WO2009000819A1 - 5-phenyl-1,3,4-oxadiazol-2-yl-acetyl-4-piperidinyl derivatives as cgrp receptor antagonists - Google Patents

5-phenyl-1,3,4-oxadiazol-2-yl-acetyl-4-piperidinyl derivatives as cgrp receptor antagonists Download PDF

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Publication number
WO2009000819A1
WO2009000819A1 PCT/EP2008/057985 EP2008057985W WO2009000819A1 WO 2009000819 A1 WO2009000819 A1 WO 2009000819A1 EP 2008057985 W EP2008057985 W EP 2008057985W WO 2009000819 A1 WO2009000819 A1 WO 2009000819A1
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Prior art keywords
piperidinyl
oxadiazol
phenyl
acetyl
chloro
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PCT/EP2008/057985
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French (fr)
Inventor
Paula Louise Nichols
John Skidmore
Robert William Ward
David Matthew Wilson
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Glaxo Group Limited
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Publication of WO2009000819A1 publication Critical patent/WO2009000819A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present invention relates to novel compounds, and to the use thereof in treating diseases and conditions mediated by Calcitonin-Gene-Related Peptide (CGRP).
  • CGRP Calcitonin-Gene-Related Peptide
  • the invention relates to compositions containing compounds of the invention and processes for their preparation.
  • Calcitonin Gene Related Peptide is a 37 amino acid neurotransmitter, which is widely distributed throughout the central and peripheral nervous system. It is a potent dilator of arteries and veins, particularly in the cerebral vasculature and is released into the venous circulation in migraineurs. These actions together with its localisation in the trigeminovascular system, suggests a role for CGRP in the pathogenesis of migraine. This includes a vasodilator role as well as a possible involvement in the central sensitisation of nociceptive pathways, which are also thought to be a component of migraine.
  • CGRP1 receptors which have a molecular correlate in the calcitonin receptor like receptor (CL) and the accessory protein, RAMP1 , the association between which is essential for function.
  • CGRP receptor antagonists would therefore be expected to be effective in the treatment of migraine and other headache syndromes.
  • the novel non-peptide CGRP receptor antagonist, BIBN 4096 antagonised the vasodilator effects of CGRP on human cerebral vessels and, when given intravenously, was effective in treating headache in migraineurs, thereby providing proof of concept for the use of CGRP receptor antagonists to treat migraine. It would therefore be desirable to identify a CGRP receptor antagonist that is selective for the human CGRP receptor and which could be given by a convenient route of administration, e.g. orally from a convenient pharmaceutical dosage form.
  • BIBN 4096 In trials, the compound was administered by intravenous infusion.
  • MK-0974 is described and claimed in WO04/092168.
  • WO04/092166, WO06/044504, and WO06/099268 inter alia describe as CGRP antagonists for the treatment of headache, migraine, and cluster headache certain compounds of formula
  • R' is a carbon-linked nitrogen-containing cyclic group, n is 0, 1 or 2, and R' and R'" together form a fused six-membered aromatic ring which is optionally substituted and contains 0, 1 or 2 nitrogen atoms.
  • the object of the present invention is to identify a CGRP antagonist which is selective for the hCGRP receptor and, preferably, readily bioavailable from a convenient pharmaceutical dosage form.
  • the invention provides the compound of formula (I):
  • R1 is selected from the group consisting of halogen, trifluoromethyl, methyl, and methoxy
  • R2 is hydrogen, or R1 and R2 together form a fused phenyl
  • R3 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, alkoxy, optionally substituted phenyl, trifluoromethyloxy, heterocyclyl, dialkylamino, and -N(CH3)CH2CH2OCH3;
  • R4 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, and methoxy;
  • R5 is hydrogen, methyl or methoxy;
  • n is 0, 1 or 2; and
  • R6 and R7 together form a fused six-membered aromatic ring which is optionally substituted and contains 0, 1 or 2 nitrogen atoms; with the proviso that, if R2 is hydrogen, at least one of R3 and R4 is not hydrogen, or a pharmaceutically acceptable salt thereof.
  • Suitable substituents for six-membered aromatic rings such as phenyl include halogen, trifluoromethyl, methyl and methoxy.
  • halogen means fluorine, chlorine, bromine or iodine.
  • heterocyclyl means a saturated, partially saturated or unsaturated four to seven membered ring, containing one or two heteroatoms selected from nitrogen, oxygen and sulphur, and optionally substituted by one or two groups independently selected from the group consisting of alkyl (e.g. methyl, ethyl or isopropyl), haloalkyl (e.g. difluoroethyl or trifluoroethyl), methoxy, hydroxy, dialkylamino, oxo and/or -COOC(Me)3. Further optional substituents for heterocyclyl groups include methyl, methoxy, hydroxy, dialkylamino and/or oxo.
  • the heterocyclyl group may be linked via a ring carbon atom or via a ring nitrogen atom.
  • alkyl' refers to a C1-7 linear or branched saturated hydrocarbon group.
  • alkyl groups include methyl and ethyl. Further examples of alkyl groups include n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), hexyl, 4- methylpentyl, 3,3-dimethylbutyl or heptyl and the like.
  • alkoxy refers to an -O-alkyl group, wherein alkyl is as defined hereinbefore.
  • haloalkyl refers to an alkyl group as hereinbefore defined substituted by one or more (e.g. 1-4) halogen atoms as hereinbefore defined.
  • the invention provides the compound of formula (IA): wherein:
  • R1 is selected from the group consisting of halogen, trifluoromethyl, methyl, and methoxy, and R2 is hydrogen, or R1 and R2 together form a fused phenyl;
  • R3 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, methoxy, optionally substituted phenyl, trifluoromethyloxy, heterocyclyl, dialkylamino, and -N(CH3)CH2CH2OCH3;
  • R4 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, and methoxy;
  • R5 is hydrogen, methyl or methoxy; n is 0, 1 or 2; and
  • R6 and R7 together form a fused six-membered aromatic ring which is optionally substituted and contains 0, 1 or 2 nitrogen atoms; with the proviso that, if R2 is hydrogen, at least one of R3 and R4 is not hydrogen.
  • R1 and R2 together form a fused phenyl; and R3 and R4 are both hydrogen; or
  • R1 is selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, methyl, and methoxy, and R2 is hydrogen; and at least one of R3 and R4 is not hydrogen; and/or
  • R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, alkoxy (e.g. methoxy), phenyl, trifluoromethyloxy, -N(Me)2, - N(CH3)CH2CH2OCH3, and heterocyclyl (e.g.
  • heterocyclyl groups may be optionally substituted by 1 or 2 substituents independently selected from haloalkyl (e.g. difluoroethyl or trifluoroethyl), hydroxy, alkyl (e.g.
  • R4 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine and methoxy; and/or R5 is hydrogen; and/or n is 0 and R6 and R7 together form a fused pyridyl optionally substituted by methoxy, or n is 0 and R6 and R7 together form a fused phenyl optionally substituted by chlorine or methoxy, or n is 1 and R6 and R7 together form a fused phenyl, or n is 2 and R6 and R7 together form a fused phenyl; or
  • R1 and R2 together form a fused phenyl; and R3 and R4 are both hydrogen; or
  • R1 is selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, methyl, and methoxy, and R2 is hydrogen; and at least one of R3 and
  • R4 is not hydrogen
  • R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxy, phenyl, trifluoromethyloxy, piperidinyl, N- methylpiperazinyl, morpholinyl, and -N(CH3)CH2CH2OCH3; and/or
  • R4 is selected from the group consisting of hydrogen, fluorine, chlorine, and methoxy; and/or
  • R5 is hydrogen; and/or n is 0 and R6 and R7 together form a fused pyridyl, or n is 2 and R6 and R7 together form a fused phenyl; or
  • the compound of formula (I) is selected from: 1-[1-( ⁇ 5-[3-Chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl ⁇ acetyl)-4-piperidinyl]- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E1 );
  • the compound of formula (I) is a compound of Example 1-28.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable acids including inorganic and organic acids.
  • Such acids include acetic, L-ascorbic acid (vitamin C), L-aspartic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanedisulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, nicotinic, phosphoric, succinic, sulphuric, tartaric, p-toluenesulfonic, perchloric, fluoboric, and the like.
  • the compound of formula (I) may exist in stereoisomeric forms (e.g. diastereoisomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms of the compound of formula (I) may be obtained according to methods well known in the literature, for example by separation one from the other by the usual methods such as preparative HPLC or by chromatographic purifications.
  • a racemic mixture may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. Any given isomer may also be obtained by stereospecific or asymmetric synthesis.
  • racemic intermediate compounds may be resolved and used to prepare individual stereoisomeric forms of chiral compounds of the invention.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the compounds of the invention may exist as pharmaceutically acceptable solvates such as hydrates and may form polymorphs and pseudopolymorphs.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may 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.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Descriptions hereafter using appropriate isotopic variations of suitable reagents.
  • the compounds of the present invention have potential utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; visceral pain; eye pain; tooth pain; cancer pain; diabetes; non- insulin dependant diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity; asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; encephalitis, brain trauma; epilepsy; neurodegenerative diseases; skin diseases; psoriasis; prevention of tumour growth; neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus; thermal injury; circulatory shock; Reynaud's syndrome; peripheral arterial insufficiency; subarachnoid/cranial haemorrhage; ischaemia; stroke; inflammatory bowel disease
  • compounds of the invention are particularly useful for the treatment of migraine, headache, and cluster headache.
  • the invention provides compounds of the invention for use as a medicament, such as a human medicament.
  • the invention further provides a method of treating migraine, headache, or cluster headache, which method comprises administering to a patient in need thereof an effective amount of a compound of the the invention.
  • the invention provides the use of compounds of the invention in the manufacture of a medicament for treating or preventing migraine, headache or cluster headache.
  • references herein to "treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • the compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • the carrier, diluent and/or excipient must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • compositions may be formulated for administration by any route.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 10-500, such as from 50-500, mg of the active ingredient.
  • the dosage as employed for adult human treatment will preferably range from 10 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 0.1 to 50 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the compounds of the present invention may be used in combination with one or more other drugs, which other drug(s) may be administered contemporaneously or sequentially with a compound of the invention.
  • a pharmaceutical composition in unit dosage form containing the other drug(s) and the compound of of the invention is preferred.
  • the compound of the invention and one or more other drugs may alternatively be administered on different overlapping schedules.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
  • the present compounds may be used in conjunction with an antiinflammatory or analgesic agent or an anti-migraine agent, such as an ergotamine and dihydroergotamine, or other serotonin agonists (e.g. 5-HT 1 agonists), especially a 5-HT- I B / 1 D agonist, for example sumatriptan, naratriptan, zolmitriptam, eletriptan, almotriptan, frovatriptan, doniitriptan, and rizatriptan; a 5-HT 1D agonist such as PNU- 142633 and a 5-HT 1 F agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-
  • anti-inflammatory agents examples include prostanoid receptor agonists or antagonists (e.g. EP1 , EP2, EP3 or EP4) and VR1 receptor antagonists.
  • the compounds of the invention may be administered with an analgesic such as aspirin, choline magnesium trisalicylate, diflunisal, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine, hydromorphone, levorphanol, meperidine, oxycodone, oxymorphone, propoxyphene, butorpanol, dezocine, nalbuphine, pentazocine or morphine.
  • the compounds of the invention may also be used in combination with COX-2 inhibitors.
  • an interleukin inhibitor such as an interleukin-1 inhibitor; an NK-I receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin- 1 receptor antagonist; an adenosine A1 receptor agonist; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; a renin inhibitor; a granzyme B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5-HT 2 receptor antagonists; opiod agonists such
  • the compounds of the invention may also be used in conjunction with ergot alkaloids other than ergotamine and dihydroergotamine, for example ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergocornine dihydroergocristine, dihydroergocryptine, dihydro- ⁇ -ergocryptine, dihydro- ⁇ - ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, ⁇ - ergocryptine, ⁇ -ergocryptine,ergosine, ergostane, bromocriptine, or methysergide.
  • ergonovine ergonovine, methylergonovine, metergoline, ergoloid mesylates
  • dihydroergocornine dihydroergocristine dihydroergocryptine, dihydro- ⁇ -ergocryptine,
  • the compounds of the present invention may be used in conjunction with a beta- adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, nifedipine, or prochlorperazine; neuroleptics such as olanzapine, droperidol, prochlorperazine, chlorpromazine and quetiapine; an anticonvulsant such as topiramate, tonabersat, carabersat, levetiracetam, or tiagabine; an anti-hypertensive such as an angiotensin I l antagonist, for example losartan,
  • the compounds of the present invention may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antitussive such as caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone; a sedating or non- sedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phenindamine,
  • nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds ofthe invention.
  • anesthesiology intraspinal infusion, neural blockade
  • neurosurgical neurolysis of CNS pathways
  • neurostimulatory transcutaneous electrical nerve stimulation, dorsal column stimulation
  • physiatric physical therapy, orthotic devices, diathermy
  • psychologic psychologic
  • the present invention also provides a process for the preparation of a compound of formula (I), which process comprises:
  • a suitable coupling agent such as O-(7-azabenzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluroniumhexafluorophosphate (HATU)
  • HATU hydroxybenzotriazol-1-yl
  • DIPEA diisopropylethylamine
  • PG is a protecting group such as lower alkyl.
  • Burgess Reagent is (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt.
  • the hydrazide starting material in Scheme 1 may be prepared from the corresponding ester by reaction with hydrazine.
  • the esters used in the first reaction of Scheme 1 are either known compounds or may be prepared in accordance with known procedures or procedures described herein.
  • bromine groups referred to above may be substituted for other halogen atoms (e.g. iodine or chlorine) or other suitable coupling partners such as triflate or tosylate.
  • the coupling can be carried out with a boronic acid or boronate ester on the phenyl ring and a halogenated (or triflate, tosylate) derivative as part of R3:
  • the UV detection range is from 220 to 330nm.
  • a 2 minute generic LC/MS method may be employed using a Waters Acquity system coupled with a Waters ZQ Mass Spectrometer.
  • NMR Nuclear Magnetic Resonance
  • Mass Directed Automated Preparative (MDAP) HPLC instruments consist of the following: Waters 2525 Binary Gradient Module, Waters 515 Makeup Pump, Waters Pump Control Module, Waters 2767 Inject Collect, Waters Column Fluidics Manager, Waters 2996 Photodiode Array Detector, Waters ZQ Mass Spectrometer, Gilson 202 fraction collector, Gilson Aspec waste collector. Column: Waters Atlantis, dimensions are 19mm x 100mm ( ⁇ 100mg scale) and 30mm x 100mm (>100mg scale), particle size is 5 ⁇ m.
  • Organic solvent Acetonitrile + 0.1 % Formic Acid.
  • the methods A-N are exemplified hereinbelow for certain Examples, and may be varied with respect to routine parameters such as time, temperature, workup conditions, etc.
  • routine parameters such as time, temperature, workup conditions, etc.
  • the detailed conditions described hereinabove for carrying out LCMS, NMR, chromatography and MDAP can, similarly, be varied with respect to routine parameters.
  • the product did not stick to the cartridges and was washed through with the methanol.
  • the product containing fractions were combined and concentrated under reduced pressure.
  • the product in dimethyl sulfoxide was partitioned between diethyl ether and water, and a white precipitate formed. More water was added to encourage precipitation.
  • the title compound, a white solid, was collected by filtration and air dried under low vacuum.
  • the intermediate D16 is a precursor to Example 7.
  • N- dimethylformamide 212 ml.
  • N-methylmorpholine 9.34 ml_, 85 mmol
  • N- ethyl- ⁇ /'-(3-dimethylaminopropyl)carbodiimide hydrochloride 12.21 g, 63.7 mmol
  • 1- hydroxybenzotriazole (6.50 g, 42.5 mmol)
  • ethyl 3-hydrazino-3-oxopropanoate 6.21 g, 42.5 mmol.
  • Chloro(1 ,1-dimethylethyl)climethylsilane (0.326 g, 2.163 mmol) and imidazole (0.147 g, 2.163 mmol) were added to a stirred solution of ethyl 3-(2- ⁇ [3-chloro-5-(3-hydroxy- 1-pyrrolidinyl)phenyl]carbonyl ⁇ hydrazino)-3-oxopropanoate (0.32 g, 0.865 mmol) in acetonitrile (8 ml_). The reaction mixture was stirred overnight at room temperature under an atmosphere of argon.
  • reaction mixture was transferred directly to a silica column and purified by column chromatography, eluting with 0-20% 2N ammonia in methanol in dichloromethane to give the title compound.
  • the reaction mixture was subjected to microwave conditions (100°C for 20 minutes). The reaction mixture was returned to the microwave for a further 20 minutes at 12O 0 C. The mixture was then partitioned between ethyl acetate (100 ml.) and water (150 ml_). The layers were separated and the aqueous mixture further extracted with ethyl acetate (2 x 75 ml_). The organic extracts were combined and washed with brine before being dried (magnesium sulfate) and evaporated in vacuo to a dark brown oil.
  • Trifluoroacetic acid (7.68 ml_, 100 mmol) was cautiously added to a solution of 1 ,1- dimethylethyl 4- ⁇ 3-chloro-5-[(ethyloxy)carbonyl]phenyl ⁇ -1 -piperidinecarboxylate (D44, 1.223g, 3.32 mmol) in dichloromethane (8 ml_).
  • the resulting solution was stirred for 2 hours and then the reaction mixture was diluted with ethanol and cautiously added to a 20 g SCX cartridge preconditioned with ethanol.
  • the cartridge was washed with several column volumes of ethanol before the basic material was eluted with 2M ammonia in methanol.
  • the basic fractions were combined and evaporated in vacuo to give the title compound as an oil.
  • Example 49 is prepared from D46 by standard methods described herein.
  • Ethyl 3-chloro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)benzoate (979 mg, 3.68 mmol) [prepared from D43 by reaction with trifluoracetic acid in dichloromethane followed by conversion to the free base by elution from an SCX column with 2M ammonia in methanol] was suspended in acetone (19.6 ml_), potassium carbonate (611 mg, 4.42 mmol) added, followed by 2,2,2-trifluoroethyl trichloromethanesulfonate (1.037 g, 3.68 mmol). The reaction was stirred at room temperature under argon overnight and then partitioned between ethyl acetate and water/brine.
  • the aqueous layer was re- extracted with ethyl acetate.
  • the organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo.
  • the mixture was purified by chromatography (SP4 Biotage, 50 g, 0-30% ethyl acetate/hexane over 10 column volumes). Relevant fractions were combined and concentrated in vacuo to give the title compound which was taken forward without additional purification.
  • D47 is taken forward by standard methods described herein to afford E60 and E63.
  • 3-chloro-5-iodobenzoate (D53, 2.139 g, 6.32 mmol) were transferred into a dried round-bottomed flask vial and capped with a rubber septum. The flask was then evacuated and backfilled with argon - this process was repeated several times. Butyronitrile (3.12 ml.) was then added and the mixture was stirred at 80 0 C overnight during which time the reaction had evaporated to dryness. Further butyronitrile (3.12 ml.) was added and the mixture stirred at 80 0 C over the weekend.
  • alkylating agent 200 mg was added and re-heated in the microwave at 12O 0 C for 1 hour then partitioned between ethyl acetate and water. The aqueous was re-extracted with ethyl acetate. Organics were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purified by chromatography (SP4 Biotage, 0-30% ethyl acetate in hexane over 10 column volumes, 25M). Relevant fractions were combined and concentrated in vacuo to give the title compound.
  • N-methylpyrrolidinone may be used as a solvent instead of N, N- dimethylformamide;
  • 1-hydroxyaza-7-azabenzotriazole may be used in conjunction with O-(7-azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /',-tetramethyluroniumhexafluorophosphate as in Example 32.
  • Example 12 After a 2 hour reaction time the product was obtained after concentrating the reaction mixture and trituration with methanol.
  • reaction mixture was concentrated and the residue was dissolved in ethyl acetate and was washed with water.
  • the ethyl acetate layer was concentrated and the residue was purified by chromatography (Biotage SP4, gradient of 0% to 10% methanol in dichloromethane over a total of 30 column volumes). Appropriate fractions were combined and concentrated to give the title compound.
  • Example 22 Other Examples designated Method B were prepared similarly.
  • the aqueous work-up was not necessary as the product was obtained as a solid from the reaction mixture and was collected by filtration, then washed with diethyl ether, methanol and water and dried.
  • the mixture was stirred at room temperature for 3 hours and then diluted with ethyl acetate, washed with sodium bicarbonate and brine and evaporated.
  • the residue was diluted with ethyl acetate, washed with sodium bicarbonate and brine and evaporated.
  • the residue was purified using a 25+S Biotage cartridge, eluting with a gradient of 0-20% methanol/ethyl acetate, and then repurified by MDAP to give the title compound.
  • Examples 27 and 28 were prepared similarly.
  • a few drops of water were also added at the same time as the additional portions of O-(7-azabenzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluroniumhexafluorophosphate, 1- (4-piperidinyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, and N, N- diisopropylethylamine.
  • reaction mixture was diluted with ethyl acetate and washed with water 3 times.
  • Dichloromethane and methanol were added to aid solubility of a white solid that had precipitated.
  • the organic extractions were concentrated and the residue washed with water and the undissolved solid collected by filtration and purified by MDAP to give the title compound.
  • Example 38 also from ⁇ 5-[3-chloro-5-(5-pyrimidinyl)phenyl]-
  • Example 41 used 1- hydroxy-7-azabenzotriazole, an aqueous work-up with ethyl acetate extraction, and MDAP purification.
  • Other examples designated as method G may use an aqueous workup with dichloromethane or ethyl acetate extraction as appropriate (see Example 60 below).
  • Example 60 1 - ⁇ 1 -[(5- ⁇ 3-Chloro-5-[1 -(2,2,2-trifluoroethyl)-1 , 2,3,6 -tetra hydro -4- pyridinyl]phenyl ⁇ -1 ,3,4-oxadiazol-2-yl)acetyl]-4-piperidinyl ⁇ -1 ,3-dihydro-2H- imidazo[4,5- ⁇ ]pyridin-2-one (E60)
  • Example 67 In the case of Example 67 an equivalent of 1 M hydrochloric acid in diethyl ether was added (to neutralise an extra equivalent of lithium hydroxide used in the previous hydrolysis step).
  • Example 21 may be prepared by method B (see Table) but also by method G as shown below:
  • Example 21 1 -[1 -( ⁇ S-IS-Chloro-S-ftrifluoromethylJphenyll-i ,3,4-oxadiazol-2-yl ⁇ acetyl)-4- piperidinyl]-1,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one (E21)
  • Example 55 D41 after hydrolysis to the corresponding lithium salt was also used to prepare Example 55 by a similar procedure to Example 43.
  • N-ethylation with ethyl bromide affords a mixture of the 2 isomers which was carried through stages analogous to D37 - D41 with separation of isomers at the stage corresponding to D40.
  • Subsequent hydrolysis to the lithium salt and coupling analogous to the above procedures under Method G afforded Examples 54, 59, 61 and 64 for the separate N-ethyl isomers.
  • heterocycles may be introduced by an analogous sequence to sequence D37 - D41 , followed by hydrolysis and coupling (by method G or N).
  • imidazoles E48, E82, E52, E83
  • the bromoimidazoles were commercially available. For these single isomers no separation was required at a stage equivalent to D40.
  • Example 75 was prepared from 3-[1-( ⁇ 5-[3-chloro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1 ,3,4- oxadiazol-2-yl ⁇ acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one trifluoroacetic acid salt using acetone instead of formaldehyde.
  • Method M
  • N-methylmorpholine 0.032 ml_, 0.288 mmol
  • 1-hydroxybenzotriazole 24.26 mg, 0.158 mmol
  • ⁇ /-ethyl- ⁇ /'-(3- dimethylaminopropyl)carbodiimide hydrochloride 33.1 mg, 0.173 mmol
  • the reaction mixture was concentrated by evaporation under reduced pressure and the residue partitioned between dichloromethane (50 ml.) and saturated sodium bicarbonate solution (50 ml_).
  • the organics were extracted and washed with water (50 ml_), passed through a hydrophobic frit, then concentrated by evaporation under reduced pressure.
  • the crude mixture was purified by column chromatography (Biotage SP4 25+S) eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound.
  • Method N were prepared similarly. In other examples of this method the addition of additional coupling reagents and base was not always necessary, or was added from the start.
  • CALCRL and Rampi stable cell line Human calcitonin receptor like receptor (CALCRL or CRLR) (Genbank U17473) and Rampi (Genbank AJ001014) were cloned into bicistronic mammalian expression vectors (BioTechniques, 1996, 20:102-110) pCIN3 and pCIH5.
  • HEK293 Human embryonic kidney 293cells (HEK293) were maintained in DMEM containing 2mM glutamine (Gibco 41966-029) with 10% Heat inactivated FCS (Gibco 10100- 147)
  • Both of the plasmids were transfected into a 50% confluent T75 flask of HEK293 cells using Lipofectamine according to the manufacturers guidelines (Invitrogen 18324-012). 48 hours following transfection, the cells were dilution cloned into 96-well plates using selection media containing DMEM containing 2mM glutamine (Gibco 41966- 029), 10% Heat inactivated FCS (Gibco 10100-147), 500 ⁇ g/ml Geneticin (Gibco 10131-027) and 200 ⁇ g/ml of hygromycin B (Gibco 10687-010). 10 to 14 days post dilution cloning, antibiotic resistant clones were grown on and expanded.
  • the clones were screened for increases in cAMP production on addition of human ⁇ - CGRP using cAMP SPA screening Biotrack assay (GE healthcare RPA556) according to the manufacturers instructions. A positive clone from this screening was then chosen and used for all subsequent assay work.
  • Calcitonin Receptor Like Receptor CRLR
  • RAMP1 Receptor Activity Modifying Protein
  • CRLR-RAMP1 CRLR-RAMP1
  • CGRP Calcitonin Gene Related Peptide
  • Receptor activity can therefore be measured using a cAMP accumulation immunoassay. This assay is based on competition between a europium labelled cAMP complex and cellular cAMP for binding sites on anti-cAMP antibodies labelled with Alexa Fluor 647(Trade Mark).
  • TR-FRET Time Resolved Fluorescence Resonance Energy Transfer
  • the compounds of Examples 1 to 28 were tested in this assay and exhibited fpKi values greater than or equal to 7.0.
  • the compounds of Examples 29 to 93 were also tested in this assay: all except the compound of Example 92 exhibited fpKi values greater than or equal to 7.0.

Abstract

The present invention relates to novel compounds that are CGRP receptor antagonists, processes for their preparation, to compositions containing them and to their use in the treatment of migraine, headache, and cluster headache.

Description

' 5-PHENYL-l , 3 , 4-OXADIAZOL-2-YL-ACETYL-4-PIPERIDINYL DERIVATIVES AS CGRP RECEPTOR ANTAGONISTS
The present invention relates to novel compounds, and to the use thereof in treating diseases and conditions mediated by Calcitonin-Gene-Related Peptide (CGRP). In addition, the invention relates to compositions containing compounds of the invention and processes for their preparation.
Calcitonin Gene Related Peptide, CGRP, is a 37 amino acid neurotransmitter, which is widely distributed throughout the central and peripheral nervous system. It is a potent dilator of arteries and veins, particularly in the cerebral vasculature and is released into the venous circulation in migraineurs. These actions together with its localisation in the trigeminovascular system, suggests a role for CGRP in the pathogenesis of migraine. This includes a vasodilator role as well as a possible involvement in the central sensitisation of nociceptive pathways, which are also thought to be a component of migraine. The actions of CGRP in the cerebral vasculature are mediated by CGRP1 receptors, which have a molecular correlate in the calcitonin receptor like receptor (CL) and the accessory protein, RAMP1 , the association between which is essential for function.
CGRP receptor antagonists would therefore be expected to be effective in the treatment of migraine and other headache syndromes. The novel non-peptide CGRP receptor antagonist, BIBN 4096 antagonised the vasodilator effects of CGRP on human cerebral vessels and, when given intravenously, was effective in treating headache in migraineurs, thereby providing proof of concept for the use of CGRP receptor antagonists to treat migraine. It would therefore be desirable to identify a CGRP receptor antagonist that is selective for the human CGRP receptor and which could be given by a convenient route of administration, e.g. orally from a convenient pharmaceutical dosage form.
US Patent No 6,344,449 describes the compound N-[(1 R)-2-[[(1 S)-5-amino-1 -[[4-(4- pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4- hydroxyphenyl)methyl]-2-oxoethyl]-4-(1 ,4-dihydro-2-oxo-3(22H)-quinazolinyl)-1- piperidinecarboxamide (olcegepant; BIBN 4096) as an antagonist of CGRP for the treatment of migraine:
Figure imgf000002_0001
BIBN 4096 In trials, the compound was administered by intravenous infusion.
The pharmacological profile of MK-0974 (Merck & Co.), an oral calcitonin gene- related peptide (CGRP) receptor antagonist, was described at a recent meeting of the American Hea
Figure imgf000003_0001
MK-0974
MK-0974 is described and claimed in WO04/092168.
WO04/092166, WO06/044504, and WO06/099268 inter alia describe as CGRP antagonists for the treatment of headache, migraine, and cluster headache certain compounds of formula
Figure imgf000003_0002
wherein R' is a carbon-linked nitrogen-containing cyclic group, n is 0, 1 or 2, and R' and R'" together form a fused six-membered aromatic ring which is optionally substituted and contains 0, 1 or 2 nitrogen atoms.
The object of the present invention is to identify a CGRP antagonist which is selective for the hCGRP receptor and, preferably, readily bioavailable from a convenient pharmaceutical dosage form.
According to a first aspect, the invention provides the compound of formula (I):
Figure imgf000003_0003
wherein: R1 is selected from the group consisting of halogen, trifluoromethyl, methyl, and methoxy, and R2 is hydrogen, or R1 and R2 together form a fused phenyl; R3 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, alkoxy, optionally substituted phenyl, trifluoromethyloxy, heterocyclyl, dialkylamino, and -N(CH3)CH2CH2OCH3;
R4 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, and methoxy; R5 is hydrogen, methyl or methoxy; n is 0, 1 or 2; and R6 and R7 together form a fused six-membered aromatic ring which is optionally substituted and contains 0, 1 or 2 nitrogen atoms; with the proviso that, if R2 is hydrogen, at least one of R3 and R4 is not hydrogen, or a pharmaceutically acceptable salt thereof.
Suitable substituents for six-membered aromatic rings such as phenyl include halogen, trifluoromethyl, methyl and methoxy.
As used herein halogen means fluorine, chlorine, bromine or iodine.
As used herein heterocyclyl means a saturated, partially saturated or unsaturated four to seven membered ring, containing one or two heteroatoms selected from nitrogen, oxygen and sulphur, and optionally substituted by one or two groups independently selected from the group consisting of alkyl (e.g. methyl, ethyl or isopropyl), haloalkyl (e.g. difluoroethyl or trifluoroethyl), methoxy, hydroxy, dialkylamino, oxo and/or -COOC(Me)3. Further optional substituents for heterocyclyl groups include methyl, methoxy, hydroxy, dialkylamino and/or oxo. The heterocyclyl group may be linked via a ring carbon atom or via a ring nitrogen atom.
The term 'alkyl' as used herein refers to a C1-7 linear or branched saturated hydrocarbon group. Examples of alkyl groups include methyl and ethyl. Further examples of alkyl groups include n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), hexyl, 4- methylpentyl, 3,3-dimethylbutyl or heptyl and the like.
The term "alkoxy" as used herein refers to an -O-alkyl group, wherein alkyl is as defined hereinbefore.
The term "haloalkyl" as used herein refers to an alkyl group as hereinbefore defined substituted by one or more (e.g. 1-4) halogen atoms as hereinbefore defined.
According to a further aspect, the invention provides the compound of formula (IA):
Figure imgf000005_0001
wherein:
R1 is selected from the group consisting of halogen, trifluoromethyl, methyl, and methoxy, and R2 is hydrogen, or R1 and R2 together form a fused phenyl;
R3 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, methoxy, optionally substituted phenyl, trifluoromethyloxy, heterocyclyl, dialkylamino, and -N(CH3)CH2CH2OCH3;
R4 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, and methoxy;
R5 is hydrogen, methyl or methoxy; n is 0, 1 or 2; and
R6 and R7 together form a fused six-membered aromatic ring which is optionally substituted and contains 0, 1 or 2 nitrogen atoms; with the proviso that, if R2 is hydrogen, at least one of R3 and R4 is not hydrogen.
In particular aspects of the invention:
R1 and R2 together form a fused phenyl; and R3 and R4 are both hydrogen; or
R1 is selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, methyl, and methoxy, and R2 is hydrogen; and at least one of R3 and R4 is not hydrogen; and/or
R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, alkoxy (e.g. methoxy), phenyl, trifluoromethyloxy, -N(Me)2, - N(CH3)CH2CH2OCH3, and heterocyclyl (e.g. piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl) wherein said heterocyclyl groups may be optionally substituted by 1 or 2 substituents independently selected from haloalkyl (e.g. difluoroethyl or trifluoroethyl), hydroxy, alkyl (e.g. methyl, ethyl or isopropyl) and -COOC(Me)3; and/or R4 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine and methoxy; and/or R5 is hydrogen; and/or n is 0 and R6 and R7 together form a fused pyridyl optionally substituted by methoxy, or n is 0 and R6 and R7 together form a fused phenyl optionally substituted by chlorine or methoxy, or n is 1 and R6 and R7 together form a fused phenyl, or n is 2 and R6 and R7 together form a fused phenyl; or
R6 and R7 together with the ring to which they are attached form a group selected from Table I: Table
Figure imgf000006_0001
In further particular aspects of the invention: R1 and R2 together form a fused phenyl; and R3 and R4 are both hydrogen; or
R1 is selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, methyl, and methoxy, and R2 is hydrogen; and at least one of R3 and
R4 is not hydrogen; and/or
R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxy, phenyl, trifluoromethyloxy, piperidinyl, N- methylpiperazinyl, morpholinyl, and -N(CH3)CH2CH2OCH3; and/or
R4 is selected from the group consisting of hydrogen, fluorine, chlorine, and methoxy; and/or
R5 is hydrogen; and/or n is 0 and R6 and R7 together form a fused pyridyl, or n is 2 and R6 and R7 together form a fused phenyl; or
R6 and R7 together with the ring to which they are attached form a group selected from Table II:
Table Il
Figure imgf000006_0002
Compounds of the invention include those described hereinbelow in the Examples. In a particular aspect, compounds of the invention include those described hereinbelow in the Examples, and pharmaceutically acceptable salts thereof.
In a further aspect, the compound of formula (I) is selected from: 1-[1-({5-[3-Chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E1 );
1-[1-({5-[3-(4-Morpholinyl)-5-(trifluoromethyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E2); 1-(1-{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl](methyloxy)acetyl}-4-piperidinyl)- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E3); 1-(1-{2-[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]propanoyl}-4-piperidinyl)-1 ,3- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E4);
1-[1-({5-[3-Chloro-5-(4-methyl-1-piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E5);
3-(1 -{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3,4,5- tetrahydro-2H-1 ,3-benzodiazepin-2-one (E6)
1-(1-{[5-(5-Chloro-3-biphenylyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E7)
^(^{^-(S.S-DibromophenylJ-I .S^-oxadiazol^-ylJacetyl^-piperidinylJ-I .S-dihydro-
2H-imidazo[4,5-ib]pyridin-2-one (E8); 1-(1-{[5-(3-Chloro-5-{methyl[2-(methyloxy)ethyl]amino}phenyl)-1 ,3,4-oxadiazol-2- yl]acetyl}-4-piperidinyl)-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E9);
1-[1-({5-[3-Chloro-5-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E10);
1-[1-({5-[3,5-Dibromo-2-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- 1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E1 1 );
1-[1-({5-[3,5-Dichloro-2-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E12);
^(^{^-(S-Bromo-S-chlorophenylJ-I .S^-oxadiazol^-ylJacetyl^-piperidinylJ-I .S- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E13); 1-(1-{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3-dihydro-
2/-/-imidazo[4,5-b]pyridin-2-one (E14);
^(^{^-(S-Chloro-S-fluorophenylJ-I .S^-oxadiazol^-ylJacetyll^-piperidinylJ-I .S- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E15);
1-[1-({5-[5-Chloro-2-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- 1 ,3-dihydro-2H-imidazo[4,5-jb]pyridin-2-one (E16);
^(^{^-(S.S-DifluorophenylJ-I .S^-oxadiazol^-ylJacetyll^-piperidinylJ-I .S-dihydro-
2/-/-imidazo[4,5-b]pyridin-2-one (E17);
1-(1-{[5-(2,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3-dihydro-
2/-/-imidazo[4,5-b]pyridin-2-one (E18); 1-[1-({5-[3-Bromo-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E19);
1-[1-({5-[3-Methyl-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E20); i-ti-Uδ-tS-Chloro-S-^πfluoromethyOphenyO-I .S^-oxadiazol^-ylϊacetylH- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E21 );
1-[1-({5-[3-Chloro-5-(1-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E22); i-ii-tCS-iS-Chloro-S-KtrifluoromethyOoxylphenyll-I .S^-oxadiazol^-yOacetyl]^- piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E23); 1-[1-({5-[3,5-Bis(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-1 ,3- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E24);
1-(1-{[5-(5-Chloro-2-fluorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E25);
1-(1-{[5-(2-Naphthalenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (E26); i-ti-^S-^.S-Bis^rifluoromethyOphenyO-I .S^-oxadiazol^-ylJacetylH-piperidinyO-I .S- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E27);
1-(1-{[5-(3,5-Dimethylphenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3-dihydro-
2H-imidazo[4,5-b]pyridin-2-one (E28); 1-[1-({5-[3-Chloro-5-(dimethylamino)phenyl]-1 !3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E29);
1-(1-{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-4-(methyloxy)-
1 ,3-dihydro-2H-benzimidazol-2-one (E30);
3-[1-({5-[3-(Methyloxy)-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E31 );
Formic acid - 4-chloro-1-[1-({5-[3-chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one (1 :1 ) (E32);
1-[1-({5-[3-Chloro-5-(3-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E33); 1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-2,3-dihydro-1 /-/-imidazo[4,5- b]pyridin-1-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-1- piperazinecarboxylate (E34);
1-[1-({5-[3-Fluoro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1.S-dihydro^H-imidazo^.S-^pyridin^-one (E35); 3-[1-({5-[3-Chloro-5-(4-methyl-1-piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E36);
3-[1-({5-[3-Chloro-5-(5-pyrimidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E37);
1-[1-({5-[3-Chloro-5-(5-pyrimidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- i ^-dihydro^H-imidazo^.S-^pyridin^-one (E38);
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-1 ,2,4,5-tetrahydro-3H-1 ,3- benzodiazepin-3-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-3,6-dihydro-
1 (2H)-pyridinecarboxylate (E39);
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5- b]pyridin-1-yl)-1-piperidinyl]ethyl}-1 !3!4-oxadiazol-2-yl)phenyl]-3,6-dihydro-1 (2H)- pyridinecarboxylate (E40);
3-(1-{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-3,4-dihydro-
2(1 H)-quinazolinone (E41 );
S-ti-US-^-Chloro-S^I ^-dimethyl-I H-imidazol-δ-yOphenyO-I .S^-oxadiazol^- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E42);
S-ti-Uδ-^-Chloro-S^I ^-dimethyl-I H-imidazoM-yOphenyO-I .S^-oxadiazol^- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E43);
3-[1-({5-[3-Chloro-5-(3-pyridinyl)phenyl]-1 !3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E44); i-ti-^δ-^-Chloro-δ-CI H-imidazol-i-yOphenyO-I .S^-oxadiazol^-ylϊacetylH- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E45); i-ti-Uδ-tS-Chloro-S^I ^-dimethyl-I H-imidazol-S-yOphenyO-I .S^-oxadiazol^- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E46);
1-[1-({5-[3-Chloro-5-(1-methyl-1 H-pyrazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E47); 3-[1-({5-[3-Chloro-5-(1-methyl-1 /-/-imidazol-5-yl)phenyl]-1 !3,4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E48);
1 -{1 -[(5-{3-Chloro-5-[1 -(2,2-difluoroethyl)-4-piperidinyl]phenyl}-1 ,3,4-oxadiazol-2- yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2H-imidazo[4,5-ιb]pyridin-2-one (E49); 3-[1-({5-[3-Chloro-5-(1-methyl-1 H-pyrazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E50);
1-[1-({5-[3-Chloro-5-(6-methyl-3-pyridinyl)phenyl]-1 !3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E51 );
3-[1-({5-[3-Chloro-5-(1-methyl-1 H-imidazol-4-yl)phenyl]-1 !3!4-oxadiazol-2-yl}acetyl)- 4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E52);
1 -{1 -[(5-{3-Chloro-5-[1 -(2,2-difluoroethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-1 ,3,4- oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E53);
1-[1-({5-[3-Chloro-5-(1-ethyl-2-methyl-1 H-imidazol-5-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E54);
1-[1-({5-[3-Chloro-5-(1 ,2-dimethyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E55);
3-[1-({5-[3-Chloro-5-(6-methyl-3-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E56); 1-[1-({5-[3-Chloro-5-(1-methyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E57);
1-{1-[(5-{3-Chloro-5-[1-(2,2-difluoroethyl)-3-pyrrolidinyl]phenyl}-1 ,3,4-oxadiazol-2- yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E58);
3-[1-({5-[3-Chloro-5-(1-ethyl-2-methyl-1 H-imidazol-5-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E59);
1-{1-[(5-{3-Chloro-5-[1-(2,2,2-trifluoroethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-
1 ,3,4-oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E60);
1-[1-({5-[3-Chloro-5-(1-ethyl-2-methyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E61 );
1-[1-({5-[3-Chloro-5-(2-methyl-3-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E62);
3-{1-[(5-{3-Chloro-5-[1-(2,2,2-trifluoroethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-
1 ,3,4-oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2- one (E63);
3-[1-({5-[3-Chloro-5-(1-ethyl-2-methyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E64);
3-[1-({5-[3-Chloro-5-(2-methyl-3-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E65); 1-{1-[(5-{3-Chloro-5-[1-(2,2,2-trifluoroethyl)-4-piperidinyl]phenyl}-1 ,3,4-oxadiazol-2- yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E66);
1-[1-({5-[3-Chloro-5-(2,4-dimethyl-1 H-imidazol-1-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E67);
3-[1-({5-[3-Chloro-5-(4-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- 1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E68); 1-[1-({5-[3-Chloro-5-(4-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2H-imidazo[4,5-fc]pyridin-2-one (E69);
Formic acid - 1-[1-({5-[3-chloro-5-(1-piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-ιb]pyridin-2-one (1 :1 ) (E70); 1-[1-({5-[3-Chloro-5-(3-hydroxy-1-pyrrolidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-ιb]pyridin-2-one (E71 );
3-[1-({5-[3-Chloro-5-(1 ,2!3!6-tetrahydro-4-pyridinyl)phenyl]-1 !3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one trifluoroacetate (E72); 1-[1-({5-[3-Chloro-5-(1 ,2!3!6-tetrahydro-4-pyridinyl)phenyl]-1 !3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one trifluoroacetate
(E73);
3-[1-({5-[3-Chloro-5-(1-methyl-1 !2!3!6-tetrahydro-4-pyridinyl)phenyl]-1 !3,4-oxadiazol-
2-yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E74); 3-{1-[(5-{3-Chloro-5-[1-(1-methylethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-1 ,3,4- oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E75);
1-[1-({5-[3-Chloro-5-(1-methyl-1 ,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1 ,3,4-oxadiazol-
2-yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E76); 1-[1-({5-[3-Chloro-5-(1-methyl-4-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E77);
1-[1-({5-[3-Chloro-5-(1-ethyl-4-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E78);
1-[1-({5-[3-Chloro-5-(1-ethyl-1 ,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E79);
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-1 ,2,4,5-tetrahydro-3H-1 ,3- benzodiazepin-3-yl)-1 -piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-1 - piperidinecarboxylate (E80);
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5- b]pyridin-1-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-1- piperidinecarboxylate (E81 );
3-[1-({5-[3-Chloro-5-(1-methyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E82);
3-[1-({5-[3-Chloro-5-(1 ,5-dimethyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E83);
3-[1-({5-[3-Chloro-5-(1 ,4-dimethyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E84);
1-[1-({5-[3-Chloro-5-(1 ,5-dimethyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E85); 1-[1-({5-[3-Chloro-5-(1-methyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E86);
1-[1-({5-[3-Chloro-5-(1 ,4-dimethyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E87);
1-(1-{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-5-(methyloxy)- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E88); 3-{1 -[(5-{3-Chloro-5-[1 -(2,2-difluoroethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-1 ,3,4- oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3,4,5-tetrahydro-2/-/-1 ,3-benzodiazepin-2-one (E89);
3-{1 -[(5-{3-Chloro-5-[1 -(2,2-difluoroethyl)-4-piperidinyl]phenyl}-1 ,3,4-oxadiazol-2- yl)acetyl]-4-piperidinyl}-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E90):
1-[1-({5-[3-Chloro-5-(4-pyridazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- 1 ,3-dihydro-2H-imidazo[4,5-jb]pyridin-2-one (E91 );
3-[1-({5-[3-Chloro-5-(4-pyridazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- 1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E92); and 1-(1-{[5-(2-Bromo-5-chlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3- dihydro-2H-imidazo[4,5-ib]pyridin-2-one (E93) .
In a yet further aspect, the compound of formula (I) is a compound of Example 1-28.
Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable acids including inorganic and organic acids. Such acids include acetic, L-ascorbic acid (vitamin C), L-aspartic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanedisulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, nicotinic, phosphoric, succinic, sulphuric, tartaric, p-toluenesulfonic, perchloric, fluoboric, and the like.
It will be appreciated by the person skilled in the art that the compound of formula (I) may exist in stereoisomeric forms (e.g. diastereoisomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
The different stereoisomeric forms of the compound of formula (I) may be obtained according to methods well known in the literature, for example by separation one from the other by the usual methods such as preparative HPLC or by chromatographic purifications. A racemic mixture may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. Any given isomer may also be obtained by stereospecific or asymmetric synthesis. In addition, racemic intermediate compounds may be resolved and used to prepare individual stereoisomeric forms of chiral compounds of the invention.
The invention also extends to any tautomeric forms and mixtures thereof.
Hereinafter, the compounds of formula (I) and their pharmaceutically acceptable salts are referred to as "the compounds of the invention".
The compounds of the invention may exist as pharmaceutically acceptable solvates such as hydrates and may form polymorphs and pseudopolymorphs. The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 180, 31P, 32P, 35S, 18F and 36CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may 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. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Descriptions hereafter using appropriate isotopic variations of suitable reagents.
The compounds of the present invention have potential utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; visceral pain; eye pain; tooth pain; cancer pain; diabetes; non- insulin dependant diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity; asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; encephalitis, brain trauma; epilepsy; neurodegenerative diseases; skin diseases; psoriasis; prevention of tumour growth; neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus; thermal injury; circulatory shock; Reynaud's syndrome; peripheral arterial insufficiency; subarachnoid/cranial haemorrhage; ischaemia; stroke; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by antagonism of CGRP receptors. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache.
As discussed hereinabove, it is believed that compounds of the invention are particularly useful for the treatment of migraine, headache, and cluster headache.
Therefore, according to a further aspect, the invention provides compounds of the invention for use as a medicament, such as a human medicament.
The invention further provides a method of treating migraine, headache, or cluster headache, which method comprises administering to a patient in need thereof an effective amount of a compound of the the invention.
According to a further aspect the invention provides the use of compounds of the invention in the manufacture of a medicament for treating or preventing migraine, headache or cluster headache.
It will be appreciated that references herein to "treatment" extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions. The compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
According to a further aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s). The carrier, diluent and/or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
The compositions may be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 10-500, such as from 50-500, mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 10 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 0.1 to 50 mg/kg per day.
It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
The compounds of the present invention may be used in combination with one or more other drugs, which other drug(s) may be administered contemporaneously or sequentially with a compound of the invention. When the compounds are to be used contemporaneously, a pharmaceutical composition in unit dosage form containing the other drug(s) and the compound of of the invention is preferred. However, the compound of the invention and one or more other drugs may alternatively be administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
For example, the present compounds may be used in conjunction with an antiinflammatory or analgesic agent or an anti-migraine agent, such as an ergotamine and dihydroergotamine, or other serotonin agonists (e.g. 5-HT1 agonists), especially a 5-HT-I B/1 D agonist, for example sumatriptan, naratriptan, zolmitriptam, eletriptan, almotriptan, frovatriptan, doniitriptan, and rizatriptan; a 5-HT1D agonist such as PNU- 142633 and a 5-HT1 F agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent , for example with a compound such as, ibuprofen, ketoprofen, fenoprofen, flurbiprofen, naproxen, naproxen sodium, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, oxyphenylbutazone, diflunisal, salsalate, olsalazine or sulfasalazine and the like; or glucocorticoids; or a steroidal analgesic; or antidepressants such as amitriptyline or venlafaxine; or anticonvulsants such as gabapentin, pregabalin or memantine; or fatty acid derivative anticonvulsants such as divalproex; or carbonic anhydrase inhibitor anticonvulsants such as topiramate; or benzodiazepine anticonvulsants such as clonazepam; or N-type, P-type or Q-type calcium channel blocking anticonvulsants such as flunarizine, verapamil or cinnarizine; or sodium channel blocking anticonvulsants such as lamotrigine, lidocaine or zonisamide; or centrally acting antiadrenergic agents such as clonidine; or gamma aminobutyric acid analogs such as pregabalin; or calcium channel blocking agents such as verapamil or nimodipine. Examples of anti-inflammatory agents which may be used in combinations of the invention include prostanoid receptor agonists or antagonists (e.g. EP1 , EP2, EP3 or EP4) and VR1 receptor antagonists. Similarly, the compounds of the invention may be administered with an analgesic such as aspirin, choline magnesium trisalicylate, diflunisal, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine, hydromorphone, levorphanol, meperidine, oxycodone, oxymorphone, propoxyphene, butorpanol, dezocine, nalbuphine, pentazocine or morphine. The compounds of the invention may also be used in combination with COX-2 inhibitors.
Additionally, the present compounds may be used in conjunction with an interleukin inhibitor, such as an interleukin-1 inhibitor; an NK-I receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin- 1 receptor antagonist; an adenosine A1 receptor agonist; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; a renin inhibitor; a granzyme B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5-HT2 receptor antagonists; opiod agonists such as codeine, hydrocodone, tramadol, dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist or potentiator; a GABA A receptor modulator, for example acamprosate calcium; nicotinic antagonists or agonists including nicotine; muscarinic agonists or antagonists; a selective serotonin reuptake inhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, or citalopram; an antidepressant, for example amitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine, doxepin, protriptyline, desipramine, trimipramine, or imipramine; a leukotriene antagonist, for example montelukast or zafirlukast; an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide. The compounds of the invention may also be used in conjunction with gap junction inhibitors; neuronal calcium channel blockers such as civamide; AMPA/KA antagonists such as LY293558; sigma receptor agonists; and vitamin B2.
The compounds of the invention may also be used in conjunction with ergot alkaloids other than ergotamine and dihydroergotamine, for example ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergocornine dihydroergocristine, dihydroergocryptine, dihydro-α-ergocryptine, dihydro-β- ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, α- ergocryptine, β-ergocryptine,ergosine, ergostane, bromocriptine, or methysergide.
The compounds of the present invention may be used in conjunction with a beta- adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, nifedipine, or prochlorperazine; neuroleptics such as olanzapine, droperidol, prochlorperazine, chlorpromazine and quetiapine; an anticonvulsant such as topiramate, tonabersat, carabersat, levetiracetam, or tiagabine; an anti-hypertensive such as an angiotensin I l antagonist, for example losartan, irbesartin, valsartan, eprosartan, telmisartan, ohnesartan, medoxomil, candesartan and candesartan cilexetil, an angiotensin I antagonist, an angiotensin converting enzyme inhibitor such as lisinopril, enalapril, captopril, benazepril, quinapril, perindopril, ramipril and trandolapril; or botulinum toxin type A or B.
The compounds of the present invention may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antitussive such as caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone; a sedating or non- sedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine, phenylpropanolamine, or pseudoephedrine. The compounds of the present invention may also be used in conjunction with anti-emetics.
Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds ofthe invention. For example, anesthesiology (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized.
The present invention also provides a process for the preparation of a compound of formula (I), which process comprises:
(a) reacting a compound of formula (II) or a salt thereof:
Figure imgf000018_0001
(H) with a compound of formula (III) or a salt thereof:
Figure imgf000018_0002
in the presence of a suitable coupling agent such as O-(7-azabenzotriazol-1-yl)- Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexafluorophosphate (HATU), and a suitable base such as Λ/,Λ/-diisopropylethylamine (DIPEA); and/or
(b) converting the compound of formula (I) to a different compound of formula (I); and/or
(c) as appropriate, separating diastereomeric or enantiomeric mixtures of compounds of formula (I).
Compounds of formula (II) wherein R5 is not hydrogen can be prepared (as the sodium salt) as shown in Scheme 1 :
Scheme 1
Figure imgf000018_0003
PG is a protecting group such as lower alkyl. Burgess Reagent is (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt. The hydrazide starting material in Scheme 1 may be prepared from the corresponding ester by reaction with hydrazine. The esters used in the first reaction of Scheme 1 are either known compounds or may be prepared in accordance with known procedures or procedures described herein.
Compounds of formula (II) wherein R5 is hydrogen can be prepared (as the carboxylic acid or sodium salt) from a compound of formula (IV) as shown in Scheme 2:
Scheme 2
CO0PG o
Figure imgf000019_0001
Compounds of formula (IV) are commercially available and/or can be prepared using known methods and/or as exemplified below in the Descriptions and Examples. Compounds of formula (IV) in which R3 is dialkylamino or nitrogen-linked heterocyclyl can be prepared as shown in Scheme 3:
Scheme 3
Figure imgf000019_0002
Compounds of formula (I), (II) or (IV) in which R3 is bromine can be converted to corresponding compounds in which R3 is heteroaryl or phenyl by reaction (as an ester in the case of a compound of formula (II) or (IV)) with the corresponding arylboronic acid - e.g. phenylboronic acid - in the presence of a palladium catalyst.
Further interconversions of R3 from bromine to corresponding compounds in which R3 is heterocyclyl may be performed in accordance with Schemes 4 to 6 below. Scheme 4
Figure imgf000020_0001
D50
Scheme 5
Figure imgf000020_0002
D43 D44
Figure imgf000020_0003
Figure imgf000020_0004
See also D48 for introduction of CH2CF3 Scheme 6
Figure imgf000021_0001
D28
D57 D58
Figure imgf000021_0002
It will be appreciated that the bromine groups referred to above may be substituted for other halogen atoms (e.g. iodine or chlorine) or other suitable coupling partners such as triflate or tosylate. Alternatively, the coupling can be carried out with a boronic acid or boronate ester on the phenyl ring and a halogenated (or triflate, tosylate) derivative as part of R3:
Scheme 7
Figure imgf000021_0003
Compounds of formula (III) can be prepared as described in inter alia WO 04/092168. Certain compounds of formula (III) may also be prepared in accordance with analogous procedures to those described in WO 04/092168 or those described herein. Specific procedures for preparing certain compounds of formula (III) are described inter alia at WO2007016087, pp51-52, 55, and 57-58 respectively and in H. Takei et al., Chem. Pharm. Bulletin 1985, 33 (3), 1116-1128.
The invention is illustrated by the Examples described below.
In the procedures that follow, after each starting material, reference to a description is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to. Compounds of the invention are named using ACD/Name PRO Vn 6.02 or Vn 9 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).
LC/Mass spectra were obtained using an Agilent 1100 series HPLC system coupled with a Waters ZQ Mass Spectrometer. LC analysis was performed on a Waters Atlantis column (50 x 4.6 mm, 3μm) (mobile phase: 97% [water +0.05% HCO2H]/ 3% [CH3CN +0.05% HCO2H] for 0.1 min, then a gradient to 3% [water +0.05% HCO2H]/97% [CH3CN +0.05% HCO2H] over 3.9 min, and then held under these conditions for 0.8 min); temperature = 30 0C; flow rate = 3 mL/min; Mass spectra were collected using electrospray and/or APCI. The UV detection range is from 220 to 330nm. Alternatively a 2 minute generic LC/MS method may be employed using a Waters Acquity system coupled with a Waters ZQ Mass Spectrometer. LC analysis was performed on a Waters Acquity BEH UPLC C18 (50 x 2.1 mm, 1.7μm) (mobile phase: 97% [water +0.05% HCO2H]/ 3% [CH3CN +0.05% HCO2H] for 0.1 min, then a gradient to 3% [water +0.05% HCO2H]/97% [CH3CN +0.05% HCO2H] over 1.4 min, and then held under these conditions for 0.4 min); temperature = 40 0C; flow rate = 1 mL/min.
Proton Magnetic Resonance (NMR) spectra were recorded on a Bruker instrument at 250 or 400 MHz. Chemical shifts are reported in ppm (δ) using tetramethylsilane as internal standard. Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The NMR spectra were recorded at a temperature ranging from 25 to 9O0C. When more than one conformer was detected the chemical shifts for the most abundant one are reported.
Chromatography was carried out on silica gel cartridges either on a Flashmaster Il (Argonaut), Biotage Horizon or a Biotage SP4 automated chromatography system and an appropriate elution solvent system. Where indicated a free base was isolated from a salt using a Varian SCX cartridge.
Mass Directed Automated Preparative (MDAP) HPLC instruments consist of the following: Waters 2525 Binary Gradient Module, Waters 515 Makeup Pump, Waters Pump Control Module, Waters 2767 Inject Collect, Waters Column Fluidics Manager, Waters 2996 Photodiode Array Detector, Waters ZQ Mass Spectrometer, Gilson 202 fraction collector, Gilson Aspec waste collector. Column: Waters Atlantis, dimensions are 19mm x 100mm (<100mg scale) and 30mm x 100mm (>100mg scale), particle size is 5μm. Solvents, A : Aqueous solvent = Water + 0.1 % Formic Acid B : Organic solvent = Acetonitrile + 0.1 % Formic Acid. Gradients range from 5-30%B in A to 80-99%B in A, depending on HPLC retention time, run time = 13.5 minutes. Flow rate = 20ml/min (<100mg scale), 40ml/min (>100mg scale) Table of Examples
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
The methods A-N are exemplified hereinbelow for certain Examples, and may be varied with respect to routine parameters such as time, temperature, workup conditions, etc. The detailed conditions described hereinabove for carrying out LCMS, NMR, chromatography and MDAP can, similarly, be varied with respect to routine parameters.
Description 1 3-Chloro-5-(4-morpholinyl)benzonitrile (D1)
Figure imgf000038_0002
A solution of 3-chloro-5-fluorobenzonitrile (1.0 g, 6.4 mmol) in dimethyl sulfoxide (20 ml.) was stirred at room temperature under an atmosphere of argon. Potassium carbonate (1.33 g, 9.6 mmol) and then morpholine (1.12 ml_, 12.8 mmol) were added. The reaction mixture was heated at 800C under an atmosphere of argon overnight. The reaction mixture was cooled to room temperature, filtered to remove the solid potassium carbonate and then acidified to pH 5 using 1 M hydrochloric acid. No precipitate formed and so the product was applied to 2 x 10 g SCX cartridges (pre-wetted with methanol). The product did not stick to the cartridges and was washed through with the methanol. The product containing fractions were combined and concentrated under reduced pressure. The product (in dimethyl sulfoxide) was partitioned between diethyl ether and water, and a white precipitate formed. More water was added to encourage precipitation. The title compound, a white solid, was collected by filtration and air dried under low vacuum.
LC/MS (ES+ve): [M+H]+ at m/z 223, 225 (CH H11 CIN2O requires [M+H]+ at m/z 223, 225).
A variation of this procedure was used to prepare 3-methyl-5-(4- morpholinyl)benzonitrile (a precursor to Example 20) wherein 3-fluoro-5- methylbenzonitrile was reacted with morpholine under similar conditions with the exception that after initial heating at 800C for 4 hours, and then microwave heating at 1500C for half an hour, the mixture was heated at 100°C for 2 days.
Description 2
3-Chloro-5-(4-morpholinyl)b
Figure imgf000039_0001
A solution of 3-chloro-5-(4-morpholinyl)benzonitrile (D1 , 1.35 g, 6.06 mmol) and sodium hydroxide (2N) (20 ml_, 40.42 mmol) in ethanol (10 ml.) was heated at reflux under an atmosphere of argon overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 5-6 using 2M hydrochloric acid. This was then extracted twice with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid.
LC/MS (ES+ve): [M+H]+ at m/z 242, 244 (C11H12CINO3 requires [M+H]+ at m/z 242, 244).
Description 3
Ethyl 3-chloro-5-(4-morphol
Figure imgf000039_0002
A solution of 3-chloro-5-(4-morpholinyl)benzoic acid (D2, 0.95 g, 3.93 mmol) and concentrated sulfuric acid (0.74 ml.) in ethanol (9 ml.) was heated at reflux for 4 hours under an atmosphere of argon. The reaction mixture was left to cool to room temperature overnight, was adjusted to pH 7 by the addition of 1 M sodium carbonate and was then partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate. The combined organics were washed with aqueous saturated sodium bicarbonate, water and then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a clear oil which solidified on standing to give the title compound as a white solid.
LC/MS (ES+ve): [M+H]+ at m/z 270, 272 (Ci3H16CINO3 requires [M+H]+ at m/z 270,
272).
Description 4 3-Chloro-5-(4-morpholinyl)b
Hydrazine hydrate (1.56 ml_, 50.1 mmol) was added to a stirred solution of ethyl 3- chloro-5-(4-morpholinyl)benzoate (D3, 0.45 g, 1.67 mmol) in ethanol (4 ml_). The reaction mixture was heated at reflux under an atmosphere of argon for 4 hours. The reaction mixture was concentrated under reduced pressure (with care) and azeotroped with ethanol to leave the title compound as an off-white solid that was used without further purification. (The waste solvent was quenched with acetone before disposal).
LC/MS (ES+ve): [M+H]+ at m/z 256, 258 (C11H14CIN3O2 requires [M+H]+ at m/z 256, 258).
Description 5
Ethyl 3-(2-{[3-chloro-5-(4-morpholinyl)phenyl]carbonyl}hydrazino)-3- oxopropanoate (D5)
Figure imgf000040_0002
A solution of 3-chloro-5-(4-morpholinyl)benzohydrazide (D4, 0.38 g, 1.49 mmol) and ethylmalonyl chloride (0.19 ml_, 1.49 mmol) in tetrahydrofuran (3 ml.) was stirred at room temperature under an atmosphere of argon for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound as a gummy solid that was used without further purification.
LC/MS (ES+ve): [M+H]+ at m/z 370, 372 (C16H20CIN3O5 requires [M+H]+ at m/z 370, 372).
Description 6
Ethyl {5-[3-chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetate (D6)
Figure imgf000041_0001
A suspension of ethyl 3-(2-{[3-chloro-5-(4-morpholinyl)phenyl]carbonyl}hydrazino)-3- oxopropanoate (D5, 0.76 g, 2.06 mmol) and
(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (Burgess reagent) (0.91 g, 3.80 mmol) in dichloromethane (5 ml.) was heated at 1000C in the microwave at high absorption for 10 minutes. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was then washed with dichloromethane and the combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil which was used without further purification.
LC/MS (ES+ve): [M+H]+ at m/z 352, 354 (Ci6H18CIN3O4 requires [M+H]+ at m/z 352, 354).
Description 7 {5-[3-Chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetic acid (D7)
Figure imgf000041_0002
A solution of ethyl {5-[3-chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetate (D6, 0.40 g, 1.14 mmol) and sodium hydroxide (2N) (1.14 ml_, 2.28 mmol) in ethanol (6 ml.) was stirred at room temperature under an atmosphere of argon for 20 minutes. The reaction mixture was diluted with a few drops of water to aid solubility and was applied directly to a 20 g PE-AX cartridge (pre-wetted with methanol). The cartridge was washed with methanol and the acid product was eluted with 10% acetic acid/methanol. The product containing fractions were combined and concentrated under reduced pressure and then azeotroped with toluene/methanol to give the title compound as an oil that was used without further purification. LC/MS (ES+ve): [M+H]+ at m/z 324, 326 (Ci4H14CIN3O4 requires [M+H]+ at m/z 324, 326).
Description 8
3-(4-Morpholinyl)-5-(trifluoromethyl)benzonitrile (D8)
Figure imgf000042_0001
A mixture of 3-fluoro-5-trifluoromethylbenzonitrile (1.5 g, 7.93 mmol), morpholine (1.382 g, 15.86 mmol) and potassium carbonate (1.644 g, 11.9 mmol) in dimethylsulfoxide (15 ml.) were heated at 80°C for 1.5 days. Water (100 ml.) was added to the reaction mixture and the product was extracted with diethyl ether twice. The diethyl ether extract was concentrated to give the product as a creamy solid. LC/MS (ES+ve): [M+H]+ at m/z 257 (C12H11F3N2O requires [M+H]+ at m/z 257).
Description 9 3-(4-Morpholinyl)-5-(trifluorom (D9)
Figure imgf000042_0002
A mixture of 3-(4-morpholinyl)-5-(trifluoromethyl)benzonitrile (D8, 2.1 1 g, 8.23 mmol) and sodium hydroxide (2M, 27.5 ml_, 54.9 mmol) in ethanol (10 ml.) was heated at reflux for 1 day. The reaction mixture was concentrated and the residue was dissolved in water and washed with ethyl acetate. The water layer was acidified with 2M hydrochloric acid and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated to give the title compound as a solid. LC/MS (ES+ve): [M+H]+ at m/z 276 (C12H12F3NO3 requires [M+H]+ at m/z 276).
Description 10
Ethyl 3-(2-{[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]carbonyl}hydrazino)-3- oxopropanoate (D10)
Figure imgf000042_0003
A mixture of 3-(4-morpholinyl)-5-(trifluoromethyl)benzoic acid (D9, 400 mg, 1.453 mmol), ethyl 3-hydrazino-3-oxopropanoate (212 mg, 1.453 mmol), N-ethyl-N'-(3- dimethylaminopropyl)carbodiimide hydrochloride (334 mg, 1.744 mmol), 1- hydroxybenzotriazole (245 mg, 1.599 mmol) and N-methylmorpholine (294 mg, 2.91 mmol) in N,N-dimethylformamide (5 ml.) was stirred at room temperature for 1 day. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with water, saturated sodium bicarbonate and water. The ethyl acetate layer was concentrated to give the title compound which was used without further purification. LC/MS (ES+ve): [M+H]+ at m/z 404 (Ci7H20F3N3O5 requires [M+H]+ at m/z 404).
Description 11
Ethyl {5-[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2- yl}acetate (D11)
Figure imgf000043_0001
A mixture of ethyl 3-(2-{[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]carbonyl} hydrazino)-3-oxopropanoate (D10, 710 mg, 1.408 mmol) and Burgess reagent (587 mg, 2.464 mmol) in 1 ,2-dichloroethane (5 ml.) was heated in a microwave at 1200C for 10 minutes. The reaction mixture was concentrated and the residue purified by chromatography (Biotage SP4, gradient elution with 0% to 50% ethyl acetate in hexane, over 15 column volumes of solvent). The appropriate fractions were combined and concentrated to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 386 (C17H18F3N3O4 requires [M+H]+ at m/z 386).
Description 12
{5-[3-(4-Morpholinyl)-5-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}acetic acid
Figure imgf000043_0002
A mixture of ethyl {5-[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetate (D1 1 , 170 mg, 0.441 mmol), sodium hydroxide (2M, 0.441 ml_, 0.882 mmol) in ethanol (5 ml.) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was dissolved in water. The solution was acidified with 2M hydrochloric acid and the product was extracted with ethyl acetate. The ethyl acetate extract was concentrated to give the title compound as a white solid.
LC/MS (ES+ve): [M+H]+ at m/z 358 (C15H14F3N3O4 requires [M+H]+ at m/z 358).
Description 13 Ethyl 3-{2-[(3,5-dichlorophenyl)carbonyl]hydrazino}-2-(methyloxy)-3- oxopropanoate (D13)
Figure imgf000044_0001
A solution of diethyl 2-methoxymalonate (1.1 1 ml_, 8.0 mmol) in ethanol (10 ml.) was treated with a solution of potassium hydroxide (448 mg, 8 mmol) in water (10 ml.) and the mixture stirred at room temperature for 2 hours. About 70% of the solvent was evaporated at 200C. The mixture was then diluted with ethyl acetate and acidified with 2N hydrochloric acid. The aqueous was further extracted (x2) then dried over magnesium sulfate, filtered, evaporated, azeotroped with toluene and dried under high vacuum to give 3-(ethyloxy)-2-(methyloxy)-3-oxopropanoic acid.
3-(Ethyloxy)-2-(methyloxy)-3-oxopropanoic acid (assumed 8 mmol) and N, N- diisopropylethylamine (4.33 ml_, 24.8 mmol) in dichloromethane (60 ml.) was treated with O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexafluorophosphate (3.35 g, 8.8 mmol), then 3,5-dichlorobenzohydrazide (1.24 g, 8.8 mmol) and the mixture stirred at room temperature overnight. The mixture was then washed with water (x3), dried with magnesium sulfate, filtered and evaporated to dryness. The residue was purified by Biotage chromatography using a gradient of 30-70% ethyl acetate/hexane to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 349, 351 (Ci3H14CI2N2O5 requires [M+H]+ at m/z 349, 351 ).
Description 14
Ethyl [5-(3,5-dichloroph yloxy)acetate (D14)
Figure imgf000044_0002
A mixture of ethyl 3-{2-[(3,5-dichlorophenyl)carbonyl]hydrazino}-2-(methyloxy)-3- oxopropanoate (D13, 509 mg, 1.458 mmol), Burgess reagent (695 mg, 2.92 mmol) and 1 ,2-dichloroethane (3 ml.) was heated in the microwave at 1200C for 20 minutes.
The mixture was transferred to a separating funnel and washed with water (x3), dried
(magnesium sulfate), filtered and evaporated. The residue was purified by chromatography using a 25+M Biotage cartridge, eluting with gradient of 0-60% ethyl acetate/hexane to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 331 , 333, 335 (Ci3H12CI2N2O4 requires [M+H]+ at m/z
331 , 333, 335).
Description 15
[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl](methyloxy)acetic acid, sodium salt (D15)
Figure imgf000045_0001
To a solution of ethyl [5-(3,5-dichlorophenyl)-1 ,3,4-oxadiazol-2-yl](methyloxy)acetate (D14, 349 mg, 1.054 mmol) in ethanol (10 ml.) was added sodium hydroxide, 2M solution (0.527 ml_, 1.054 mmol). The mixture was stirred at room temperature for 2 hours and then evaporated and azeotroped with toluene to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 303, 305, 307 (C11H8CI2N2O4 requires [M+H]+ at m/z 303, 305, 307 for the parent acid).
Description 16 Ethyl δ-chloro-S-biphenylca
Figure imgf000045_0002
A solution of ethyl 3-bromo-5-chlorobenzoate (prepared from commercially available 3-bromo-5-chlorobenzoic acid by a method analogous to Description 3) (0.3 g, 1.14 mmol), phenylboronic acid (0.28 g, 2.28 mmol), dichloro(bistriphenylphosphine)palladium (II) (0.040 g, 0.057 mmol) and sodium carbonate (0.24 g, 2.28 mmol) in 1 ,2-dimethoxyethane (3 ml.) and water (1 ml.) was heated at 1000C with stirring in a microwave for 20 minutes. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a dark brown oil. Purification by column chromatography on a Biotage SP4, 25M column, with a gradient of 0-40% ethyl acetate in hexane gave the title compound as a clear oil. LC/MS (ES+ve): [M+H]+ at m/z 261 , 263 (C15H13CIO2 requires [M+H]+ at m/z 261 , 263).
The intermediate D16 is a precursor to Example 7.
Description 17 3-Chloro-5-(4-methyl-1 -piperazinyl)benzonitrile (D17)
Figure imgf000045_0003
3-Chloro-5-fluorobenzonitrile (0.50 g, 3.21 mmol) in dimethyl sulfoxide (10 ml.) was stirred at room temperature under an atmosphere of argon (following a similar method to that of WO200670195). Potassium carbonate (0.67 g, 4.82 mmol) and then 1-methylpiperidine (0.71 ml_, 6.42 mmol) were added. The reaction mixture was heated at 80 0C overnight. The reaction mixture was cooled to room temperature and diethyl ether (5 ml.) was added. A white precipitate formed which was filtered off. The filtrate was acidified using 1 M hydrochloric acid to pH 5. The white precipitate was filtered. Further product precipitated out in the filtrate and was collected. This was repeated twice to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 236, 238 (Ci2H14CIN3 requires [M+H]+ at m/z 236, 238).
Description 18
3-Chloro-5-(4-methyl-1 -pipe sodium salt (D18)
Figure imgf000046_0001
A solution of 3-chloro-5-(4-methyl-1-piperazinyl)benzonitrile (D17, 0.71 g, 3.01 mmol) and sodium hydroxide (2N, 10 ml_, 20 mmol) in ethanol (5 ml.) was heated at reflux under an atmosphere of argon for 2.5 hours. The reaction mixture was then concentrated under reduced pressure to give the crude title compound as a yellow oil which was used without further purification.
LC/MS (ES+ve): [M+H]+ at m/z 255, 257 (C12H15CIN2O2 requires [M+H]+ at m/z 255, 257 for the parent acid).
Description 19 Ethyl 3-chloro-5-(4-methyl-1 -piperazinyl)benzoate (D19)
Figure imgf000046_0002
3-Chloro-5-(4-methyl-1-piperazinyl)benzoic acid, sodium salt, (D18, 0.83 g, 3.0 mmol) was stirred in ethanol (8 ml.) under an atmosphere of argon. The sodium salt was insoluble at room temperature. Concentrated sulfuric acid (0.57 ml.) was added and the reaction mixture was heated at reflux for 2 days. The starting material slowly became more soluble as further concentrated sulfuric acid (3x0.57 ml.) was added over the course of 2 days. An off-white precipitate was left at the end of the reaction. The reaction mixture was cooled to room temperature overnight and adjusted to pH 7-8 with 1 M sodium carbonate (white precipitate formed). The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate, water and then brine, dried over magnesium sulfate and then concentrated under reduced pressure to give the title compound as a clear oil. LC/MS (ES+ve): [M+H]+ at m/z 283, 285 (Ci4H19CIN2O2 requires [M+H]+ at m/z 283, 285).
Description 20
3-Chloro-5-(4-methyl-1 -piperazinyl)benzohydrazide (D20)
Figure imgf000047_0001
Hydrazine hydrate (1.06 ml_, 33.95 mmol) was added to a stirred solution of ethyl 3- chloro-5-(4-methyl-1-piperazinyl)benzoate (D19, 0.32 g, 1.13 mmol) in ethanol (2.5 ml_). The reaction mixture was heated at reflux under an atmosphere of argon for 4 hours. The reaction mixture was concentrated under reduced pressure (with care) and azeotroped with ethanol to leave the title compound an off-white solid which was used without further purification. (The waste solvent was quenched with acetone before disposal). LC/MS (ES+ve): [M+H]+ at m/z 269, 271 (C12H17CIN4O requires [M+H]+ at m/z 269, 271 ).
Description 21
Ethyl 3-(2-{[3-chloro-5-(4-methyl-1-piperazinyl)phenyl]carbonyl}hydrazino)-3- oxopropanoate (D21)
Figure imgf000047_0002
A solution of 3-chloro-5-(4-methyl-1-piperazinyl)benzohydrazide (D20, 0.29 g, 1.08 mmol) and ethyl malonyl chloride (0.14 ml_, 1.08 mmol) in tetrahydrofuran (2 ml.) was stirred at room temperature under an atmosphere of argon for 30 minutes. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound as an off-white solid. LC/MS (ES+ve): [M+H]+ at m/z 383, 385 (Ci7H23CIN4O4 requires [M+H]+ at m/z 383, 385).
Description 22 Ethyl {5-[3-chloro-5-(4-methyl-1 -piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetate
Figure imgf000048_0001
A suspension of ethyl 3-(2-{[3-chloro-5-(4-methyl-1- piperazinyl)phenyl]carbonyl}hydrazino)-3-oxopropanoate (D21 , 0.58 g, 1.51 mmol) and Burgess reagent (0.67 g, 2.80 mmol) in dichloromethane (5 ml.) was heated at 100 0C in the microwave at high absorption for 10 minutes. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was then washed with dichloromethane and the combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a dark yellow oil.
LC/MS (ES+ve): [M+H]+ at m/z 365, 367 (Ci7H2i CIN4O3 requires [M+H]+ at m/z 365, 367).
Description 23 {5-[3-Chloro-5-(4-methyl-1 -piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetic acid
Figure imgf000048_0002
Sodium hydroxide (1.37 ml_, 2.74 mmol) was added to a stirred solution of ethyl {5- [3-chloro-5-(4-methyl-1-piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetate (D22, 0.50 g, 1.37 mmol) in ethanol (7 ml_). The reaction mixture was stirred at room temperature under an atmosphere of argon for 20 minutes. The reaction mixture was diluted with a few drops of water to aid solubility, and was applied to a 20 g PE-AX cartridge (pre- wetted with methanol). The cartridge was washed with methanol and the acid product was eluted using 10% acetic acid/methanol. The product containing fractions were combined and concentrated under reduced pressure and then azeotroped with toluene/methanol to give the title compound as a yellow oil. LC/MS (ES+ve): [M+H]+ at m/z 337, 339 (with additional peaks at 338, 340 and 341 ) (Ci5H17CIN4O3 requires [M+H]+ at m/z 337, 339). Description 24
Ethyl 3-{2-[(3-bromo-5-chlorophenyl)carbonyl]hydrazino}-3-oxopropanoate
Figure imgf000049_0001
3-Bromo-5-chlorobenzoic acid (5 g, 21.23 mmol) and Λ/,Λ/-diisopropylethylamine (11.13 ml_, 63.7 mmol ) were stirred in dimethylformamide (20 ml.) at room temperature for 10 minutes. O-(7-azabenzotriazol-1-yl)-Λ/, N,N',N',- tetramethyluroniumhexafluorophosphate (9.69 g, 25.5 mmol) and ethyl 3-hydrazino- 3-oxopropanoate (3.72 g, 25.5 mmol) were added. The reaction was stirred at room temperature for 45 minutes and was then partitioned between dichloromethane and water. After further extraction with dichloromethane (x2) the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound which was used without further purification. LC/MS (ES+ve): [M+H]+ at m/z cluster containing 363, 365, 367 (Ci2H12BrCIN2O4 requires [M+H]+ at m/z 363, 365, 367).
Description 25
Ethyl [5-(3-bromo-5-chlor ]acetate (D25)
Figure imgf000049_0002
Ethyl 3-{2-[(3-bromo-5-chlorophenyl)carbonyl]hydrazino}-3-oxopropanoate (D24, 13 g, 35.8 mmol) was suspended in dichloromethane (45 ml_). Burgess reagent (8.52 g, 35.8 mmol) was added. The reaction mixture was split into 3 portions and stirred for 20 minutes each at 100 0C in the microwave. All 3 reactions were then combined and partitioned between dichloromethane and water, and further extracted with dichloromethane (x2). The organic layer was washed with water (x2), dried over magnesium sulfate and concentrated under reduced pressure. Material insoluble in methanol was removed by filtration. The filtrate was concentrated and purified by column chromatography, eluting with ethyl acetate/iso-hexane (0-100% ethyl acetate over 18 column volumes). Product containing fractions were evaporated and dried under high vacuum to leave the title compound as a thick yellow liquid. 1H NMR δ (MeOH-d4): 1.29 (3H, t), 4.24 (2H, q), 4.87 (assumed 2H, overlapping with water signal), 7.87 (1 H, m), 8.04 (1 H, m), 8.14 (1 H, m).
Description 26
Ethyl {5-[3-chloro-5-(5-pyrimidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetate (D26)
Figure imgf000050_0001
To a suspension of ethyl [5-(3-bromo-5-chlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetate (D25, 300 mg, 0.868 mmol) in 1 ,2-dimethoxyethane (3 ml.) was added 5-pyrimidinyl boronic acid (108 mg, 0.868 mmol), sodium carbonate (92 mg, 0.868 mmol), bis(triphenylphosphine)palladium(ll) chloride (60.9 mg, 0.087 mmol) and water (1 ml_). The reaction was stirred in the microwave for 20 minutes at 100 0C. LCMS showed incomplete reaction so a further 1 equivalent of boronic acid and 0.1 equivalent of bis(triphenylphosphine)palladium(ll) chloride were added and the reaction stirred for another 20 minutes at 100 0C in the microwave. The reaction mixture was passed over a hydromatrix cartridge, washing with dichloromethane. The residue after evaporation was purified using column chromatography, eluting with ethyl acetate in iso-hexane (0-10% 5 column volumes, 10-25% 5 column volumes, 25-50% 3 column volumes, 100% 3 column volumes) to give the title compound as a pale brown film after removal of solvents. LC/MS (ES+ve): [M+H]+ at m/z 345, 347 (Ci6H13CIN4O3 requires [M+H]+ at m/z 345, 347).
Description 27
{5-[3-Chloro-5-(5-pyrimidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetic acid (D27)
Figure imgf000050_0002
Ethyl {5-[3-chloro-5-(5-pyrimidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetate (D26, 230 mg,
0.667 mmol) was stirred in ethanol (10 ml.) and 0.5M lithium hydroxide (1.334 ml_,
0.667 mmol) for 30 minutes at room temperature. Solvents were removed in vacuo. The mixture was passed over a PE-AX cartridge, washing with methanol then 10% acetic acid in methanol. Acidic fractions were combined and concentrated, azeotroping with toluene to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 317, 319 (Ci4H9CIN4O3 requires [M+H]+ at m/z 317,
319).
Description 28
Ethyl 3-bromo-5-chlorobenzoate (D28)
Figure imgf000051_0001
3-Bromo-5-chlorobenzoic acid (3 g, 12.74 mmol) and sulfuric acid (6.79 ml_, 12.7 mmol) were stirred in ethanol (20 ml.) at reflux. After 1 hour the mixture was cooled to room temperature, basified with saturated sodium bicarbonate solution and extracted (x3) with ethyl acetate. The organics were dried over magnesium sulfate and concentrated under reduced pressure to give the title compound. 1H NMR δ (MeOH-d4): 1.39 (3H, t), 4.38 (2H, q), 7.82 (1 H, m), 7.92 (1 H, m), 8.03 (1 H, m).
Description 29
3-Bromo-5-chlorobenzohydrazide (D29)
Figure imgf000051_0002
Ethyl 3-bromo-5-chlorobenzoate (D28, 2.8 g, 10.63 mmol) was dissolved in ethanol (20 ml.) at room temperature. Hydrazine hydrate (10.34 ml_, 213 mmol) was added and the reaction was stirred at 800C overnight. Solvents were removed in vacuo and then azeotroped with toluene to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 249, 251 , 253 (C7H6BrCIN2O requires [M+H]+ at m/z 249, 251 , 253)
Description 30
Ethyl 3-{2-[(3-bromo-5-chlorophenyl)carbonyl]hydrazino}-3-oxopropanoate
Figure imgf000051_0003
3-Bromo-5-chlorobenzohydrazide (D29, 2.5 g, 10.02 mmol) was dissolved in tetrahydrofuran (10 ml.) at room temperature. Ethyl malonyl chloride (1.283 g, 10.02 mmol) was added and the reaction stirred at room temperature for 20 minutes.
Solvents were removed in vacuo to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 363, 365, 367 (C12H12BrCIN2O4 requires [M+H]+ at m/z 363, 365, 367)
Alternative preparation of D30:
To a stirring solution of 3-bromo-5-chlorobenzoic acid (10 g, 42.5 mmol) in N, N- dimethylformamide (212 ml.) was added N-methylmorpholine (9.34 ml_, 85 mmol), N- ethyl-Λ/'-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.21 g, 63.7 mmol), 1- hydroxybenzotriazole (6.50 g, 42.5 mmol) and ethyl 3-hydrazino-3-oxopropanoate (6.21 g, 42.5 mmol). The reaction was stirred at room temperature under argon for 4 hours, then concentrated in vacuo and partitioned between water and dichloromethane. Solids were filtered off, and the filtrate collected. The aqueous layer was washed with further dichloromethane. The organic layers were combined, washed well with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography (Biotage SP4, 4OM column, 0-10% 2M ammonia in methanol in dichloromethane over 10 column volumes) gave the title compound after combining relevant fractions and concentrating in vacuo. LC/MS (ES+ve): [M+H]+ at m/z 363, 365, 367 (Ci2H12BrCIN2O4 requires [M+H]+ at m/z 363, 365, 367)
Description 31
Ethyl [5-(3-bromo-5-chlo acetate (D31)
Figure imgf000052_0001
Ethyl 3-{2-[(3-bromo-5-chlorophenyl)carbonyl]hydrazino}-3-oxopropanoate (D30, 4 g,
11.0 mmol) was split into 2x2g reactions.
Ethyl 3-{2-[(3-bromo-5-chlorophenyl)carbonyl]hydrazino}-3-oxopropanoate (D30, 2 g,
5.50 mmol) and Burgess reagent (1.311 g, 5.50 mmol) were stirred in dichloromethane (10 ml.) for 20 minutes at 1000C in the microwave. The reaction mixtures were combined, water was added and extracted with dichloromethane (x2).
The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The mixture was purified by column chromatography, eluting with
0-50% ethyl acetate in hexane to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 345, 347, 349 (Ci2H10BrCIN2O3 requires [M+H]+ at m/z 345, 347, 349).
Description 32
1,1 -Dimethylethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)- pyridinecarboxylate (D32)
Figure imgf000052_0002
To a solution of diisopropylamine (0.858 ml_, 6.02 mmol) in tetrahydrofuran (20.99 ml.) at -78 0C was added n-butyl lithium (3.76 ml_, 6.02 mmol). The reaction mixture was stirred for 5 minutes at -78 0C. A solution of 1 ,1-dimethylethyl 4-oxo-1- piperidinecarboxylate (1 g, 5.02 mmol) in tetrahydrofuran (6.00 mL) was added, and the reaction mixture was stirred for 10 minutes. Then a solution of 1 ,1 ,1 -trifluoro-N- phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (1.972 g, 5.52 mmol) in tetrahydrofuran (2 mL) was added. The reaction mixture was stirred at -78 0C for 30 minutes and the cooling bath was removed to allow warming to room temperature for 1.5 hours, until no more starting material remained. The reaction was quenched with saturated sodium bicarbonate solution and left to stand overnight. The mixture was then extracted with diethyl ether and 5% citric acid and the organic layer washed with 1 M sodium hydroxide solution, water and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SP4 Biotage, 25M, 0-20% ethyl acetate/hexane), and relevant fractions combined and concentrated in vacuo to give the title compound. 1H NMR δ (DMSOd6): 1.41 (9H, s), 2.41 (2H, m), 3.54 (2H, m), 3.98 (2H, m), 6.02 (1 H, app s).
Description 33
1,1 -Dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-
1(2H)-pyridinecarboxylate (D33)
Figure imgf000053_0001
1 ,1-Dimethylethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1 (2H)- pyridinecarboxylate (D32, 990 mg, 2.99 mmol), bis(pinacolato)diboron (835 mg, 3.29 mmol), potassium acetate (880 mg, 8.96 mmol), 1 ,1 '- bis(diphenylphosphino)ferrocene (49.7 mg, 0.090 mmol) and 1 ,1 'bis(diphenylphosphino)ferrocenedichloropalladium(ll) (73.2 mg, 0.090 mmol) were suspended in 1 ,4-dioxane (14.9 mL) and stirred at 8O0C for 18 hours. The mixture was cooled to room temperature and concentrated. Ethyl acetate was added, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (SP4 Biotage, 25M, 0-10% ethyl acetate in hexane over 10 column volumes, collecting all fractions). Relevant fractions were combined and concentrated in vacuo to give the title compound. 1H NMR δ (CDCI3): 1.26 (12H, m), 1.46 (9H, s), 2.22 (2H, app br s), 3.44 (2H, m), 3.95 (2H, m), 6.46 (1 H, app br s).
Description 34
1,1 -Dimethylethyl 4-(3-chloro-5-{5-[2-(ethyloxy)-2-oxoethyl]-1,3,4-oxadiazol-2- yl}phenyl)-3,6-dihydro-1 (2H)-pyridinecarboxylate (D34)
Figure imgf000054_0001
1 ,1-Dimethylethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-1 (2H)- pyridinecarboxylate (D33, 230 mg, 0.745 mmol), ethyl [5-(3-bromo-5-chlorophenyl)- 1 ,3,4-oxadiazol-2-yl]acetate (D31 , 234 mg, 0.677 mmol), sodium carbonate (79 mg, 0.745 mmol) and bis(triphenylphosphine)palladium(ll) dichloride (47.5 mg, 0.068 mmol) were heated together in 1 ,2-dimethoxyethane (3.386 ml.) and water (1.129 ml.) in the microwave at 100 0C for 20 minutes at normal absorption. The mixture was partitioned between ethyl acetate and water and the organic layer separated. The aqueous layer was washed with more ethyl acetate, and the organics combined, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SP4 Biotage, 12M, 0-50% ethyl acetate/hexane over 10 column volumes). Relevant fractions were combined and concentrated in vacuo to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 448, 450 (C22H26CIN3O5 requires [M+H]+ at m/z 448, 450)
Description 35
{5-[3-Chloro-5-(1 -{[(1 ,1 -dimethylethyl)oxy]carbonyl}-1 ,2,3,6-tetrahydro-4- pyridinyl)phenyl]-1 salt (D35)
Figure imgf000054_0002
To a stirring solution of 1 ,1-dimethylethyl 4-(3-chloro-5-{5-[2-(ethyloxy)-2-oxoethyl]-
1 ,3,4-oxadiazol-2-yl}phenyl)-3,6-dihydro-1 (2H)-pyridinecarboxylate (D34, 1.23 g, 2.75 mmol) in tetrahydrofuran (9.15 ml.) was added 0.5M lithium hydroxide (5.49 ml_, 2.75 mmol). The reaction was stirred at room temperature for 2 hours, concentrated in vacuo, azeotroped with toluene, and dried under high vacuum for 2 hours to give the title compound.
1H NMR δ (MeOH-d4): 1.50 (9H, m), 2.57 (2H, m), 3.65 (2H, m), 3.86 (2H, s), 4.1 1 (2H, br s), 6.30 (1 H, br s), 7.66 (1 H, m), 7.94 (1 H, m), 8.04 (1 H, m). Description 36 Ethyl 3-(2-{[3-chloro-5-(3-{[(1,1 -dimethylethyl)(dimethyl)silyl]oxy}-1- pyrrolidinyl)phenyl]carbonyl}hydrazino)-3-oxopropanoate (D36)
Figure imgf000055_0001
Chloro(1 ,1-dimethylethyl)climethylsilane (0.326 g, 2.163 mmol) and imidazole (0.147 g, 2.163 mmol) were added to a stirred solution of ethyl 3-(2-{[3-chloro-5-(3-hydroxy- 1-pyrrolidinyl)phenyl]carbonyl}hydrazino)-3-oxopropanoate (0.32 g, 0.865 mmol) in acetonitrile (8 ml_). The reaction mixture was stirred overnight at room temperature under an atmosphere of argon. Diethyl ether (10 ml.) was added, followed by 2N hydrochloric acid (4 ml.) and the reaction mixture was stirred for a few minutes. Sodium hydroxide (2N, 10 ml.) was then added and the layers were separated. The organic layer formed a precipitate which was collected by filtration. The pale yellow solid was dried under suction to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 484, 486 (C22H34CIN3O5Si requires [M+H]+ at m/z 484, 486).
D36 was taken forward by standard methods described herein to afford E71 (see Method J)
Description 37
4-Bromo-1,2-dimethyl-1 H-imidazole (D37a) and 5-bromo-1,2-dimethyl-1H- imidazole (D37b)
Figure imgf000055_0002
To a solution of 4-bromo-2-methyl-1 H-imidazole (2 g, 12.42 mmol) in N, N- dimethylformamide (10 ml.) was added potassium carbonate (3.78 g, 27.3 mmol) followed by methyl iodide (0.928 ml_, 14.91 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between dichloromethane and water and the layers separated. The aqueous layer was extracted with dichloromethane (x2) and the organic layers were combined and concentrated, azeotroping with toluene to give a mixture of the title compounds. 1H NMR δ (MeOH-d4): Major isomer: 2.31 (3H, s), 3.58 (3H, s), 6.97 (1 H, s). Minor isomer: 2.38 (3H, s), 3.55 (3H, s), 6.82 (1 H, s). Description 38
Methyl 3-chloro-5-(1,2-dimethyl-1 H-imidazol-4-yl)benzoate (D38a) and methyl 3- chloro-5-(1 ,2-dimethyl-1 H-imidazol-5-yl)benzoate (D38b)
Figure imgf000056_0001
A mixture of {3-chloro-5-[(methyloxy)carbonyl]phenyl}boronic acid (1.703 g, 7.94 mmol), 4-bromo-1 ,2-dimethyl-1 H-imidazole (D37a, 1.1 12 g, 6.35 mmol) and 5- bromo-1 ,2-dimethyl-1 H-imidazole (D37b, 222 mg, 1.271 mmol) as an isomeric mixture, sodium carbonate (1.347 g, 12.71 mmol) and bis(triphenylphosphine)palladium(ll) dichloride (446 mg, 0.635 mmol) in toluene (10 ml.) and ethanol (1 ml.) was stirred under reflux overnight. The reaction mixture was partitioned between dichloromethane and water and the layers separated. The aqueous layer was extracted with dichloromethane (x2) and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was acidified and purified using SCX chromatography, eluting with methanol then 2N ammonia in methanol. The basic fractions were combined and concentrated to leave the crude mixture of title compounds which was used without further purification. LC/MS (ES+ve): [M+H]+ 265, 267 (Ci3H13CIN2O2 requires [M+H]+ 265, 267)
Description 39
3-Chloro-5-(1,2-dimethyl-1H-imidazol-4-yl)benzohydrazide (D39a) and 3-chloro- 5-(1 ,2-dimethyl-1 H-imidazol-5-yl)benzohy
Figure imgf000056_0003
Figure imgf000056_0002
To a solution of methyl 3-chloro-5-(1 ,2-dimethyl-1 H-imidazol-4-yl)benzoate (D38a, 1.17g, 4.42 mmol) and methyl 3-chloro-5-(1 ,2-dimethyl-1 H-imidazol-5-yl)benzoate (D38b, 0.1 17 g, 0.442 mmol) in ethanol (10 ml.) was added hydrazine hydrate (13.87 ml_, 442 mmol). The reaction was stirred at 800C overnight. The solvents were removed in vacuo, azeotroping with toluene, to leave the mixture of title compounds. LC/MS (ES+ve): [M+H]+ 265, 267 (C12H13CIN4O requires [M+H]+ 265, 267).
Description 40
Ethyl 3-(2-{[3-chloro-5-(1 ,2-dimethyl-1 H-imidazol-4- yl)phenyl]carbonyl}hydrazino)-3-oxopropanoate (D40a) and ethyl 3-(2-{[3-chloro-5-(1 ,2-dimethyl-1H-imidazol-5- yl)ph ropanoate (D40b)
Figure imgf000057_0001
Figure imgf000057_0002
To a solution of 3-chloro-5-(1 ,2-dimethyl-1 H-imidazol-4-yl)benzohydrazide (D39a, 1.17 g, 4.42 mmol) and 3-chloro-5-(1 ,2-dimethyl-1 H-imidazol-5-yl)benzohydrazide (D39b, 0.176 g, 0.663 mmol) in tetrahydrofuran (5 ml.) was added ethyl 3-chloro-3- oxopropanoate (1.947 ml_, 15.47 mmol). The reaction was stirred at room temperature for 2 hours. The solvents were removed in vacuo and then the residue was purified using column chromatography, eluting with 0-20% 2N ammonia in methanol in dichloromethane to give separately the title compounds D40a and D40b. LC/MS (ES+ve): [M+H]+ 379, 381 (Ci7H19CIN4O4 requires [M+H]+ 379, 381 ) for both sets of fractions containing separately D40a and D40b.
Description 41 Ethyl {5-[3-chloro-5-(1 ,2-dimethyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetate (D41)
Figure imgf000057_0003
A solution of ethyl 3-(2-{[3-chloro-5-(1 ,2-dimethyl-1 H-imidazol-4- yl)phenyl]carbonyl}hydrazino)-3-oxopropanoate (D40a, 480mg, 1.267 mmol) and Burgess reagent (604 mg, 2.53 mmol) in dichloromethane (5 ml.) was stirred for 20 minutes at 1000C in the microwave. To the reaction mixture was added further
Burgess reagent (604 mg, 2.53 mmol) and the reaction stirred for a further 20 minutes at 100 0C in the microwave.
The reaction mixture was transferred directly to a silica column and purified by column chromatography, eluting with 0-20% 2N ammonia in methanol in dichloromethane to give the title compound.
LC/MS (ES+ve): [M+H]+ 361 , 363 (Ci7H17CIN4O3 requires [M+H]+ 361 , 363).
D41 was converted by standard methods described herein to Examples 43 and 55.
Similarly D40b was separately converted to the isomeric ester ethyl {5-[3-chloro-5- (1 ,2-dimethyl-1 H-imidazol-5-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetate which was then converted via standard methods described herein to Examples 42 and 46. Description 42
Ethyl 3-chloro-5-(1H-imidazol-
Figure imgf000058_0001
To a stirring suspension of ethyl 3-bromo-5-chlorobenzoate (D28, 1.25 g, 4.74 mmol) in N-methyl-2-pyrrolidone (23.72 ml.) at room temperature under argon was added imidazole (0.420 g, 6.17 mmol), followed by potassium carbonate (0.852 g, 6.17 mmol), 2,4-pentanedione (0.122 ml_, 1.186 mmol) and copper (I) chloride (0.047 g, 0.474 mmol). The reaction was then heated at 130 0C under argon overnight then cooled to room temperature. Ethyl acetate and water were added, organics extracted x2, combined and washed well with brine and water, dried over magnesium sulfate and then concentrated in vacuo. The mixture was purified by chromatography (SP4 Biotage, 50 g snap cartridge, 50-100% ethyl acetate in hexane over 10 column volumes). Relevant fractions were combined and concentrated in vacuo to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 251 , 253 (C12H11CIN2O2 requires [M+H]+ at m/z 251 , 253).
D42 was taken forward by standard methods described herein to afford E45
Description 43
1,1 -Dimethylethyl 4-{3-chloro-5-[(ethyloxy)carbonyl]phenyl}-3,6-dihydro-1(2H)- pyridinecarboxylate (D43)
Figure imgf000058_0002
The reaction was split into two reaction vessels. [1 ,1 - Bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (0.638 g, 0.782 mmol) and sodium carbonate (1.823 g, 17.20 mmol) were added to a solution of ethyl 3-bromo-5-chlorobenzoate (D28, 4.12 g, 15.63 mmol) and 1 ,1- dimethylethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-1 (2H)- pyridinecarboxylate (D33, 5.32 g, 17.20 mmol) in 1 ,4-dioxane (25 ml.) and water (5 ml_). The reaction mixture was subjected to microwave conditions (100°C for 20 minutes). The reaction mixture was returned to the microwave for a further 20 minutes at 12O0C. The mixture was then partitioned between ethyl acetate (100 ml.) and water (150 ml_). The layers were separated and the aqueous mixture further extracted with ethyl acetate (2 x 75 ml_). The organic extracts were combined and washed with brine before being dried (magnesium sulfate) and evaporated in vacuo to a dark brown oil. The oil was purified by chromatography (Biotage SP4, 40+M silica cartridge) eluting with an isohexane: ethyl acetate gradient (0-50% ethyl acetate over 50 minutes). Product containing fractions were combined and evaporated in vacuo to give the title compound as a golden yellow oil. LC/MS (ES+ve): [M-Boc+H]+ at m/z 266, 268 (Ci9H24CINO4 requires [M+H]+ at m/z 366, 368).
Description 44 1,1 -Dimethylethyl 4-{3-chloro-5-[(ethyloxy)carbonyl]phenyl}-1 - piperidinecarboxylate (D44)
Figure imgf000059_0001
Platinum (IV) oxide (0.137 g, 0.601 mmol) was added to a solution of 1 ,1- dimethylethyl 4-{3-chloro-5-[(ethyloxy)carbonyl]phenyl}-3,6-dihydro-1 (2H)- pyridinecarboxylate (D43, 1.1 g, 3.01 mmol) in tetrahydrofuran (40 ml_). The resulting mixture was subjected to hydrogenation conditions (room temperature and pressure) for 3 hours. A further 150 mg of catalyst was added to the reaction mixture which was subsequently stirred over the weekend. The reaction mixture was filtered to remove catalyst before being concentrated in vacuo to give the title compound as a colourless oil.
1H NMR δ (CDCI3): 1.41 (3H, t), 1.49 (9H, s), 1.58 (2H, m), 1.82 (2H, br d), 2.69 (1 H, m), 2.80 (2H, br m), 4.25 (2H, app br s), 4.38 (2H, q), 7.38 (1 H, m), 7.77 (1 H, m), 7.86 (1 H, m).
Description 45
Ethyl 3-chloro-5-(4-piperidinyl
Figure imgf000059_0002
Trifluoroacetic acid (7.68 ml_, 100 mmol) was cautiously added to a solution of 1 ,1- dimethylethyl 4-{3-chloro-5-[(ethyloxy)carbonyl]phenyl}-1 -piperidinecarboxylate (D44, 1.223g, 3.32 mmol) in dichloromethane (8 ml_). The resulting solution was stirred for 2 hours and then the reaction mixture was diluted with ethanol and cautiously added to a 20 g SCX cartridge preconditioned with ethanol. The cartridge was washed with several column volumes of ethanol before the basic material was eluted with 2M ammonia in methanol. The basic fractions were combined and evaporated in vacuo to give the title compound as an oil.
LC/MS (ES+ve): [M+H]+ at m/z 268, 270 (Ci4H18CINO2 requires [M+H]+ at m/z 268, 270).
Description 46
Ethyl 3-chloro-5-[1 -(2,2-difluoroethyl)-4-piperidinyl]benzoate (D46)
Figure imgf000060_0001
Potassium carbonate (1.203 g, 8.71 mmol) and 2-bromo-1 ,1-difluoroethane (841 mg, 5.80 mmol) were added to a solution of ethyl 3-chloro-5-(4-piperidinyl)benzoate (D45, 777mg, 2.90 mmol) in acetonitrile (12 ml_). The resulting mixture was subjected to microwave conditions (2.5 hours at 12O0C). The reaction was returned to the microwave for a further 2.5 hours at 12O0C and then the reaction mixture was subsequently diluted with methanol and loaded onto a 20 g preconditioned SCX cartridge. The cartridge was washed with several column volumes of methanol before the basic material was eluted with 2M ammonia in methanol. The basic fractions were combined and evaporated to give a pale brown oil. The oil was then purified by chromatography (Biotage SP4, 25+M silica cartridge) eluting with an isohexane:ethyl acetate gradient (0-50% ethyl acetate over 35 minutes). Product containing fractions, were combined and evaporated to give the title compound as a colourless oil containing in addition the corresponding methyl ester. LC/MS (ES+ve): [M+H]+ at m/z 332, 334 (C16H20CIF2NO2 requires [M+H]+ at m/z 332, 334).
Example 49 is prepared from D46 by standard methods described herein.
Description 47
Ethyl 3-chloro-5-[1 -(2,2,2-trifluoroethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]benzoate
Figure imgf000060_0002
Ethyl 3-chloro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)benzoate (979 mg, 3.68 mmol) [prepared from D43 by reaction with trifluoracetic acid in dichloromethane followed by conversion to the free base by elution from an SCX column with 2M ammonia in methanol] was suspended in acetone (19.6 ml_), potassium carbonate (611 mg, 4.42 mmol) added, followed by 2,2,2-trifluoroethyl trichloromethanesulfonate (1.037 g, 3.68 mmol). The reaction was stirred at room temperature under argon overnight and then partitioned between ethyl acetate and water/brine. The aqueous layer was re- extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The mixture was purified by chromatography (SP4 Biotage, 50 g, 0-30% ethyl acetate/hexane over 10 column volumes). Relevant fractions were combined and concentrated in vacuo to give the title compound which was taken forward without additional purification.
LC/MS (ES+ve): [M+H]+ at m/z 348, 350 (Ci6H17CIF3NO2 requires [M+H]+ at m/z 348, 350).
D47 is taken forward by standard methods described herein to afford E60 and E63.
Description 48
Ethyl 3-chloro-5-[1 -(2,2,2-trifluoroethyl)-4-piperidinyl]benzoate (D48)
Figure imgf000061_0001
Ethyl 3-chloro-5-(4-piperidinyl)benzoate (D45, 1.08 g, 4.03 mmol) was suspended in acetone (19.6 ml_), then potassium carbonate (0.669 g, 4.84 mmol) added, followed by 2,2,2-trifluoroethyl trichloromethanesulfonate (1.135 g, 4.03 mmol). The reaction was stirred at room temperature under argon overnight then partitioned between ethyl acetate and water/brine. The aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The mixture was purified by chromatography (SP4 Biotage, 50 g, 0-30% ethyl acetate/hexane over 10 column volumes). Relevant fractions were combined and concentrated in vacuo to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 350, 352 (C16H19CIF3NO2 requires [M+H]+ at m/z 350, 352).
D48 was taken forward by standard methods described herein to afford E66.
Description 49 3-Chloro-5-(dimethylamino)benzonitrile (D49)
Figure imgf000062_0001
3-Chloro-5-fluorobenzonitrile (600 mg, 3.86 mmol), dimethylamine hydrochloride (629 mg, 7.71 mmol) and potassium carbonate (1.866 g, 13.50 mmol) were added together in dimethyl sulfoxide (12 ml.) and the resulting mixture heated in the microwave at 100 0C for 2 hours at high absorption. The reaction mixture was filtered and the filtrate diluted with water and extracted with diethyl ether (x 3). The diethyl ether layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by Biotage column chromatography eluting with 1 :9 ethyl acetate/iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid. LC/MS (ES+ve): [M+H]+ at m/z 181 , 183 (C9H9CIN2 requires [M+H]+ at m/z 181 , 183).
D49 was taken forward by standard methods described herein to afford E29.
Description 50
Ethyl 3-(methyloxy)-5-(4-morpholinyl)benzoate (D50)
Figure imgf000062_0002
Ethyl 3-bromo-5-(methyloxy)benzoate (500 mg, 1.930 mmol), morpholine (0.252 ml_, 2.89 mmol), cesium carbonate (1.006 g, 3.09 mmol), xantphos (67.0 mg, 0.116 mmol) and tris (dibenzylideneacetone) dipalladium (0) (35.3 mg, 0.039 mmol) were added together in 1 ,4-dioxane (5 ml.) and the resulting mixture was heated under reflux under argon for 4 hours. The reaction mixture was allowed to cool to room temperature, filtered and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-50 % ethyl acetate/iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil. LC/MS (ES+ve): [M+H]+ at m/z 266 (C14H19NO4 requires [M+H]+ at m/z 266).
D50 was taken forward by standard methods described herein to afford E31.
Description 51 3-Fluoro-5-(4-morpholinyl)benzonitrile (D51)
Figure imgf000063_0001
3,5-Difluorobenzonitrile (1 g, 7.19 mmol), morpholine (1.253 g, 14.38 mmol) and potassium carbonate (1.490 g, 10.78 mmol) were heated at 8O0C in dimethyl sulfoxide (10 ml.) for 2 days. Water (50 ml.) was added to the reaction mixture and the product was extracted with diethyl ether (x2). The diethyl ether layer was concentrated to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 207 (C11H11FN2O requires [M+H]+ at m/z 207).
D51 was taken forward by standard methods described herein to afford E35.
Description 52 3-Chloro-5-iodobenzoic acid (D
Figure imgf000063_0002
Water (20 ml.) was added to methyl 3-chloro-5-iodobenzoate (5 g, 16.86 mmol) and lithium hydroxide monohydrate (1.769 g, 42.2 mmol) in tetrahydrofuran (183 ml.) and the solution was stirred for ca. 1 hour at room temperature. The volume was reduced by ca. 50% and water was then added and the pH adjusted to about 4. The product was extracted into ethyl acetate (x3), the organics combined, washed with brine, dried over magnesium sulfate and then concentrated in vacuo to give the title compound. 1H NMR δ (DMSOd6): 7.89 (1 H, dd), 8.12 (1 H, t), 8.16 (1 H, t), 13.6 (1 H, br s).
Description 53 1,1 -Dimethylethyl 3-chloro- )
Figure imgf000063_0003
3-Chloro-5-iodobenzoic acid (D52, 4.72 g, 16.71 mmol) in dichloromethane (16.71 ml.) was added to a stirring solution of 1 ,1-dimethylethyl 2,2,2-trichloroethanimidoate (7.30 g, 33.4 mmol) in toluene (33.4 ml.) at room temperature under argon. Boron trifluoride etherate (0.334 ml_, 2.64 mmol) was then added to the mixture and left to stir for 18 hours. 1 ,1-Dimethylethyl 2,2,2-trichloroethanimidoate (7.30 g, 33.4 mmol) was added and the solution allowed to stir for another 6 hours. Solid sodium bicarbonate was added to the reaction mixture which was then filtered through silica and eluted with dichloromethane. The crude material (10.6 g) was then purified by flash chromatography (eluting with dichloromethane) to afford the title compound as a white solid.
1H NMR δ (DMSOd6): 1.54 (9H, s), 7.85 (1 H, dd), 8.1 1-8.13 (2H, m)
Description 54
1,1 -Dimethylethyl 3-chloro-5-(2,4-dimethyl-1H-imidazol-1-yl)benzoate (D54)
Figure imgf000064_0001
Copper oxide (0.045 g, 0.316 mmol), 4,7-bis(methyloxy)-1 ,10-phenanthroline (0.228 g, 0.948 mmol), polyethylene glycol (1.248 g, 11.76 mmol), cesium carbonate (2.88 g, 8.84 mmol), 2,4-dimethyl-1 H-imidazole (0.729 g, 7.58 mmol) and 1 ,1-dimethylethyl
3-chloro-5-iodobenzoate (D53, 2.139 g, 6.32 mmol) were transferred into a dried round-bottomed flask vial and capped with a rubber septum. The flask was then evacuated and backfilled with argon - this process was repeated several times. Butyronitrile (3.12 ml.) was then added and the mixture was stirred at 80 0C overnight during which time the reaction had evaporated to dryness. Further butyronitrile (3.12 ml.) was added and the mixture stirred at 80 0C over the weekend.
The mixture was diluted with dichloromethane and then filtered through celite. The filtrate was concentrated in vacuo and the resulting crude material (2.8 g) was purified by flash chromatography with a gradient of 0 - 100% ethyl acetate in hexane to afford the title compound as a white solid.
LC/MS (ES+ve): [M+H]+ at m/z 307, 309 (C16H19CIN2O2 requires [M+H]+ at m/z 307, 309)
Description 55
3-Chloro-5-(2,4-dimethyl-1 nzoic acid (D55)
Figure imgf000064_0002
1 ,1-Dimethylethyl 3-chloro-5-(2,4-dimethyl-1 H-imidazol-1-yl)benzoate (D54, 396 mg, 1.291 mmol) in hydrochloric acid (4M in 1 ,4-dioxane, 10 ml_, 40 mmol) was stirred at room temperature for 6 hours. Hydrochloric acid (4M in 1 ,4-dioxane, 3 ml_, 12 mmol) was added and left overnight. The mixture was concentrated in vacuo to give a white solid which was then triturated with diethyl ether to afford the title compound as a white solid. LC/MS (ES+ve): [M+H]+ at m/z 251 , 253 (C12H11CIN2O2 requires [M+H]+ at m/z 251 , 253).
Description 56
Methyl 3-chloro-5-(2,4-dimethyl-1H-imidazol-1-yl)benzoate (D56)
Figure imgf000065_0001
3-Chloro-5-(2,4-dimethyl-1 H-imidazol-1-yl)benzoic acid (D55, 56 mg, 0.223 mmol) and concentrated sulphuric acid (0.3 ml_, 1.2 mmol) in methanol (3 ml.) was refluxed at 70 0C overnight. Methanol was evaporated and then half-saturated sodium bicarbonate was added until the pH reached about 7. Product was extracted into ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a white solid.
LC/MS (ES+ve): [M+H]+ at m/z 265, 267 (Ci3H13CIN2O2 requires [M+H]+ at m/z 265, 267).
D56 was converted through standard methods described herein to Example 67.
Description 57
Ethyl 3-chloro-5-[(1 E)-3-(ethyloxy)-3-oxo-1 -propen-1 -yl]benzoate (D57)
Figure imgf000065_0002
The reaction was split between 4 vessels. To a vial containing ethyl 3-bromo-5- chlorobenzoate (D28, 9.25 g, 35.1 mmol) in N,N-dimethylformamide (40 ml.) was added ethyl 2-propenoate (4.20 ml_, 38.6 mmol), triethylamine (5.38 ml_, 38.6 mmol), tri-ortho-tolylphosphine (1.603 g, 5.27 mmol) and palladium acetate (0.394 g, 1.755 mmol). The reactions were heated in the microwave for 3.5 hours each at 14O0C, high absorption. The mixture was partitioned between ethyl acetate and water and the aqueous layer re-extracted with ethyl acetate. The organics were combined, washed well with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SP4 Biotage, 0- 20% ethyl acetate in hexane over 15 column volumes, 4OM cartridge), relevant fractions combined, and concentrated in vacuo to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 283, 285 (Ci4H15CIO4 requires [M+H]+ at m/z 283, 285).
Description 58 Ethyl 3-chloro-5-[3-(ethyloxy)-1 -(nitromethyl)-3-oxopropyl]benzoate (D58)
Figure imgf000066_0001
To a solution of ethyl 3-chloro-5-[(1 E)-3-(ethyloxy)-3-oxo-1-propen-1-yl]benzoate (D57, 9.29 g, 32.9 mmol) in nitromethane (8.86 mL, 164 mmol) and acetonitrile (46.9 mL) (to aid solubility) at O0C under argon was added 1 ,8-diazabicyclo[5.4.0]undec-7- ene (4.95 mL, 32.9 mmol) dropwise. The reaction was stirred at O0C for 10 minutes, before being allowed to warm to room temperature and stirred at room temperature overnight. Ethyl acetate and 1 M hydrochloric acid were added, organics extracted x2, combined and washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. Purified by chromatography (SP4 Biotage, 4OM, 0-30% ethyl acetate in hexane over 20 column volumes). Relevant fractions were combined and concentrated in vacuo to give the title compound.
LC/MS (ES+ve): [M-OEt]+ at m/z 298, 300 (Ci5H18CINO6 requires [M+H]+ at m/z 344, 346).
Description 59
Ethyl 3-chloro-5-(5-oxo-3-pyrrolidinyl)benzoate (D59)
Figure imgf000066_0002
A solution of ethyl 3-chloro-5-[3-(ethyloxy)-1-(nitromethyl)-3-oxopropyl]benzoate (D58, 6.11 g, 17.77 mmol) and zinc (9.30 g, 142 mmol) in acetic acid (120 mL) and ethanol (120 mL) was heated at 750C under argon over 3 nights. The reaction mixture was then cooled to room temperature, filtered through celite and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organics were washed with 2N hydrochloric acid, water, saturated sodium bicarbonate solution, water and then brine, dried over magnesium sulfate and then concentrated in vacuo to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 268, 270 (Ci3H14CINO3 requires [M+H]+ at m/z 268, 270).
Description 60
Ethyl 3-chloro-5-(3-pyrrolidinyl)benzoate (D60)
Figure imgf000067_0001
To a stirring solution of ethyl 3-chloro-5-(5-oxo-3-pyrrolidinyl)benzoate (D59, 3.93 g, 14.68 mmol) in tetrahydrofuran (73.4 mL) at O0C was added borane tetrahydrofuran complex (24.96 mL, 24.96 mmol) dropwise. The reaction was then heated at 7O0C overnight. 2M Hydrochloric acid (10 mL) was added and refluxed for 2 hours then cooled to room temperature. Methanol was added and then passed down an SCX cartridge (3x20 g). The cartridge was washed well with methanol and eluted with 2M ammonia in methanol. Basic fractions were combined and concentrated in vacuo to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 254, 256 (Ci3H16CINO2 requires [M+H]+ at m/z 254, 256).
Description 61
Ethyl 3-chloro-5-[1-(2,2-difluoroethyl)-3-pyrrolidinyl]benzoate (D61)
Figure imgf000067_0002
Ethyl 3-chloro-5-(3-pyrrolidinyl)benzoate (D60, 696 mg, 2.74 mmol), 1 ,1-difluoro-2- iodoethane (579 mg, 3.02 mmol), and potassium carbonate (1.251 g, 9.05 mmol) were heated in the microwave in acetonitrile (10.5 mL) at 1200C for 1 hour, normal absorption.
A further portion of of alkylating agent (200 mg) was added and re-heated in the microwave at 12O0C for 1 hour then partitioned between ethyl acetate and water. The aqueous was re-extracted with ethyl acetate. Organics were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purified by chromatography (SP4 Biotage, 0-30% ethyl acetate in hexane over 10 column volumes, 25M). Relevant fractions were combined and concentrated in vacuo to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 318, 320 (C15H18CIF2NO2 requires [M+H]+ at m/z 318, 320)
D61 was taken forward by standard methods described herein to afford E58.
Description 62 Ethyl 4-{[3-(methyloxy)-2-nitrophenyl]amino}-1 -piperidinecarboxylate (D62)
Figure imgf000068_0001
1-Fluoro-3-(methyloxy)-2-nitrobenzene (25.81 g, 0.151 mol) was combined with ethyl 4-amino-1 -piperidinecarboxylate (29.78 g, 0.166 mol) with potassium iodide (0.25 g, 1.51 mmol) in N,N-dimethylformamide (239 ml.) and the mixture heated at
14O0C for 6 hours. The mixture was left to stand over the weekend and then diluted with ethyl acetate (478 ml.) and water (478 ml.) and washed with water (2x478 ml_).
After drying over sodium sulfate and evaporation to dryness a dark oil was obtained.
After purification by column chromatography (5-15% ethyl acetate in dichloromethane) the title compound was obtained as a red oil.
Description 63
Ethyl 4-{[2-amino-3-(methyloxy)phenyl]amino}-1 -piperidinecarboxylate (D63)
Figure imgf000068_0002
Ethyl 4-{[3-(methyloxy)-2-nitrophenyl]amino}-1 -piperidinecarboxylate (D62, 20 g, 0.062 mol) in methanol (500 ml.) with 5% palladium on charcoal (2.1 g) was hydrogenated at room temperature and 200 psi in an autoclave with stirring for 2.5 hours. The resulting suspension was filtered through a pad of celite and the filtrate evaporated under reduced pressure to give the title compound as a dark brown solid which was used without further purification. After combining with another batch the mixture gave m. p. 1 14-1160C.
Description 64 Ethyl 4-[4-(methyloxy)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1 - piperidinecarboxylate (D64)
Figure imgf000068_0003
A solution of ethyl 4-{[2-amino-3-(methyloxy)phenyl]amino}-1 -piperidinecarboxylate (D63, 23.4 g, 0.073 mol) and 1 ,1 '-carbonyldiimidazole (17.8 g, 0.11 mol) in acetonitrile (250 ml.) was stirred at room temperature for 48 hours. The resulting precipitate was collected by filtration and dried in vacuo to give the title compound as a colourless solid, m.p. 197-1980C. Description 65
4-(Methyloxy)-1 -(4-piperidinyl zimidazol-2-one (D65)
Figure imgf000069_0001
Ethyl 4-[4-(methyloxy)-2-oxo-2,3-dihydro-1 H-benzimidazol-1 -yl]-1 - piperidinecarboxylate (D64, 4.4 g, 13.8 mmol), was added to a solution of sodium hydroxide (3.4 g, 84.1 mmol) in water (40 ml.) and the resulting solution stirred for 20 hours at 100°C. The solution was allowed to cool and then 6M hydrochloric acid (ca. 17 ml.) was added until pH 7 was obtained. The solution was then concentrated under reduced pressure and the resulting solution was suspended in water (20 ml_). The pH was adjusted to ca 8.7 using 1 M sodium hydroxide (2 ml.) and the precipitate collected by filtration and washed with ice cold water (5 ml.) and ether (5 ml_). The title compound was obtained as a brown solid after drying. LC/MS (ES+ve): [M+H]+ at m/z 248 (C13H17N3O2 requires [M+H]+ at m/z 248).
D65 was taken forward by standard methods described herein to afford E30.
Method A Example 1
1 -[1 -({5-[3-Chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one (E1)
Figure imgf000069_0002
A solution of {5-[3-chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetic acid (D7, 0.080 g, 0.25 mmol), 1-(4-piperidinyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2- one (prepared from the dihydrochloride, see for example WO2007016087, by applying an aqueous solution to an SCX cartridge and eluting with 2M ammonia in methanol) (0.059 g, 0.27 mmol), O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',/V- tetramethyluroniumhexafluorophosphate (0.10 g, 0.27 mmol) and N, N- diisopropylethylamine (0.047 ml_, 0.27 mmol) in N,N-dimethylformamide (3 ml.) was stirred at room temperature under an atmosphere of argon overnight. The reaction mixture was concentrated under reduced pressure and purified by MDAP. The product containing fractions were combined and concentrated under reduced pressure to give the title compound as an off-white solid which was dried overnight at 400C under vacuum. LC/MS (ES+ve): [M+H]+ at m/z 524, 526 (C25H26CIN7O4 requires [M+H]+ at m/z 524, 526). 1H NMR δ (DMSO-de): 1.72-1.85 (2H, m), 2.05-2.18 (1 H, m), 2.31-2.40 (1 H, m), 2.72- 2.80 (1 H, m), 3.25 (4H, br s), 3.30-3.40 (1 H + water signal, br s), 3.75 (4H, br s), 4.05-4.11 (1 H, m), 4.30-4.59 (4H, m), 6.98-7.00 (1 H, m), 7.25 (1 H, br s), 7.46 (1 H, br s), 7.50 (1 H, br s), 7.60-7.65 (1 H, m), 7.90-7.94 (1 H, m), 11.55-11.60 (NH, br s).
Alternatively N-methylpyrrolidinone may be used as a solvent instead of N, N- dimethylformamide; 1-hydroxyaza-7-azabenzotriazole may be used in conjunction with O-(7-azabenzotriazol-1 -yl)-Λ/, Λ/,Λ/',Λ/',-tetramethyluroniumhexafluorophosphate as in Example 32.
Other Examples designated Method A were prepared similarly. In the case of Example 12 after a 2 hour reaction time the product was obtained after concentrating the reaction mixture and trituration with methanol.
Method B Example 2
1 -[1 -({5-[3-(4-Morpholinyl)-5-(trifluoromethyl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one (E2)
Figure imgf000070_0001
A mixture of {5-[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetic acid (D12, 165 mg, 0.44 mmol), 1-(4-piperidinyl)-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (106 mg, 0.484 mmol), O-(7-azabenzotriazol-1-yl)- Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexafluorophosphate (184 mg, 0.484 mg), and N, N- diisopropylethylamine (85 uL, 0.484 mmol) in N,N-dimethylformamide (5 ml.) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and was washed with water. The ethyl acetate layer was concentrated and the residue was purified by chromatography (Biotage SP4, gradient of 0% to 10% methanol in dichloromethane over a total of 30 column volumes). Appropriate fractions were combined and concentrated to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 558 (C26H26F3N7O4 requires [M+H]+ at m/z 558). 1H NMR δ (DMSO-d6): 1.70-1.87 (2H, m), 2.04-2.20 (1 H, m), 2.31-2.47 (1 H, m, partially overlapping with dmso signal at 2.5), 2.70-2.83 (1 H, m), 3.20-3.40 (assumed 5H, m, overlapped by water signal), 3.69-3.83 (4H, m), 4.01-4.16 (1 H, m), 4.30-4.60 (4H, overlapping m), 6.93-7.02 (1 H, m), 7.47 (1 H, s), 7.58 (1 H, s), 7.60-7.67 (1 H, m), 7.70 (1 H, s), 7.87-7.95 (1 H, m), 11.58 (1 H, s).
Other Examples designated Method B were prepared similarly. In the case of Example 22 the aqueous work-up was not necessary as the product was obtained as a solid from the reaction mixture and was collected by filtration, then washed with diethyl ether, methanol and water and dried.
Method C
Example 3
1 -{1 -[[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl](methyloxy)acetyl]-4- piperidinyl}-1 ,3-di
Figure imgf000071_0001
To a solution of [5-(3,5-dichlorophenyl)-1 ,3,4-oxadiazol-2-yl](methyloxy)acetic acid sodium salt (D15, 100 mg, 0.307 mmol) in N,N-dimethylformamide (2 ml.) was added Λ/,Λ/-diisopropylethylamine (0.063 ml_, 0.363 mmol), followed by O-(J- azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexafluorophosphate (138 mg, 0.361 mmol) and 1-(4-piperidinyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (72 mg, 0.330 mmol). The mixture was stirred at room temperature for 3 hours and then diluted with ethyl acetate, washed with sodium bicarbonate and brine and evaporated. The residue was diluted with ethyl acetate, washed with sodium bicarbonate and brine and evaporated. The residue was purified using a 25+S Biotage cartridge, eluting with a gradient of 0-20% methanol/ethyl acetate, and then repurified by MDAP to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 503, 505, 507 (C22H20CI2N6O4 requires [M+H]+ at m/z 503, 505, 507).
1H NMR δ (DMSO-de): 1.81 (2H, m), 2.08-2.38 (2H, m), 2.84 (1 H, t), 3.17-32 (1 H, m partially overlapped by water signal), 3.47 (3H, d), 4.12 (1 H, br m), 4.49 (2H, br m), 5.94 (1 H, d), 6.97 (1 H, m), 7.54 (1 H, m), 7.90 (1 H, m), 7.98-8.01 (3H, m), 11.58 (1 H, br s).
Other Examples designated Method C were prepared similarly.
Method D Example 5
1 -[1 -({5-[3-Chloro-5-(4-methyl-1 -piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)- 4-piperidinyl]-1 ,3-dih (E5)
Figure imgf000071_0002
To a stirred solution of {5-[3-chloro-5-(4-methyl-1-piperazinyl)phenyl]-1 ,3,4-oxadiazol- 2-yl}acetic acid (obtainable by hydrolysis of D22, 0.15 g, 0.45 mmol) in N, N- dimethylformamide (5 mL) was added 1-(4-piperidinyl)-1 ,3-dihydro-2H-imidazo[4,5-b] pyridin-2-one (0.107 g, 0.49 mmol), O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',/V- tetramethyluroniumhexafluorophosphate (0.19 g, 0.49 mmol) and N, N- diisopropylethylamine (0.086 mL, 0.49 mmol). The reaction mixture was stirred at room temperature under an atmosphere of argon for 3 hours. LC/MS showed acid starting material present and so further 1-(4-piperidinyl)-1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one (0.107 g, 0.49 mmol), O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',/V- tetramethyluroniumhexafluorophosphate (0.19 g, 0.49 mmol) and N, N- diisopropylethylamine (0.086 mL, 0.49 mmol) were added and the reaction mixture was stirred overnight under an atmosphere of argon. The reaction mixture was concentrated under reduced pressure to give dark yellow oil. The crude product was purified by MDAP. The product containing fractions were combined and concentrated under reduced pressure to give a yellow oil. The title compound was transferred to a sample vial and dried at 40 0C under vacuum for 3 days. LC/MS (ES+ve): [M+H]+ at m/z 537, 539 (C26H29CIN8O3 requires [M+H]+ at m/z 537, 539).
1H NMR δ (DMSO-de): 1.68-1.88 (2H, m), 2.04-2.17 (1 H, m), 2.22 (3H, s), 2.30-2.48 (5H, overlapping m), 2.72-2.82 (1 H, m), 3.20-3.40 (assumed 5H, overlapped by water signal, br m), 4.02-4.12 (1 H, m), 4.30-4.58 (4H, overlapping m), 6.90-6.99 (1 H, m), 7.20-7.25 (1 H, m), 7.30-7.33 (1 H, m), 7.38-7.40 (1 H, m), 7.57-7.62 (1 H, m), 7.87- 7.90 (1 H, m), 1 1.25 (1 H, br s).
Other Examples designated Method D were prepared similarly. In Examples 27 and 28 a few drops of water were also added at the same time as the additional portions of O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexafluorophosphate, 1- (4-piperidinyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, and N, N- diisopropylethylamine.
Method E
Example 6
3-(1 -{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3,4,5- tetrahydro-2H-1 ,3-benzodiazepin-2-one (E6)
Figure imgf000072_0001
The free base of 3-(4-piperidinyl)-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one hydrochloride (WO 2007016087) was combined with O-(7-azabenzotriazol-1-yl)- Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexafluorophosphate (133 mg, 0.35 mmol), [5-(3,5- dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetic acid (prepared analogously to D7 starting from 3,5-dichlorobenzohydrazide) (86 mg, 0.32 mmol), and N, N- diisopropylethylamine (0.059 mL, 0.363 mmol) in N,N-dimethylformamide (2 mL) and stirred at room temperature or 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water 3 times. Dichloromethane and methanol were added to aid solubility of a white solid that had precipitated. The organic extractions were concentrated and the residue washed with water and the undissolved solid collected by filtration and purified by MDAP to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 500, 502, 504 (C24H23CI2N5O3 requires [M+H]+ at m/z 500, 502, 504).
1H NMR δ (DMSO-de): 1.52-1.73 (3H, m), 1.73-1.88 (1 H, m), 2.61-2.73 (1 H, m), 2.83- 2.93 (2H, m), 3.19 (1 H, t), 3.36-3.45 (2H, m partially overlapped by water signal), 3.97-4.07 (1 H, m), 4.26-4.40 (3H, m), 4.40-4.50 (1 H, m), 6.76-6.85 (1 H, m), 6.99- 7.08 (3H, m), 7.93-7.99 (3H, m), 8.53 (1 H, s).
Other Examples designated Method E were prepared similarly.
Method F Example 37
S-II -^S-IS-Chloro-S-tS-pyrimidinylJphenyll-I.S^-oxadiazol^-y^acetyl)^- piperidinyl]-1,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E37)
Figure imgf000073_0001
{5-[3-Chloro-5-(5-pyrimidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetic acid (D27, 100 mg,
0.316 mmol) was stirred in N,N-dimethylformamide (5 ml.) at room temperature. To this was added N-methylmorpholine (0.104 ml_, 0.947 mmol), 1-hydroxybenzotriazole
(53.2 mg, 0.347 mmol), Λ/-ethyl-Λ/'-(3-dimethylaminopropyl)carbodiimide hydrochloride (72.6 mg, 0.379 mmol) followed by 3-(4-piperidinyl)-1 ,3,4,5-tetrahydro-
2H-1 ,3-benzodiazepin-2-one (77 mg, 0.316 mmol). The reaction was stirred at room temperature overnight and then partitioned between dichloromethane and water.
Further extraction (x3) with dichloromethane. Organic layer washed with saturated sodium bicarbonate solution, water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using column chromatography to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 544, 546 (C28H26CIN7O3 requires [M+H]+ at m/z 544,
546).
1H NMR δ (DMSO-de): 1.52-1.73 (3H, m), 1.82 (1 H, m), 2.68 (1 H, m), 2.89 (2H, m), 3.20 (1 H, t), 3.40 (2H, m), 4.04 (1 H, m), 4.26 - 4.40 (3H, m), 4.47 (1 H, d), 6.81 (1 H, m), 7.04 (3H, m), 8.08 (1 H, app s), 8.23 (1 H, app s), 8.33 (1 H, app s), 8.53 (1 H, s),
9.27 (3H, overlapping s).
Similarly was prepared Example 38, also from {5-[3-chloro-5-(5-pyrimidinyl)phenyl]-
1 ,3,4-oxadiazol-2-yl}acetic acid (D27). Method G
Example 39
1,1 -Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3- benzodiazepin-3-yl)-1-piperidinyl]ethyl}-1,3,4-oxadiazol-2-yl)phenyl]-3,6- dihydro-1(2H
Figure imgf000074_0001
To a stirring solution of {5-[3-chloro-5-(1-{[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,6- tetrahydro-4-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetic acid lithium salt (D35, 1.07 g, 2.507 mmol) in N,N-dimethylformamide (12.54 mL) at room temperature under argon was added N-methylmorpholine (0.551 mL, 5.01 mmol), Λ/-ethyl-Λ/'-(3- dimethylaminopropyl)carbodiimide hydrochloride (1.202 g, 6.27 mmol), 1- hydroxybenzotriazole (0.384 g, 2.507 mmol) and 3-(4-piperidinyl)-1 ,3,4,5-tetrahydro- 2H-1 ,3-benzodiazepin-2-one (0.615 g, 2.507 mmol). The reaction was stirred at room temperature under argon overnight then concentrated in vacuo and purified by chromatography (Biotage SP4, 25M column, 0-20% 2M ammonia in methanol/ethyl acetate over 10 column volumes). Relevant fractions were combined and concentrated in vacuo, then further washed with water to remove residual N, N- dimethylformamide and dried in a vacuum oven overnight to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 647, 649 (C34H39CIN6O5 requires [M+H]+ at m/z 647, 649).
1H NMR δ (DMSO-de): 1.43 (9H, m), 1.52 - 1.70 (3H, overlapping m), 1.82 (1 H, m), 2.49-2.53 (3H, m overlapping with DMSO signal), 2.69 (1 H, m), 2.88 (2H, m), 3.21 (1 H, t), 3.39 (2H, m), 3.55 (2H, m), 4.03 (2H, m), 4.29 - 4.38 (3H, m), 4.46 (1 H, br d), 6.40 (1 H, br s), 6.81 (1 H, m), 7.04 (3H, m), 7.78 (1 H, m), 7.87 (1 H, m), 7.93 (1 H, m), 8.53 (1 H, s).
Other Examples designated Method G were prepared similarly. Example 41 used 1- hydroxy-7-azabenzotriazole, an aqueous work-up with ethyl acetate extraction, and MDAP purification. Other examples designated as method G may use an aqueous workup with dichloromethane or ethyl acetate extraction as appropriate (see Example 60 below).
Example 60 1 -{1 -[(5-{3-Chloro-5-[1 -(2,2,2-trifluoroethyl)-1 , 2,3,6 -tetra hydro -4- pyridinyl]phenyl}-1 ,3,4-oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2H- imidazo[4,5-ϋ]pyridin-2-one (E60)
Figure imgf000075_0001
To a stirring solution of (5-{3-chloro-5-[1-(2,2,2-trifluoroethyl)-1 ,2,3,6-tetrahydro-4- pyridinyl]phenyl}-1 ,3,4-oxadiazol-2-yl)acetic acid lithium salt (obtained from D47 analagously to D19-22 followed by hydrolysis) (231 mg, 0.565 mmol) in N, N- dimethylformamide (3 ml.) at room temperature under argon was added N- methylmorpholine (0.124 mL, 1.130 mmol), Λ/-ethyl-Λ/'-(3- dimethylaminopropyl)carbodiimide hydrochloride (271 mg, 1.413 mmol), 1- hydroxybenzotriazole (87 mg, 0.565 mmol) and 1-(4-piperidinyl)-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (123 mg, 0.565 mmol). The reaction was stirred at room temperature under argon overnight. Ethyl acetate and sodium bicarbonate were added, organics extracted (x2), combined and washed with brine. After drying over magnesium sulfate and concentration in vacuo the crude material was purified by chromatography (SP4 Biotage, 10 g snap, 0-10% methanolic ammonia in dichloromethane over 10 column volumes). Relevant fractions were combined, concentrated in vacuo and azeotroped with toluene. The residue was dried in a vacuum oven overnight and then further purified by chromatography (SP4 Biotage, 10 g snap, 0-12% methanolic ammonia in ethyl acetate over 12 column volumes). Relevant fractions were combined and concentrated in vacuo to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 602, 604 (C28H27CIF3N7O3 requires [M+H]+ at m/z 602, 604).
1H NMR δ (MeOH-d4): 1.93 (1 H, br t), 2.32 (1 H, m), 2.50 (1 H, m), 2.61 (2H, m), 2.89 (1 H, m), 2.99 (2H, m), 3.23 (2H, m), 3.37 (1 H, m overlapping with MeOH), 3.41 (3H, m), 4.24 (1 H, m), 4.31 (1 H, m), 4.42 (1 H, m), 4.60 (1 H, m), 4.77 (1 H, m), 6.30 (1 H, s), 7.05 (1 H, m), 7.63 (1 H, m), 7.68 (1 H, s), 7.95 (2H, m), 8.07 (1 H, s).
In the case of Example 67 an equivalent of 1 M hydrochloric acid in diethyl ether was added (to neutralise an extra equivalent of lithium hydroxide used in the previous hydrolysis step).
Example 21 may be prepared by method B (see Table) but also by method G as shown below:
Example 21 1 -[1 -({S-IS-Chloro-S-ftrifluoromethylJphenyll-i ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one (E21)
Figure imgf000076_0001
{5-[3-Chloro-5-(trifluoromethyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetic acid lithium salt (300 mg, 0.957 mmol) was dissolved in N,N-dimethylformamide (15 ml.) and N- methylmorpholine (0.210 ml_, 1.913 mmol), 1-hydroxybenzotriazole (176 mg, 1.148 mmol), Λ/-ethyl-Λ/'-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.052 mmol) were added. The mixture was stirred during 5 minutes before adding 1- (4-piperidinyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (219 mg, 1.005 mmol). Then the mixture was stirred at room temperature during 72 hours. The N, N- dimethylformamide was evaporated and then saturated sodium bicarbonate solution and dichloromethane were added. The two layers were separated with a phase separator. The solvent was evaporated. 1 :1 acetonitrile/dimethylsulfoxide (3.5 ml.) was added. Not all of the material dissolved so the solid was filtered and the filtrate purified by MDAP. The solid was dissolved in warm dimethylsulfoxide and purified by MDAP. Products were combined, washed with toluene, triturated with ether and dried to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 507, 509 (C22Hi8CIF3N6O3 requires [M+H]+ at m/z 507, 509).
1H NMR δ (DMSOd6): 1.79 (2H, app t), 2.12 (1 H, m), 2.39 (1 H, m), 2.78 (1 H, t), 3.23-3.43 (assumed 1 H, overlapped by water signal), 4.02 (1 H, m), 4.34-4.60 (4H, overlapping m), 6.99 (1 H, m), 7.64 (1 H, m), 7.91 (1 H, m), 8.21 (1 H, m), 8.32 (1 H, m), 11.58 (1 H, br s).
Example 43
3-[1 -({5-[3-Chloro-5-(1,2-dimethyl-1H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E43)
Figure imgf000076_0002
To a solution of {5-[3-chloro-5-(1 ,2-dimethyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4- oxadiazol-2-yl}acetic acid lithium salt (97 mg, 0.286 mmol) [prepared by hydrolysis of D41 with lithium hydroxide] in N,N-dimethylformamide (5 ml.) at room temperature was added Λ/-ethyl-Λ/'-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg, 0.628 mmol), 1-hydroxybenzotriazole (96 mg, 0.628 mmol), 3-(4-piperidinyl)-1 , 3,4,5- tetrahydro-2H-1 ,3-benzodiazepin-2-one (140 mg, 0.571 mmol) and N- methylmorpholine (0.094 ml_, 0.857 mmol) and the reaction was stirred at room temperature overnight.
The mixture was partitioned between dichloromethane and water and the layers separated. The aqueous layer was extracted with dichloromethane (x2) and the organic fractions were combined and dried (magnesium sulfate). The residue was purified using column chromatography, eluting with 0-20% 2M ammonia in methanol in dichloromethane. The title compound was obtained after drying under argon. LC/MS (ES+ve): [M+H]+ at m/z 560, 562 (C29H30CIN7O3 requires [M+H]+ at m/z 560, 562).
1H NMR δ (CDCI3): 1.65 (2H, m overlapping with water), 1.88 (2H, m), 2.44 (3H, s), 2.71 (1 H, t), 2.96 (2H, m), 3.30 (1 H, t), 3.42 (2H, m), 3.63 (3H, s), 4.02 - 4.18 (3H, overlapping m), 4.52 (1 H, m), 4.76 (1 H, d), 6.37 (1 H, s), 6.68 (1 H, d), 6.91 (1 H, m), 7.03 - 7.11 (2H, overlapping m), 7.22 (1 H, s overlapping with CHCI3), 7.88 (1 H, m), 7.93 (1 H, m), 8.23 (1 H, m).
D41 after hydrolysis to the corresponding lithium salt was also used to prepare Example 55 by a similar procedure to Example 43.
Similarly, from Description D40, the isomer D40b was taken forward by the same sequence to afford Examples 42 and 46.
N-ethylation with ethyl bromide (chemistry analogous to D37, ethylation instead of methylation) affords a mixture of the 2 isomers which was carried through stages analogous to D37 - D41 with separation of isomers at the stage corresponding to D40. Subsequent hydrolysis to the lithium salt and coupling analogous to the above procedures under Method G afforded Examples 54, 59, 61 and 64 for the separate N-ethyl isomers.
Other heterocycles may be introduced by an analogous sequence to sequence D37 - D41 , followed by hydrolysis and coupling (by method G or N). For further examples of imidazoles (E48, E82, E52, E83) the bromoimidazoles were commercially available. For these single isomers no separation was required at a stage equivalent to D40.
Example 91 1 -[1 -({5-[3-Chloro-5-(4-pyridazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E91 )
Figure imgf000077_0001
{5-[3-Chloro-5-(4-pyridazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetic acid lithium salt (86 mg, 0.266 mmol) [prepared by routes described herein, the first step being the coupling of 3-chloro-5-[(methyloxy)carbonyl]phenyl}boronic acid and 4- bromopyridazine by a method similar to Description 38 with the exception that the solvent was aqueous dichloromethane and the reaction was heated for 20 minutes in the microwave at 1000C] was dissolved in N,N-dimethylformamide (5 ml.) and N- methylmorpholine (0.058 ml_, 0.531 mmol), 1-hydroxybenzotriazole hydrate (48.8 mg, 0.319 mmol) and Λ/-[3-(dimethylamino)propyl]-Λ/'-ethylcarbodiimide hydrochloride (56.0 mg, 0.292 mmol) were added. The mixture was stirred for 5 minutes before adding 1-(4-piperidinyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (60.9 mg, 0.279 mmol). The mixture was stirred at room temperature for 19 hours then heated at 5O0C for 3 hours. The reaction was allowed to cool to room temperature and the solvent was evaporated. Saturated sodium bicarbonate solution and dichloromethane were added and the mixture was filtered to remove an insoluble solid. The two layers were separated with a phase separator. The organic layer was evaporated to give a second solid. Both solids contained product so they were combined and dissolved in dimethyl sulfoxide and then purified by MDAP. Product- containing fractions were combined and concentrated under reduced pressure. The residue was triturated with diethyl ether and dried to give the title compound as a white solid. LC/MS (ES+ve): [M+H]+ at m/z 517, 519 (C25H21CIN8O3 requires [M+H]+ at m/z 517, 519).
1H NMR δ (DMSOd6): 1.77-1.84 (2H, m), 2.08-2.17 (1 H, m), 2.32-2.45 (1 H, m), 2.75- 2.81 (1 H, m), 3.27-3.43 (1 H + water signal, br s), 4.09-4.13 (1 H, m), 4.37-4.56 (4H, ovelapping m), 6.97-7.00 (1 H, m), 7.63-7.64 (1 H, m), 7.90-7.92 (1 H, m), 8.15-8.20 (2H, m), 8.32-8.33 (1 H, m), 8.41-8.42 (1 H, m), 9.36-9.37 (1 H, m), 9.76-9.77 (1 H, m), 11.55-1 1.60 (1 H, br s).
Method H Example 68
3-[1 -({5-[3-Chloro-5-(4-piperidinyl)phenyl]-1,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E68)
Figure imgf000078_0001
To a stirring solution of 1 ,1-dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-1 ,2,4,5- tetrahydro-3H-1 ,3-benzodiazepin-3-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2- yl)phenyl]-1-piperidinecarboxylate (60 mg, 0.092 mmol) in dichloromethane (1 ml.) was added trifluoroacetic acid (1 ml_, 12.98 mmol). The reaction was stirred at room temperature for 2 hours, concentrated in vacuo, azeotroped with toluene and then triturated with diethyl ether. After drying in a vacuum oven overnight the mixture was purified by chromatography (SP4 Biotage, 12M, 0-20% 2M ammonia in methanol/dichloromethane). Relevant fractions were combined and concentrated in vacuo to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 549, 551 (C29H33CIN6O3 requires [M+H]+ at m/z 549, 551 ).
1H NMR δ (DMSOd6): 1.54 - 1.70 (4H, overlapping m), 1.80 (2H, m), 2.50 (assumed 1 H, overlapped by DMSO signal), 2.68 (3H, m), 2.79-2.85 (3H, overlapping m), 3.10- 3.22 (3H, overlapping m), 3.33-3.46 (assumed 4H, m overlapping with water signal), 4.03 (1 H, m), 4.29 - 4.38 (3H, m), 4.47 (1 H, br d), 6.80 (1 H, m), 7.04 (3H, m), 7.58 (1 H, m), 7.79 (1 H, m), 7.82 (1 H, m), 8.53 (1 H, s).
Other Examples designated Method H were prepared similarly.
Method I Example 70
1 -[1 -({5-[3-Chloro-5-(1 -piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, formate salt (E70)
Figure imgf000079_0001
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5- b]pyridin-1-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-1- piperazinecarboxylate (180 mg, 0.289 mmol) was dissolved in 1 ,4-dioxane (2 ml_),
4M hydrochloric acid in dioxane (2 ml_, 8.00 mmol) was added and the reaction mixture was stirred for 10 minutes. The reaction mixture was concentrated. The residue was dissolved in methanol and purified by SCX. The basic fractions were combined and concentrated and the residues were purified by MDAP.
Corresponding fractions were combined and concentrated to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 523, 525 (C25H27CIN8O3 requires [M+H]+ at m/z 523,
525 for the free base).
1H NMR δ (DMSO-d6): 1.79 (2H, t), 2.03-2.18 (1 H, m), 2.30-2.45 (1 H, m), 2.77 (1 H, m), 2.96 (4H, m), 3.29 (5H, m), 4.08 (1 H, d), 4.38 (1 H, d), 4.42 (1 H, d), 4.45-4.60
(2H, m), 6.99 (1 H, dd), 7.24 (1 H, m), 7.33 (1 H, m), 7.40 (1 H, m), 7.63 (1 H, m), 7.91
(1 H, m), 8.23 (1 H, s), 1 1.55 (1 H, br s).
Method J Example 71
1 -[1 -({5-[3-Chloro-5-(3-hydroxy-1 -pyrrolidinyl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E71 )
Figure imgf000080_0001
A solution of 1-[1-({5-[3-chloro-5-(3-{[(1 ,1-dimethylethyl)(climethyl)silyl]oxy}-1- pyrrolidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (0.1 16 g, 0.182 mmol) and tetrabutylammonium fluoride (0.909 ml_, 0.909 mmol) in tetrahydrofuran (1.5 ml.) was stirred at room temperature under an atmosphere of argon for 90 minutes. The reaction mixture was concentrated under reduced pressure to give a dark yellow oil. The residue was purifed by chromatography (Biotage, 0-10% 2M ammonia in methanol/dichloromethane, 40+S column). The product containing fractions were combined and concentrated under reduced pressure to give a clear oil. After dryng at 4O0C under vacuum overnight the title compound was obtained as a white solid. LC/MS (ES+ve): [M+H]+ at m/z 524, 526 (C25H26CIN7O4 requires [M+H]+ at m/z 524, 526). 1H NMR δ (MeOH-d4): 1.88-2.00 (2H, m), 2.03-2.1 1 (1 H, m), 2.13-2.33 (1 H, m), 2.37- 2.40 (1 H, m), 2.43-2.54 (1 H, m), 2.83-2.94 (1 H, m), 3.23-3.33 (3H + MeOD, m), 3.36- 3.46 (2H, m), 3.46-3.58 (1 H + ether, m), 4.18-4.33 (2H, m), 4.52-4.65 (2H, m), 4.72- 4.80 (1 H, m), 6.73-6.78 (1 H, m), 7.02-7.08 (1 H, m), 7.10-7.14 (1 H, m), 7.23-7.27 (1 H, m), 7.61-7.67 (1 H, m), 7.92-7.97 (1 H, m).
Method K Example 73
1 -[1 -({5-[3-Chloro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one trifluoroacetic acid salt (E73)
Figure imgf000080_0002
TFA
To a stirring suspension of 1 ,1-dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-2,3- dihydro-1 H-imidazo[4,5-b]pyridin-1-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2- yl)phenyl]-3,6-dihydro-1 (2H)-pyridinecarboxylate (E40, 350 mg, 0.564 mmol) in dichloromethane (8 ml.) at room temperature under argon was added trifluoroacetic acid (4.348 ml_, 56.4 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and azeotroped with toluene then dried in a vacuum oven overnight to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 520, 522 (C26H26CIN7O3 requires [M+H]+ at m/z 520, 522). 1H NMR δ (DMSO-de): 1.79 (2H, br t), 2.10 (1 H, m), 2.48 (1 H, m), 2.70 - 2.81 (3H, overlapping m), 3.28 - 3.38 (3H, overlapping m), 3.82 (2H, app s), 4.10 (1 H, d), 4.40 - 4.59 (4H, overlapping m), 6.46 (1 H, s), 6.99 (1 H, m), 7.62 (1 H, m), 7.89 (1 H, s), 7.90 - 7.99 (3H, overlapping m), 8.91 (2H, br s), 1 1.60 (1 H, s).
Other Examples designated Method K were prepared similarly.
Method L Example 74 3-[1 -({5-[3-Chloro-5-(1 -methyl-1 ,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1 ,3,4- oxadiazol-2-yl}acetyl)-4-piperidinyl]-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2- one
Figure imgf000081_0001
To a stirring solution of 3-[1-({5-[3-chloro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)phenyl]- 1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2- one trifluoroacetic acid salt (100 mg, 0.151 mmol) [prepared from E39 by Method K] in dichloromethane (3 ml.) was added acetic acid (0.866 μl_, 0.015 mmol) and formaldehyde (0.5 ml_, 6.72 mmol). After 5 minutes of stirring at room temperature under argon sodium triacetoxyborohydride (64.1 mg, 0.303 mmol) was added. The reaction was stirred at room temperature under argon for 3 hours, before being left to stand overnight. The reaction mixture was adjusted to pH 8 using 2M sodium hydroxide solution, partitioned between water and dichloromethane. The aqueous was re-extracted with dichloromethane, organics combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was triturated with diethyl ether, dried in vacuum oven overnight and then purified by
MDAP. Relevant fractions were combined, concentrated in vacuo, azeotroped with toluene, dried in vacuum oven overnight to give the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 561 , 563 (C30H33CIN6O3) requires [M+H]+ at m/z 561 , 563)
1H NMR d (DMSO-de): 1.54 - 1.70 (3H, overlapping m), 1.82 (1 H, m), 2.39 (3H, s), 2.60 (2H, m), 2.69 (1 H, m), 2.75 (2H, m), 2.89 (2H, m), 3.20 (3H, m), 3.41 (2H, m overlapping with water signal), 4.01 (1 H, d), 4.29 - 4.38 (3H, overlapping m), 4.45 (1 H, d), 6.42 (1 H, s), 6.81 (1 H, m), 7.04 (3H, m), 7.79 (1 H, s), 7.86 (1 H, s), 7.93 (1 H, s), 8.53 (1 H, s).
Other Examples designated Method L were prepared similarly. Example 75 was prepared from 3-[1-({5-[3-chloro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1 ,3,4- oxadiazol-2-yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one trifluoroacetic acid salt using acetone instead of formaldehyde. Method M
Example 80
1,1 -Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-1,2,4,5-tetrahydro-3H-1,3- benzodiazepin-3-yl)-1-piperidinyl]ethyl}-1,3,4-oxadiazol-2-yl)phenyl]-1- piperidinecar
Figure imgf000082_0001
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-1 ,2,4,5-tetrahydro-3H-1 ,3- benzodiazepin-3-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-3,6-dihydro- 1 (2H)-pyridinecarboxylate (E39, 140 mg, 0.216 mmol was dissolved in tetrahydrofuran (5 ml_), platinum(IV) oxide (9.82 mg, 0.043 mmol) was added, and the reaction was hydrogenated at room temperature and pressure over the weekend. The mixture was filtered through celite, washed with tetrahydrofuran, and then concentrated in vacuo. After purification by chromatography (SP4 Biotage, 12M, 0- 10% ammonia in methanol/dichloromethane over 10 column volumes) relevant fractions were combined then concentrated in vacuo to give the title compound. LC/MS (ES+ve): [M+Na]+ at m/z 671 , 673 (C34H4ICIN6O5 requires [IvHNa]+ at m/z 671 , 673).
1H NMR δ (DMSO-de): 1.42 (9H, s), 1.50 - 1.70 (6H, m), 1.80 (3H, m), 2.55 (1 H, overlapping with DMSO signal), 2.68 (1 H, t), 2.79 - 2.90 (3H, m), 3.40 (2H, m), 3.88 - 4.12 (4H, m), 4.32 (3H, m), 4.45 (1 H, m), 6.80 (1 H, m), 7.05 (3H, m), 7.65 (1 H, s), 7.81 (2H, m), 8.53 (1 H, s).
Other Examples designated Method M were prepared similarly.
Method N
Example 82
3-[1 -({5-[3-Chloro-5-(1 -methyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E82)
Figure imgf000082_0002
{5-[3-Chloro-5-(1 -methyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetic acid lithium salt (94 mg, 0.288 mmol), 1-hydroxybenzotriazole (48.5 mg, 0.317 mmol), N- ethyl-Λ/'-(3-dimethylaminopropyl)carbodiimide hydrochloride (66.3 mg, 0.346 mmol), N-methylmorpholine (0.063 ml_, 0.576 mmol) and 3-(4-piperidinyl)-1 ,3,4,5-tetrahydro- 2H-1 ,3-benzodiazepin-2-one hydrochloride (107 mg, 0.288 mmol) were combined in anhydrous N,N-dimethylformamide (4 ml.) and stirred at room temperature under an atmosphere of argon for 16 hours. Further N-methylmorpholine (0.032 ml_, 0.288 mmol), 1-hydroxybenzotriazole (24.26 mg, 0.158 mmol) and Λ/-ethyl-Λ/'-(3- dimethylaminopropyl)carbodiimide hydrochloride (33.1 mg, 0.173 mmol) were added and the reaction mixture stirred at room temperature for 3 hours. The reaction mixture was concentrated by evaporation under reduced pressure and the residue partitioned between dichloromethane (50 ml.) and saturated sodium bicarbonate solution (50 ml_). The organics were extracted and washed with water (50 ml_), passed through a hydrophobic frit, then concentrated by evaporation under reduced pressure. The crude mixture was purified by column chromatography (Biotage SP4 25+S) eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound.
LC/MS (ES+ve): [M+H]+ at m/z 546, 548 (C28H28CIN7O3 requires [M+H]+ at 546, 548). 1H NMR δ (CDCI3 + D2O): 1.69 (2H, m), 1.98 (2H, overlapping m), 2.72 (1 H, m), 2.99 (2H, m), 3.25 (1 H, m), 3.47 (2H, m), 3.84 (3H, s), 4.09 (3H, overlapping m), 4.52 (1 H, m), 4.74 (1 H, m overlapping with HOD signal), 6.46 (s, partially exchanged by D2O, 1 H in absence of D2O), 6.70 (1 H, d), 6.92 (1 H, m), 7.04 (2H, m), 7.13 (2H, m), 7.85 (1 H, t), 8.09 (1 H, t), 8.24 (1 H, t).
Other Examples designated Method N were prepared similarly. In other examples of this method the addition of additional coupling reagents and base was not always necessary, or was added from the start.
Method O Example 88
1 -(1 -{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-5- (methyloxy)-1 ,3-dihy 8)
Figure imgf000083_0001
A mixture of polymer supported 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (196 mg, 270 μmol) and PS-morpholine (212 mg, 360 μmol) was treated successively with a solution of 1-hydroxybenzotriazole (4.59 mg, 30 μmol) in anhydrous N,N-dimethylformamide (5 ml_), solid [5-(3,5-dichlorophenyl)-1 ,3,4- oxadiazol-2-yl]acetic acid (36.9 mg, 135 μmol) and the hydrochloride salt of 5- (methyloxy)-1-(4-piperidinyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (25.6 mg, 90 μmol). The resultant mixture was shaken at room temperature for 20 hours, after which time the resin was removed by filtration and the filtrate evaporated in vacuo to yield a white solid. The crude product was purified by MDAP to yield the title compound as a white solid.
LC/MS (ES+ve): [M+H]+ at m/z 503, 505, 507 (C22H20CI2N6O4 requires [M+H]+ at 503, 505, 507). 1H NMR δ (MeOH-d4): 1.92 (2H, m), 2.28 (1 H, m), 2.45 (1 H, m), 2.88 (1 H, m), 3.25- 3.40 (assumed 4H, m overlapping with MeOH-d4 residual signal), 3.85 (3H, s), 4.21 (1 H, m), 4.55 (1 H, m), 6.47 (1 H, d), 7.60 (1 H, d), 7.72 (1 H, s), 8.02 (2H, d).
Biological Assay
The activity of the compounds of the Examples was investigated using the following assay.
Generation of CALCRL and Rampi stable cell line Human calcitonin receptor like receptor (CALCRL or CRLR) (Genbank U17473) and Rampi (Genbank AJ001014) were cloned into bicistronic mammalian expression vectors (BioTechniques, 1996, 20:102-110) pCIN3 and pCIH5.
Human embryonic kidney 293cells (HEK293) were maintained in DMEM containing 2mM glutamine (Gibco 41966-029) with 10% Heat inactivated FCS (Gibco 10100- 147)
Both of the plasmids were transfected into a 50% confluent T75 flask of HEK293 cells using Lipofectamine according to the manufacturers guidelines (Invitrogen 18324-012). 48 hours following transfection, the cells were dilution cloned into 96-well plates using selection media containing DMEM containing 2mM glutamine (Gibco 41966- 029), 10% Heat inactivated FCS (Gibco 10100-147), 500μg/ml Geneticin (Gibco 10131-027) and 200 μg/ml of hygromycin B (Gibco 10687-010). 10 to 14 days post dilution cloning, antibiotic resistant clones were grown on and expanded.
The clones were screened for increases in cAMP production on addition of human β- CGRP using cAMP SPA screening Biotrack assay (GE healthcare RPA556) according to the manufacturers instructions. A positive clone from this screening was then chosen and used for all subsequent assay work.
CRLR-RAMP1 cAMP TR-FRET assay
Calcitonin Receptor Like Receptor (CRLR) and Receptor Activity Modifying Protein (RAMP1 ) form a 7-transmembrane G protein coupled receptor that is positively coupled to adenylate cyclase by Ga. Stimulation of CRLR-RAMP1 with the agonist Calcitonin Gene Related Peptide (CGRP) produces an increase in the intracellular secondary messenger cAMP. Receptor activity can therefore be measured using a cAMP accumulation immunoassay. This assay is based on competition between a europium labelled cAMP complex and cellular cAMP for binding sites on anti-cAMP antibodies labelled with Alexa Fluor 647(Trade Mark). Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) occurs when the europium labelled cAMP tracer complex is bound by an Alexa Fluor 647 labelled anti-cAMP antibody. Light at 340nm excites the europium-cAMP which transfers energy to the Alexa647 which in turns emits at 665nm. The fluorescence intensity measured at 665nm is inversely proportional to the cAMP concentration of the sample.
Assay plates containing 10OnI test compounds (dissolved in 100% DMSO and serially diluted with DMSO), positive and negative controls wells, are thawed. Frozen recombinant cells expressing CRLR-RAMP1 are thawed and diluted in stimulation buffer. 5μl of this is added to all wells and the plates are incubated for 15 minutes at room temperature. 5μl of stimulation buffer containing an ECso concentration of CGRP and europium-cAMP is added to all wells and the plates are incubated for a further 45 minutes at room temperature. Finally 10μl of detection mix containing Alexa Fluor 647anti-cAMP antibody is added to all wells, plates are incubated (lidded) for a minimum of 4 hours before reading the TR-FRET signal on the ViewLux (Trade Mark) imager. The raw data (acceptor counts) is processed using
ActivityBase software and % inhibition values determined. These values are then plotted to provide dose response curves giving plC50 and fpKi values. The compounds of Examples 1 to 28 were tested in this assay and exhibited fpKi values greater than or equal to 7.0. The compounds of Examples 29 to 93 (except for the compound of Example 31 ) were also tested in this assay: all except the compound of Example 92 exhibited fpKi values greater than or equal to 7.0.

Claims

1. A compound of formula (I):
Figure imgf000086_0001
wherein:
R1 is selected from the group consisting of halogen, trifluoromethyl, methyl, and methoxy, and R2 is hydrogen, or R1 and R2 together form a fused phenyl; R3 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, alkoxy, optionally substituted phenyl, trifluoromethyloxy, heterocyclyl, dialkylamino, and -N(CH3)CH2CH2OCH3;
R4 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, methyl, and methoxy; R5 is hydrogen, methyl or methoxy; n is 0, 1 or 2; and
R6 and R7 together form a fused six-membered aromatic ring which is optionally substituted and contains 0, 1 or 2 nitrogen atoms; with the proviso that, if R2 is hydrogen, at least one of R3 and R4 is not hydrogen, or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R1 is selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, methyl, and methoxy, and R2 is hydrogen; and at least one of R3 and R4 is not hydrogen.
3. A compound according to claim 1 or claim 2, wherein R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, alkoxy, phenyl, trifluoromethyloxy, -N(Me)2, -N(CH3)CH2CH2OCH3 and heterocyclyl, wherein heterocyclyl is optionally substituted by 1 or 2 substituents selected from haloalkyl , hydroxy, alkyl and -COOC(Me)3.
4. A compound according to any one of the preceding claims, wherein R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxy, phenyl, trifluoromethyloxy, -N(Me)2, - N(CH3)CH2CH2OCH3 and heterocyclyl, wherein heterocyclyl is optionally substituted by 1 or 2 substituents selected from difluoroethyl, trifluoroethyl, hydroxy, methyl, ethyl, isopropyl, and -COOC(Me)3.
5. A compound according to any one of the preceding claims, wherein R4 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine and methoxy.
6. A compound according to claim 5, wherein R4 is fluorine, chlorine or methoxy and R3 is hydrogen or halogen.
7. A compound according to claim 5, wherein R4 is hydrogen.
8. A compound according to claim 1 , wherein R1 and R2 together form a fused phenyl and R3 and R4 are both hydrogen
9. A compound according to any one of the preceding claims, wherein R5 is hydrogen.
10. A compound according to any one of the preceding claims, wherein R6 and R7 together with the ring to which they are attached form a group selected from Table I:
Table I
Figure imgf000087_0001
11. A compound according to claim 10, wherein R6 and R7 together with the ring to which they are attached form a group selected from Table II:
Table Il
Figure imgf000087_0002
12. A compound of formula (I) as defined in claim 1 which is selected from: 1-[1-({5-[3-Chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E1 );
1-[1-({5-[3-(4-Morpholinyl)-5-(trifluoromethyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (E2); 1-(1-{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl](methyloxy)acetyl}-4-piperidinyl)-
1.S-dihydro^H-imidazoμ.S-bJpyridin^-one (E3);
1-(1-{2-[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]propanoyl}-4-piperidinyl)-1 ,3- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E4);
1-[1-({5-[3-Chloro-5-(4-methyl-1-piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E5);
3-(1 -{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3,4,5- tetrahydro-2H-1 ,3-benzodiazepin-2-one (E6)
1-(1-{[5-(5-Chloro-3-biphenylyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E7) 1-(1-{[5-(3,5-Dibromophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3-dihydro-
2/-/-imidazo[4,5-b]pyridin-2-one (E8);
1-(1-{[5-(3-Chloro-5-{methyl[2-(methyloxy)ethyl]amino}phenyl)-1 ,3,4-oxadiazol-2- yl]acetyl}-4-piperidinyl)-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E9);
1-[1-({5-[3-Chloro-5-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- 1 ,3-dihydro-2H-imidazo[4,5-jb]pyridin-2-one (E10);
1-[1-({5-[3,5-Dibromo-2-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E1 1 );
1-[1-({5-[3,5-Dichloro-2-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E12); ^(^{^-(S-Bromo-S-chlorophenyO-I .S^-oxadiazol^-yOacetylH-piperidinyO-I .S- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E13);
^(^{^-(S.S-DichlorophenylJ-I .S^-oxadiazol^-ylJacetyl^-piperidinylJ-I .S-dihydro-
2H-imidazo[4,5-ιb]pyridin-2-one
(E14);
^(^{^-(S-Chloro-S-fluorophenyO-i ^^-oxadiazol^-yOacetyl^-piperidinyO-i ^- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E15);
1-[1-({5-[5-Chloro-2-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E16);
^(^{^-(S.S-DifluorophenyO-i ^^-oxadiazol^-yOacetyl^-piperidinyO-i ^-dihydro-
2/-/-imidazo[4,5-b]pyridin-2-one
(E17); 1-(1-{[5-(2,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3-dihydro-
2/-/-imidazo[4,5-b]pyridin-2-one
(E18);
1-[1-({5-[3-Bromo-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1.S-dihydro^H-imidazo^.S-^pyridin^-one
(E19);
1-[1-({5-[3-Methyl-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- i ^-dihydro^H-imidazo^.S-^pyridin^-one
(E20); i-ti-Uδ-tS-Chloro-S-^πfluoromethyOphenyO-I .S^-oxadiazol^-ylϊacetylH- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E21 );
1-[1-({5-[3-Chloro-5-(1-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1.S-dihydro^H-imidazo^.S-^pyridin^-one
(E22); 1-{1-[(5-{3-Chloro-5-[(trifluoromethyl)oxy]phenyl}-1 !3,4-oxadiazol-2-yl)acetyl]-4- piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E23);
1-[1-({5-[3,5-Bis(methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-1 ,3- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E24);
1-(1-{[5-(5-Chloro-2-fluorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E25); 1-(1-{[5-(2-Naphthalenyl)-1 !3!4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 !3-dihydro-2H- imidazo[4,5-b]pyridin-2-one
(E26); i-ti-^S-^.S-Bis^rifluoromethyOphenyO-I .S^-oxadiazol^-ylJacetylH-piperidinyO-I .S- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E27); 1-(1-{[5-(3,5-Dimethylphenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3-dihydro-
2H-imidazo[4,5-b]pyridin-2-one
(E28);
1-[1-({5-[3-Chloro-5-(dimethylamino)phenyl]-1 !3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E29);
1-(1-{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-4-(methyloxy)- 1 ,3-dihydro-2H-benzimidazol-2-one
(E30);
3-[1-({5-[3-(Methyloxy)-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E31 );
Formic acid - 4-chloro-1-[1-({5-[3-chloro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one (1 :1 )
(E32); 1-[1-({5-[3-Chloro-5-(3-pyridinyl)phenyl]-1 !3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
(E33);
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-2,3-dihydro-1/-/-imidazo[4,5- b]pyridin-1-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-1- piperazinecarboxylate
(E34); 1-[1-({5-[3-Fluoro-5-(4-morpholinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1.S-dihydro^H-imidazoμ.S-jbJpyridin^-one
(E35);
3-[1-({5-[3-Chloro-5-(4-methyl-1-piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E36);
3-[1-({5-[3-Chloro-5-(5-pyrimidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]- i ^^^-tetrahydro^H-i ^-benzodiazepin^-one
(E37);
1-[1-({5-[3-Chloro-5-(5-pyrimidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one
(E38);
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-1 ,2,4,5-tetrahydro-3H-1 ,3- benzodiazepin-3-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-3,6-dihydro- 1 (2H)-pyridinecarboxylate
(E39);
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5- b]pyridin-1-yl)-1-piperidinyl]ethyl}-1 !3!4-oxadiazol-2-yl)phenyl]-3,6-dihydro-1 (2H)- pyridinecarboxylate
(E40);
3-(1-{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-3,4-dihydro- 2(1 H)-quinazolinone
(E41 );
S-ti-US-^-Chloro-S^I ^-dimethyl-I H-imidazol-δ-yOphenyO-I .S^-oxadiazol^- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E42);
S-ti-Uδ-^-Chloro-S^I ^-dimethyl-I H-imidazoM-yOphenyO-I .S^-oxadiazol^- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E43); 3-[1-({5-[3-Chloro-5-(3-pyridinyl)phenyl]-1 !3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E44);
1-[1-({5-[3-Chloro-5-(1H-imidazol-1-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E45); i-ti-Uδ-tS-Chloro-S^I ^-dimethyl-I H-imidazol-S-yOphenyO-I .S^-oxadiazol^- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E46); 1-[1-({5-[3-Chloro-5-(1-methyl-1 H-pyrazol-4-yl)phenyl]-1 !3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E47);
3-[1-({5-[3-Chloro-5-(1-methyl-1 H-imidazol-5-yl)phenyl]-1 !3!4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E48); 1 -{1 -[(5-{3-Chloro-5-[1 -(2,2-difluoroethyl)-4-pipeιϊdinyl]phenyl}-1 ,3,4-oxadiazol-2- yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2H-imidazo[4,5-ιb]pyridin-2-one
(E49);
3-[1-({5-[3-Chloro-5-(1-methyl-1 H-pyrazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E50);
1-[1-({5-[3-Chloro-5-(6-methyl-3-pyridinyl)phenyl]-1 !3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E51 );
3-[1-({5-[3-Chloro-5-(1-methyl-1 H-imidazol-4-yl)phenyl]-1 !3!4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E52);
1 -{1 -[(5-{3-Chloro-5-[1 -(2,2-difluoroethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-1 ,3,4- oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E53);
1-[1-({5-[3-Chloro-5-(1-ethyl-2-methyl-1 H-imidazol-5-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E54);
1-[1-({5-[3-Chloro-5-(1 ,2-dimethyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E55); 3-[1-({5-[3-Chloro-5-(6-methyl-3-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E56);
1-[1-({5-[3-Chloro-5-(1-methyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E57);
1-{1-[(5-{3-Chloro-5-[1-(2,2-difluoroethyl)-3-pyrrolidinyl]phenyl}-1 ,3,4-oxadiazol-2- yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E58);
3-[1-({5-[3-Chloro-5-(1-ethyl-2-methyl-1 H-imidazol-5-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E59);
1-{1-[(5-{3-Chloro-5-[1-(2,2,2-trifluoroethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-
1 ,3,4-oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E60);
1-[1-({5-[3-Chloro-5-(1-ethyl-2-methyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E61 );
1-[1-({5-[3-Chloro-5-(2-methyl-3-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E62); 3-{1-[(5-{3-Chloro-5-[1-(2,2,2-trifluoroethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-
1 ,3,4-oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2- one
(E63);
3-[1-({5-[3-Chloro-5-(1-ethyl-2-methyl-1 H-imidazol-4-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E64); 3-[1-({5-[3-Chloro-5-(2-methyl-3-pyridinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E65);
1-{1-[(5-{3-Chloro-5-[1-(2,2,2-trifluoroethyl)-4-piperidinyl]phenyl}-1 ,3,4-oxadiazol-2- yl)acetyl]-4-piperidinyl}-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E66);
1-[1-({5-[3-Chloro-5-(2,4-dimethyl-1 H-imidazol-1-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E67); 3-[1-({5-[3-Chloro-5-(4-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E68);
1-[1-({5-[3-Chloro-5-(4-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2H-imidazo[4,5-fc]pyridin-2-one
(E69); Formic acid - 1-[1-({5-[3-chloro-5-(1-piperazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (1 :1 )
(E70);
1-[1-({5-[3-Chloro-5-(3-hydroxy-1-pyrrolidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E71 );
3-[1-({5-[3-Chloro-5-(1 ,2!3!6-tetrahydro-4-pyridinyl)phenyl]-1 !3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one trifluoroacetate
(E72);
1-[1-({5-[3-Chloro-5-(1 ,2!3!6-tetrahydro-4-pyridinyl)phenyl]-1 !3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one trifluoroacetate
(E73); 3-[1-({5-[3-Chloro-5-(1-methyl-1 !2,3,6-tetrahydro-4-pyridinyl)phenyl]-1 ,3,4-oxadiazol-
2-yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E74);
3-{1-[(5-{3-Chloro-5-[1-(1-methylethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-1 ,3,4- oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3,4,5-tetrahydro-2/-/-1 ,3-benzodiazepin-2-one
(E75); 1-[1-({5-[3-Chloro-5-(1-methyl-1 !2,3,6-tetrahydro-4-pyridinyl)phenyl]-1 ,3,4-oxadiazol-
2-yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one
(E76);
1-[1-({5-[3-Chloro-5-(1-methyl-4-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E77);
1-[1-({5-[3-Chloro-5-(1-ethyl-4-piperidinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4- piperidinyl]-1 ,3-dihydro-2/-/-imidazo[4,5-b]pyridin-2-one
(E78);
1-[1-({5-[3-Chloro-5-(1-ethyl-1 ,2!3!6-tetrahydro-4-pyridinyl)phenyl]-1 !3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one
(E79);
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-1 ,2,4,5-tetrahydro-3H-1 ,3- benzodiazepin-3-yl)-1 -piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-1 - piperidinecarboxylate
(E80);
1 ,1-Dimethylethyl 4-[3-chloro-5-(5-{2-oxo-2-[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5- b]pyridin-1-yl)-1-piperidinyl]ethyl}-1 ,3,4-oxadiazol-2-yl)phenyl]-1- piperidinecarboxylate
(E81 );
3-[1-({5-[3-Chloro-5-(1-methyl-1 /-/-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)- 4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E82);
3-[1-({5-[3-Chloro-5-(1 ,5-dimethyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E83);
3-[1-({5-[3-Chloro-5-(1 ,4-dimethyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E84); 1-[1-({5-[3-Chloro-5-(1 ,5-dimethyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one
(E85);
1-[1-({5-[3-Chloro-5-(1-methyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-
4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one
(E86);
1-[1-({5-[3-Chloro-5-(1 ,4-dimethyl-1 H-imidazol-2-yl)phenyl]-1 ,3,4-oxadiazol-2- yl}acetyl)-4-piperidinyl]-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
(E87); 1-(1-{[5-(3,5-Dichlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-5-(methyloxy)-
1 ,3-dihydro-2H-imidazo[4,5-fc]pyridin-2-one
(E88);
3-{1 -[(5-{3-Chloro-5-[1 -(2,2-difluoroethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}-1 ,3,4- oxadiazol-2-yl)acetyl]-4-piperidinyl}-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one
(E89);
3-{1 -[(5-{3-Chloro-5-[1 -(2,2-difluoroethyl)-4-piperidinyl]phenyl}-1 ,3,4-oxadiazol-2- yl)acetyl]-4-piperidinyl}-1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E90):
1-[1-({5-[3-Chloro-5-(4-pyridazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3-dihydro-2H-imidazo[4,5-jb]pyridin-2-one (E91 );
3-[1-({5-[3-Chloro-5-(4-pyridazinyl)phenyl]-1 ,3,4-oxadiazol-2-yl}acetyl)-4-piperidinyl]-
1 ,3,4,5-tetrahydro-2H-1 ,3-benzodiazepin-2-one (E92); and
1-(1-{[5-(2-Bromo-5-chlorophenyl)-1 ,3,4-oxadiazol-2-yl]acetyl}-4-piperidinyl)-1 ,3- dihydro-2/-/-imidazo[4,5-b]pyridin-2-one (E93); and pharmaceutically acceptable salts thereof.
13. A process for the preparation of a compound of formula (I) as defined in claim 1 , which process comprises:
(a) reacting a compound of formula (II) or a salt thereof:
Figure imgf000092_0001
(H) with a compound of formula (III) or a salt thereof:
Figure imgf000092_0002
in the presence of a suitable coupling agent and a suitable base; and/or
(b) converting the compound of formula (I) to a different compound of formula (I); and/or (c) as appropriate, separating diastereomeric or enantiomeric mixtures of compounds of formula (I).
14. A pharmaceutical composition which comprises a compound as defined in any one of claims 1 to 12 and a pharmaceutically acceptable carrier or excipient.
15. A compound as defined in any one of claims 1 to 12 for use in the treatment of migraine, headache, or cluster headache.
16. Use of a compound as defined in any one of claims 1 to 12 in the manufacture of a medicament for the treatment of migraine, headache, or cluster headache.
17. A method of treatment of migraine, headache, or cluster headache which comprises administering to a host in need thereof an effective amount of a compound as defined in any one of claims 1 to 12.
PCT/EP2008/057985 2007-06-26 2008-06-24 5-phenyl-1,3,4-oxadiazol-2-yl-acetyl-4-piperidinyl derivatives as cgrp receptor antagonists WO2009000819A1 (en)

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WO2021005497A1 (en) * 2019-07-05 2021-01-14 Allergan Pharmaceuticals International Limited Cgrp antagonists and clostridial derivatives for the treatment of cortical spreading depression associated disorders

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WO2006044504A1 (en) * 2004-10-13 2006-04-27 Merck & Co., Inc. Cgrp receptor antagonists
WO2006099268A2 (en) * 2005-03-14 2006-09-21 Merck & Co., Inc. Cgrp receptor antagonists

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WO2004092168A1 (en) * 2003-04-15 2004-10-28 Merck & Co., Inc. Cgrp receptor antagonists
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