180 g, 0.314 mmol), [(1 S)-1-phenylethyl]amine (0.042 g, 0.345 mmol), and /V,/V-diisopropylethylamine (0.164 ml_, 0.941 mmol). The reaction mixture was stirred overnight before it was quenched with water and concentrated in vacuo. The crude residue was purified via HPLC (20-60% MeCN/H20 with 0.1 % TFA) to afford 3-(1 ,4'- bipiperidin-1 '-ylmethyl)-6-phenyl-/\/-[(1 S)-1 -phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxamide (0.026 g, 12% yield). 1H NMR (400 MHz, METHANOL-d4) 8.06 - 8.22 (m, 2H), 7.98 (s, 1 H), 7.83 (t, J = 7.55 Hz, 2H), 7.74 (d, J = 7.55 Hz, 2H), 7.53 (d, J = 7.05 Hz, 3H), 7.45 (br. s., 3H), 7.37 (d, J = 7.05 Hz, 4H), 5.45 (br. s., 1 H), 3.67 (br. s., 1 H), 2.67 (br. s., 1 H), 2.34 - 2.59 (m, 5H), 2.21 (br. s., 1 H), 1.93 (br. s., 2H), 1.60 (br. s., 9H), 1.40 - 1.53 (m, 3H), 1.00 - 1 .38 (m, 2H); MS (m/z) 677.3 (M+H+).
The following compound was prepared using a procedure analogous to that described in Example 22, replacing (1 S)-1-phenylethyl]amine with (1 /?)-2,2,2-trifluoro-1- phenylethyl]amine. As is appreciated by those skilled in the art, this analogous example may involve variations in general reaction conditions.
Figure imgf000042_0001
EXAMPLE 24
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[4-(methyloxy)-1 -piperidinyll-2-[3-(trifluoromethyl)phenyll- A/-(2,2,2-trifluoro-1-phenylethyl)-4-quinolinecarboxamide methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-r4-(methyloxy)-1 -piperidinyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxylate
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (200 mg, 0.339 mmol), 4-methoxypiperidine (46.8 mg, 0.406 mmol), palladium(ll) acetate (7.60 mg, 0.034 mmol), cesium carbonate (221 mg, 0.677 mmol), and di-t-butylbiphenylphosphine (20.19 mg, 0.068 mmol) were weighed into a microwave vial and suspended in dioxane. The reaction was heated to 100°C for 15 minutes, and the reaction was further heated in a 100°C oil bath for 18 h. The reaction was cooled to room temperature, and filtered through a 1 in pad of silica gel eluting with EtOAc. The washings were concentrated to afford a yellow oil, which was carried on to the next step without further purification. MS (m/z) 625.3 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-r4-(methyloxy)-1 -piperidinyll-2-r3-(trifluoromethyl)phenyll- N-(2,2,2-trifluoro-1-phenylethyl)-4-quinolinecarboxamide
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[4-(methyloxy)-1 -piperidinyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (61.5 mg, 0.0984 mmol) was dissolved in 2 ml. of 1 N HCI and 1 ml. of THF. The solution was heated to 100°C in the microwave for 15 minutes. The reaction mixture was diluted with dichloromethane and sat. aqueous NaHC03. The layers were shaken and separated. The organic phase was dried over MgS04, filtered, and concentrated to afford 60 mg of crude acid. The residue was dissolved in 1 ml. of dichloromethane and cooled to 0°C. Diisopropylethylamine (21 .76 μΙ_, 0.1 18 mmol) and (1 R)-2,2,2-trifluoro-1 -phenylethyl]amine (17.2 mg, 0.098 mmol) was added to the reaction followed by T3P (82 μΙ_, 0.138 mmol). The reaction was stirred overnight and allowed to warm slowly to ambient temperature. The reaction was quenched with sat. aqueous NaHC03. The phases were separated, and the organic phase was concentrated to a film. The residue was dissolved in 1 ml. of DMSO, filtered through a pipette filter, and purified by reverse phase HPLC (Waters Sunfire 30x100mm Acetonitrile:Water TFA 15-70%) to afford the title compound (13.7 mg, 15%). MS (m/z) 768.4 (M+H+).
EXAMPLE 25
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1 -pyrrolidinylcarbonyl)-2-r3-(trifluoromethyl)phenyll-/\/- Γ(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-pyrrolidinylcarbonyl)-2-r3-(trifluoromethyl)phenyll-/\/- Γ(1 f?)-2 ,2 , 2-trif I u pro- 1 -phenylethyll-4-quinolinecarboxamide
3-(1 ,4'-Bipiperidin-1 '-ylmethyl)-6-bromo-2-[3-(trifluoromethyl)phenyl]-A -[(1 R)-2,2,2- trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.200 g, 0.273 mmol), molybdenum hexacarbonyl (0.108 g, 0.409 mmol), PdCI2(dppf CH2Cl2 (0.022 g, 0.027 mmol), and pyrrolidine (1 .6 g, 22.5 mmol) were heated in the microwave at 160 °C for 20 min. The reaction mixture was concentrated in vacuo and the residue purified via SCX column (10 g, methanol, then 2N ammonia in methanol). The material was purified via HPLC
(Waters, 20-60% MeCN/H20 with 0.1 %TFA). The pure fractions were passed through an SCX column (10 g, methanol, then 2N ammonia in methanol) to afford 3-(1 ,4'-bipiperidin- 1 '-ylmethyl)-6-(1 -pyrrolidinylcarbonyl)-2-[3-(trifluoromethyl)phenyl]-/V-[(1 R)-2,2,2-trifluoro- 1-phenylethyl]-4-quinolinecarboxamide (0.065 g, 30% yield). 1H NMR (400 MHz, METHANOL-d4) 8.17 (br. s., 2H), 7.89 - 8.04 (m, 2H), 7.83 (d, J = 6.53 Hz, 2H), 7.69 - 7.78 (m, 1 H), 7.57 - 7.69 (m, 2H), 7.50 (br. s., 3H), 6.16 (br. s., 1 H), 3.64 - 3.79 (m, 2H), 3.59 - 3.64 (m, 1 H), 3.55 (d, J = 8.28 Hz, 2H), 2.99 (br. s., 1 H), 2.47 - 2.72 (m, 5H), 2.27 - 2.47 (m, 2H), 1 .84 - 2.09 (m, 4H), 1 .67 - 1 .83 (m, 2H), 1 .61 (br. s., 4H), 1 .45 (br. s., 3H), 1 .15 - 1 .37 (m, 2H), 0.88 - 1 .09 (m, 1 H); MS (m/z) 753.3 (M+H+).
The following compounds were prepared using a procedure analogous to that described in Example 25, substituting an appropriate amine for pyrrolidine. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.
Figure imgf000044_0001
EXAMPLE 29
Figure imgf000045_0001
(trifluoromethyl)phenyll-4-quinolinecarboxamide 6-(ethyloxy)-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxyli acid
To a solution of 5-(ethyloxy)-1 /-/-indole-2,3-dione (1.1 g, 5.75 mmol) in ethanol (5.6 mL) was added potassium hydroxide (1.94 g, 34.5 mmol) as a solution in water (4.79 mL). The reaction mixture was stirred at ambient temperature for 30 min. 3- Trifluoromethylpropiophenone (1.16 g, 5.75 mmol) was dissolved in ethanol (4 mL) and added to the reaction mixture. The reaction was heated to reflux for 18 h. After cooling to ambient temperature, the reaction was concentrated, diluted with ethyl acetate, and the phases were separated. The aqueous phase was acidified to pH 7 and washed with ethyl acetate. The aqueous phase was acidified to pH 3 and washed with ethyl acetate. The organic phases were combined, dried over MgS04, filtered, and concentrated to give 6- (ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.16 g, >99% yield) as a light orange solid. MS (m/z) 376.1 (M+H+).
6-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
To a mixture of 6-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (2.16 g, 5.75 mmol) in dichloromethane (19.17 mL) at 0°C was added oxalyl chloride (6.33 mL, 12.65 mmol) dropwise. Two drops of DMF were added. An additional 10 mL of THF was added to aid in solubility. The reaction mixture was stirred at 0°C for 1 h. Methanol (15 mL) was added slowly to the reaction mixture. The reaction became completely homogeneous and was allowed to warm slowly to ambient temperature overnight. The reaction mixture was concentrated. The crude product was dissolved in methylene chloride and washed with saturated aqueous NaHC03 (2 x 10 mL). The organic phase was dried in a phase separator and concentrated. The compound was dissolved in methylene chloride and passed through a half-inch plug of silica gel and concentrated to afford 6-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (1.8 g, 80% yield) as a pale yellow solid. MS (m/z) 390.1 (M+H+). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
Methyl 6-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1 .8 g, 4.62 mmol) was dissolved in carbon tetrachloride (23 mL). /V-Bromosuccinimide (1 .070 g, 6.01 mmol) and benzoyl peroxide (0.1 12 g, 0.462 mmol) were added, and the reaction was heated to 100°C for 24 h. The reaction was filtered, cooled to room temperature, and concentrated. The oil was dissolved in 24 ml. MeCN. Half of the solution (12 ml.) was treated with 1 ,4'-bipiperidine (0.778 g, 4.62 mmol). The reaction mixture was stirred at ambient temperature for 18 h, concentrated, dissolved in
dichloromethane, and washed with saturated aqueous NaHC03. The phases were separated with a phase separator, and the organic phase was concentrated onto silica gel. The crude material was purified via column chromatography (ISCO, 40 g silica gel cartridge, 100% ethyl acetate) to afford methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-
2- [3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.623 g, 29% yield) as a pale yellow oil. MS (m/z) 556.3 (M+H+).
3- (1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
Methyl-3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (0.934 g, 1 .681 mmol) was dissolved in methanol (9.04 ml_), tetrahydrofuran (3.01 ml_), and water (3.01 ml_). Potassium hydroxide (0.472 g, 8.40 mmol) was added and the reaction mixture was heated to 70°C. After 3 days the reaction was cooled to room temperature and concentrated. The crude product was suspended in ethyl acetate and water. The product quickly precipitated out of the biphasic mixture and the solid was collected by filtration and dried to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6- (ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.980 g, >99% yield). This material was used in the next step without further purification. MS (m/z) 542.0 (M+H+).
3-(1.4'-bipiperidin-1 '-ylmethvn-6-(ethyloxyV/V-r(1 SV1-phenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
3-(1 ,4'-Bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (0.100 g, 0.185 mmol) was dissolved in dichloromethane (615 μΙ_) and cooled to 0 °C. Hunig's base (6.81 μΙ_, 0.037 mmol) was added followed by the 1 S- methylbenzylamine (0.025 g, 0.203 mmol). T3P (154 μΙ_ of a 50% solution in ethyl acetate, 0.258 mmol) was added dropwise. The reaction mixture was allowed to stir at 0°C for 2 h before it was quenched with water and stirred for 30 min. The phases were separated, and the organic phase was concentrated to crude yellow product. The crude product was purified via HPLC (Waters, Sunfire 30 x 100 mm, 15-70% CH3CN/H20 with 0.1 % TFA). The product fractions were concentrated and dissolved in methylene chloride. The organic solution was washed with saturated aqueous Na2C03 solution, and passed through a phase separator to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-/V-[(1 S)-1- phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (0.017 g, 14% yield) as a pale yellow foam after concentration under reduced pressure. MS (m/z) 645.1 (M+H+).
The following example was prepared using procedures analogous to that described for Example 29, replacing 1 S-methylbenzylamine with (1 /?)-2,2,2-trifluoro-1- phenylethanamine. As is appreciated by those skilled in the art, this analogous example may involve variations in general reaction conditions.
Figure imgf000047_0001
EXAMPLE 31
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(ethyloxy)-2-r3-(trifluoromethyl)phenyll-/V-r(1 /?)-2,2,2- trifluoro-1 -phenylethyll-4-quinolinecarboxamide
7-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
To a solution of 3-(ethoxy)aniline (2 g, 14.58 mmol) in ethanol (40 mL) was added
3-(trifluoromethyl)benzaldehyde (2.54 g, 14.58 mmol). The resulting solution was heated to reflux for 1 h. 2-Oxobutanoic acid (1.49 g, 14.58 mmol) was added and the reaction mixture was heated for an additional 3 h. The reaction mixture was cooled to room temperature and stirred for 18 h. The mixture was filtered, washed with cold ethanol, and dried to afford 7-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1 g, 18% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) 7.89 - 7.94 (m, 2H), 7.83 (d, J = 7.61 Hz, 1 H), 7.73 (t, J = 7.75 Hz, 1 H), 7.69 (d, J = 9.15 Hz, 1 H), 7.42 (d, J = 2.54 Hz, 1 H), 7.30 (dd, J = 2.59, 9.15 Hz, 1 H), 4.17 (q, J = 6.95 Hz, 2H), 2.32 (s, 3H), 1 .37 (t, J = 6.97 Hz, 3H); MS (m/z) 376.0 (M+H+). methyl 7-(ethyloxy)-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
A mixture of 7-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (1 g, 2.66 mmol) in thionyl chloride (10 mL) was heated to reflux for 2 hours. The thionyl chloride was removed in vacuo, and the residue was suspended in methanol (20 mL). Triethylamine (1.08 g, 10.66 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The crude material was purified via column chromatography (50:1 petroleum ether/ethyl acetate) to afford methyl 7-(ethyloxy)-3- methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.750 g, 72% yield). 1 H NMR (400 MHz, CHLOROFORM-d) 7.77 (s, 1 H), 7.62 - 7.70 (m, 2H), 7.52 - 7.59 (m, 2H), 7.36 (d, J = 2.38 Hz, 1 H), 7.15 - 7.20 (m, 1 H), 4.10 (q, J = 6.96 Hz, 2H), 4.02 (s, 3H), 2.28 (s, 3H), 1 .42 (t, J = 7.00 Hz, 3H); MS (m/z) 390.2 (M+H+). methyl 3-(bromomethyl)-7-(ethyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate Methyl 7-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.750 g, 1.93 mmol), benzoyl peroxide (0.280 g, 1.16 mmol) and NBS (0.377 g, 2.12 mmol) were dissolved in carbon tetrachloride (15 ml.) and refluxed for 18 h. The solvent was removed under reduced pressure, and the residue was dissolved in methylene chloride and washed with water. The phases were separated and the organic phase was dried over Na2S04, filtered and concentrated. The crude product was purified via column chromatography (50:1 , petroleum ether/ethyl acetate) to afford methyl 3-(bromomethyl)-7- (ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.820 g, 84% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) 8.00 (s, 1 H), 7.93 (d, J = 7.61 Hz, 1 H), 7.73 - 7.81 (m, 2H), 7.65 - 7.71 (m, 1 H), 7.45 (d, J = 2.54 Hz, 1 H), 7.29 (dd, J = 2.56, 9.23 Hz, 1 H), 4.62 (s, 2H), 4.20 (q, J = 7.02 Hz, 2H), 4.16 (s, 3H), 1 .51 (t, J = 7.00 Hz, 3H); MS (m/z) 470.1 (M+H+). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(ethyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
A suspension of methyl 3-(bromomethyl)-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]- 4-quinolinecarboxylate (0.360 g, 0.77 mmol), 1 ,4'-bipiperidine (0.136 g, 0.81 mmol), and potassium carbonate (0.213 g, 1.54 mmol) in acetonitrile (8 ml.) was heated to reflux for 18 h. The acetonitrile was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified via column chromatography (1 :100 methanol/methylene chloride) to give methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(ethyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.360 g, 84% yield) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) 7.78 (s, 1 H), 7.74 (d, J = 9.26 Hz, 1 H), 7.63 - 7.72 (m, 2H), 7.55 - 7.62 (m, 1 H), 7.40 (d, J = 2.32 Hz, 1 H), 7.20 - 7.24 (m, 1 H), 4.15 (q, J = 6.93 Hz, 2H), 4.02 (s, 3H), 3.55 (s, 2H), 2.73 (d, J = 1 1 .30 Hz, 2H), 2.43 (br. s., 4H), 2.13 (t, J = 1 1 .19 Hz, 1 H), 1.83 (t, J = 1 1.05 Hz, 2H), 1 .64 (d, J = 13.01 Hz, 3H), 1.50 - 1.59 (m, 4H), 1 .47 (t, J = 6.92 Hz, 3H), 1 .34 - 1 .44 (m, 4H); MS (m/z) 556.4 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(ethyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
A solution of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(ethyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.360 g, 0.648 mmol) in 6N HCI (8 ml.) was heated to reflux for 18 h. The resulting mixture was concentrated to afford 3-(1 ,4'- bipiperidin-1 '-ylmethyl)-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid hydrochloride (0.400 g, 100% yield) which was used in the next step without further purification. MS (m/z) 542.4 (M+H+).
3-(1.4'-bipiperidin-1 '-ylmethvn-7-(ethyloxyV2-r3-(trifluoromethvnphenyll-/V-r(1 ffl-2.2.2- trifluoro-1 -phenylethyll-4-quinolinecarboxamide
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]amine (0.097 g, 0.554 mmol), HATU (0.077 g,
0.203 mmol), EDC (0.039 g, 0.203 mmol) and 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(ethyloxy)- 2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid hydrochloride (0.100 g, 0.185 mmol) were dissolved in dichloromethane (1.846 ml_). The reaction mixture was stirred for 24 h at room temperature. The reaction was quenched with H20 (1 drop) and concentrated. The residue was then dissolved in DMF, filtered, and purified via HPLC
(Agilent, Restek Biphenyl, 40-80% CH3CN/H20) to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7- (ethyloxy)-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4- quinolinecarboxamide (0.037 g, 28% yield). 1H NMR (400 MHz, DMSO-d6) 10.00 (br. s., 1 H), 7.94 (br. s., 1 H), 7.82 (d, J = 7.78 Hz, 2H), 7.63 - 7.78 (m, 4H), 7.37 - 7.53 (m, 5H), 6.19 (quin, J = 8.66 Hz, 1 H), 4.22 (d, J = 6.27 Hz, 2H), 4.05 (s, 1 H), 3.15 (d, J = 13.80 Hz, 1 H), 2.29 - 2.43 (m, 2H), 2.24 (br. s., 3H), 2.09 (br. s., 1 H), 1 .72 (br. s., 1 H), 1.41 (br. s., 8H), 1 .33 (br. s., 3H), 1 .10 - 1.28 (m, 2H), 0.79 - 1 .03 (m, 2H); MS (m/z) 699.2 (M+H+).
EXAMPLE 32
3-(1 ,4'-bipiperidin-1 '-ylmethvn-7-(propyloxyV2-r3-(trifluoromethvnphenyll-/\/-r(1 /?V2,2,2- trifluoro-1 -phenylethyll-4-quinolinecarboxamide
3-methyl-7-(propyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
3-(Trifluoromethyl)benzaldehyde (20.50 g, 1 18 mmol) was added to a solution of the 3-(propyloxy)aniline (17.8 g, 1 18 mmol) in ethanol (300 ml_). The mixture was stirred at reflux for 1 h. 2-Oxobutanoic acid (12.02 g, 1 18 mmol) was added, and the reaction mixture was stirred at reflux for an additional 3 h, cooled to room temperature, and stirred overnight. The solid precipitate was collected by filtration, washed with ethanol, and air dried to afford 3-methyl-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (5.65 g, 12% yield). 1 H NMR (400 MHz, DMSO-d6) 14.23 (br. s., 1 H), 7.93 - 7.98 (m, 2H), 7.88 (d, J = 7.78 Hz, 1 H), 7.77 (t, J = 7.78 Hz, 1 H), 7.72 (d, J = 9.04 Hz, 1 H), 7.46 (d, J = 2.51 Hz, 1 H), 7.35 (dd, J = 2.51 , 9.29 Hz, 1 H), 4.12 (t, J = 6.53 Hz, 2H), 2.36 (s, 3H), 1.81 (sxt, J = 7.08 Hz, 2H), 1 .03 (t, J = 7 AO Hz, 3H); MS (m/z) 390.1 (M+H+). methyl 3-methyl-7-(propyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
DMF (5 drops) was added to a suspension of 3-methyl-7-(propyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (5.65 g, 14.51 mmol) in
dichloromethane (60 ml.) at 0 °C. Oxalyl chloride (1.905 ml_, 21.77 mmol) was added slowly. The mixture was stirred at 0°C for 1 h. Methanol (30 ml.) was added. The resulting mixture was maintained at 0°C for 2 h, warmed to room temperature, and stirred overnight. The solvent was removed under reduced pressure. The residue was diluted with water and treated with saturated aqueous NaHC03 until the pH >7. The aqueous mixture was extracted with methylene chloride (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 120 g silica, 0-30% ethyl acetate/hexanes) to afford methyl 3-methyl-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (5.8 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) 7.94 - 8.00 (m,
2H), 7.88 (d, J = 8.03 Hz, 1 H), 7.78 (d, J = 7.53 Hz, 1 H), 7.69 (d, J = 9.29 Hz, 1 H), 7.48 (d, J = 2.51 Hz, 1 H), 7.34 (dd, J = 2.51 , 9.03 Hz, 1 H), 4.09 - 4.15 (m, 3H), 4.05 (s, 3H), 2.32 (s, 3H), 1.81 (sxt, J = 7.03 Hz, 2H), 1 .03 (t, J = 7 AO Hz, 3H); MS (m/z) 404.1 (M+H+). methyl 3-(bromomethyl)-7-(propyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate A suspension of methyl 3-methyl-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (5.8 g, 14.38 mmol), NBS (3.33 g, 18.69 mmol) and
diphenylperoxyanhydride (0.348 g, 1 .438 mmol) in carbon tetrachloride (30 mL) was heated to 100°C and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to afford methyl 3-(bromomethyl)-7-
(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used in the next step without further purification. MS (m/z) 484.0 (M+H+). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(propyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
1 ,4'-Bipiperidine (1 .573 g, 9.35 mmol) was added to a suspension of methyl 3- (bromomethyl)-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.47 g, 7.19 mmol) in acetonitrile (30 mL). The mixture was stirred for 3 h. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and purified via HPLC (Biotage RP, 0-50% MeCN/H20 with 0.1 % TFA). The fractions containing the product were neutralized with saturated aqueous NaHC03 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2S04, filtered and concentrated in vacuo to afford methyl 3-(1 ,4'-bipiperidin-1 '- ylmethyl)-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.1 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) 7.92 (s, 1 H), 7.82 - 7.90 (m, 2H), 7.71 - 7.79 (m, 2H), 7.47 (d, J = 2.51 Hz, 1 H), 7.35 (dd, J = 2.51 , 9.29 Hz, 1 H), 4.12 (t, J = 6.53 Hz, 2H), 3.98 (s, 3H), 3.55 (s, 2H), 2.61 (d, J = 10.04 Hz, 2H), 2.36 (br. s., 4H), 1 .99 - 2.12 (m, 1 H), 1.72 - 1.88 (m, 4H), 1.49 - 1 .59 (m, 2H), 1 .39 - 1 .49 (m, 4H), 1.35 (br. s., 2H), 1 .27 (d, J = 12.30 Hz, 2H), 1 .02 (t, J = 7.28 Hz, 3H); MS (m/z) 570.1 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(propyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
Potassium hydroxide (1 .527 g, 27.2 mmol) was added to a solution of methyl 3- (1 ,4'-bipiperidin-1 '-ylmethyl)-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (3.1 g, 5.44 mmol) in methanol (30 mL) and water (10 mL). The mixture was heated to reflux for 5 hours. The solvent was removed under reduced pressure, and the residue was adjusted to pH~5-6 with 2N HCI and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2S04, filtered, and concentrated in vacuo to afford 3-(1 ,4'-bipiperidin- 1 '-ylmethyl)-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.9 g, 96% yield). This material was used in the next step without further purification. MS (m/z) 556.3 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethvn-7-(propyloxyV2-r3-(trifluoromethvnphenyll-/\/-r(1 ffl-2,2,2- trifluoro-1 -phenylethyll-4-quinolinecarboxamide
A mixture of 3-(1 ,4'-bipiperidin-1 '-yl methyl )-7-(propyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.360 mmol), (1 R)-2,2,2- trifluoro-1 -phenylethanamine (0.095 g, 0.540 mmol), EDC (0.276 g, 1.440 mmol), HOBT (0.055 g, 0.360 mmol), and /V,/V-diisopropylethylamine (0.629 mL, 3.60 mmol) in N,N- dimethylformamide (2 mL) and tetrahydrofuran (2 mL) was heated to 50°C overnight. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire, 30 x 75mm column, 50 mL/min, 20-60% MeCN/H20 with 0.1 % TFA). The fractions containing the product were neutralized with saturated aqueous NaHC03 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2S04, filtered, and concentrated in vacuo to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(propyloxy)-2-[3- (trifluoromethyl)phenyl]-/\/-[(1 /?)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.160 g, 59% yield). 1H NMR (400 MHz, DMSO-d6) 9.92 - 10.16 (m, 1 H), 7.94 (br. s., 1 H), 7.83 (d, J = 7.78 Hz, 2H), 7.62 - 7.79 (m, 4H), 7.47 (d, J = 9.29 Hz, 4H), 7.12 - 7.31 (m, OH), 6.20 (quin, J = 8.72 Hz, 1 H), 4.13 (br. s., 2H), 3.36 - 3.63 (m, 1 H), 3.02 - 3.25 (m, 1 H), 2.29 - 2.44 (m, 2H), 2.24 (br. s., 3H), 2.09 (br. s., 1 H), 1 .63 - 1 .87 (m, 3H), 1 .41 (br. s., 4H), 1 .33 (br. s., 2H), 1 .18 (br. s., 2H), 1 .02 (t, J = 7.15 Hz, 3H), 0.75 - 0.98 (m, 2H); MS (m/z) 713.3 (M+H+).
The following examples were prepared using procedures analogous to that described for Example 32, selecting an appropriate aniline in the first step, and selecting (1 /?)-2,2,2- trifluoro-1 -phenylethanamine or 1 S-methylbenzylamine as required. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.
Figure imgf000052_0001
Figure imgf000053_0001
EXAMPLE 37
3-(1.4'-biDiDeridin-1 lmethvn-6-chloro-/V-r(1 S)-1-Dhenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
6-chloro-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
To a stirred suspension of 5-chloro-1 H-indole-2,3-dione (3.00 g, 16.52 mmol) in glacial acetic acid (45 mL) was added 1 -[3-(trifluoromethyl)phenyl]-1-propanone (2.83 mL, 16.52 mmol). The resulting mixture was heated to 75°C. Concentrated HCI was added, and the mixture was heated to 1 10°C for 48 h. The mixture was cooled to room
temperature, diluted with water (75 mL), and the precipitate was collected by filtration. The solid material was triturated with ethanol (75 mL), collected by filtration, washed with diethyl ether (2 x 45 mL), and dried to provide 6-chloro-3-methyl-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (4.07 g, 67% yield). 1H NMR (400 MHz, DMSO-d6) 14.48 (br. s., 1 H), 8.13 (d, J = 8.81 Hz, 1 H), 7.95 - 8.01 (m, 2H), 7.89 (d, J = 7.81 Hz, 1 H), 7.81 - 7.86 (m, 2H), 7.74 - 7.81 (m, 1 H), 2.41 (s, 3H); MS (m/z) 365.9 (M+H+).
3-(bromomethyl)-6-chloro-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
A stirred suspension of 6-chloro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (0.4678 g, 1.279 mmol), NBS (0.285 g, 1.599 mmol), and benzoyl peroxide (0.062 g, 0.256 mmol) in carbon tetrachloride (20 mL) was heated at reflux (oil bath 1 15°C) for 19 h. Additional NBS (0.228 g, 1 .279 mmol) and benzoyl peroxide (0.062 g, 0.256 mmol) was added and the mixture was heated at reflux for 7 h. The suspension was cooled to room temperature, and the solid precipitate was collected by filtration to afford 3-(bromomethyl)-6-chloro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.5983 g). This material was used in the next step without further purification. MS (m/z) 446.0 (M+H+). 3-(1 ,4'-bipiperidin-1 lmethyl)-6-chloro-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
A solution of 1 ,4'-bipiperidine (0.168 g, 1 .000 mmol) and N,N- diisopropylethylamine (0.175 mL, 1 .00 mmol) in tetrahydrofuran (10 mL) was stirred, under argon, at room temperature for 20 min. 3-(Bromomethyl)-6-chloro-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.4446 g, 1.000 mmol) was added in one portion and the resulting suspension was heated at 50°C for 20 h. The solvent was removed under reduced pressure, and the solid residue was triturated in water and filtered to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (0.213 g). The aqueous filtrate was concentrated in vacuo and the solid residue triturated with ether to provide additional 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6- chloro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.4502 g, 0.664 g combined, 94% total yield). MS (m/z) 532.05 (M+H+). 3-(1.4'-biDiDeridin-1 '-ylmethvn-6-chloro-/V-r(1 S)-1-Dhenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
A solution of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (0.2109 g, 0.396 mmol), HOBT (0.079 g, 0.515 mmol), EDC (0.106 g, 0.555 mmol), (1 S)-1-phenylethanamine (0.050 mL, 0.396 mmol), and Et3N (0.276 mL, 1.982 mmol) in dichloromethane (3 mL) was stirred at room temperature for 5 d. The solvent was removed under reduced pressure. The residue was dissolved in methanol and purified via HPLC (Gilson, Sunfire Prep C18 OBD, 30 x 150 mm, 10-100% CH3CN/H20 with 0.1 % TFA). The residue was diluted with water (3 mL), neutralized with Na2C03, and extracted with ethyl acetate. The organic phase was separated and washed with water, brine, dried over MgS04, filtered, and concentrated in vacuo to provide 3-(1 ,4'- bipiperidin-1 '-ylmethyl)-6-chloro-/\/-[(1 S)-1 -phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxamide (0.1 16 g, 46% yield) after recrystallization from MeOH/H20. MS (m/z) 635.5 (M+H+).
The following example was prepared as described for Example 37, using the quinoline synthesis conditions in Example 15 in place of the first step above. As is appreciated by those skilled in the art, this analogous example may involve variations in general reaction conditions. MS
Ex Name Structure (m/z)
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-8-chloro- A/-[(1 S)-1-phenylethyl]-2-[3- 635.5
38
(trifluoromethyl)phenyl]-4- (M+H+) quinolinecarboxamide
EXAMPLE 39
3-(1 ,4'-bipiperidin-1 lmethyl^
(trifluoromethyl)phenyll-4-quinolinecarboxamide
3-methyl-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarb acid
Potassium hydroxide (50 g, 892.9 mmol) in water (100 mL) was added to a solution of 5-(methyloxy)-1 H-indole-2,3-dione (26.5 g, 149.7 mmol) in ethanol (400 mL). 1-[3-(Trifluoromethyl)phenyl]-1-propanone (33.3 g, 164.9 mmol) was added, and the mixture was heated to reflux for 3 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water (500 mL) and extracted with methylene chloride (2 x 600 mL). The aqueous phase was isolated, and the pH was adjusted to 3 with 10% HCI. The solid precipitate was collected by filtration to afford 3- methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (50 g, 93% yield) as a yellow solid. MS (m/z) 362.1 (M+H+). methyl 3-methyl-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
A solution of 3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (50 g, 138.5 mmol) and thionyl chloride (400 mL) was heated to reflux for 3 h. The reaction mixture was heated to room temperature and concentrated in vacuo. Triethylamine (92 g, 910.9 mmol) was added dropwise as a solution in methanol (400 mL). The mixture was heated to reflux for 1 h and cooled to room temperature. Water (500 mL) was added, and the solid precipitate was collected by filtration to afford methyl 3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (40 g, 77% yield) as a yellow solid. MS (m/z) 376.1 (M+H+).
methyl 3-(bromomethyl)-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
A suspension of methyl 3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (8.2 g, 21.9 mmol), NBS (4.7 g, 32.8 mmol), and benzoyl chloride
(1 .1 g, 4.4 mmol) in carbon tetrachloride (100 mL) was heated to reflux overnight. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to afford methyl 3-(bromomethyl)-6-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (10 g). This material was used in the next step without further purification. MS (m/z) 455.0 (M+H+). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
A mixture of methyl 3-(bromomethyl)-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (9.9 g, 21.9 mmol), 1 ,4'-bipiperidine (4.4 g, 26.2 mmol), and K2C03 (9.1 g, 65.6 mmol) in methylene chloride (100 ml.) was heated to reflux for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water (2 x 150 ml_), dried over MgS04, filtered, and concentrated in vacuo. The crude material was purified via column chromatography (100:0 to 80:1 methylene chloride/methanol) to afford methyl 3-(1 ,4'- bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.0 g, 42% yield). MS (m/z) 542.2 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
A solution of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (4.5 g, 8.3 mmol), HCI (50 ml_), and water (50 ml.) was heated to 90°C for 2 h. The reaction mixture was cooled to room
temperature, and the pH was adjusted to 9 with 3N NaOH. The solution was extracted with methylene chloride (3 x 150 ml_). The combined organic extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified via column chromatography (100:0 to 5:1 methylene chloride/methanol) to afford 3-(1 ,4'-bipiperidin-1 '- ylmethyl)-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.0 g, 46% yield). This material was used in the next step without further purification.
3-(1.4'-biDiDeridin-1 lmethylV6-(methyloxy)-N-r(1 S)-1-Dhenylethvn-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
A mixture of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.0 g, 3.8 mmol), (1 S)-1- phenylethanamine (0.55 g, 4.6 mmol), and EDC (1 .45 g, 7.6 mmol) in methylene chloride (50 ml.) was heated to reflux for 3 h. The reaction mixture was cooled to room
temperature and washed with 1 % HCI. The aqueous phase was extracted with methylene chloride (5 x 50 ml_). The combined organic extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified via column chromatography (100:0 to 30:1 methylene chloride/methanol) to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)- A/-[(1 S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (1.7 g, 71 % yield). MS (m/z) 631 .3 (M+H+).
3-( 1 ,4'-bipiperidin-1 '-ylmethylV6-hvdroxy-A -r( 1 SV1 -phenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
A solution of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-/\/-[(1 S)-1-phenylethyl]-2- [3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (0.9 g, 1 .4 mmol) and boron tribromide (1 mL) in methylene chloride (50 mL) was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL), and the resulting biphasic mixture was extracted with methylene chloride (5 x 50 mL). The combined organic extracts were dried over MgS04, filtered, and concentrated in vacuo. The residue was purified via column chromatography (100:0 to 20:1 methylene chloride/methanol) to afford 3-(1 ,4'-bipiperidin- 1 '-ylmethyl)-6-hydroxy-/v-[(1 S)-1 -phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxamide (0.3 g, 35% yield). MS (m/z) 617.3 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-r(cvanomethyl)oxyl-/\/-r(1 S)-1-phenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
DBU (0.065 g, 0.4 mmol) was added to a solution of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-
6-hydroxy-/V-[(1 S)-1 -phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (0.130 g, 0.2 mmol) in methylene chloride (20 mL) at 0-10°C. After 20 min,
bromoacetonitrile (0.03 g, 0.25 mmol) was added. The reaction mixture was stirred overnight at room temperature. The mixture was washed with water (2 x 30 mL), dried over MgS04, filtered, and concentrated in vacuo. The residue was purified via column chromatography (100:0 to 20:1 methylene chloride/methanol) to afford 3-(1 ,4'-bipiperidin- 1 '-ylmethyl)-6-[(cyanomethyl)oxy]-/\/-[(1 S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxamide (0.030 g, 22% yield). 1H NMR (400 MHz, CDCI3) 8.47 (br. s, 1 H), 8.08 (d, J = 9.2 Hz, 1 H), 7.81 (s, 1 H), 7.72 (d, J = 7.2 Hz, 1 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.61 (m, 1 H), 7.52 (d, J = 7.2 Hz, 2 H), 7.39 - 7.45 (m, 3 H), 7.32 - 7.36 (m, 2 H), 5.56 (m, J = 6.8 Hz, 1 H), 4.75 (b. s, 2 H), 3.45 - 3.75 (m, 2 H), 2.88 - 2.75 (m, 1 1 H), 1.74 (d, J = 6.8 Hz, 3 H), 0.70 - 1 .80 (m, 8 H); MS (m/z) 656.6 (M+H+). EXAMPLE 40
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-{r2-(methyloxy)ethylloxy}-N-r(1 S)-1 -phenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
A three-necked flask equipped with an addition funnel and a reflux condenser was charged with 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-hydroxy-/\/-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide (0.5 g, 0.81 mmol), potassium carbonate (0.559g, 4.05 mmol) and acetonitrile (20 ml_). The reaction mixture was stirred for 15 minutes, potassium iodide (0.27g, 1.62 mmol) and triethylbenzylammonium chloride (0.4 mmol) were added, and the mixture was heated to reflux. A solution of 1-bromo-2- (methyloxy)ethane (0.22 g, 1.62 mmol) in acetonitrile (5 ml.) was added over 10 minutes. The reaction was stirred for 20 hours and additional portions of Kl (0.81 mmol) and triethylbenzylammonium chloride (0.4 mmol) were added. The reaction was stirred an additional 2 h, cooled to room temperature, and 200 mg of the reaction mixture was purified by chromatography over Al203 (50:1 dichloromethane: MeOH) to afford 1 10 mg of the product (20%) as a yellow solid. 1H NMR (400 MHz, CDCI3) 8.00 (d, J = 8.0 Hz, 1 H), 7.82 (s, 1 H), 7.69 (dd, J = 12.0, 12.0 Hz, 2 H), 7.61 (d, J = 10.4 Hz, 1 H), 7.47 - 7.52 (m, 2 H), 7.32 - 7.45 (m, 3 H), 7.31 (d, J = 13.6 Hz, 1 H), 7.22 (s, 1 H), 5.57 (m, J = 9.2, 9.6 Hz, 1 H), 3.90 - 4.20 (m, 2 H), 3.80 (t, J = 6.0 Hz, 2 H), 3.55 - 3.70 (m, 2 H), 3.51 (s, 3 H), 1.95 - 2.80 (m, 7 H), 1.71 (d, J = 9.2 Hz, 3 H), 0.95 - 1 .85 (m, 12 H); MS (m/z) 675.7 (M+H+).
EXAMPLE 41
3-( 1 ,4'-bipiperidin-1 '-ylmethylV6-(methyloxy)-7-r(2.2.2-trifluoroethvnoxy1-2-r3- (trifluoromethyl)phenyll-/\/-r(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
7-hvdroxy-3-methyl-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid A mixture of 3-(trifluoromethyl)benzaldehyde (12.26 g, 70.4 mmol) and 5-amino-2- (methyloxy)phenol (9.8 g, 70.4 mmol) in ethanol (100 ml.) was heated to reflux for 2 h. 2- Oxobutanoic acid (7.19 g, 70.4 mmol) was added, and the mixture was heated at reflux for 4 h and stirred at room temperature overnight. The solid was collected by filtration, washed with ethanol and air dried to afford 7-hydroxy-3-methyl-6-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (14.8 g, 56% yield). This material was used in the next step without further purification. MS (m/z) 378.0 (M+H+). methyl 7-hvdroxy-3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
Oxalyl chloride (29.0 g, 228 mmol) was added to a suspension of 7-hydroxy-3- methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (20.5 g, 54.3 mmol) in methylene chloride (150 mL) at 0°C. DMF (5 drops) was added, and the reaction mixture was stirred for 6 h. Methanol was added, and the reaction mixture was warmed to room temperature and stirred for 2.5 d. The solid precipitate was collected by filtration and dried to afford methyl 7-hydroxy-3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]- 4-quinolinecarboxylate (20.6 g, 97% yield). 1H NMR (400 MHz, DMSO-d6) 8.03 (s, 1 H), 7.98 (d, J = 7.78 Hz, 1 H), 7.93 (d, J = 8.03 Hz, 1 H), 7.77 - 7.84 (m, 1 H), 7.47 (s, 1 H), 7.01 (s, 1 H), 4.10 (s, 3H), 3.97 (s, 3H), 2.29 (s, 3H); MS (m/z) 392.0 (M+H+). methyl 3-methyl-6-(methyloxy)-7-r(2,2,2-trifluoroethyl)oxyl-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
A suspension of methyl 7-hydroxy-3-methyl-6-(methyloxy)-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3 g, 7.67 mmol), 1 , 1 , 1 -trifluoro-2- iodoethane (0.907 mL, 9.20 mmol), and potassium carbonate (3.18 g, 23.00 mmol) in N,N- dimethylformamide (25 mL) was stirred at 70 °C in a pressure tube for 18 h. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g, 1-100% methylene chloride/hexane) to methyl 3-methyl-6-(methyloxy)-7-[(2,2,2-trifluoroethyl)oxy]- 2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.500 g, 14% yield) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) 7.85 (s, 1 H), 7.72 - 7.79 (m, 2H), 7.62 - 7.68 (m, 1 H), 7.49 (s, 1 H), 7.04 (s, 1 H), 4.54 (q, J = 8.03 Hz, 2H), 4.13 (s, 3H), 4.03 (s, 3H), 2.40 (s, 3H); MS (m/z) 474.1 (M+H+). methyl 3-(1.4'-biDiDeridin-1 '-ylmethyl)-6-(methyloxy)-7-r(2.2.2-trifluoroethvnoxy1-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxylate
A solution of methyl 3-methyl-6-(methyloxy)-7-[(2,2,2-trifluoroethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.6 g, 1.268 mmol), NBS (0.271 g, 1 .521 mmol) and benzoyl peroxide (0.031 g, 0.127 mmol) in carbon tetrachloride (15 mL) was stirred at 100°C for 18 h. The solvent was removed under reduced pressure, and the residue was dissolved in acetonitrile. The mixture was dissolved in 2 equal portions and 1 ,4'-bipiperidine (0.139 g, 0.824 mmol) was added. The mixture was stirred for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with NaHC03, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 12 g, 0-7% methanol with 0.1 M NH3/methylene chloride) to afford methyl 6-(methyloxy)-3-{[4-(4-morpholinyl)-1 - piperidinyl]methyl}-7-[(2,2,2-trifluoroethyl)oxy]-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (0.584 g, 72% yield). 1H NMR (400 MHz, CHLOROFORM-d) 7.80 (s, 1 H), 7.74 (d, J = 7.78 Hz, 1 H), 7.59 - 7.71 (m, 2H), 7.49 (s, 1 H), 7.20 (s, 1 H), 4.54 (q, J = 8.03 Hz, 2H), 4.07 (s, 3H), 4.04 (s, 3H), 3.63 (s, 2H), 2.77 (d, J = 1 1 .04 Hz, 2H), 2.47 (br. s., 4H), 2.17 (t, J = 1 1.17 Hz, 1 H), 1.88 (t, J = 1 1.04 Hz, 2H), 1.69 (d, J = 1 1.29 Hz, 2H), 1 .39 - 1 .56 (m, 8H); MS (m/z) 640.2 (M+H+).
3-(1 ,4'-biDiDeridin-1 '-ylmethvn-6-(methyloxy)-7-r(2,2,2-trifluoroethvnoxyl-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxylic acid
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-7-[(2,2,2-trifluoroethyl)oxy]-2- [3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.273 g, 0.427 mmol), potassium hydroxide (262 mg, 4.68 mmol), methanol (15 ml.) and water (5 ml.) were stirred at 97°C for 18 h. The solvent was removed under reduced pressure, and the residue was acidified with 6N HCI to pH 5.5. The solid precipitate was collected by filtration and dried under vacuum to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-7-[(2,2,2-trifluoroethyl)oxy]-
2- [3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.195 g, 67% yield) as an off-white solid. This material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) 8.14 (s, 1 H), 7.89 (d, J = 7.78 Hz, 1 H), 7.74 (d, J = 7.78 Hz, 1 H), 7.64 (t, J = 7.65 Hz, 1 H), 7.47 (s, 1 H), 7.32 (s, 1 H), 4.91 (q, J = 8.95 Hz, 2H), 3.87 (s, 3H), 3.44 (s, 2H), 2.56 (br. s., 2H), 2.34 (br. s., 4H), 1.99 - 2.10 (m, 1 H), 1 .83 (t, J = 1 1 .04 Hz, 2H), 1.38 - 1.49 (m, 6H), 1 .34 (d, J = 4.77 Hz, 2H), 0.99 - 1.13 (m, 2H); MS (m/z) 626.0 (M+H+).
3- (1 ,4'-biDiDeridin-1 '-ylmethvn-6-(methyloxy)-7-r(2,2,2-trifluoroethvnoxyl-2-r3- (trifluoromethyl)phenyll-/\/-r(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
A mixture of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-7-[(2,2,2- trifluoroethyl)oxy]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.094 g, 0.150 mmol), EDC (0.1 15 g, 0.601 mmol), HOBT (0.023 g, 0.150 mmol), [(1 R)-2,2,2-trifluoro-1 - phenylethyl]amine (0.034 g, 0.195 mmol), and A/JV-diisopropylethylamine (0.131 ml_, 0.751 mmol) in THF (1 ml.) and DMF (1 ml.) was stirred at 50 °C overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3 times), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-10% methanol with 0.1 M NH3/methylene chloride) to afford 3-(1 ,4'-bipiperidin-1 '- ylmethyl)-6-(methyloxy)-7-[(2,2,2-trifluoroethyl)oxy]-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)- 2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.085 g, 69% yield). 1 H NMR (400 MHz, CHLOROFORM-d) 9.84 (br. s., 1 H), 7.78 (s, 1 H), 7.73 (d, J = 7.28 Hz, 1 H), 7.59 - 7.68 (m, 2H), 7.54 - 7.59 (m, 2H), 7.43 - 7.48 (m, 4H), 7.33 (br. s., 1 H), 6.20 - 6.32 (m, 1 H), 4.54 (q, J = 8.03 Hz, 2H), 3.91 (br. s., 3H), 3.51 - 3.62 (m, 2H), 2.59 (br. s., 1 H), 2.37 (br. s., 4H), 2.1 1 - 2.22 (m, 1 H), 1.99 - 2.1 1 (m, 1 H), 1 .48 - 1 .59 (m, 7H), 1 .37 - 1 .47 (m, 3H), 1 .19 - 1 .34 (m, 1 H), 1.05 - 1 .19 (m, 1 H); MS (m/z) 783.0 (M+H+). EXAMPLE 42
3-(1.4'-bipiperidin-1 lmethvn-6^
2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
6-chloro-7-hvdroxy-3-methyl-2-r3-(trifluorom acid
To a solution of 5-amino-2-chlorophenol (5.74 g, 40 mmol) in ethanol (100 mL) was added 3-(trifluoromethyl)benzaldehyde (6.96 g, 40.0 mmol) dropwise. The mixture was stirred at reflux for 1 h. 2-Oxobutanoic acid (4.08 g, 40.0 mmol) was added portionwise. The reaction mixture was stirred at reflux for additional 3 h, cooled to room temperature and stirred overnight. The mixture was filtered, and the filter cake was washed with ethanol and air dried to give 6-chloro-7-hydroxy-3-methyl-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1 1.2 g, 73% yield). 1H NMR (400 MHz, DMSO-d6) 14.33 (br. s., 1 H), 1 1.24 (s, 1 H), 7.91 - 7.97 (m, 2H), 7.88 (d, J = 8.03 Hz, 1 H), 7.73 - 7.80 (m, 2H), 7.49 (s, 1 H), 2.33 (s, 3H); MS (m/z) 382.0 (M+H+). ethyl 6-chloro-7-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylate To a solution of 6-chloro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (10.2 g, 26.7 mmol) in A/JV-dimethylformamide (100 mL) was added sodium hydride (1 .603 g, 66.8 mmol) slowly. The mixture was stirred at room temperature for 20 min. lodoethane (12.50 g, 80 mmol) was added slowly, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NH4CI and extracted with ethyl acetate. The phases were separated, and the organic phase was washed with saturated aqueous NH4CI and brine, dried over Na2S04, filtered, and concentrated. The residue was purified via column chromatography (ISCO, 0-40% ethyl acetate/hexanes) to afford ethyl 6-chloro-7-(ethyloxy)-3-methyl-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (10.5 g, 90% yield). 1 H NMR (400 MHz,
DMSO-d6) 7.95 - 8.01 (m, 2H), 7.86 - 7.91 (m, 2H), 7.74 - 7.80 (m, 1 H), 7.67 (s, 1 H), 4.57 (q, J = 7.1 1 Hz, 2H), 4.31 (q, J = 6.94 Hz, 2H), 2.34 (s, 3H), 1.45 (t, J = 7.03 Hz, 3H), 1 .39 (t, J = 7.15 Hz, 3H); MS (m/z) 438.1 (M+H+). 6-chloro-7-(ethyloxy)-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
To a solution of ethyl 6-chloro-7-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (10.5 g, 23.98 mmol) in ethanol (150 mL) and water (50.0 mL) was added potassium hydroxide (6.73 g, 120 mmol). The mixture was heated to reflux overnight. The solvent was removed under reduced pressure, and the residue was acidified to pH 5-6 with 2N HCI. The mixture was allowed to stand overnight, and the precipitate was collected by filtration. The filter cake was washed with H20 and air dried to give 6-chloro-7-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (9.85 g, 100% yield). MS (m/z) 410.0 (M+H+). methyl 6-chloro-7-(ethyloxy)-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate To a suspension of 6-chloro-7-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (9.85 g, 24.04 mmol) in dichloromethane (50 mL) was added 3 drops of DMF. Oxalyl chloride (3.16 mL, 36.1 mmol) was added slowly, and the mixture was stirred for 1 h. The solvent was removed, and the residue was redissolved in MeOH (50 mL). Triethylamine (6.70 mL, 48.1 mmol) was added slowly, and the mixture was stirred overnight. The solvent was removed under reduced pressure. The residue was diluted with saturated aqueous NaHC03 and extracted with ethyl acetate. The phases were separated, and the organic phase was washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The crude material was purified via column
chromatography (ISCO, 0-40% ethyl acetate/hexanes) to yield methyl 6-chloro-7- (ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.1 g, 50% yield). 1H NMR (400 MHz, DMSO-d6) 7.95 - 8.01 (m, 2H), 7.86 - 7.91 (m, 2H), 7.74 - 7.80 (m,
1 H), 7.66 (s, 1 H), 4.31 (q, J = 6.94 Hz, 2H), 4.07 (s, 3H), 2.33 (s, 3H), 1 .45 (t, J = 6.90 Hz, 3H); MS (m/z) 424.1 (M+H+). methyl 3-(bromomethyl)-6-chloro-7-(ethyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
A mixture of methyl 6-chloro-7-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (5.1 g, 12.03 mmol), /V-bromosuccinimide (2.78 g, 15.64 mmol) and diphenylperoxyanhydride (0.291 g, 1 .203 mmol) in carbon tetrachloride (60 mL) was heated to 100°C and stirred overnight. The solvent was removed to provide methyl 3- (bromomethyl)-6-chloro-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate which was used in the next reaction without further purification. MS (m/z) 504.0 (M+H+). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-(ethyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
To a suspension of methyl 3-(bromomethyl)-6-chloro-7-(ethyloxy)-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.016 g, 4.01 mmol) in acetonitrile (25 mL) was added 1 ,4'-bipiperidine (0.877 g, 5.21 mmol). The mixture was stirred for 3 hours, and the solvent was removed under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The phases were separated, and the organic phase was washed with brine, dried over Na2S04, filtered, and concentrated. The crude material was purified via reverse phase HPLC (Biotage, C18 column, 0-50% MeCN/H20 with 0.1 % TFA), to afford methyl 3-(1 ,4'- bipiperidin-1 '-ylmethyl)-6-chloro-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (1.65 g, 70% yield). 1 H NMR (400 MHz, DMSO-d6) 8.09 (d, J = 9.29 Hz, 2H), 7.95 (d, J = 7.78 Hz, 1 H), 7.85 (d, J = 7.78 Hz, 1 H), 7.73 (t, J = 7.65 Hz, 1 H), 7.52 (s, 1 H), 4.28 (q, J = 7.19 Hz, 2H), 3.63 (br. s., 2H), 2.94 (br. s., 3H), 2.81 (d, J = 1 1 .54 Hz, 3H), 2.1 1 (br. s., 2H), 1 .72 - 1.89 (m, 6H), 1 .57 (br. s., 2H), 1.40 - 1.48 (m, 6H); MS (m/z) 590.2 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-(ethyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
To a solution of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-(ethyloxy)-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.65 g, 2.80 mmol) in methanol (30 mL) and water (10 mL) was added potassium hydroxide (0.784 g, 13.98 mmol). The mixture was heated to reflux overnight. The solvent was removed under reduced pressure, and the residue was acidified with 2N HCI to pH 5-6. The mixture was filtered to collect the precipitate, and the filter cake was washed with water and dried to afford 3-(1 ,4'- bipiperidin-1 '-ylmethyl)-6-chloro-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (0.780 g, 48% yield). MS (m/z) 577.2 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethvn-6-chloro-7-(ethyloxyV2-r3-(trifluoromethvnphenyll-/\/-r(1 /?V 2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
A mixture of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-(ethyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.150 g, 0.260 mmol), (1 /?)-2,2,2- trifluoro-1 -phenylethanamine (0.068 g, 0.391 mmol), EDC (0.200 g, 1.042 mmol), HOBT (39.9 mg, 0.260 mmol), and /VJv-diisopropylethylamine (0.455 mL, 2.60 mmoL) in N,N- dimethylformamide (2 mL) and 1 ,2-dichloroethane (2 mL) was stirred at 50 °C overnight. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and was purified via HPLC (Waters, 30-80% MeCN/H20 with 0.1 % TFA). The collected fractions were neutralized with saturated aqueous NaHC03 and were extracted with methylene chloride (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2S04, filtered, and concentrated to afford 3-(1 ,4'-bipiperidin-1 '- ylmethyl)-6-chloro-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2-trifluoro-1- phenylethyl]-4-quinolinecarboxamide (0.073 g, 36% yield). 1H NMR (400 MHz, DMSO-d6) 9.97 - 10.21 (m, 1 H), 7.96 (br. s., 1 H), 7.84 (d, J = 7.53 Hz, 3H), 7.70 - 7.76 (m, 1 H), 7.64 - 7.70 (m, 3H), 7.47 (br. s., 3H), 6.15 - 6.28 (m, 1 H), 4.32 (q, J = 6.69 Hz, 2H), 3.39 - 3.49 (m, 1 H), 3.18 (d, J = 12.30 Hz, 1 H), 2.40 (br. s., 1 H), 2.25 (br. s., 4H), 2.09 (br. s., 1 H), 1.75 (br. s., 1 H), 1.36 - 1 .52 (m, 8H), 1.28 - 1.36 (m, 3H), 1.1 1 - 1.28 (m, 2H), 0.95 (d, J = 6.53 Hz, 1 H), 0.78 - 0.91 (m, 1 H); MS (m/z) 733.3 (M+H+).
EXAMPLE 43
3-(1 ,4'-bipiperidin-1 '-ylmethvn-6-chloro
(trifluoromethyl)phenyl1-/V-r(1 ^
6-chloro-7-hvdroxy-3-methyl-2-r3-(trifluorom acid
To a solution of 5-amino-2-chlorophenol (8.61 g, 60 mmol) in ethanol (100 ml.) was added 3-(trifluoromethyl)benzaldehyde (10.45 g, 60.0 mmol) dropwise. The mixture was stirred at reflux for 1 h, and 2-oxobutanoic acid (6.13 g, 60.0 mmol) was added portionwise. The reaction mixture was stirred at reflux for an additional 3 h, cooled to room temperature, and stirred overnight. The mixture was filtered, and the solids were washed with ethanol and air dried to give 6-chloro-7-hydroxy-3-methyl-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (14.9 g, 65% yield). MS (m/z) 382.0 (M+H+). methyl 6-chloro-7-hvdroxy-3-methyl-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylate To a suspension of 6-chloro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (5.0 g, 13.10 mmol) in dichloromethane (80 ml.) at 0 °C was added 5 drops of DMF. Oxalyl chloride (1.720 ml_, 19.65 mmol) was added slowly, and the mixture was stirred at 0 °C for 1 h. Methanol was added (50 ml_), and the resulting mixture was stirred at 0 °C for 2 h and allowed to warm up to room temperature overnight. The solvent was removed under reduced pressure to afford methyl 6-chloro-7-hydroxy-3- methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.2 g, 100% yield). MS (m/z) 396.0 (M+H+). methyl 6-chloro-3-methyl-7-{r2-(methyloxy)ethylloxy}-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
A mixture of methyl 6-chloro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (5.2 g, 13.14 mmol), 2-chloroethyl methyl ether (1.491 g, 15.77 mmol), potassium carbonate (9.08 g, 65.7 mmol), and potassium iodide (2.181 g, 13.14 mmol) in /V,/V-Dimethylformamide (50 ml.) was heated at 90 °C overnight. The mixture was diluted with saturated NH4CI and extracted with methylene chloride. The combined organic extracts were washed with saturated NH4CI, brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified via column chromatography (ISCO, 0-40% ethyl acetate/hexanes) to give methyl 6-chloro-3-methyl-7-{[2- (methyloxy)ethyl]oxy}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.98 g, 67% yield). MS (m/z) 454.1 (M+H+). methyl 3-(bromomethyl)-6-chloro-7-{r2-(methyloxy)ethylloxy}-2-r3-(trifluoromethyl)phenyll- 4-quinolinecarboxylate
A mixture of methyl 6-chloro-3-methyl-7-{[2-(methyloxy)ethyl]oxy}-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.98 g, 8.77 mmol), /V-bromosuccinimide (2.029 g, 1 1.40 mmol) and diphenylperoxyanhydride (0.212 g, 0.877 mmol) in carbon tetrachloride (50 mL) was heated to 100 °C and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed in vacuo to afford methyl 3- (bromomethyl)-6-chloro-7-{[2-(methyloxy)ethyl]oxy}-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate. This material was used directly in the next step without further purification. methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-{[2-(methyloxy)ethylloxy}-2-[3- (trifluoromethyl)phenvH-4-quinolinecarboxylate
To a suspension of methyl 3-(bromomethyl)-6-chloro-7-{[2-(methyloxy)ethyl]oxy}-2-
[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.333 g, 4.38 mmol) in acetonitrile (30 mL) was added 1 ,4'-bipiperidine (0.958 g, 5.69 mmol). The resulting mixture was stirred for 3 h at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and purified via reverse phase HPLC (Biotage RP, 0-50% MeCN/H20 with 0.1 % TFA). The appropriate fractions were neutralized with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated in vacuo to afford methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-{[2-(methyloxy)ethyl]oxy}-
2- [3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.46 g, 54% yield). MS (m/z) 620.2 (M+H+).
3- (1 ,4'-biDiDeridin-1 '-ylmethvn-6-chloro-7-fr2-(methyloxy)ethylloxy>-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxylic acid
To a solution of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-{[2- (methyloxy)ethyl]oxy}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1 .46 g, 2.354 mmol) in methanol (60 mL) and water (20 mL) was added potassium hydroxide (0.660 g, 1 1 .77 mmol). The mixture was heated to reflux for 5 hours. The solvent was removed, and the residue was acidified to pH 5-6 with 2N HCI. After standing overnight, the precipitate was collected by filtration, washed with water and dried. The solid material was azeotroped with benzene to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-{[2- (methyloxy)ethyl]oxy}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1.3 g, 91 % yield). MS (m/z) 606.2 (M+H+).
3-(1 ,4'-biDiDeridin-1 '-ylmethvn-6-chloro-7-fr2-(methyloxy)ethylloxy>-2-r3- (trifluoromethyl)phenyll-/\/-r(1 f?)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
A mixture of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-{[2-(methyloxy)ethyl]oxy}-2- [3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.150 g, 0.247 mmol), (1 R)-2,2,2- trifluoro-1 -phenylethanamine (0.065 g, 0.371 mmol), EDC (190 mg, 0.990 mmol), HOBT (37.9 mg, 0.247 mmol), and A/JV-diisopropylethylamine (0.432 mL, 2.475 mmol) in N,N- dimethylformamide (2 mL) and tetrahydrofuran (2 mL) was stirred at 50 °C overnight. The solvent was removed under reduced pressure, and the residue was dissolved in DMSO, and purified via HPLC (Waters, 20-60% MeCN/H20 with 0.1 % TFA). The collected fractions were neutralized with saturated aqueous NaHC03 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2S04, filtered, and concentrated in vacuo to afford 3-(1 ,4'-bipiperidin-1 '-ylmethyl)- 6-chloro-7-{[2-(methyloxy)ethyl]oxy}-2-[3-(trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2-trifluoro-1- phenylethyl]-4-quinolinecarboxamide (0.103 g, 52% yield). 1H NMR (400 MHz, DMSO-d6) 10.06 (br. s., 1 H), 7.95 (br. s., 1 H), 7.84 (d, J = 7.53 Hz, 2H), 7.65 - 7.76 (m, 5H), 7.47 (br. s., 3H), 6.21 (quin, J = 8.41 Hz, 1 H), 4.39 (br. s., 2H), 3.78 (br. s., 2H), 3.44 (d, J = 14.05 Hz, 1 H), 3.36 (s, 3H), 3.1 1 - 3.27 (m, 1 H), 2.37 - 2.47 (m, 1 H), 2.25 (br. s., 4H), 2.10 (br. s., 1 H), 1 .62 - 1 .87 (m, 1 H), 1.41 (br. s., 5H), 1 .33 (br. s., 3H), 1 .09 - 1 .27 (m, 2H), 0.90 - 1.09 (m, 1 H), 0.72 - 0.90 (m, 1 H); MS (m/z) 763.3 (M+H+).
The following examples were prepared using a procedure analogous to that described in Example 43, substituting [(1 S)-1-phenylethyl]amine for [(1 R)-2,2,2-trifluoro-1- phenylethyl]amine. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.
Figure imgf000067_0001
EXAMPLE 46 3-(1 ,4'-bipiperidin-1 lmethyl)-6-r(dimethylamino)sulfonyll-2-r3-(trifluorom
r(1 R)-2,2,2-trifluoro-1-phenylethyll-4-quinolinecarboxamide
3-methyl-6-sulfo-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
To a stirred red suspension of 2,3-dioxo-2,3-dihydro-1 /-/-indole-5-sulfonic acid (14.9 g, 59.8 mmol) and 1 -[3-(trifluoromethyl)phenyl]-1-propanone (13.3 g, 65.8 mmol) in ethanol (100 ml.) and water (25.0 ml.) was added potassium hydroxide (26.8 g, 478 mmol). The reaction mixture immediately darkened, and was heated to 100°C for 2hrs. The reaction mixture was cooled and concentrated in vacuo. The resultant yellow suspension was dissolved in ~150ml water, stirred vigorously, and cooled in an ice bath. The solution was adjusted to pH 1 with concentrated HCI, at which point a yellow solid precipitated out of solution. The product was collected by filtration, and washed with additional water. The collected solid was dried in the vacuum oven at 60°C overnight to afford 3-methyl-6-sulfo-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (17 g, 41.3 mmol, 69.1 % yield) as a cream powder: MS (m/z) 412.0 (M+H). 3-(1 ,4'-bipiperidin-1 lmethyl)-4-[(methyloxy)carbonyll-2-[3-(trifluoromethyl)phenyll-6- quinolinesulfonic acid
A stirred suspension of 3-methyl-6-sulfo-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (14g, 34.0 mmol) in CH2CI2 (150 mL) and A/JV-dimethylformamide (0.5 mL) was cooled in a ice bath to 0°C. Oxalyl chloride (6.55 mL, 74.9 mmol) was added dropwise over 10 minutes, and the resultant mixture was stirred and warmed to room temperature over two hours. The reaction was cooled to 0 °C, and methanol (40 mL) was added carefully. The resultant mixture was allowed to warm to room temperature, and heated to 45°C for two hours. The reaction mixture was cooled and concentrated in vacuo to give a cream oily solid, which was partitioned between water (-100 mL) and CH2CI2 (200 mL). The phases were separated the aqueous phase was extracted three more times with CH2CI2. The combined organic extracts were washed with brine (twice), dried, and concentrated in vacuo to afford the title compound as a light brown solid (4.3g, 10.1 1 mmol, 29.7 % yield). The aqueous extract was filtered, and the filter cake washed with a small amount of water and dried in a vacuum oven at 60°C overnight to afford an additional portion of the title compound as a white solid ( (1 1 .8 g, 27.7 mmol, 82 % yield). MS (m/z) 426.0 (M+H+). methyl 6-[(dimethylamino)sulfonyll-3-methyl-2-[3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
3-methyl-4-[(methyloxy)carbonyl]-2-[3-(trifluoromethyl)phenyl]-6-quinolinesulfonic acid (4.1 g, 9.64 mmol) was suspended in thionyl chloride (2 mL, 27.4 mmol), and a few drops of DMF were added. The resultant mixture was heated to 90°C for 1 hour. The reaction mixture was cooled, concentrated, and azeotroped with CH2CI2 (twice) to give a cream solid. The solid was dissolved in CH2CI2 (20 mL), and the resulting solution was cooled in an ice bath. 2N dimethylamine in methanol (19.28 mL, 38.6 mmol) was carefully added to the solution, the resultant mixture was stirred for 30 minutes, and the mixture was concentrated. The resultant solid was partitioned between water and CH2CI2, the phases were separated, and the aqueous phase was extracted twice with CH2CI2. The combined organic phases were washed with satd. aqueous sodium bicarbonate and brine, dried over sodium sulphate, and concentrated in vacuo. The solid residue was purified by ISCO silica gel chromatography (120 g) eluting with 0→5% MeOH/CH2CI2 over 20 column volumes to afford the title compound (3.8g, 8.40 mmol, 87 % yield). MS (m/z) 453 (M+H+). methyl 3-(1 ,4'-bipiperidin-1 lmethyl)-6-[(dimethylamino)sulfonyll-2-[3- (trifluoromethyl)phenyll-4-quinolinecarboxylate
A stirred suspension of methyl 6-[(dimethylamino)sulfonyl]-3-methyl-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.9g, 4.20 mmol), /V-bromosuccinimide (0.897 g, 5.04 mmol), and benzoyl peroxide (0.102 g, 0.420 mmol) in carbon tetrachloride (20 mL, 207 mmol) was heated to reflux and stirred for 4 hrs. The reaction was cooled and concentrated in vacuo to afford a yellow oil. The residue was dissolved in acetonitrile (20 mL) and 1 ,4'-bipiperidine (0.848 g, 5.04 mmol) was added. The resultant mixture was stirred at 50°C for 1 hr. The reaction was concentrated in vacuo, and the residue was partitioned between CH2CI2 and 10% sodium carbonate solution. The phases were separated, and the organic phase was washed with 10% sodium carbonate (twice) and brine and concentrated to afford a light brown solid. The residue was partitioned between 2N HCI and CH2CI2, and the phases were separated. The aqueous phase was washed once with CH2CI2 and cooled in an ice bath, and the pH was adjusted to ~1 1 with 6N NaOH. The basic aqueous phase was extracted with CH2CI2 (three times) and the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford a yellow solid: The solid was purified by ISCO silica gel chromatography (40g) eluting with 0→20% CH2CI2/MeOH to afford: the title compound as a yellow solid (930 mg, 1.428 mmol, 34.0 % yield). MS (m/z) 619.2 (M+H+).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-r(dimethylamino)sulfonyll-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
Potassium hydroxide (506 mg, 9.02 mmol) was added in one portion to a stirred suspension of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(dimethylamino)sulfonyl]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylate (930 mg, 1.503 mmol) in methanol (10 mL) and water (3.33 mL). The resultant mixture was heated to 80°C and stirred overnight. The reaction was cooled and concentrated in vacuo, and the resultant yellow oil was partitioned between dichloromethane and water. The pH was adjusted to 5/6 with 2N HCI, and the phases were separated. The aqueous phase was extracted twice with
dichloromethane, and the combined organic phases were washed with brine, dried and concentrated in vacuo to afford the title compound (720 mg, 1 .191 mmol, 79 % yield) as a light yellow solid. MS (m/z) 605.2 (M+H+). 3-(1 ,4'-bipiperidin-1 lmethyl)-6-[(dimethylamino)sulfonyll-2-[3-(trifluoromethyl)phenyll-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
3-(1 ,4'-Bipiperidin-1 '-ylmethyl)-6-[(dimethylamino)sulfonyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (150 mg, 0.248 mmol), [(1 R)-2,2,2- trifluoro-1 -phenylethyl]amine (0.065 mL, 0.298 mmol), and DIPEA (0.043 mL, 0.248 mmol) were dissolved in dichloromethane (5 mL) to give a colorless solution. T3P (0.205 mL, 0.322 mmol) was added in one portion, and the resultant mixture was stirred for 30 minutes. The reaction was quenched with a small amount of water, concentrated in vacuo, dissolved in MeOH and purified by Waters reverse phase HPLC (20% to 60% MeCN, 0.1 %TFA, 16mins, 50ml/min, Sunfire column). The purified fractions were combined and diluted with dichloromethane and 10% sodium carbonate solution. The phases were separated, and the aqueous phase was extracted once more with
dichloromethane. The combined organic phases were washed with 10% sodium carbonate solution and brine, dried, and concentrated to afford the title compound as a white solid (1 10 mg, 0.144 mmol, 58.2 % yield). MS (m/z) 762.2 (M+H+).
EXAMPLE 47
6-[(dimethylamino)sulfonyll-3-{[4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-[3— (trifluoromethyl)phenyll-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide methyl 6-r(dimethylamino)sulfonyll-3-{r4-(4-morpholinyl)-1-piperidinyllmethyl}-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxylate
A stirred suspension of methyl 6-[(dimethylamino)sulfonyl]-3-methyl-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.8 g, 3.98 mmol), /V-bromosuccinimide (0.850 g, 4.77 mmol) and benzoyl peroxide (0.096 g, 0.398 mmol) in carbon tetrachloride (20 ml, 207 mmol) was heated to reflux and stirred for 18 hours. The reaction mixture was concentrated, the resulting yellow oil was dissolved in acetonitrile (20 mL), 4-(4- piperidinyl)morpholine (0.813 g, 4.77 mmol) was added in one portion, and the solution was stirred for 3 hours. The reaction mixture was concentrated in vacuo, the residue was partitioned between CH2CI2 (~75 ml) and 10% aqueous sodium carbonate solution, and the layers were separated. The organic phase was washed twice more with carbonate solution. The organic phase was extracted three times with 30 ml aqueous 2N HCI, and the combined acidic aqueous extracts were washed once with CH2CI2. The acidic aqueous phase was cooled in an ice bath, and the pH was adjusted to 1 1/12 with 6N NaOH. A white solid precipitated, and the mixture was extracted three times with CH2CI2. The combined organic phases were washed with water and brine, dried over sodium sulphate, and concentrated in vacuo to afford the title compound (1.6g, 2.58 mmol, 64.8 % yield), which was also contaminated with the demethylated sulfonamide methyl 6- [(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate, MS (m/z) 607.2 (M+H). The mixture was purified by ISCO silica gel chromatography (40g) loading in dichloromethane and eluting with 0→20% MeOH/CH2Cl2 over 15 column volumes. The purified title compound was isolated as a yellow solid (350 mg, 0.564 mmol, 14.17 % yield). MS (m/z) 621 .2 (M+H).
The remaining fractions were combined and repurified by ISCO (40 g column, 0→5% MeOH/ CH2CI2) to afford 930 mg of a mixture of the title compound (66%) and 6- [(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylate (33%) MS (m/z) 607.2 (M+H).
6-r(dimethylamino)sulfonyll-3-{r4-(4-morpholinyl)-1-piperidinyllmethyl}-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxylic acid
To a yellow solution of methyl 6-[(dimethylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1- piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (350 mg, 0.564 mmol) in a mixture of methanol (6 mL) and water (2.000 mL) was added potassium hydroxide (190 mg, 3.38 mmol) in one portion. The resultant mixture was heated to 80°C for 1 hr at which time LCMS indicated complete hydrolysis. The reaction mixture was cooled to ~50°C and stirred overnight. The reaction mixture was cooled and concentrated in vacuo to remove methanol, and the resultant oily solid was partitioned between CH2CI2 and water. The solution pH was adjusted to 5/6 with 2N HCI, and the layers were separated. The aqueous phase was extracted twice more with CH2CI2, and the combined organics were washed with brine, dried, and concentrated to afford the title compound as a white solid (360 mg, 0.593 mmol, 105 % yield). LCMS (m/z) 607.2 (M+H).
6-r(dimethylamino)sulfonyll-3-{r4-(4-morpholinyl)-1-piperidinyllmethyl}-2-r3—
(trifluoromethyl)phenyll-/\/-r(1 ft)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide 6- [(Dimethylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (180 mg, 0.297 mmol), DIPEA (0.052 mL, 0.297 mmol), and [(1 R)-2,2,2-trifluoro-1-phenylethyl]amine (0.078 mL, 0.356 mmol) were dissolved in dichloromethane (5 mL) to give a yellow solution. T3P (0.245 mL, 0.386 mmol) was added in one portion and the resultant mixture was stirred for one hour. The reaction mixture was concentrated in vacuo, and the residue was dissolved in methanol and purified by Waters reverse phase HPLC (20% to 60% MeCN, 0.1 %TFA, 16mins,
50ml/min, Sunfire column). The fractions containing the pure product were combined, and CH2CI2 and 10% sodium carbonate solution were added. The phases were separated, and the aqueous phase was extracted once more with CH2CI2. The combined organic phases were washed with 10% sodium carbonate solution, and brine, passed through a phase separator, and concentrated to afford: the title compound (90 mg, 0.1 18 mmol, 39.7 % yield) as a white solid. MS (m/z) 764.2 (M+H).
EXAMPLE 48
6-r(methylamino)sulfonyll-3-{r4-(4-morpholinyl)-1-piperidinyllmethyl}-2-r3- (trifluoromethyl)phenyl1-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide 6-r(methylamino)sulfonyll-3-{r4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-r3- (trifluoromethyl)phenyl1-4-quinolinecarboxylic acid
Methyl 6-[(dimethylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (900 mg, 1.450 mmol, contaminated with -30% methyl 6-[(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate, synthesis described in Example 45) was dissolved in methanol (10 ml.) to give a yellow solution. Water (2.5 ml.) was added, followed by potassium hydroxide (488 mg, 8.70 mmol), and the resultant suspension was heated to reflux (90°C) for 8 hrs. The reaction was cooled and stirred overnight. LCMS indicated complete consumption of both starting materials to the respective acids. The methanol was removed in vacuo, the aqueous phase was diluted, and CH2CI2 was added. The pH was carefully adjusted to ~5 with 2N HCI, and the phases were separated. The aqueous phase was extracted twice more with CH2CI2, and the combined organic extracts were washed with brine, dried and concentrated to afford a mixture of 6- [(dimethylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid [MS (m/z) 607.2 (M+H)] and 6- [(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid [MS (m/z) 593.1 (M+H)] as a light yellow solid (1 g, 1 .648 mmol, 1 14 % yield). 6-[(methylamino)sulfonyl1-3-{[4-(4-morpholinyl)-1 -piperidinyl1methyl}-2-[3-
(trifluoromethyl)phenyl1-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl1-4-quinolinecarboxamide
To a solution of methyl 6-[(dimethylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1- piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (500 mg, 0.806 mmol, contaminated with -30% 6-[(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1 - piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid), [(1 R)-2,2,2- trifluoro-1 -phenylethyl]amine (205 mg, 0.967 mmol), and DIPEA (0.141 ml_, 0.806 mmol) in CH2CI2 (10 ml.) was added 50% w/v T3P in ethyl acetate (0.615 ml_, 0.967 mmol) in one portion. The resultant mixture was stirred overnight. The reaction mixture was quenched with water and concentrated in vacuo. The residue was dissolved in methanol and purified by Waters reverse phase HPLC (10% to 50% MeCN, 0.1 %TFA, 16mins, 50ml/min, Sunfire column). The purified demethylated fractions were combined and diluted with CH2CI2, water and satd. aqueous NaHC03. The phases were separated, and the aqueous phase was extracted once more with CH2CI2. The combined organic phases were washed with satd. aqueous NaHC03 and brine, dried over Na2S04, and
concentrated to afford 6-[(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1- piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4- quinolinecarboxamide (70 mg, 0.089 mmol, 1 1.01 % yield). MS (m/z) 750.2 (M+H).
The following example was prepared using a procedure analogous to that described in Example 48, substituting [(1 S)-1-phenylethyl]amine for [(1 R)-2,2,2-trifluoro-1- phenylethyl]amine. As is appreciated by those skilled in the art, this analogous example may involve variations in general reaction conditions.
Figure imgf000073_0001
EXAMPLE 50
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(2-methylpropyl)oxyl-2-[3-(trifluoromethyl)phenyll-N- r(1 R)-2,2,2-trifluoro-1-phenylethyll-4-quinolinecarboxamide
3-methyl-7-r(2-methylpropyl)oxyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid To a solution of 3-[(2-methylpropyl)oxy]aniline (5.8 g, 35.1 mmol) in ethanol (300 mL) was added 3-(trifluoromethyl)benzaldehyde (6.1 1 g, 35.1 mmol) dropwise. The mixture was stirred at reflux for 1 h, and then 2-oxobutanoic acid (3.58 g, 35.1 mmol) was added portionwise. The reaction mixture was stirred at reflux for and additional 3 h, and allowed to warm to room temperature overnight. The mixture was filtered, and the filter cake was washed with EtOH and air dried to provide 2.35 g of the title compound (17%). MS (m/z) 404.1 (M+H). methyl 3-methyl-7-[(2-methylpropyl)oxyl-2-[3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
To a suspension of 3-methyl-7-[(2-methylpropyl)oxy]-2-[3-(trifluoromethyl)phenyl]- 4-quinolinecarboxylic acid (2.35 g, 5.83 mmol) in CH2CI2 (30 mL) at 0 °C was added 5 drops of DMF. Oxalyl chloride (0.765 mL, 8.74 mmol) was added slowly. The mixture was stirred at 0°C for 1 h. MeOH (30 mL) was added, and the resulting mixture was stirred at 0°C for 2 h and allowed to warm to room temperature overnight. The solvent was removed, and the residue was diluted with H20 and treated with satd. aqueous. NaHC03 until the solution was basic. The solution was extracted three times with CH2CI2, and the combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified via ISCO chromatography (120 g Silica, 0%-30% EtOAc/Hexanes) to afford 2.38 g (98%) of the title compound. MS (m/z) 418.1 (M+H). methyl 3-(bromomethyl)-7-r(2-methylpropyl)oxyl-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
Methyl 3-methyl-7-[(2-methylpropyl)oxy]-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (2.38 g, 5.70 mmol), NBS (1 .319 g, 7.41 mmol) and
diphenylperoxyanhydnde (0.138 g, 0.570 mmol) were combined in a 250 mL round bottom flask, and carbon tetrachloride (30 ml) was added. The mixture was heated to 100°C and stirred overnight. The reaction was cooled to room temperature, and the solvent was removed in vacuo to afford the title compound. Half of the residue was carried forward to the following reaction with no additional purification. MS (m/z) 498.1 (M+H). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-r(2-methylpropyl)oxyl-2-r3-(trifluoromethyl)phenyll- 4-quinolinecarboxylate
To a suspension of methyl 3-(bromomethyl)-7-[(2-methylpropyl)oxy]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.415 g, 2.85 mmol) in acetonitrile (10 mL) was added 1 ,4'-bipiperidine (0.623 g, 3.71 mmol). The mixture was stirred for 3 hours, then concentrated in vacuo. The residue was dissolved in DMSO and purified via Biotage RP chromatography (0%-50% MeCN/H2O+0.1 % TFA). Appropriate fractions were collected, made basic with saturated NaHC03, and extracted three times with CH2CI2. The combined organic extracts were washed twice with brine, dried over Na2S04, filtered, and concentrated to afford the title compound (1.5 g, 90%). MS (m/z) 584.3 (M+H).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(2-methylpropyl)oxyl-2-[3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid To a solution of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(2-methylpropyl)oxy]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (1 .50 g, 2.57 mmol) in MeOH (30 mL) and H20 (10 mL) was added potassium hydroxide (0.721 g, 12.85 mmol). The mixture was heated to reflux for 5 hours. The reaction was concentrated to remove solvent, and the remaining aqueous solution was adjusted to pH~5-6 with 2N HCI. The solution was extracted three times with CH2CI2, and the combined organic extracts were washed twice with brine, and dried over Na2S04, filtered and concentrated to afford the title compound (1 .45 g,. 99%). MS (m/z) 570.3 (M+H). 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-r(2-methylpropyl)oxyl-2-r3-(trifluoromethyl)phenyll-/\/- Γ(1 f?)-2 ,2 , 2-trif I u pro- 1 -phenylethyll-4-quinolinecarboxamide
To a mixture of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(2-methylpropyl)oxy]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (200 mg, 0.351 mmol), (1 /?)-2,2,2- trifluoro-1 -phenylethanamine (73.8 mg, 0.421 mmol), EDC (269 mg, 1 .404 mmol), and HOBT (53.8 mg, 0.351 mmol) in Ν,Ν-Dimethylformamide (DMF) (2 mL) and
Tetrahydrofuran (THF) (2 mL) was added DIPEA (0.613 mL, 3.51 mmol). The mixture was stirred at 50°C overnight. The reaction mixture was concentrated to remove THF, and the residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire,
30x75mm column, 50 mL/min, 20-60%MeCN/H2O+0.1 % TFA). Appropriate fractions were collected and made basic by treatment with saturated aqueous NaHC03. The solution was extracted three times with CH2CI2, and the combined organic extracts were washed with brine, dried over Na2S04, and concentrated to afford the title compound (146 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6) 9.92 - 10.16 (m, 1 H), 7.95 (br. s., 1 H), 7.83 (d, J = 7.78 Hz, 2H), 7.10-7.79 (m, 9H), 6.20 (quin, J = 9.80 Hz, 1 H), 3.95 (br. s., 2H), 3.26 - 3.68 (m, 1 H), 3.02 - 3.26 (m, 1 H), 1 .97- 2.44 (m, 6H), 1.63 - 1.86 (m, 2H), 1.09-1.53 (m, 9H), 1.02 (d, J = 7.92 Hz, 6H), 0.75 - 0.98 (m, 3H). MS (m/z) 727.3 (M+H+).
The following example was prepared using a procedure analogous to that described in Example 48, substituting 3-isopropoxyaniline for 3-[(2-methylpropyl)oxy]aniline in the first step. As is appreciated by those skilled in the art, this analogous example may involve variations in general reaction conditions.
Figure imgf000075_0001
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(1- methylethyl)oxy]-N-[(1 S)-1 -phenylethyl]-
713.3
51 2-[3-(trifluoromethyl)phenyl]-4- (M+H+) quinolinecarboxamide
EXAMPLE 52
3-(1 ,4'-bipiperidin-1 lmethylV7-cM^
(trifluoromethyl)phenyll-4-quinolinecarboxamide
7-chloro-3-methyl-6-(methyloxy)-2-r3-(trifluorom acid To a suspension of the 6-chloro-5-(methyloxy)-1 /-/-indole-2,3-dione (15.6 g, 73.7 mmol) in ethanol (100 ml.) was added a solution of potassium hydroxide (24.82 g, 442 mmol) in water (40.00 ml.) slowly. 1-[3-(Trifluoromethyl)phenyl]-1 -propanone (14.90 g, 73.7 mmol) was added, and the mixture was heated to reflux for 1 h. The solvent was removed, the residue was dissolved in water, and the mixture was washed three times with Et20. The aqueous mixture was chilled and adjusted to pH~3 with concentrated HCI. The solid was collected by filtration, washed with H20, and air dried to afford 9.8 g (34%) of the title compound. MS (m/z) 396.0 (M+H).
Methyl 7-chloro-3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
7-chloro-3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (9.8 g, 24.76 mmol) was suspended in CH2CI2 (100 ml.) and 3 drops of DMF was added slowly. Oxalyl chloride (3.25 ml_, 37.1 mmol) was added slowly, and the mixture was stirred for 1 h. The solvent was removed, the residue was redissolved in MeOH (50 ml_), triethylamine (10.35 ml_, 74.3 mmol) was added slowly, the mixture was stirred overnight. The reaction was concentrated, diluted with saturated aqueous. NaHC03, and extracted with EtOAc three times. The combined organic extracts were washed twice with brine, dried over Na2S04, filtered, and concentrated. The residue was purified via ISCO chromatography (0%-40%EtOAc/Hexanes) to afford 3.54 g (35%) of the title compound. MS (m/z) 410.0 (M+H). methyl 3-(bromomethyl)-7-chloro-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate Methyl 7-chloro-3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (3.54 g, 8.64 mmol), NBS (1.999 g, 1 1 .23 mmol) and
diphenylperoxyanhydride (0.209 g, 0.864 mmol) were suspended in CCI4 (50 mL). The mixture was heated to 100°C and stirred overnight. The mixture was cooled to room temperature and concentrated to remove solvent. The crude was divided into two portions and used directly in the next reaction. MS (m/z) 490.0 (M+H). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll- 4-quinolinecarboxylate
To a suspension of methyl 3-(bromomethyl)-7-chloro-6-(methyloxy)-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.1 1 g, 4.32 mmol) in acetonitrile (30 ml) was added 1 ,4'-bipiperidine (0.945 g, 5.62 mmol). The mixture was stirred for 3 hours. The solvent was removed in vacuo. The residue was dissolved in DMSO and purified using Biotage reverse phase chromatography (0%-50% MeCN/H2O+0.1 % TFA).
Fractions containing the product were collected, made basic with saturated aqueous NaHC03, and extracted three times with CH2CI2. The combined organic extracts were washed twice with brine, dried over Na2S04, filtered, and concentrated to afford 1 .85 g product.(74.3%). MS (m/z) 576.2 (M+H). 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-6-(methyloxy)-2-[3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
To a solution of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-6-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.85 g, 3.21 mmol) in methanol (90 mL) and water (30.0 mL) was added potassium hydroxide (0.901 g, 16.06 mmol). The mixture was heated to reflux for 5 hours. The methanol was removed, and the residual solution was adjusted to pH~5-6 with 2N HCI and allowed to stand overnight. The solution was filtered to collect the solid, and the filter cake was washed with H20 and air dried. The solid was azeotropically dried with benzene to afford 1 .58 g (88%) of the title compound. MS (m/z) 562.2 (M+H).
3-(1 ,4'-bipiperidin-1 '-ylmethvn-7-chloro-6-(methyloxy)-N-r(1 SV1-phenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
To a mixture of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-6-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (150 mg, 0.267 mmol), (1 S)-1- phenylethanamine (48.5 mg, 0.400 mmol), EDC (205 mg, 1 .068 mmol), and HOBT (40.9 mg, 0.267 mmol) in DMF (2 mL) and THF (2 mL) was added DIPEA (0.466 mL, 2.67 mmol). The mixture was stirred at 50°C overnight. The reaction mixture was concentrated to remove THF, and the residue was dissolved in DMSO and purified via reverse phase HPLC (Waters, 20-60% MeCN/H2O+0.1 % TFA). Fractions containing the product were collected and made basic with saturated aqueous NaHC03. The solution was extracted three times with CH2CI2. The combined organic extracts were washed twice with brine, dried over Na2S04, filtered, and concentrated to afford 130 mg (70%) of the title compound. 1 H NMR (400 MHz, DMSO-d6) 9.25 (d, J = 4.00 Hz, 1 H), 8.18 (br. s., 1 H), 7.96 (br. s., 1 H), 7.85 (d, J = 8.00 Hz, 1 H), 7.82 (d, J = 7.86 Hz, 1 H), 7.71 (t, J = 7.86 Hz, 1 H), 7.44-7.55 (m, 2H), 7.34-7.44 (m, 2H), 7.29 (t, J = 7.80 Hz, 1 H), 6.66-6.99 (m, 1 H), 5.21 - 5.42 (m, 1 H), 3.79-4.30 (m, 1 H), 3.25-3.79 (m, 4H), 2.16-2.53 (m, 5H), 1 .64- 2.1 1 (m, 3H), 1 .20-1 .64 (m, 12H), 0.74-1 .17 (m, 2H). MS (m/z) 665.3 (M+H+).
The following examples were prepared using a procedure analogous to that described in Example 52, substituting [(1 R)-2,2,2-trifluoro-1 -phenylethyl]amine for (1 S)-1 - phenylethanamine in the final step and selecting an appropriate isatin in the first step. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.
Figure imgf000078_0001
EXAMPLE 55
3-(1 ,4'-bipiperidin-1 lmethylV6-(methyloxy)-A -r(1 S)-1-phenylethyl1-2-r3-
(trifluoromethyl)phenyll-4-quinolinecarboxamide
3-Methyl-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxy acid
A solution of potassium hydroxide (7.6 g, 135 mmol) dissolved in water (20 mL) was added slowly to a stirred suspension of 5-(methyloxy)-1 /-/-indole-2,3-dione (4.0 g, 22.6 mmol) in ethanol (60 mL). 1-[3-(trifluoromethyl)phenyl]-1 -propanone (4.6 g, 22.6 mmol) was added in one portion, and the reaction mixture was heated to reflux for 1 h and concentrated in vacuo to give a dark red solid. The solid was dissolved in water, and the solution was extracted with ether. The aqueous phase (600 mL) was chilled in an ice bath and acidified to pH 6 with cone. HCI. The resulting yellow suspension was filtered to collect the precipitate, and the solid was dried in a vacuum oven for 3 days to afford 5.6 g (75 %) of the product as a dark red-colored powder. LC/MS (m/z): 362.1 (M+H).
Methyl 3-methyl-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
To a 50 mL flask was added 3-methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]- 4-quinolinecarboxylic acid (2 g, 5.5 mmol) and thionyl chloride (4 mL, 55.4 mmol). The reaction was heated to reflux for 1.5 h, cooled to room temperature, and concentrated in vacuo to give a reddish brown solid. The solid was suspended in methanol (20 mL) and treated with triethylamine (3.1 mL, 22.1 mmol). The reaction was stirred at room temperature overnight, diluted with water, and extracted with CH2CI2. The organic phase (30 mL) was dried over Na2S04, filtered, and concentrated in vacuo to afford 1.4 g (67 %) of the product as a reddish-brown powder. LC/MS (m/z): 376.1 (M+H).
Methyl 3-(bromomethyl)-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate To a 50 mL flask was added methyl 3-methyl-6-(methyloxy)-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (1 .4 g, 3.73 mmol) and carbon tetrachloride (20 mL). /V-bromosuccinimide (800 mg, 4.48 mmol) and benzoyl peroxide (90 mg, 0.37 mmol) were added, and the reaction was heated to reflux. After 6 h, the reaction was cooled to room temperature and concentrated to afford 700 mg (21 %) of the crude product as a dark brown solid. LC/MS (m/z): 454.0 (M+H).
Methyl 3-( 1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate Methyl 3-(bromomethyl)-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (300 mg, 0.66 mmol) in acetonitrile (3 mL) was treated with sodium bicarbonate (200 mg, 2.38 mmol), followed by 1 ,4'-bipiperidine (130 mg, 0.77 mmol). The reaction was heated at 55 °C overnight, concentrated, and partitioned between dichloromethane and water. The organic phase (20 mL) was dried over Na2S04 and concentrated to afford 330 mg (37 %) of the crude product as a dark brown oil. LC/MS (m/z): 542.3 (M+H).
3-(1.4'-biDiDeridin-1 '-ylmethvn-6-(methyloxyV/V-r(1 S)-1-Dhenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (1 10 mg, 0.203 mmol) in isopropanol (1.5 mL) was treated with (1 S)- 1-phenylethanamine (100 μί, 0.79 mmol). The reaction was heated in the microwave at 170 °C for 45 min. The solvent was evaporated, and the residue was dissolved in DMSO and purified by preparative HPLC (30-80% ACN/water + TFA over 16 minutes) to afford 1 1 mg (9 %) of the product as a white solid. 1 H NMR (400 MHz, DMSO-c/6) ppm 9.23 (s, 1 H) 8.84 (br. s., 1 H) 7.99 (s, 2 H) 7.96 (d, J=8.03 Hz, 1 H) 7.73 (s, 1 H) 7.53 (s, 1 H) 7.50 (d, J=10.04 Hz, 4 H) 7.41 (br. s., 3 H) 7.31 (d, J=6.78 Hz, 1 H) 6.74 (br. s., 1 H) 5.34 (br. s., 1 H) 3.91 (br. s., 1 H) 3.66 (s, 1 H) 3.51 (br. s., 2 H) 2.83 (br. s., 2 H) 2.68 (s, 1 H) 2.59 (s, 1 H) 2.34 (s, 1 H) 1.80 (br. s., 4 H) 1.66 (br. s., 2 H) 1.50 (br. s., 4 H) 1.24 (br. s., 1 H). LC/MS (m/z): 631.3 (M+H);
EXAMPLE 56
3-{r4-(4-morDholinvn-1-DiDeridinyllmethyl>-/\/-r(1 SV1 -Dhenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
Methyl 3-{r4-(4-morpholinyl)-1-piperidinyllmethyl}-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
4-(4-Piperidinyl)morpholine (0.61 g, 3.60 mmol) was added to a solution of methyl 3-(bromomethyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1 .39 g, 3.28 mmol) and /V,/V-diisopropylethylamine (DIPEA) (1.27 g, 9.83 mmol) in dichloromethane (20 mL). The reaction mixture was stirred overnight at room temperature. The resulting mixture was diluted with saturated NaHC03. The two layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified via column chromatography on silica gel (Hexane/EtOAc) to give the desired product (0.85 g, 51 %) as an off-white solid. LCMS (m/z): 514.5 (M+H).
3-{r4-(4-morpholinyl)-1 -piperidinyllmethyl}-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
To a 100 mL flask was added methyl 3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2- [3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.85 g, 1.66 mmol) and 6 N HCI (20 mL). The resulting mixture was refluxed for 2 hours. The solvent was removed, and the residue was dried under vacuum to give the HCI salt of the product (0.83 g, 82 %) as a light yellow solid. This material was used for the next step without further purification. LCMS (m/z): 500.20 (M+H).
Figure imgf000081_0001
(trifluoromethyl)phenyll-4-quinolinecarboxamide
[(1 S)-1-Phenylethyl]amine (0.20 g, 1.63 mmol) was added to a solution of 3-{[4-(4- morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.83 g, 1 .36 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium- hexaflurophosphate (BOP) (0.60 g, 1 .36 mmol), and N,N-diisopropylethylamine
(DIPEA)(0.72 g, 5.44 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for three hours at room temperature and diluted with saturated aqueous NaHC03. The layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified via column chromatography on silica gel
(Hexane/EtOAc) to give the desired product (0.20 g, 24 %) as an off-white solid. 1H NMR (400 MHz, MeOD-d4) 0.94-2.07 (m, 1 1 H), 2.36 - 2.71 (m, 6H), 3.67(s, 4H), 5.46 (m, 2H), 7.30- 7.51 (m, 4H), 7.50 - 7.52 (d, 2H), 7.73- 7.99 (m, 5H), 8.03-8.04 (s, 1 H), 8.08 - 8.10 (d, 1 H). LCMS (m/z): 603.3 (M+H).
EXAMPLE 57
3-(1 ,4'-bipiperidin-1 '-ylmethvn-7-r(1-methylethvnoxyl-6-(2-oxo-1-pyrrolidinvn-2-r3- (trifluoromethvDphenyll-N-rn R)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
6-bromo-3-methyl-7-r(1 -methylethyl)oxyl-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylic acid
To a solution of {4-bromo-3-[(1-methylethyl)oxy]phenyl}amine (16.7 g, 72.9 mmol) in ethanol (200 mL) was added 3-trifluoromethylbenzaldehyde. The mixture was refluxed for two hours. 2-Oxobutanoic acid (8.9 g, 87.1 mmol) was added, and the mixture was refluxed for an additional three hours. The mixture was stirred at room temperature for sixteen hours, and concentrated to dryness to afford 34 g of the title compound as an orange solid. The material was used directly in the next reaction without further purification. MS (m/z) 468.0 (M+H).
methyl 6-bromo-3-methyl-7-r(1-methylethyl)oxyl-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
A solution of oxalyl chloride (27.56g, 218.7 mmol) in dicloromethane (30 ml_) was added dropwise to a solution of 6-bromo-3-methyl-7-[(1 -methylethyl)oxy]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (34 g, 72.9 mmol) in dichloromethane (100 mL), and the mixture was stirred for 30 minutes. Two drops of DMF were added and the mixture was stirred for 30 minutes. The mixture was concentrated to dryness, and dissolved in dichloromethane (50 mL). Methanol (90 mL) in dichloromethane (20 mL) was added and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated to dryness, and dissolved in 100 mL dichloromethane. The solution was washed three times with saturated aqueous NaHC03 (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column
chromatography (Si02, 100:1→ 50:1 Petroleum ether/ethyl acetate to afford the title compound as a white solid (5.5 g, 15.7%) 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.45 - 1.52 (m, 6 H) 2.36 (s, 3 H) 4.1 1 (s, 3 H) 4.73 - 4.83 (m, 1 H) 7.48 (s, 1 H) 7.61 - 7.68 (m, 1 H) 7.71 - 7.78 (m, 2 H) 7.83 - 7.87 (m, 1 H) 7.98 (s, 1 H). MS (m/z) 482.1 (M+H). methyl 6-bromo-3-(bromomethyl)-7-r(1 -methylethyl)oxyl-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
To a solution of methyl 6-bromo-3-methyl-7-[(1 -methylethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (2 g, 4.15 mmol) in carbon tetrachloride (20 mL) was added /V-bromosuccinimide (0.78 g, 4.36 mmol) and benzoyl peroxide (0.5 g, 2.08 mmol). The mixture was heated to reflux for eight hours, and cooled to room temperature. The resulting suspension was filtered, and the filtrate was concentrated to afford 2.6 g of the title compound as a yellow solid, which was used directly in the next reaction without further purification. methyl 3-( 1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-7-[( 1 -methylethyl)oxyl-2-[3- (trifluoromethyl)phenyll-4-quinolinecarboxylate
To a solution of methyl 6-bromo-3-(bromomethyl)-7-[(1-methylethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.1 g, 1.87 mmol) in acetonitrile (10 ml.) was added 1 ,4'-bipiperidine (0.331 g, 1.87 mmol) and potassium carbonate (0.543 g, 3.94 mmol). The mixture was heated to reflux for two hours, cooled to room temperature, and concentrated to dryness. The residue was dissolved in ethyl acetate, and the solution was washed twice with water and twice with brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (Si02, 200:1→ 199:1→ 50:1 dichloromethane: MeOH) to afford the title compound (1 g, 78%) as a yellow solid. MS (m/z) 648.1 (M+H). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-r(1 -methylethyl)oxyl-6-(2-oxo-1 -pyrrolidinyl)-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxylate
To a mixture of methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-7-[(1- methylethyl)oxy]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (300 mg, 0.46 mmol),
2- pyrollidinone (78 mg, 0.82 mmol), and cesium carbonate (224 mg, 0.69 mmol in anhydrous dioxane (5 ml.) was added Pd2(dba3) (150 mg) and Xantphos (150 mg). The mixture was stirred at 80°C for sixteen hours. The mixture was diluted with
dichloromethane and water, and extracted three times with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated to afford the title compound, which was combined with two identical reactions run on 0.77 mmol and 0.046 mmol scale. The combined residue was purified by silica gel chromatography (200:1→ 199:1→ 50:1 dichloromethane: MeOH) to afford the title compound as a brown solid (300 mg, 78%). MS (m/z) 653.3 (M+H).
3- (1 ,4'-bipiperidin-1 '-ylmethvn-7-r(1 -methylethvnoxyl-6-(2-oxo-1-pyrrolidinvn-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxylic acid
To methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(1-methylethyl)oxy]-6-(2-oxo-1 - pyrrolidinyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (300 mg, 0.46 mmol) was added TFA (0.3 N in CH3CN/H20, 5 ml_). The reaction was heated to reflux for 1 hour. The solution was cooled to room temperature, adjusted to pH 4-5 with 1 N NaOH, and concentrated to remove acetonitrile. The residue was extracted with dichloromethane (3 x 10 ml_). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford 300 mg of the title compound as a yellow solid. This material was used in the next step without additional purification. 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(1 -methylethyl)oxy]-6-(2-oxo-1-pyrrolidiny (trifluoromethyl)phenyl]-/\/-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide To a solution of 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(1 -methylethyl)oxy]-6-(2-oxo-1 -pyrrolidinyl)-2- [3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (60 mg, 0.093 mmol) in
THF/dichloromethane (4:1 , 2 mL) was added [(1 R)-2,2,2-trifluoro-1 -phenylethyl]amine (33 mg, 0.18 mmol), HBTU (72 mg, 0.18 mmol), and TEA (0.066 mL, 0.465 mmol). The reaction mixture was refluxed under N2 (80 °C) for 18 hours. The mixture was diluted with dichloromethane, and the solution was washed with saturated NaHC03 and brine. The aqueous washes were extracted with additional dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (52-82% CH3CN/H20 + 0.1 % TFA over 21 min, 15 mL/min, VYA 2515 305 column). Fractions containing the product were made basic with saturated NaHC03, concentrated to remove acetonitrile, and extracted three times with
dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the title compound (35 mg, 46.8% yield) 1H NMR (400 MHz, CDCIs) 7.19 - 8.04 (m, 1 1 H), 6.1 1 - 6.29 (m, 1 H), 4.66 - 4.69 (m, 1 H), 3.42 - 3.75 (m, 5H), 2.10 - 2.73 (m, 1 1 H), 1 .18 - 1.67 (m, 17H). MS (m/z) 796.3 (M+H+). EXAMPLE 58
Figure imgf000084_0001
(trifluoromethyl)phenyll-4-quinolinecarboxamide methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-cvano-7-r(1 -methylethyl)oxyl-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxylate
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-7-[(1 -methylethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (800 mg, 1.23 mmol) and Zn(CN)2 (578 mg, 4.94 mmol) were combined in anhydrous DMF (15 mL) and Pd(PPh3)4 (286 mg, 0.147 mmol) was added. The mixture was heated to 120 °C for 16 hours. The mixture was filtered, the filtrate was diluted with CH2CI2 and water, and the phases were separated. The aqueous phase was extracted with CH2CI2, and the combined organic extracts were washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (200:1→ 60:1 CH2CI2:MeOH) to afford (385 mg, 52%) of the title compound as a yellow oil. MS (m/z) 595.2 (M+H). 3- (1 ,4'-bipiperidin-1 lmethyl)-6-cvano-7-[(1 -methylethyl)oxyl-2-[3-(trifl^
4- quinolinecarboxylic acid
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-cyano-7-[(1 -methylethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate was dissolved in TFA (0.3 N in 3:2
CH3CN/water) and heated to reflux for one hour. The mixture was concentrated to remove the acetonitrile, and saturated NaHC03 was added to adjust the pH to 5-6. The mixture was extracted three times with CH2CI2, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was combined with additional material from a separate reaction run on 0.046 mmol scale and used without additional purification.
3-( 1 ,4'-bipiperidin-1 '-ylmethylV6-cvano-7-r( 1 -methylethynoxyl-M-K 1 SV1 -phenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
3-(1 ,4'-Bipiperidin-1 '-ylmethyl)-6-cyano-7-[(1-methylethyl)oxy]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (100 mg, 0.172 mmol) was dissolved in THF/ CH2CI2 (4:1 , 4 ml_). [(1 S)-1-phenylethyl]amine (42 mg, 0.345 mmol), HBTU (130 mg, 0.345 mmol), and TEA (87 mg, 0.86 mmol) were added and the reaction mixture was refluxed for 18 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in ethyl acetate, and the solution was washed once with water, twice with 1 N NaOH, once with water, and once with brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (43-73% CH3CN/H20 + 0.1 % TFA over 21 min, 15 mL/min, VYA 2515 305 column). Fractions containing the product were made basic with saturated NaHC03, concentrated to remove acetonitrile, and extracted three times with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the title compound (75 mg, 64.1 % yield) as a yellow solid. 1H NMR (400 MHz, CDCI3) 9.09 (s, 1 H), 8.38 (s, 1 H), 7.19 - 7.69 (m, 10H), 5.44 - 5.52 (m, 1 H), 4.68 - 4.74 (m, 1 H), 3.41 - 3.44 (m, 2H), 1 .94 - 2.51 (m, 7H), 1.16 - 1 .65 (m, 18H), 0.77 - 1 .07 (m, 3H). MS (m/z) 684.4 (M+H+). EXAMPLE 59
3-( 1 ,4'-bipiperidin-1 '-ylmethyl)-6-methyl-7-r( 1 -methylethyl)oxyl-2-r3- (trifluoromethvDphenyll-N-rd R)-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide methyl 3-(1 ,4'-bipiperidin-1 '-ylmethvn-6-methyl-7-r(1-methylethvnoxyl-2-r3-
(trifluoromethyl)phenyll-4-quinolinecarboxylate
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-7-[(1 -methylethyl)oxy]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylate (850 mg, 1.33 mmol) and Pd(dppf)CI2 (286 mg, 0.147 mmol) were combined in anhydrous dioxane (10 mL) under nitrogen and ZnMe2
(4 mL, 4.0 mmol) was added dropwise. The mixture was heated to reflux for 4 hours.
Water was added to the mixture, and the reaction was concentrated to remove the solvent. Water was added to the residue, the resulting solution was extracted three times with CH2CI2, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep TLC (10:1 Ch^C^MeOH) to afford
(520 mg, 67%) of the title compound as a yellow oil. MS (m/z) 584.3 (M+H).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-methyl-7-r(1 -methylethyl)oxyl-2-r3- (trifluoromethyl)phenvH-4-quinolinecarboxylic acid
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-methyl-7-[(1-methylethyl)oxy]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxylate (520 mg, 0.892 mmol) was dissolved in TFA (0.3 N in 3:2 CH3CN/water) and heated to reflux for one hour. The mixture was concentrated to remove the acetonitrile, and saturated NaHC03 was added to adjust the pH to 5-6. The mixture was extracted three times with CH2CI2, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The title compound was isolated as a yellow solid (420 mg) which was used without additional purification. MS (m/z) 570.3 (M+H).
3-(1 ,4'-bipiperidin-1 '-ylmethvn-6-methyl-7-r(1 -methylethvnoxyl-2-r3- (trifluoromethyl)phenyll-/\/-r(1 ffl-2,2,2-trifluoro-1 -phenylethyll-4-quinolinecarboxamide
3-(1 ,4'-Bipiperidin-1 '-ylmethyl)-6-methyl-7-[(1-methylethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (100 mg, 0.126 mmol) was dissolved in THF/ CH2CI2 (4:1 , 4 mL). [(1 R)-2,2,2-trifluoro-1 -phenylethyl]amine (66 mg, 0.579 mmol), HBTU (1 19 mg, 0.315 mmol), and TEA (64 mg, 0.63 mmol) were added and the reaction mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature, combined with an identical reaction run on 0.088 mmol scale, and concentrated to dryness. The residue was dissolved in ethyl acetate, and the solution was washed once with water, twice with 1 N NaOH, once with water, and once with brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (60-90% CH3CN/H20 + 0.1 % TFA over 21 min, 15 mL/min, VYA 2515 305 column). Fractions containing the product were made basic with saturated NaHC03, concentrated to remove acetonitrile, and extracted three times with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the title compound (65 mg, 42% yield) as a yellow solid. 1H NMR (400 MHz, CDCI3) 7.28 - 7.70 (m, 1 1 H), 6.12 - 6.16 (m, 1 H), 4.64 - 4.70 (m, 1 H), 3.34 - 3.49 (m, 2H), 1 .99 - 2.53 (m, 10H), 1.35 - 1 .95 (m, 18H). MS (m/z) 727.4 (M+H+).
EXAMPLE 60
3-(1.4'-bipiperidin-1 '-ylmethylV7-chloro-N-r(1 SV1 -phenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
7-chloro-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
Potassium hydroxide (45.6 g, 650 mmol) in water (93 ml.) was added to 6- chloroisatin (1 .0 g, 5.51 mmol) in ethanol over 15 minutes. 3- Trifluoromethylpropiophenone (1.1 1 g, 5.51 mmol) was added, and the reaction was heated to reflux for 18 hours, then cooled to room temperature and concentrated. The resulting solid was dissolved in water, washed three times with diethyl ether, cooled in an ice-water bath, and acidified with acetic acid. The crude product was collected by filtration and recrystallized from acetic acid. The solid was washed with diethyl ether three times, and the solid was dried in vacuo. The title compound was isolated as a pale yellow solid (23.7g, 66%) and used in the next step without additional purification. MS (m/z) 366.1 (M+H). methyl 7-chloro-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate
Thionyl chloride (10 ml.) was added dropwise to 7-chloro-3-methyl-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1 g, 2.73 mmol), and the reaction was heated to reflux under nitrogen for three hours. The reaction mixture was cooled to room temperature, and the thionyl chloride was removed in vacuo. The last traces of thionyl chloride were removed with diethyl ether to afford the acid chloride as a yellow solid. Triethylamine (3 ml.) in MeOH (39 ml.) was added dropwise, and the reaction was stirred at room temperature for 18h. Ice water was added, and the solution was extracted three times with CH2CI2. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated en vacuo. The title compound was isolated as a yellowish solid (635 mg, 61 %) and was used in the next step without further purification. MS (m/z) 380.1 (M+H). methyl 3-(bromomethyl)-7-chloro-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate To a solution of methyl 7-chloro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (635 mg, 1.67 mmol) in CCI4 (15 mL) was added NBS (312 mg, 1.76 mmol) and benzoyl peroxide (202 mg, 0.8 mmol). The mixture was heated in an oil bath to 80-90 °C and refluxed for 10 hours. The reaction was concentrated to dryness, and the crude material was purified by flash column chromatography (Pet. Ether: EtOAc 20:1 ). The title compound was obtained as a light yellow solid (736 mg, 96%). MS (m/z) 458.1 (M+H). methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-2-r3-(trifluoromethyl)phenyll-4- quinolinecarboxylate
To a solution of methyl 3-(bromomethyl)-7-chloro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (736 mg, 1 .6 mmol) in acetonitrile (5 mL) was added 1 ,4'bipiperidine (270 mg, 1.6 mmol) and potassium carbonate (442 mg, 3.2 mmol). The suspension was heated to 90-100°C in an oil bath and refluxed for three hours. The reaction mixture was concentrated under reduced pressure to dryness. The residue was redissolved in EtOAc. The solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to dryness. The title compound was obtained as a light yellow solid (770 mg, 88%). MS (m/z) 546.3 (M+H).
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid
Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (770 mg, 1 .41 mmol) was dissolved in 20 mL 6N HCI and heated to reflux for 4 hours. The suspension was concentrated to dryness to afford the title compound as a dark brown solid (650 mg, 87% yield) which was used without additional purification. MS (m/z) 532.1 (M+H).
3-(1.4'-bipiperidin-1 '-ylmethvn-7-chloro-N-r(1 S V1 -phenylethyll-2-r3- (trifluoromethyl)phenyll-4-quinolinecarboxamide
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (200 mg, 0.376 mmol), [(1 S)-1 -phenylethyl]amine (73 mg, 0.6 mmol), HBTU (143 mg, 0.376 mmol), and TEA (178 mg, 1.76 mmol) were dissolved in THF/ CH2CI2 (4:1 , 5 mL), and the reaction mixture was refluxed for 10 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in ethyl acetate, and the solution was washed once with water, 1 N NaOH, once with water, and once with brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (45-75% CH3CN/H20 + 0.1 % TFA over 21 min, 15 mL/min, VYA 2515 305 column) to afford the title compound (60 mg, 25% yield) as a yellow solid. MS (m/z) 635.4 (M+H).

Claims

Claims:
1. A compound selected from the group consisting of:
6-[(methylsulfonyl)amino]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
6-[(ethylsulfonyl)amino]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
6-(acetylamino)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-[(2-methylpropanoyl)amino]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3-
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-6-[(trifluoroacetyl)amino]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide ;
3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-6-[(propylsulfonyl)amino]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
6-[(cyclopropylsulfonyl)amino]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
6-{[(2-methylpropyl)sulfonyl]amino}-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-amino-3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(methylsulfonyl)amino]-2-[3-(trifluoromethyl)phenyl]- N-[(1 R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(ethylsulfonyl)amino]-2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(cyclopropylsulfonyl)amino]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
6-{[(dimethylamino)sulfonyl]amino}-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-N-[(1 S)-1 -phenylethyl]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-methyl-1 H-pyrazol-5-yl)-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(3,5-dimethyl-4-isoxazolyl)-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1 H-pyrazol-3-yl)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)- 2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(3-pyridinyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-
2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[2-(methyloxy)-3-pyridinyl]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-methyl-1 H-pyrazol-4-yl)-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-phenyl-N-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-phenyl-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide ;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[4-(methyloxy)-1 -piperidinyl]-2-[3-
(trifluoromethyl)phenyl]-N-(2,2,2-trifluoro-1 -phenylethyl)-4-quinolinecarboxamide trifluoroacetate;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-pyrrolidinylcarbonyl)-2-[3-(trifluoromethyl)phenyl]- N-[(1 R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(4-morpholinylcarbonyl)-2-[3-(trifluoromethyl)phenyl]-
N-[(1 R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(1-piperidinylcarbonyl)-2-[3-(trifluoromethyl)pheny ^ [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-N6,N6-dimethyl-2-[3-(trifluoromethyl)phen
2,2,2-trifluoro-1 -phenylethyl]-4,6-quinolinedicarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-N-[(1 S)-1 -phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)^
(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(1 -methylethyl)oxy]-2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-8-chloro-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-N-
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-[(1 -methylethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-N-[(1 S)-1 -phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-8-chloro-N-[(1 S)-1 -phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide trifluoroacetate;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(cyanomethyl)oxy]-N-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-{[2-(methyloxy)ethyl]oxy}-N-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-7-[(2,2,2-trifluoroethyl)oxy]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-{[2-(methyloxy)ethyl]oxy}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-[(2-methylpropyl)oxy]-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-N-
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(dimethylamino)sulfonyl]-2-[3-(trifluoromethyl)phen N-[(1 R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide;
6-[(dimethylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide
6-[(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
6-[(methylamino)sulfonyl]-3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-N-[(1 S)-1 - phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide; 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(2-methylpropyl)oxy]-2-[3-(trifluoromethyl)pheny ^ [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(1 -methylethyl)oxy]-2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-6-(methyloxy)-N-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[(trifluoromethyl)oxy]-2-[3-(trifluoromethyl)phen
[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(methyloxy)-N-[(1 S)-1-phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-{[4-(4-morpholinyl)-1 -piperidinyl]methyl}-N-[(1 S)-1 -phenylethyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-[(1 -methylethyl)oxy]-6-(2-oxo-1-pyrrolidinyl)-2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-cyano-7-[(1 -methylethyl)oxy]-N-[(1 S)-1 -phenylethyl]-2- [3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-methyl-7-[(1 -methylethyl)oxy]-2-[3-
(trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; and
3-(1 ,4'-bipiperidin-1 '-ylmethyl)-7-chloro-N-[(1 S)-1 -phenylethyl]-2-[3-
(trifluoromethyl)phenyl]-4-quinolinecarboxamide;
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
3. A method of treating congestive heart failure, overactive bladder, pain, cardiovascular disease, motor neuron disorders, or osteoarthritis, which comprises administering to a human in need thereof, a compound of claim 1 .
4. A method according to claim 3 wherein the compound is administered orally.
5. A method according to claim 3 wherein the compound is administered intravenously.
6. A method according to claim 3 wherein the compound is administered by inhalation.
PCT/US2011/029570 2010-03-23 2011-03-23 Trpv4 antagonists WO2011119693A1 (en)

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Cited By (6)

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US20130012499A1 (en) * 2010-03-23 2013-01-10 Glaxosmithkline Llc Trpv4 antagonists
CN105481702A (en) * 2015-11-27 2016-04-13 浙江鸿盛化工有限公司 Synthesis method of m-phenetidine by one-pot reaction
US9499533B2 (en) 2012-03-27 2016-11-22 Shionogi & Co., Ltd. Aromatic 5-membered heterocyclic derivative having TRPV4-Inhibiting activity
US9708338B2 (en) 2013-09-25 2017-07-18 Shionogi & Co., Ltd. Aromatic heterocyclylamine derivative having TRPV4-inhibiting activity
WO2021014415A3 (en) * 2019-07-25 2021-03-04 Curadev Pharma Pvt. Ltd. Small molecule inhibitors of acetyl coenzyme a synthetase short chain 2 (acss2)
WO2022014707A1 (en) 2020-07-16 2022-01-20 ラクオリア創薬株式会社 Trpv4 inhibitor as therapeutic drug for eye disease

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US20070129363A1 (en) * 2000-11-06 2007-06-07 Astrazeneca Ab N-type calcium channel antagonists for the treatment of pain
US20050070574A1 (en) * 2000-11-28 2005-03-31 Glaxosmithkline Spa And Laboratoire Novel compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130012499A1 (en) * 2010-03-23 2013-01-10 Glaxosmithkline Llc Trpv4 antagonists
US8658636B2 (en) * 2010-03-23 2014-02-25 GlaxoSmithKline, LLC TRPV4 antagonists
US9499533B2 (en) 2012-03-27 2016-11-22 Shionogi & Co., Ltd. Aromatic 5-membered heterocyclic derivative having TRPV4-Inhibiting activity
US9708338B2 (en) 2013-09-25 2017-07-18 Shionogi & Co., Ltd. Aromatic heterocyclylamine derivative having TRPV4-inhibiting activity
CN105481702A (en) * 2015-11-27 2016-04-13 浙江鸿盛化工有限公司 Synthesis method of m-phenetidine by one-pot reaction
CN105481702B (en) * 2015-11-27 2018-05-11 浙江鸿盛化工有限公司 The method of one pot process m-phenetidine
WO2021014415A3 (en) * 2019-07-25 2021-03-04 Curadev Pharma Pvt. Ltd. Small molecule inhibitors of acetyl coenzyme a synthetase short chain 2 (acss2)
CN114269720A (en) * 2019-07-25 2022-04-01 库拉德夫制药私人有限公司 Small molecule inhibitor of acetyl-CoA synthase short chain 2 (ACSS2)
WO2022014707A1 (en) 2020-07-16 2022-01-20 ラクオリア創薬株式会社 Trpv4 inhibitor as therapeutic drug for eye disease

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