WO2009079624A1 - 4-imidazolidinones as kv1.5 potassium channel inhibitors - Google Patents

4-imidazolidinones as kv1.5 potassium channel inhibitors Download PDF

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WO2009079624A1
WO2009079624A1 PCT/US2008/087397 US2008087397W WO2009079624A1 WO 2009079624 A1 WO2009079624 A1 WO 2009079624A1 US 2008087397 W US2008087397 W US 2008087397W WO 2009079624 A1 WO2009079624 A1 WO 2009079624A1
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Prior art keywords
ethyl
methoxypheπyl
oπe
methyl
ferf
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PCT/US2008/087397
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French (fr)
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Benjamin Eric Blass
John Michael Janusz
Shengde Wu
James Madison Ii Ridgeway
Keith Coburn
Wenlin Lee
Andrew J. Fluxe
Ronald E. White
Christopher M. Jackson
Neil Fairweather
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Wyeth
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Priority to AU2008338368A priority Critical patent/AU2008338368A1/en
Priority to JP2010539792A priority patent/JP2011507883A/en
Priority to EP08861728A priority patent/EP2234615A1/en
Priority to BRPI0820698A priority patent/BRPI0820698A2/en
Priority to CA2709186A priority patent/CA2709186A1/en
Publication of WO2009079624A1 publication Critical patent/WO2009079624A1/en
Priority to ZA2010/05087A priority patent/ZA201005087B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds that are effective as Kv1.5 potassium channel inhibitors.
  • the present invention also relates to compositions comprising certain Kv1.5 potassium channel inhibitors, and to methods for treating cardiac arrhythmia.
  • Atrial fibrillation is a frequently encountered cardiac arrhythmia in the clinical setting. It affects nearly 3 million people in the United States and its prevalence increases with the aging of the population. AF is most often treated with class III antiarrhythmic agents, acting at both the atrial and ventricular levels. Commonly used or prescribed antiarrhythmic drugs inhibit various potassium channels, and prolong ventricular repolarization. Prolongation of ventricular repolarization can in turn precipitate the occurrence of life-threatening-ventricular arrhythmias, mainly Torsades de Pointes (TdP).
  • TdP Torsades de Pointes
  • Certain atrial-selective antiarrhythmic agents offer one possibility of increased therapeutic efficacy and safety by minimizing cardiac proarrhythmia inherent in conventional antiarrhythmic therapies.
  • Kv1.5 potassium channel include: Brendel, J., et al., Curr. Med. Chem. 2003, 1 , 273- 287; Firth, A. L., et al., 2008, 33, 31-47; Vidaillet, H., et al., Am. J. Med. 2002, 1 13,
  • the present invention provides compounds of Formula (I):
  • Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m, n, and p are defined as described herein.
  • compositions comprising an effective amount of one or more compounds of Formula (I) and one or more excipients.
  • the present invention also provides a method for treating or preventing cardiac arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, the method comprising administering to a subject an effective amount of a compound of Formula (I) according to the present invention.
  • the present invention also provides a method for treating or preventing cardiac arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, wherein the method comprises administering to a subject a composition comprising an effective amount of one or more compounds of Formula (I) according to the present invention and one or more excipients.
  • the present invention also provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure.
  • the methods comprise administering to a subject an effective amount of a compound of Formula (I) according to the present invention.
  • the present invention further provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds of Formula (I) according to the present invention and one or more excipients.
  • the present invention also provides a method for inducing cardioversion, comprising administering a therapeutically effective amount of a compound of Formula (I) to the subject.
  • the present invention also provides a method for inhibiting Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of Formula (I) to the subject.
  • the present invention also provides a method for treating or preventing a disorder associated with inhibition of Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of Formula (I) to the subject.
  • these compounds are useful in treating atrial arrhythmia, thromboembolism, stroke or cardiac failure.
  • Kv1.5 potassium channel inhibitors of the present invention are capable of treating and preventing arrhythmia in the atrial portion of the human heart or in the heart of certain animals. It has been discovered that functional Kv1.5 potassium channels are found in human atrial tissue but not in human ventricular myocytes. Without wishing to be limited by theory, it is believed the inhibition of the Kv1.5 voltage-gated Shaker-like potassium (K + ) ion channel can ameliorate, abate, or otherwise cause to be controlled, atrial fibrillation and flutter without prolonging ventricular repolarization.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
  • alkyl whether used alone or as part of a substituent group refers to saturated straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C ⁇ 6 ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent.
  • alkyl groups include methyl, ethyl, n-propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, te/t-butyl, and the like. Where so indicated, alkyl groups can be optionally substituted. In substituent groups with multiple alkyl groups such as N(Ci -6 alkyl) 2 , the alkyl groups may be the same or different.
  • alkoxy refers to groups of formula -Oalkyl and -Operfluoroalkyl. Designated numbers of carbon atoms (e.g. -OC 1-6 and -OC 1-6 perfluoroalkyl) shall refer independently to the number of carbon atoms in the alkoxy group. Non-limiting examples of alkyl groups include methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, sec-butoxy, /so-butoxy, fe/f-butoxy, and the like. Where so indicated, alkoxy groups can be optionally substituted.
  • alkenyl and alkynyl groups refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, having at least one carbon-carbon double bond (“alkenyl”) or at least one carbon-carbon triple bond (“alkynyl”). Where so indicated, alkenyl and alkynyl groups can be optionally substituted.
  • alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2- methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like.
  • alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring including cyclized alkyl, alkenyl, or alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, for example, from 3 to 7 or 3 to 6 ring carbon atoms, and optionally containing one or more (e.g., 1 , 2, or 3) double or triple bonds.
  • Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system.
  • cycloalkyl groups include: cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, octahydropentalenyl, octahydro-1 /-/-indenyl, 3a,4,5,6,7,7a-hexahydro-3/-/-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1 /-/-
  • cycloalkyl also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1 ,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
  • Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms.
  • halogen refers to F, Cl, Br and I.
  • Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF 3 , -CF 2 CF 3 ).
  • the halogens can be the same (e.g., CHF 2 , -CF 3 ) or different (e.g., CF 2 CI).
  • haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen.
  • haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.
  • aryl wherein used alone or as part of another group, is defined herein as an aromatic monocyclic ring of 6 carbons or an aromatic polycyclic ring of from 10 to 14 carbons.
  • Aryl groups include but are not limited to, for example, phenyl or naphthyl (e.g., naphthylen-1-yl or naphthylen-2-yl). Where so indicated, aryl groups may be optionally substituted with one or more substituents.
  • Aryl groups also include, but are not limited to for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1 ,3,5- trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1 ,3,5- trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • heterocyclic refers herein as groups having one or more rings (e.g., 1 , 2 or 3 rings) and having from 3 to 20 atoms (e.g., 3 to 10 atoms, 3 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein the ring that includes the heteroatom is non-aromatic.
  • any non- heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl).
  • Exemplary heterocyclyl groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heterocyclyl group can be oxidized (e.g., N ⁇ O " , S(O), SO 2 ). Where so indicated, heterocyclyl groups can be optionally substituted.
  • Non-limiting examples of monocyclic heterocyclyl groups include, for example: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1 /-/-azepinyl, 2,3-dihydro-1 /-/-indolyl, and 1 ,
  • Non-limiting examples of heterocyclic groups having 2 or more rings include, for example: hexahydro-1 /-/-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1 H- benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1 H-indolyl, 1 ,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1 H- cyclooctatbjpyrrolyl.
  • heteroaryl whether used alone or as part of another group, is defined herein as a single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic.
  • any non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5/-/-cyclopentapyrimidinyl) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl).
  • exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heteroaryl group can be oxidized (e.g., N ⁇ O ' , S(O), SO 2 ). Where so indicated, heteroaryl groups can be substituted.
  • Non-limiting examples of monocyclic heteroaryl rings include, for example: 1 ,2,3,4-tetrazolyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, triazinyl, thiazolyl, 1 H- imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, and pyridinyl.
  • heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7/-/-purinyl, 9/-/-purinyl, 5H-pyrrolo[3,2-c/]pyrimidinyl, 7H-pyrrolo[2,3- c/]pyrimidinyl, pyrido[2,3-cf]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1 /-/-indolyl, 4,5,6,7- tetrahydro-1-/-/-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, and isoquinolinyl.
  • heteroaryl group as described above is C 1 -C 5 heteroaryl, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and sulfur (S).
  • C 1 -C 5 heteroaryl examples include, but are not limited to for example, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1 /-/-imidazol-2-yl, 1 H- imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
  • fused ring groups, spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring.
  • 1 ,2,3,4-tetrahydroquinoline having the formula:
  • aryl ring When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine having the formula:
  • treat and “treating,” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.
  • therapeutically effective refers to a substance or an amount that elicits a desirable biological activity or effect.
  • the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered.
  • accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, but are not limited to for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.
  • substituted is used throughout the specification.
  • the term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more (e.g. 1- 10) hydrogen atoms replaced by a substituent as defined herein below.
  • Substituents include those that are capable of replacing one or two hydrogen atoms of a single moiety at a time, and also those that can replace two hydrogen atoms on two adjacent carbons to form said substituent.
  • substituents that replace single hydrogen atoms includes, for example, halogen, hydroxyl, and the like.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • Substituents that replace two hydrogen atoms from adjacent carbon atoms include, for example, epoxy, and the like.
  • any number of its hydrogen atoms can be replaced, as described above.
  • difluoromethyl is a substituted C 1 alkyl
  • trifluoromethyl is a substituted C 1 alkyl
  • 4-hydroxyphenyl is a substituted aryl ring
  • (N,N-dimethyl-5-amino)octanyl is a substituted C 8 alkyl
  • 3- guanidinopropyl is a substituted C 3 alkyl
  • 2-carboxypyridinyl is a substituted heteroaryl.
  • Ci -6 alkyl is specifically intended to individually disclose Ci , C 2 , C 3 , C 4 , C 5 , C 6 , Ci-C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 alkyl.
  • the present invention provides compounds of Formula I:
  • Ar 1 is selected from C 6 -Ci 0 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1- 5 R 11 groups;
  • R 2 is selected from H, Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3-I0 cycloalkyl, Ci -3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR 18 , SR 18 , NR 28 R 29 , SO 2 R 30 , C 6 -Ci 0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci -6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, and C 3- io cycloalkyl each is optionally substituted with 1-5 R 15 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R 16 groups;
  • R 3 is selected from H, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3-I0 cycloalkyl, Ci -3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR 18 , SR 18 , NR 31 R 32 , SO 2 R 30 , C 6 -Ci 0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and
  • Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, and C 3 _i 0 cycloalkyl each is optionally substituted with 1-5 R 15 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R 16 groups;
  • R 4 is selected from H and Ci -6 alkyl
  • each R 5 and R 6 is independently selected from H, Ci -6 alkyl, halogen and NHSO 2 Ci -6 alkyl;
  • any two R 5 and R 6 taken together with the carbon to which they are bound, can form a carbonyl group
  • each R 7 and R 8 is independently selected from H, Ci -6 alkyl, and halogen;
  • any two R 7 and R 8 taken together with the carbon to which they are bound, can form a carbonyl group
  • each R 9 and R 10 is independently are selected from H, Ci -6 alkyl, and halogen; alternatively, any two R 9 and R 10 taken together with the carbon to which they are bound, can form a carbonyl group;
  • each R 11 is independently selected from C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C3-10 cycloalkyl, C 1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR 12 , SR 12 , NO 2 and NR 13 R 14 , wherein the Ci -6 alkyl, the C 2 . 6 alkenyl, the C 2 . 6 alkynyl, and the C 3- io cycloalkyl is optionally substituted with 1-5 R 15 groups, and wherein the cycloheteroalkyl is optionally substituted with 1-5 R 16 groups;
  • each R 12 is independently selected from H, Ci -6 alkyl, and Ci -3 perhaloalkyl;
  • each R 13 and R 14 is independently selected from H and Ci -6 alkyl
  • each R 15 is independently selected from halogen, CN, OH, Ci -6 alkoxy, Ci -3 perhaloalkoxy, SH, SCi_ 6 alkyl, NH 2 , NH(Ci_ 6 alkyl), and N(Ci_ 6 alkyl) 2 ;
  • each R 16 is independently selected from Ci -6 alkyl, Ci -3 perhaloalkyl, halogen, CN, OH, OCi -6 alkyl, Od_ 3 perhaloalkyl, SH, SCi -6 alkyl, NH 2 , NH(Ci -6 alkyl), and N(Ci -6 alkyl) 2 ;
  • each R 17 is independently selected from C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, NO 2 , C 3 . 10 cycloalkyl, C 1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR 18 , SR 18 , NR 19 R 20 , C 6 -C 10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, and C 3-10 cycloalkyl is optionally substituted with 1-5 R 21 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with 1-5 R 22 groups;
  • each R 18 is independently selected from H, Ci -6 alkyl, Ci -3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci -6 alkyl optionally is substituted with 1-4 R 23 groups;
  • each R 21 is independently selected from halogen, CN, OH, Ci -6 alkoxy, SH, SCi -6 alkyl, NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 , 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;
  • each R 22 is independently is selected from Ci -6 alkyl, Ci -3 perhaloalkyl, halogen, CN, OH, OCi_ 6 alkyl, Ci_ 3 perhaloalkoxy, SH, SCi_ 6 alkyl, NH 2 , NH(Ci_ 6 alkyl), -CH 2 - heteroaryl and N(Ci -6 alkyl) 2 ;
  • each R 23 is independently is selected from halogen, CN, OH, OCi -6 alkyl, NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 , 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the cycloheteroalkyl, aryl , and heteroaryl each is optionally substituted with 1-4 groups selected from Ci -6 alkyl, Ci -3 perhaloalkyl, and halogen;
  • R 24 is Ci -6 alkyl optionally substituted with 1-4 groups selected fromhalogen, CN, OH, OCi_ 6 alkyl, OCi_ 3 perhaloalkyl, SH, SCi_ 6 alkyl, NH 2 , NH(Ci_ 6 alkyl), and N(Ci_ 6 alkyl) 2 ;
  • each R 25 , R 26 and R 27 is independently selected from H and Ci -6 alkyl
  • R 30 is selected from Ci -6 alkyl, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1-4 groups selected from Ci -6 alkyl, halogen, CN, OH, OCi_ 6 alkyl, OCi_ 3 perhaloalkyl, SH, SCi_ 6 alkyl, NH 2 , NH(Ci_6 alkyl), and N(Ci_6 alkyl) 2 ;
  • R 33 is selected from Ci -6 alkyl optionally substituted with 1-4 R 36 groups, C 6 -Ci 0 aryl optionally substituted with 1-4 R 37 groups, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-4 R 37 groups;
  • R 34 and R 35 each independently is selected from H, Ci -6 alkyl optionally substituted with 1-4 R 36 groups, C 6 -Ci 0 aryl optionally substituted with 1-4 R 37 groups, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-4 R 37 groups;
  • each R 36 is independently selected from halogen, CN, OH, Ci -6 alkoxy, Ci -3 perhaloalkoxy, SH, SCi -6 alkyl, NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 , C 6 or Ci 0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;
  • each R 37 is independently selected from Ci -6 alkyl, Ci -3 perhaloalkyl, halogen, CN, OH, Ci -6 alkoxy, Ci -3 perhaloalkoxy, SH, SCi -6 alkyl, NH 2 , NH(Ci -6 alkyl), and N(Ci -6 alkyl) 2 ;
  • n O, 1 2, 3, or 4;
  • n is O, 1 , 2, 3, 4, 5 or 6; and p is O, 1 , 2, 3, 4, 5 or 6.
  • R 1 is H.
  • R 4 is H or C 1-6 alkyl.
  • m is 0, 1 , 2, or 3. In some embodiments, m is 1 and R 5 and R 6 , are each methyl or H (e.g., both R 5 and R 6 are H). In some embodiments, m is 2 and R 5 and R 6 , at each occurrence, are each methyl or H (e.g., R 5 and R 6 , at each occurrence, are each H). In some embodiments, m is 3 and R 5 and R 6 , at each occurrence, are each methyl or H (e.g., R 5 and R 6 , at each occurrence, are each H).
  • Ar 1 is a C 6 -C 10 aryl ring or a 5-14 membered heteroaryl ring, each aryl or heteroaryl ring having at least one substituent selected from C r6 alkyl, halogen, C r6 alkoxy, OH, NH 2 , NH(d_ 6 alkyl), N(d_ 6 alkyl) 2 , NO 2 , C 1 - S haloalkyl, d_ 3 haloalkoxy, SH, SC 1 ⁇ alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to
  • Ar 1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from C r6 alkyl, halogen, C r6 alkoxy, OH, NH 2 , NH(C ⁇ 6 alkyl), N(d_ 6 alkyl) 2 , NO 2 , C 1-3 haloalkyl, C 1-3 haloalkoxy, SH, SC 1-6 alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, wherein the C 1-6 alkyl group optionally is substituted with R 15 and wherein the 3-10 membered cycloheteroalkyl optionally is substituted with R 16 .
  • Ar 1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, F, Cl, OH, OCH 3 , OCF 3 , SCH 3 , CH 2 N(CH 3 ) 2 , and pyrrolidinyl, piperidinyl, piperazinyl, N- methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl.
  • Ar 1 is para-substituted phenyl (e.g., 4-methoxyphenyl).
  • Ar 1 is selected from pyridine and pyrimidine, each optionally substituted with 1-5 R 11 groups.
  • Ar 2 is phenyl substituted with 1 , 2, or 3 substituents independently selected from halogen, C r6 alkyl, C 3 . 10 cycloalkyl, Ci -3 perhaloalkyl, 3-
  • Ci -6 alkyl and the C 3-I0 cycloalkyl are each optionally substituted with 1-5 R 21 groups, and wherein the cycloheteroalkyl and heteroaryl each optionally is substituted with 1-5 R 22 groups.
  • Ar 2 is phenyl substituted with Ci -6 alkyl (e.g., 4-(tert- butyl)phenyl) or C 3 _i 0 cycloalkyl (e.g., 4-cyclopropylphenyl).
  • Ci -6 alkyl e.g., 4-(tert- butyl)phenyl
  • C 3 _i 0 cycloalkyl e.g., 4-cyclopropylphenyl
  • Ar 2 is phenyl substituted with 1 , 2 or 3 substitutents independently selected from F, Cl, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyclopropyl, trifluoromethyl, pyrrolidine, piperidine, piperazine N-methylpiperazine, N- ethylpiperazine, morpholine, pyridine, imidazole and 2-methylimidazole.
  • Ar 2 is phenyl substituted with 1 , 2, or 3 OR 18 groups.
  • R 18 is selected from H, Ci -6 alkyl, Ci -3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci -6 alkyl optionally is substituted with 1-4 R 23 groups.
  • R 18 is Ci -6 alkyl.
  • R 18 is Ci -6 alkyl substituted with 1-4 groups selected from halogen, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, a C 6 -Ci 0 aryl ring, and a 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O and S.
  • R 18 is Ci -6 alkyl substituted with 1-2 groups selected from F, phenyl, pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl.
  • Ar 2 is phenyl substituted with 1 , 2, or 3 NR 19 R 20 groups.
  • Ar 2 is phenyl substituted with two R 17 groups, wherein the two R 17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring selected from pyrrolidine, 1 ,3-dioxolane, 1 ,4-dioxane, pyrrolidine, piperidine, piperazine and morpholine, each optionally substituted with 1-5 R 22 groups.
  • Examples of these compounds include those wherein Ar 2 is benzo[d][1 ,3]dioxolyl, 2,2-difluorobenzo[d][1 ,3]dioxolyl, indolinyl, N-methylindolinyl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1 ,4]oxazinyl, N-methyl-3,4- dihydro-2H-benzo[b][1 ,4]oxazinyl, 1 ,2,3,4-tetrahydroquinolinyl, and N-methyl-1 , 2,3,4- tetrahydroquinolinyl.
  • Ar 2 is para-substituted phenyl.
  • Ar 2 is 5-10 membered heteroaryl optionally substituted with 1- 5 R 17 groups.
  • Ar 2 can be selected from furanyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, and quinolinyl, each optionally substituted with 1-5 R 17 groups.
  • R 2 is selected from H, CN, Ci -6 alkyl optionally substituted with 1-5 R 15 groups, and C 2 . 6 alkenyl optionally substituted with 1-5 R 15 groups.
  • R 2 is C 6 -Ci 0 aryl (e.g., phenyl) optionally substituted with 1-5 R 16 groups.
  • R 2 is OR 18 .
  • R 18 is phenyl optionally substituted with 1-4 R 23 groups or 5-10 membered heteroaryl optionally substituted with 1-4 R 23 groups.
  • R 2 is SO 2 R 30 .
  • R 30 is optionally substituted C 1 -C 6 alkyl, or optionally substituted 6-10 membered aryl.
  • R 2 is 5-10 membered heteroaryl (e.g., pyridinyl, pyrimidinyl, imidazolyl or pyrazolyl) optionally substituted with 1-5 R 16 groups
  • R 2 is C 3 . 10 cycloalkyl (e.g., C 3 . 6 cycloalkyl) optionally substituted with 1-5 R 15 groups.
  • R 2 is 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S (e.g., piperidinyl) optionally substituted with 1- 5 R 16 groups.
  • R 2 is NR 28 R 29 .
  • R 28 is H, and R 29 is C(O)R 30 .
  • R 30 can be optionally substituted 5-10 membered heteroaryl (e.g., pyridinyl, imidaziolyl, pyrimidinyl or pyrazinyl).
  • R 28 is H, and R 29 is C(O)OR 30 .
  • R 30 can be C 1 -C 6 alkyl.
  • R 28 and R 29 are each independently H or C 1 -C 6 alkyl.
  • R 28 is H, and R 29 is C(O)NR 26 R 27 .
  • R 28 and R 29 can each independently be H or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 5-10 membered heteroaryl or 6-10 membered aryl, wherein the 6-10 membered aryl and the 5-10 membered heteroaryl are each optionally and independently substituted with 1-5 R 16 groups.
  • n is 0, 1 , 2, 3, or 4. In some embodiments, n is 1 and R 7 and R 8 each is H. In some embodiments, n is 1 and R 7 and R 8 , taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, n is 2 and each R 7 and R 8 , at each occurrence, is H. In some embodiments, n is 2 and one R 7 and R 8 , taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, n is 3 and each R 7 and R 8 , at each occurrence, is H.
  • n is 3 and one R 7 and R 8 , taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, n is 4 and each R 7 and R 8 , at each occurrence, is H. In some embodiments, n is 4 and one R 7 and R 8 , taken together with the carbon to which they are bound, form a carbonyl.
  • p is 0. In some embodiments, p is 0 and R 3 is H or C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl or tert-butyl). In some embodiments, R 4 is H. In some embodiments, R 3 and R 4 are each independently H or C 1-6 alkyl.
  • R 3 is C 6 -C 10 aryl (e.g., phenyl) or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., pyrrolyl, imidazolyl, pyridinyl, or pyrimidinyl), each optionally substituted with 1-5 R 16 groups.
  • aryl e.g., phenyl
  • 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S e.g., pyrrolyl, imidazolyl, pyridinyl, or pyrimidinyl
  • R 3 is NR 31 R 32 .
  • one of R 31 and R 32 is H and the other is SO 2 R 33 .
  • R 33 can be C 1-6 alkyl optionally substituted with 1-4 R 34 groups (e.g., C 6 or C 10 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S).
  • R 33 is benzyl or CH 2 -pyridinyl.
  • R 3 is NR 31 R 32 and one of R 31 and R 32 is H and the other is C(O)NR 34 R 35 .
  • R 34 and R 35 can each independently be H or C 1-6 alkyl. In some embodiments, one of R 34 and R 35 is H and the other is C 1-6 alkyl. In other embodiments, one of R 34 and R 35 is H and the other is C 6 -C 10 aryl (e.g., phenyl) or 5- 10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., pyridinyl or pyrimidinyl).
  • one of R 34 and R 35 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl or tert-butyl) and the other is C 6 -C 10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., phenyl, pyridinyl or pyrimidinyl).
  • C 1-6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl or tert-butyl
  • the other is C 6 -C 10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., phenyl, pyridinyl or pyrimidinyl).
  • R 3 is NR 31 R 32 and one of R 31 and R 32 is H and the other is C(O)OR 33 .
  • R 33 can be C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl or tert- butyl) optionally substituted with 1-4 R 36 groups (e.g., NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 6 or C 10 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S).
  • R 33 is benzyl.
  • R 3 is NR 31 R 32 and one of R 31 and R 32 is H and the other is C 6 or C 10 aryl (e.g., phenyl), or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., pyridinyl or pyrimidinyl).
  • aryl e.g., phenyl
  • heteroaryl containing 1-4 heteroatoms selected from N, O and S e.g., pyridinyl or pyrimidinyl
  • R 3 is NR 31 R 32 and each of R 31 and R 32 is H.
  • R 3 is NR 31 R 32 and each of R 31 and R 32 independently is Ci -6 alkyl optionally substituted with 1-4 R 36 groups. In some embodiments, each of R 31 and R 32 independently is selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, benzyl and CH 2 -pyridinyl.
  • R 3 is OR 18 .
  • R 18 can be H or Ci -6 alkyl optionally is substituted with 1-4 R 23 groups (e.g., R 18 can be benzyl or CH 2 -pyridinyl).
  • R 3 is C 6 -Ci 0 aryl (e.g., phenyl) or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl or quinolinyl), each optionally substituted with 1-5 R 16 groups.
  • aryl e.g., phenyl
  • 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S e.g., pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl or quinolinyl
  • p is 1 , 2, 3, or 4. In some embodiments, p is 1 and each of R 9 and R 10 is H. In some embodiments, p is 1 and R 9 and R 10 , taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, p is 2 and each of R 9 and R 10 , at each occurrence, is H. In some embodiments, p is 2 and one of R 9 and R 10 , taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, p is 3 and each of R 9 and R 10 , at each occurrence, is H.
  • p is 3 and one of R 9 and R 10 , taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, p is 4 and each of R 9 and R 10 , at each occurrence, is H. In some embodiments, p is 4 and one of R 9 and R 10 , taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, the compounds of the invention have a structure according to Formula (II):
  • m is 1 , 2 or 3 and Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , n, and p are defined as above.
  • m is 1 and R 5 and R 6 are each H. In some embodiments, m is 1 and one of R 5 and R 6 is H and the other is Ci -6 alkyl. In some embodiments, m is 1 and R 5 and R 6 , at each occurrence, are each H. In some embodiments, Ar 1 is para-substituted phenyl (e.g., 4-methoxyphenyl).
  • the compounds of the invention have a structure according to Formula (III):
  • n 0, 1 , 2, 3, 4 or 5 and Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m, and p are defined above.
  • Ar 1 when R 1 is H, Ar 2 is phenyl, n is 0 and R 2 is H, p is 1 and R 3 is phenyl, and m is 0, then Ar 1 cannot be 4-methylphenyl or cyclohexyl. In some embodiments, when R 1 is H, Ar 2 is phenyl, n is 0 and R 2 is H, p is 1 and R 3 is phenyl, and m is 1 , then Ar 1 cannot be phenyl.
  • Ar 2 when p is 0 and R 3 is H, R 4 is H, n is 1 and R 2 is phenyl, m is 1 and Ar 1 is phenyl, and R 1 is H, then Ar 2 cannot be 4-chlorophenyl or A- (dimethylamino)phenyl.
  • each R 17 is independently selected from Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3-I0 cycloalkyl, Ci -3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR 18 , SR 18 , NR 19 R 20 , C 6 -Ci 0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • two R 17 groups together with the carbon atoms to which they are bound, form a 5 or 6 membered ring containing 1-2 heteroatoms selected from N, O and S, and optionally substituted with 1-5 R 22 groups;
  • Ar 2 is selected from C 6 -Ci 0 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1- 5 R 17 groups;
  • each R 11 is independently selected from Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3-I0 cycloalkyl, Ci -3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR 12 , SR 12 , and NR 13 R 14 , wherein the Ci -6 alkyl, the C 2 . 6 alkenyl, the C 2 . 6 alkynyl, and the C 3 _i 0 cycloalkyl each is optionally substituted with 1-5 R 15 groups, and wherein the cycloheteroalkyl is optionally substituted with 1-5 R 16 groups; and
  • each R 22 is independently is selected from Ci -6 alkyl, Ci -3 perhaloalkyl, halogen, CN, OH, OCi_ 6 alkyl, Ci_ 3 perhaloalkoxy, SH, SCi_ 6 alkyl, NH 2 , NH(Ci_ 6 alkyl), and N(Ci_ 6 alkyl) 2 .
  • asymmetric atom also referred as a chiral center
  • some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers.
  • the present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to for example, chiral chromatography, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis.
  • the present invention also includes cis and trans or E/Z isomers of compounds of Formula (I) containing alkenyl moieties (e.g., alkenes and imines).
  • alkenyl moieties e.g., alkenes and imines.
  • the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
  • salts of compounds of the present invention can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation.
  • Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethy l-tert-buty I- , diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine).
  • metal salts such as alkali metal or alkaline earth metal salts, for
  • inorganic bases include NaHCO 3 , Na 2 CO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , LiOH, NaOH, KOH, NaH 2 PO 4 , Na 2 HPO 4 , and Na 3 PO 4 .
  • Internal salts also can be formed.
  • salts can be formed using organic and inorganic acids.
  • salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic, carbonic, as well as other known pharmaceutically acceptable acids.
  • the compounds described herein may be administered to humans and other animals orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, intracisternally, intravaginally, intraperitoneal ⁇ , bucally, intrathecal ⁇ or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral as used herein includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices.
  • compositions for use in the present invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Formulations comprising crystalline forms of the compositions described herein for slow absorption from subcutaneous or intramuscular injection are provided herein. Additionally, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the compounds in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes.
  • the compounds described herein can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention.
  • compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder.
  • Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
  • Effective amounts of the compounds of the invention generally include any amount sufficient to detectably modulate Kv1.5 potassium channel activity, or to alleviate symptoms of diseases associated with Kv1.5 potassium channel activity or susceptible to Kv1.5 potassium channel activity modulation.
  • kits that include one or more compounds of the invention are provided.
  • kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including directions for treating or preventing atrial arrhythmia, thromboembolism, stroke, or cardiac failure by administering an effective amount of a compound of the present invention.
  • a compound described herein e.g., a compound of Formula I
  • a package insert or other labeling including directions for treating or preventing atrial arrhythmia, thromboembolism, stroke, or cardiac failure by administering an effective amount of a compound of the present invention.
  • kits that include one or more compounds of the invention are provided.
  • Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including directions for inhibiting Kv1.5 potassium channel by administering an effective amount of a compound of the present invention.
  • kits that include one or more compounds of the invention are provided.
  • Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including directions for inducing cardioversion by administering an effective amount of a compound of the present invention.
  • the Kv1.5 potassium channel inhibitors of the present invention are certain A- imidazolidinones, and include all enantiomeric and diasteriomeric forms and salts of compounds having the formula (I):
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high-performance liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high-performance liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • HPLC high-performance liquid chromatograpy
  • GC gas chromatography
  • GPC gel-permeation
  • Preparation of the compounds can involve protection and deprotection of various chemical groups.
  • the chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th. Ed. (John Wiley & Sons, 2007), the entire disclosure of which is incorporated by reference herein for all purposes.
  • Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • the compounds of these teachings can be prepared by methods known in the art.
  • the reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes:
  • reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds in the genus may be produced by one of the following reaction schemes.
  • Functionalized amino acid amides may be prepared using standard literature procedures. Ring closure to form the 4-imiddazolidinone 3 can be accomplished by heating 1 in the presence of a suitable aldehyde (2) in an appropriate solvent or as a neat mixture of the two. Conventional or microwave heating may be employed.
  • amino acid amide 4 may be cyclized to imidazolidinone 5 by by heating in the presence of a suitable aldehyde (2) in an appropriate solvent or as a neat mixture of the two. Conventional or microwave heating may be employed.
  • Functionalization in the presence of a base and suitable electrophilic (e.g. alkyl halide, alkyl sulfonate, sulfonyl halide, acid halide) agent provides the desired imidazolidinone.
  • amino acid side chain examples e.g. 6 where PG is a suitable protecting group
  • removal of the protecting group using standard conditions provides imidazolidinone 7.
  • Amide synthesis may then be accomplished using standard literature procedure to provide 8.
  • imidazolidinone 7 may be converted to suitably protected amines (9) using methods described in the literature, which may be subsequently deprotected under the appropriate conditions to provide the free amine 10.
  • Side chain functionalization may then be accomplished with a suitable electrophile (e.g. carboxylic acid, carboxylic acid halide, sulfonyl halide, isocyanante) in the presence or absence of a suitable coupling agent (e.g. EDCI) or base (e.g. NEt 3 , DIPEA) to provide 11.
  • a suitable electrophile e.g. carboxylic acid, carboxylic acid halide, sulfonyl halide, isocyanante
  • a suitable coupling agent e.g. EDCI
  • base e.g. NEt 3 , DIPEA
  • Reduction of 7 with a suitable reducing agent may also be employed to provide alcohol 12.
  • a suitable reducing agent e.g. borane
  • Conversion of the alcohol to a leaving group e.g. halide or sulfonate
  • a nucleophile provides 13 where Nu is a suitable alcohol or amine.
  • Step 1 2-Bromo-N-[2-(4-methoxyphenyl)ethyl]acetamide: To 12.9 mL (148.6 mmol) of bromoacetylbromide in 500 mL of anhydrous methylene chloride at room temperature was added 45.7 mL (312.1 mmol) of 4-methoxyphenethyl amine. The resulting solution was stirred for 12 hours and monitored by TLC. 900 mL of 0.1 N HCI was added and the organic layer was separated in a separatory funnel. The remaining aqueous layer was extracted with methylene chloride (3 x 200 mL) and all organic layers were combined.
  • Step 2 2-(Benzylmethylamino)-N-[2-(4-methoxyphenyl)ethyl]acetamide: To 40 g (147.1 mmol) of 2-bromo-N-[2-(4-methoxyphenyl)ethyl]acetamide in 200 mL of THF at room temperature was added 36 mL (294.2 mmol) of N-methyl benzyl amine.
  • Step 3 N-[2-(4-Methoxyphenyl)ethyl]-2-methylaminoacetamide: To 44 g of 2- (benzylmethylamino)-N-[2-(4-methoxyphenyl)ethyl]acetamide in ethanol at room temperature was added 5.0 g of 10% Pd/C and the mixture was put on a hydrogen Parr reduction apparatus (40 psi of H 2 ). The resulting mixture was shaken on the Parr reduction machine and recharged with hydrogen gas to maintain the 40 psi of hydrogen gas for 16 hours. The mixture was then filtered through celite, and the solvent removed in vacuo resulting in 31.7 g (100 % yield) of product as a yellow oil.
  • Step 4 2-(4-fe/?-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin-4- one: To 20.0 g (90.1 mmol) of N-[2-(4-methoxyphenyl)ethyl]-2- methylaminoacetamide in 200 ml. of methanol at room temperature was added 13.7 g (99.1 mmol) of potassium carbonate and 13.1 ml. (99.1 mmol) of A-t- butylbenzaldehyde. The resulting mixture was stirred at reflux and monitored by
  • Examples 2-48 were prepared according to the procedures described in Example 1 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • Example 2 2-(4-fe/?-Butylphenyl)-3-[2-(3-methoxyphenyl)ethyl]-1- methylimidazolidin-4-one, 1 H NMR (300 MHz, CDCI 3 ) 87.42 (m, 1 H), 7.19 (m, 3H),
  • Example 16 R-3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-methylimidazolidin- 4-one, 1 H NMR (300 MHz, CDCI 3 ) 87.43 (m, 2H), 7.26 (m, 2H), 6.96 (m, 2H), 6.81 (m, 2H), 4.41 (s, 1 H), 3.80 (s, 3H), 3.70 (m, 2H), 3.15 (m, 1 H), 2.78 (m, 2H), 2.50 (m, 1 H), 2.26 (s, 3H), 1.36 (m, 9H); (MH + ) 367.
  • Example 17 S-3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-methylimidazolidin- 4-one, 1 H NMR (300 MHz, CDCI 3 ) 87.44 (m, 2H), 7.26 (m, 2H), 6.96 (m, 2H), 6.81 (m, 2H), 4.42 (s, 1 H), 3.80 (s, 3H), 3.70 (m, 2H), 3.15 (m, 1 H), 2.79 (m, 2H), 2.50 (m, 1 H), 2.26 (s, 3H), 1.36 (m, 9H); (MH + ) 367.
  • Example 27 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-1 -ethyl imidazolidin-4-one, 1 H-NMR (300 MHz, CDCI 3 ) ⁇ 7.50 (d, 2H, 8.4Hz), 7.22 (d, 2H,
  • Amino amides were prepared as indicated previously.
  • Examples 50-69 were prepared according to the procedures described in Example 49 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • Example 50 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(dimethylamino)phenyl)-1- methylimidazolidin-4-one, 391 mg, chemical yield 52.4%.
  • Example 70 3-(4-Methoxyphenethyl)-1-methyl-2-(1-methyl-1 , 2,3,4- tetrahydroquinolin-6-yl)imidazolidin-4-one
  • Examples 71-74 were prepared according to the procedures described in Example 69 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • corresponding reagents e.g., corresponding amino acid, amine, and aldehyde reagents
  • Step 1 fe/f-Butyl 2-(4-methoxyphenethylamino)-2-oxoethylcarbamate: To a solution of 2-(fe/?-butoxycarbonyl)acetic acid (20.0 g, 1 14.3 mmol) and 2-(4- methoxyphenyl)ethylamine (18.0 ml_, 122.9 mmol) in CH 2 CI 2 (825 ml.) was added EDCI (32.9 g, 171.8 mmol). The reaction mixture was stirred at room temperature for 4 days, washed with 0.1 N HCI (2 x 500 ml_), dried over Na 2 SO 4 and evaporated to yield 32.4 g of the desired product.
  • Step 2 N-(4-methoxyphenethyl)-2-aminoacetamide hydrochloride: To a solution of fe/t-butyl 2-(4-methoxyphenethylamino)-2-oxoethylcarbamate (32.39 g, 105.0 mmol) in MeOH (350 ml.) was slowly added a solution of HCI in dioxane (4.0 N, 100 ml_, 400.0 mmol). The reaction mixture was stirred at RT for 16 h and evaporated to yield 24.44 g of the desired product.
  • Step 3 3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)imidazolidin-4-one: To a solution N-(4-methoxyphenethyl)-2-aminoacetamide hydrochloride (5.1 g, 20.7 mmol) and 4-fe/f-butylbenzaldehyde (3.6 ml_, 21.5 mmol) in MeOH (140 ml.) was added Cs 2 CO 3 (7.3 g, 22.2 mmol). The reaction mixture was warmed to 60 0 C for 17 h followed by evaporation of the MeOH.
  • Step 4 1-(4-Methoxybenzyl)-3-(4-methoxyphenethyl)-2-(4-fe/f- butylphenyl)imidazolidin-4-one, To a solution of 3-(4-methoxyphenethyl)-2-(4-fe/f- butylphenyl)imidazolidin-4-one in 100 ml. DMF (0.5 g 1.4 mmol) sodium hydride (0.04 g 1.6 mmol) was added and stirred for 10 minutes, followed by the addition of p-methoxybenzyl chloride (02 g 1.6 mmol). The new solution was stirred overnight. 400 ml.
  • Examples 76-85 were prepared according to the procedures described in Example 74 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • corresponding reagents e.g., corresponding amino acid, amine, and aldehyde reagents
  • Examples 87-88 were prepared according to the procedures described in Example 85 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • Step 1 3-(4-methoxyphenethyl)-2-(4-te/?-butylphenyl)-1-(3-(pyridin-3- ylmethoxy)propyl)imidazolidin-4-one: To a solution of 3-(4-methoxyphenethyl)-2-(4- fe/?-butylphenyl)-1-(3-hydroxypropyl)imidazolidin-4-one (0.2 g, 0.6 mmol) in THF (6.0 ml.) was added Et 3 N (0.2 ml_, 1.2 mmol) followed by methanesulfonyl chloride (0.05 ml_, 0.65 mmol).
  • reaction mixture was stirred at room temperature for 18 hours followed by evaporation of the THF and dilution in methylene chloride.
  • methylene chloride was washed with 0.1 N HCI (2x), dried over Na 2 SO 4 and evaporated to yield 0.3 g of the desired product.
  • Step 2 3-(4-Methoxyphenethyl)-2-(4-te/?-butylphenyl)-1-(3-(pyridin-3- ylmethoxy)propyl)imidazolidin-4-one: To a solution of 3-(3-(4-methoxyphenethyl)-2- (4-fe/?-butylphenyl)-4-oxoimidazolidin-1-yl)propyl methanesulfonate (0.1 g, 0.3 mmol) in THF (7.5 ml.) was added NaH (60%, 0.02 g, 0.6 mmol) followed by pyridin- 3-ylmethanol (0.04 ml_, 0.4 mmol).
  • reaction mixture was stirred at room temperature for 17 hours at which time additional NaH (60%, 0.06 g, 1.43 mmol) and pyridin-3-ylmethanol (0.12 ml_, 1.3 mmol) were added.
  • the reaction mixture was warmed to 50 0 C for a total reaction time of 41 hours followed by evaporation to yield the crude product.
  • the crude material was purified by reverse phase HPLC to yield 0.06 g of the desired product.
  • Example 90 was prepared according to the procedures described in Examples 88 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • Examples 92-95 were prepared according to the procedures described in Examples 90 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • Example 92 3-(4-Methoxyphenethyl)-2-(4-te/?-butylphenyl)-1-(3- fluorophenylsulfonyl)imidazolidin-4-one, 1 H NMR (300 MHz, CDCI 3 ) ⁇ 7.08 (m, 12 H), 5.19 (m, 2 H), 3.89 (m, 2 H), 3.81 (s, 3 H), 2.87 (m, 2 H), 2.68 (m, 1 H), 2.28 (s, 3 H); (MH + ) 51 1.
  • Example 96 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-3-yl)propanamide
  • Step 1 (S)-benzyl 4-(3-(benzyloxy)-3-oxopropyl)-5-oxooxazolidine-3-carboxylate: The mixture Of Z-GIu(BzI)-OH (3.7 g, 10.0 mmol), p-toluenesulfonic acid (190 mg, 1.0 mmol), and paraformaldehyde (2.5 g) in toluene (120 ml.) was refluxed for 1.5 h. The solution was decanted into a separatory funnel, diluted with ether, washed with 5% NaHCO 3 and brine, and dried over Na 2 SO 4 .
  • Step2 (S)-5-(benzyloxy)-2-(benzyloxycarbonyl)-5-oxopentanoic acid: To the solution of (S)-benzyl 4-(3-(benzyloxy)-3-oxopropyl)-5-oxooxazolidine-3-carboxylate (3.5 g, 9.1 mmol) in CHCI 3 at room temperature was added triethylsilane (4.4 ml_, 27.4 mmol) followed by trifluoroacetic acid (46 ml_). The resultant solution was stirred at room temperature for 2 days.
  • Step 3 (S)-benzyl 5-(4-(trifluoromethoxy)phenethylamino)-4-(benzyloxycarbonyl)-5- oxopentanoate: To the solution of (S)-5-(benzyloxy)-2-(benzyloxycarbonyl)-5- oxopentanoic acid (1.4 g, 3.7 mmol) and trifluoromethoxyphenethylamine hydrochloride (0.84 g, 3.5 mmol) in DMF (30 ml.) was added Et 3 N (1.5 ml_, 4.7 mmol), HOBt (0.71 g, 5.2 mmol), and EDC»HCI (1.0 g, 5.2 mmol).
  • Step 4 3-((4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-3-methyl-5- oxoimidazolidin-4-yl)propanoic acid: The mixture of (S)-benzyl 5-(4- (trifluoromethoxy)phenethylamino)-4-(benzyloxycarbonyl)-5-oxopentanoate (1.70 g, 3.0 mmol) and Pd-C (10%, 0.2 g) in 2-propanol (30 ml.) was stirred under hydrogen (1 atm) at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Step 5 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/t-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)-N-(pyridin-3-yl)propanamide: To the solution of 3-((4S)-1-(4-
  • Examples 97-101 were prepared according to the procedures described in Example 95 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • Example 102 benzyl 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-te/f- butylphenyl)-3-methyl-5-oxoimidazolidin-4-yl)ethylcarbamate
  • Example 103 N-(2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-te/f- butylphenyl)-3-methyl-5-oxoimidazolidin-4-yl)ethyl)picolinamide: A mixture of benzyl 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-3-methyl-5- oxoimidazolidin-4-yl)ethylcarbamate (78 mg, 0.13 mmol) and Pd-C (10%, 5 mg) in MeOH/THF (1 ml_/1 ml_) was stirred under H 2 (1 atm) for 2 hours at room temperature.
  • Examples 104-105 were prepared according to the procedures described in Example 101 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • corresponding reagents e.g., corresponding amino acid, amine, and aldehyde reagents
  • Example 107 (2R,5S)-5-(2-(benzyl(methyl)amino)ethyl)-2-(4-tert-butylphenyl)-1- methyl-3-(4-(trifluoromethoxy)phenethyl)imidazolidin-4-one: To a solution of (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-te/?-butylphenyl)-5-(2-hydroxyethyl)- 1-methylimidazolidin-4-one (130 mg, 0.28 mmol) and Et 3 N (78 ⁇ l_, 0.56 mmol) in THF (3 ml.) was added methanesulfonyl chloride (24 ⁇ l_, 0.31 mmol).
  • the resulting mixture was stirred at room temperature overnight.
  • the mixture was diluted with ethyl acetate and washed with water and brine, and dried over Na 2 SO 4 .
  • the solvent was removed under reduced pressure to give the crude product as light brown oil (478 mg).
  • the crude product (126 mg, 0.23 mmol) was dissolved in dry THF (1 ml_ and 1 ml. wash) and added to the mixture of 2-pyridinemethanol (44 ⁇ l_, 0.46 mmol) and NaH (60% dispersion, 18 mg, 0.47 mmol) in THF (1 ml.) at -78 0 C (prepared from adding NaH to the solution of 2-pyridinemethanol in THF at -78 0 C and stirring it for 20 min).
  • the resultant mixture was stirred at -78 0 C to room temperature overnight.
  • the mixture was diluted with ethyl acetate and washed with 5% NaHCO 3 , water, and brine, and then dried over Na 2 SO 4 .
  • the solvent was removed under reduced pressure and the trans-isomer was purified by HPLC (C18, water/acetonitrile) followed by washing with 10% Na 2 CO 3 to give the product as a free base (13 mg).
  • Examples 109-110 were prepared according to the procedures described in Example 108 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • corresponding reagents e.g., corresponding amino acid, amine, and aldehyde reagents
  • Example 110 (2S,5S)-3-(4-methoxyphenethyl)-5-(benzyloxymethyl)-2-(4- (diethylamino)phenyl)-1-methylimidazolidin-4-one, 1 H NMR (300 MHz, CDCI 3 ) ⁇ 7.36
  • Example 111 N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-te/?-butylphenyl)-3-methyl-5- oxoimidazolidin-4-yl)methyl)methanesulfonamide
  • Examples 112-115 were prepared according to the procedures described in Example 1 1 1 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • Example 115 N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)(pyridin-3-yl)methanesulfonamide, 1 H NMR (300 MHz,
  • Example 116 1-(((4S)-1-(4-methoxyphenethyl)-2-(4-te/?-butylphenyl)-3-methyl-5- oxoimidazolidin-4-yl)methyl)-3-ethylurea
  • Examples 117-121 were prepared according to the procedures described in Example 1 16 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • corresponding reagents e.g., corresponding amino acid, amine, and aldehyde reagents
  • Step 1 Preparation of fe/f-butyl 1-(4-methoxyphenethylamino)-2-methyl-1- oxopropan-2-ylcarbamate:
  • the starting BOC-Aib-OH 5.0 g, 24.6 mmol
  • methylene chloride 200 ml.
  • 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (6.13 g, 32.0 mmol)
  • 1- hydroxybenzotriazole (4.32 g, 32.0 mmol
  • Step 2 Preparation of N-(4-methoxyphenethyl)-2-amino-2-methylpropanamide: The fe/t-butyl 1-(4-methoxyphenethylamino)-2-methyl-1-oxopropan-2-ylcarbamate, (4.75 g, 14.1 mmol) was dissolved with stirring in methylene chloride (50 ml.) in a 10OmL single-neck flask equipped with a stir bar under an inert N 2 atmosphere. Next, trifluoroacetic acid (10.9 ml_, 141 mmol) was added to the reaction in one portion via syringe increasing the concentration to 25% by volume in acid.
  • the reaction was then vigorously stirred at room temperature for 3 hours. After transferring the mixture to a 500 mL Erlenmeyer flask, the reaction was slowly diluted with saturated aqueous NaHCO 3 (100 mL) and d.i. H 2 O (25 mL). The biphasic mixture was then basified to a constant pH of 9 via the addition of solid KOH. The mixture was separated and the remaining aqueous phase was further extracted with methylene chloride (2 x 100 mL). The combined organic extracts were filtered over anhydrous MgSO 4 , and evaporated to dryness on a roto-evaporator to give a viscous yellow syrup (3.06 g, chemical yield 92%).
  • Step 3 Preparation of 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5- dimethylimidazolidin-4-one:
  • the N-(4-methoxyphenethyl)-2-amino-2- methylpropanamide (1 g, 4.23 mmol) was dissolved in methanol (25 mL) in single- neck 100 mL flask equipped with a stir bar under an inert N 2 atmosphere.
  • K 2 CO 3 (644 mg, 4.66 mmol) was added to the reaction in one portion.
  • Example 123 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1 ,5,5- trimethylimidazolidin-4-one: The 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5- dimethylimidazolidin-4-one (200 mg, 0.53 mmol) was dissolved in dry tetrahydrofuran (15ml_) in a single-neck 25 ml. flask equipped with a stir bar under an inert N 2 atmosphere. Next, sodium hydride (13 mg, 0.58 mmol) was added to the reaction and allowed to stir for 15 minutes.
  • iodomethane (0.06 ml_, 1.16 mmol) was added to the reaction in one portion via syringe.
  • the reaction was vigorously stirred at room for 18 hours.
  • the reaction was evaporated to dryness on a roto-evaporator.
  • the resulting residue was partitioned between methylene chloride (25 mL) and saturated aqueous NaHCO 3 (25 mL) and separated.
  • the remaining aqueous layer was further extracted with methylene chloride (2 x 25ml_).
  • the combined organic extracts were then filtered over anhydrous MgSO 4 and evaporated to dryness.
  • Example 124 3-(4-Methoxyphenethyl)-2-(4-cyclopropylphenyl)-5,5- dimethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDCI 3 ) ⁇ 7.1 1 (m, 4H), 7.06 (m, 2H),
  • Example 127 3-(4-methoxyphenethyl)-2-(4-(diethylamino)phenyl)-1 ,5,5- trimethylimidazolidin-4-one.
  • Step 1 fe/t-butyl 1-(4-methoxyphenethylamino)-2-methyl-1-oxopropan-2- yl(methyl)carbamate: The starting N-BOC- ⁇ -(methylamino)/so-butryic acid (12.1 g, 55.9 mmol) was dissolved in methylene chloride (300 ml.) in a single-neck 50OmL flask equipped with a stir bar under an inert N 2 atmosphere.
  • Step 2 N-(4-methoxyphenethyl)-2-methyl-2-(methylamino)propanamide: The tert- butyl 1-(4-methoxyphenethylamino)-2-methyl-1-oxopropan-2-yl(methyl)carbamate, (12.9g, 36.8 mmol) was dissolved in methylene chloride (105 ml.) in a single-neck 50OmL flask under an inert N 2 atmosphere. Next, trifluoroacetic acid (35 mL) was added to the reaction mixture via syringe to increase the concentration to 25% acid by volume. The reaction was vigorously stirred at room temperature for 3 hours.
  • Step 3 3-(4-methoxyphenethyl)-2-(4-(diethylamino)phenyl)-1 ,5,5- trimethylimidazolidin-4-one: The N-(4-methoxyphenethyl)-2-methyl-2-
  • Examples 128-133 were prepared according to the procedures described in Example 127 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • corresponding reagents e.g., corresponding amino acid, amine, and aldehyde reagents
  • Step 1 Preparation of (9H-fluoren-9-yl)methyl)-3-((4- methoxyphenethyl)carbamoyl)pentan-3-ylcarbamate: To a solution of 2-(((9H- fluoren-9-yl)methoxy)carbonyl)-2-ethylbutanoic acid (1.76 g, 5.0 mmole) in DMF (15 ml.) was added PyBOP (2.6 g, 5.0 mmol). After stirring at room temperature for 10 min, 4-methoxyphenethyl amine (0.76 g, 5.0 mmol) was added, and the solution was stirred for a further 5 min.
  • Step 2 Preparation of N-(4-methoxyphenethyl)-2-amino-2-ethylbutanamide: To a solution of the (9H-fluoren-9-yl)methyl)-3-((4-methoxyphenethyl)carbamoyl)pentan- 3-ylcarbamate (1.40 g, 3.0 mmol) in DMF (10 ml.) was added piperdine (1 ml_). After stirring at room temperature for 2 h, the white ppt was removed and the filtrate was evaporated in vacuo to give desired product (1.7 g). This compound is used for the next step reactions without further purification
  • Step 3 Preparation of 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5- diethylimidazolidin-4-one: To the solution of the N-(4-methoxyphenethyl)-2-amino-2- ethylbutanamide (530 mg, 2.0 mmol in 5 ml. of methanol) and K 2 CO 3 (276 mg, 2.0 mmol) in a 2.0 - 5.0 ml. Emry's process vial equipped with a stir bar was added A- fe/t-butylbenzaldehyde (356 mg, 2.2 mmol). The reaction mixture was then capped, stirred 30 sec.
  • Example 135 1-N-methyl-3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5- diethylimidazolidin-4-one: To a solution of 409 mg (1 mmol) of 1-N-methyl-3-(4- methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5-diethylimidazolidin-4-one in 10 ml_ DMF was added 46 mg (2 mmol) of sodium hydride, followed by 710 mg (5 mmol) of iodomethane. The reaction was stirred at room temperature for 2 days and then stripped of solvent.
  • the starting cyclized 4-imidazolidinone (450 mg, 1.14 mmol) was dissolved with stirring in 2 mL of DMF which was then pipetted into an Emry's 2-5 mL process vial equipped with a stir bar. Next, cesium carbonate (746 mg, 2.29 mmol) was added to the reaction vial in one portion. Lastly, iodomethane (0.23 mL, 4.58 mmol) was added to the vial in one portion via syringe. The process vial was then capped and heated in a Biotage Initiator 60 microwave for 5 minutes at 150 0 C.
  • the reaction was cooled to room temperature, de-capped, and diluted in a mixture of 30 mL of de-ionized water and 30 mL of methylene chloride.
  • the bi-phasic fluids were then transferred to a separatory funnel and separated.
  • the remaining aqueous layer was extracted with 2 more 30 mL portions of metyhlene chloride.
  • the combined organic extracts were then filtered over anhydrous MgSO 4 and evaporated to dryness. Subsequent flash column chromatography affords a clear viscous syrup, 103 mg, chemical yield 22.2%.
  • the reaction vial was then capped and heated in a Biotage Initiator 60 microwave for 8.5 minutes at 200 0 C. The reaction was then cooled to room temperature and de-capped. The material was purified by flash column chromatography to afford a clear viscous syrup, 65 mg, chemical yield 15.0%.
  • the starting C-5 geminal dimethyl amino-amide (500 mg, 2.12 mmol) was added to an Emry's 2 - 5 mL process vial equipped with a stir bar.
  • 4- methylacetophenone (5.0 mL, 37.4 mmol) was added to the reaction in one portion via syringe.
  • the reaction vial was then capped and heated in a Biotage Initiator 60 microwave at 220 0 C for 5 minutes.
  • the reaction was then cooled to room temperature and de-capped.
  • the material was then purified by flash column chromatography to afford a pale yellow viscous syrup, 488 mg, chemical yield 65.3%.
  • Example 139 3-(4-methoxyphenethyl)-1 ,2,5,5-tetramethyl-2-p-tolylimidazolidin-4- one: 3-(4-methoxyphenethyl)-2,5,5-trimethyl-2-p-tolylimidazolidin-4-one (301 mg, 0.85 mmol) was added to an Emry's 2 - 5 mL process vial equipped with a stir bar. Next, the material was dissolved in 2 mL of DMF with stirring. This was followed by the addition of cesium carbonate (557 mg, 1.71 mmol). Lastly, iodomethane (0.17 mL, 3.41 mmol) was added to the reaction in one portion via syringe.
  • the reaction vial was then capped and heated in a Biotage Initiator 60 microwave at 150 0 C for 5 minutes.
  • the reaction was then cooled to room temperature and de-capped.
  • the reaction mixture was then partitioned between 20 mL of de-ionized water and 20 mL of methylene chloride and separated. The remaining aqueous layer was further extracted with 2 more 20 mL portions of methylene chloride.
  • the combined organic extracts were filtered over anhydrous MgSO 4 and evaporated dryness.
  • the resulting material was purified by flash column chromatography to afford a clear viscous syrup, 256 mg, chemical yield 81.9%.
  • Example 140 was prepared according to the procedures described in Example 138- 139 using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
  • corresponding reagents e.g., corresponding amino acid, amine, and aldehyde reagents
  • Example 140 3-(4-methoxyphenethyl)-2-(3,4-dimethylphenyl)-1 ,2,5,5- tetramethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDCI 3 ) ⁇ 7.15 (m ,4H), 6.99 (d,
  • Example 141 2-(4-tert-butylphenyl)-1-(3-cyclohexylpropanoyl)-3-[2-(4- methoxy phenyl) ethyl]imidazolidin-4-one
  • Examples 142 - 296 were prepared according to the procedures described herein using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents).
  • High-performance liquid chromatography (HPLC) was recorded with Column Aquasil C18 (Aquasil C18 HPLC column, 50 mm length x 2 mm ID, 5 micron particle) using following conditions: Mobile Phase A: 10 mM NH 4 OAC in 95% water / 5% CAN (Pipette 6.67 mL of 7.5 M NH 4 OAC solution into 4743 mL H 2 O, then add 250 mL of ACN to the solution and mixture).
  • Mobile Phase B 10 mM NH 4 OAC in 5% water / 95% CAN (Pipette 6.67 mL of 7.5 M NH 4 OAC solution into 243 mL H 2 O. Then add 4750 mL of ACN to the solution and mixture). Flow Rate: 0.800 mL/min,
  • Kv1.5 currents are recorded by the whole cell mode of patch clamp electrophysiology. Kv1.5 is stably over expressed in HEK cells.
  • Microelectrodes are pulled from borosilicate glass (TW150) and heat polished (tip resistance, 1.5 to 3 megaohms).
  • the external solution is standard Tyrodes solution.
  • the internal (microelectrode) solution contained: 1 10 mM KCI, 5 mM K 2 ATP, 5 mM K 4 BAPTA, 1 mM MgCI 2 and 10 mM HEPES, adjusted to pH 7.2 with KOH.
  • Command potentials are applied for 1 second to +6OmV from a holding potential of -70 mV using Axon software (pClamp 8.1) and hardware (Axopatch 1 D, 200B).
  • Compounds are prepared as 10-2OmM DMSO stocks and diluted to appropriate test concentrations. After stable currents are achieved, compounds are perfused onto the cells and the cells are pulsed every 5 seconds until no further changes in current are evident at a given compound concentration. Inhibition is measured at the end of the 1 second pulses and expressed relative to controls. Kv1.5 inhibition is estimated by single point determinations done at 1 ⁇ M.

Abstract

The present teachings relate to 4-imidazolidinones of Formula (I) Insert formula here as it appears in written form in the specification (I) which are useful as Kv1.5 potassium channel inhibitors providing atrial-selective antiarrhythmic activity. The present teachings further relate to compositions and methods for treating atrial-selective antiarrhythmia.

Description

4-IMIDAZOLIDINONES AS KV1.5 POTASSIUM CHANNEL INHIBITORS
FIELD OF THE INVENTION
The present invention relates to compounds that are effective as Kv1.5 potassium channel inhibitors. The present invention also relates to compositions comprising certain Kv1.5 potassium channel inhibitors, and to methods for treating cardiac arrhythmia.
BACKGROUND OF THE INVENTION
Atrial fibrillation (AF) is a frequently encountered cardiac arrhythmia in the clinical setting. It affects nearly 3 million people in the United States and its prevalence increases with the aging of the population. AF is most often treated with class III antiarrhythmic agents, acting at both the atrial and ventricular levels. Commonly used or prescribed antiarrhythmic drugs inhibit various potassium channels, and prolong ventricular repolarization. Prolongation of ventricular repolarization can in turn precipitate the occurrence of life-threatening-ventricular arrhythmias, mainly Torsades de Pointes (TdP).
Certain atrial-selective antiarrhythmic agents offer one possibility of increased therapeutic efficacy and safety by minimizing cardiac proarrhythmia inherent in conventional antiarrhythmic therapies.
There is an unmetneed to provide certain new compounds that function as effective atrial-selective antiarrhythmic agents and which do not affect ventricular rhythm. In addition, there is an unmet need to provide certain new compounds that function as effective atrial-selective antiarrhythmic agents and that are compatible with other cardiac devices, cardiac protocols, therapies, and medications. References related to
Kv1.5 potassium channel include: Brendel, J., et al., Curr. Med. Chem. 2003, 1 , 273- 287; Firth, A. L., et al., 2008, 33, 31-47; Vidaillet, H., et al., Am. J. Med. 2002, 1 13,
365-370; Tsang, T. S. M., et al., Am. J. Med. 2002, 1 13, 432-435; Yang, Q., et al., Expert Opin. Ther. Patents 2007, 17, 1443-1456; Regan, C. P., et al., J. Cardiovasc. Pharmacol. 2007, 49, 236-245; Nattel, S. Physiol. Rev. 2007, 87, 425-456; Tombola, F., et al., Annu. Rev. Cell Dev. Biol. 2006, 22, 23-52; and Wirth, K. J., et al., J. Cardiovasc. Pharmacol. 2007, 49, 197-206.
SUMMARY OF THE INVENTION
The present invention provides compounds of Formula (I):
Figure imgf000003_0001
(I)
or pharmaceutically acceptable salts thereof, wherein Ar1, Ar2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, m, n, and p are defined as described herein.
The present invention also provides compositions comprising an effective amount of one or more compounds of Formula (I) and one or more excipients.
The present invention also provides a method for treating or preventing cardiac arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, the method comprising administering to a subject an effective amount of a compound of Formula (I) according to the present invention. The present invention also provides a method for treating or preventing cardiac arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, wherein the method comprises administering to a subject a composition comprising an effective amount of one or more compounds of Formula (I) according to the present invention and one or more excipients.
The present invention also provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure. In some embodiments, the methods comprise administering to a subject an effective amount of a compound of Formula (I) according to the present invention.
The present invention further provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds of Formula (I) according to the present invention and one or more excipients.
The present invention also provides a method for inducing cardioversion, comprising administering a therapeutically effective amount of a compound of Formula (I) to the subject.
The present invention also provides a method for inhibiting Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of Formula (I) to the subject.
The present invention also provides a method for treating or preventing a disorder associated with inhibition of Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of Formula (I) to the subject. As an example, these compounds are useful in treating atrial arrhythmia, thromboembolism, stroke or cardiac failure. These and other objects, features, and advantages will become apparent to those of skilled in the art from a reading of the following detailed description and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
Kv1.5 potassium channel inhibitors of the present invention are capable of treating and preventing arrhythmia in the atrial portion of the human heart or in the heart of certain animals. It has been discovered that functional Kv1.5 potassium channels are found in human atrial tissue but not in human ventricular myocytes. Without wishing to be limited by theory, it is believed the inhibition of the Kv1.5 voltage-gated Shaker-like potassium (K+) ion channel can ameliorate, abate, or otherwise cause to be controlled, atrial fibrillation and flutter without prolonging ventricular repolarization.
DEFINITIONS
As used herein, all percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (0C), unless otherwise specified. All documents cited are in relevant part; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
In this specification, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.
The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term "about" is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise.
It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously.
As used herein, unless otherwise noted, "alkyl" whether used alone or as part of a substituent group refers to saturated straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C^6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, te/t-butyl, and the like. Where so indicated, alkyl groups can be optionally substituted. In substituent groups with multiple alkyl groups such as N(Ci-6alkyl)2, the alkyl groups may be the same or different.
As used herein, unless otherwise noted, "alkoxy" refers to groups of formula -Oalkyl and -Operfluoroalkyl. Designated numbers of carbon atoms (e.g. -OC1-6 and -OC1-6 perfluoroalkyl) shall refer independently to the number of carbon atoms in the alkoxy group. Non-limiting examples of alkyl groups include methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, sec-butoxy, /so-butoxy, fe/f-butoxy, and the like. Where so indicated, alkoxy groups can be optionally substituted.
As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, having at least one carbon-carbon double bond ("alkenyl") or at least one carbon-carbon triple bond ("alkynyl"). Where so indicated, alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2- methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl.
As used herein, "cycloalkyl," whether used alone or as part of another group, refers to a non-aromatic hydrocarbon ring including cyclized alkyl, alkenyl, or alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, for example, from 3 to 7 or 3 to 6 ring carbon atoms, and optionally containing one or more (e.g., 1 , 2, or 3) double or triple bonds. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Where so indicated, cycloalkyl rings can be optionally substituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, octahydropentalenyl, octahydro-1 /-/-indenyl, 3a,4,5,6,7,7a-hexahydro-3/-/-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1 /-/-fluorenyl. The term "cycloalkyl" also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1 ,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
"Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms. As used herein, halogen refers to F, Cl, Br and I. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF3, -CF2CF3). The halogens can be the same (e.g., CHF2, -CF3) or different (e.g., CF2CI). Where so indicated, haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.
The term "aryl," wherein used alone or as part of another group, is defined herein as an aromatic monocyclic ring of 6 carbons or an aromatic polycyclic ring of from 10 to 14 carbons. Aryl groups include but are not limited to, for example, phenyl or naphthyl (e.g., naphthylen-1-yl or naphthylen-2-yl). Where so indicated, aryl groups may be optionally substituted with one or more substituents. Aryl groups also include, but are not limited to for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1 ,3,5- trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
The terms "heterocyclic," "heterocycle," and "heterocyclyl," whether used alone or as part of another group, are defined herein as groups having one or more rings (e.g., 1 , 2 or 3 rings) and having from 3 to 20 atoms (e.g., 3 to 10 atoms, 3 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein the ring that includes the heteroatom is non-aromatic. In heterocyclyl groups that include 2 or more fused rings, any non- heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclyl groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocyclyl group can be oxidized (e.g., N→O", S(O), SO2). Where so indicated, heterocyclyl groups can be optionally substituted.
Non-limiting examples of monocyclic heterocyclyl groups include, for example: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1 /-/-azepinyl, 2,3-dihydro-1 /-/-indolyl, and 1 ,2,3,4-tetrahydro- quinolinyl. Non-limiting examples of heterocyclic groups having 2 or more rings include, for example: hexahydro-1 /-/-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1 H- benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1 H-indolyl, 1 ,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1 H- cyclooctatbjpyrrolyl.
The term "heteroaryl," whether used alone or as part of another group, is defined herein as a single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, any non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5/-/-cyclopentapyrimidinyl) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized (e.g., N→O', S(O), SO2). Where so indicated, heteroaryl groups can be substituted. Non-limiting examples of monocyclic heteroaryl rings include, for example: 1 ,2,3,4-tetrazolyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, triazinyl, thiazolyl, 1 H- imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, and pyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7/-/-purinyl, 9/-/-purinyl, 5H-pyrrolo[3,2-c/]pyrimidinyl, 7H-pyrrolo[2,3- c/]pyrimidinyl, pyrido[2,3-cf]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1 /-/-indolyl, 4,5,6,7- tetrahydro-1-/-/-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, and isoquinolinyl.
One non-limiting example of a heteroaryl group as described above is C1-C5 heteroaryl, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and sulfur (S). Examples of C1-C5 heteroaryl include, but are not limited to for example, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1 /-/-imidazol-2-yl, 1 H- imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
For the purposes of the present invention, fused ring groups, spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1 ,2,3,4-tetrahydroquinoline having the formula:
Figure imgf000010_0001
is, for the purposes of the present invention, considered a heterocyclyl group. 6,7- Dihydro-5/-/-cyclopentapyrimidine having the formula:
Figure imgf000010_0002
is, for the purposes of the present invention, considered a heteroaryl group. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine having the formula:
Figure imgf000010_0003
is, for the purposes of the present invention, considered a heteroaryl group.
The terms "treat" and "treating," as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer. As used herein, "therapeutically effective" refers to a substance or an amount that elicits a desirable biological activity or effect.
Except when noted, the terms "subject" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term "subject" or "patient" as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, but are not limited to for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.
The term "substituted" is used throughout the specification. The term "substituted" is defined herein as a moiety, whether acyclic or cyclic, which has one or more (e.g. 1- 10) hydrogen atoms replaced by a substituent as defined herein below. Substituents include those that are capable of replacing one or two hydrogen atoms of a single moiety at a time, and also those that can replace two hydrogen atoms on two adjacent carbons to form said substituent. For example, substituents that replace single hydrogen atoms includes, for example, halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. Substituents that replace two hydrogen atoms from adjacent carbon atoms include, for example, epoxy, and the like. When a moiety is described as "substituted" any number of its hydrogen atoms can be replaced, as described above. For example, difluoromethyl is a substituted C1 alkyl; trifluoromethyl is a substituted C1 alkyl; 4-hydroxyphenyl is a substituted aryl ring; (N,N-dimethyl-5-amino)octanyl is a substituted C8 alkyl; 3- guanidinopropyl is a substituted C3 alkyl; and 2-carboxypyridinyl is a substituted heteroaryl. At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci-6 alkyl" is specifically intended to individually disclose Ci , C2, C3, C4, C5, C6, Ci-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.
In one aspect, the present invention provides compounds of Formula I:
Figure imgf000012_0001
(I) or a pharmaceutically acceptable salt thereof,
wherein:
Ar1 is selected from C6-Ci0 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1- 5 R11 groups;
Ar2 is selected from (CH2)z-C6-Ci0 aryl, wherein z = 0 or 1 and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1-5 R17 groups; R1 is selected from H and Ci_6 alkyl;
R2 is selected from H, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-I0 cycloalkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR18, SR18, NR28R29, SO2R30, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-io cycloalkyl each is optionally substituted with 1-5 R15 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R16 groups;
R3 is selected from H, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-I0 cycloalkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR18, SR18, NR31R32, SO2R30, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and
S, wherein the Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, and C3_i0 cycloalkyl each is optionally substituted with 1-5 R15 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R16 groups;
R4 is selected from H and Ci-6 alkyl;
each R5 and R6 is independently selected from H, Ci-6 alkyl, halogen and NHSO2Ci-6 alkyl;
alternatively, any two R5 and R6, taken together with the carbon to which they are bound, can form a carbonyl group;
each R7 and R8 is independently selected from H, Ci-6 alkyl, and halogen;
alternatively, any two R7 and R8, taken together with the carbon to which they are bound, can form a carbonyl group;
each R9 and R10 is independently are selected from H, Ci-6 alkyl, and halogen; alternatively, any two R9 and R10 taken together with the carbon to which they are bound, can form a carbonyl group;
each R11 is independently selected from C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR12, SR12, NO2 and NR13R14, wherein the Ci-6 alkyl, the C2.6 alkenyl, the C2.6 alkynyl, and the C3-io cycloalkyl is optionally substituted with 1-5 R15 groups, and wherein the cycloheteroalkyl is optionally substituted with 1-5 R16 groups;
each R12 is independently selected from H, Ci-6 alkyl, and Ci-3 perhaloalkyl;
each R13 and R14 is independently selected from H and Ci-6 alkyl;
each R15 is independently selected from halogen, CN, OH, Ci-6 alkoxy, Ci-3 perhaloalkoxy, SH, SCi_6 alkyl, NH2, NH(Ci_6 alkyl), and N(Ci_6 alkyl)2;
each R16 is independently selected from Ci-6 alkyl, Ci-3 perhaloalkyl, halogen, CN, OH, OCi-6 alkyl, Od_3 perhaloalkyl, SH, SCi-6 alkyl, NH2, NH(Ci-6 alkyl), and N(Ci-6 alkyl)2;
each R17 is independently selected from C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, NO2, C3. 10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR18, SR18, NR19R20, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, and C3-10 cycloalkyl is optionally substituted with 1-5 R21 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with 1-5 R22 groups;
alternatively, two R17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring containing 1-2 heteroatoms selected from N, O and S, and optionally substituted with 1-5 R22 groups; each R18 is independently selected from H, Ci-6 alkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci-6 alkyl optionally is substituted with 1-4 R23 groups;
each R19 and R20 is independently selected from H, Ci_6 alkyl, C(O)R24, C(O)OR24, C(=NR25)NR26R27, C(O)NR26R27, and SO2R24;
each R21 is independently selected from halogen, CN, OH, Ci-6 alkoxy, SH, SCi-6 alkyl, NH2, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;
each R22 is independently is selected from Ci-6 alkyl, Ci-3 perhaloalkyl, halogen, CN, OH, OCi_6 alkyl, Ci_3 perhaloalkoxy, SH, SCi_6 alkyl, NH2, NH(Ci_6 alkyl), -CH2- heteroaryl and N(Ci-6 alkyl)2;
each R23 is independently is selected from halogen, CN, OH, OCi-6 alkyl, NH2, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the cycloheteroalkyl, aryl , and heteroaryl each is optionally substituted with 1-4 groups selected from Ci-6 alkyl, Ci-3 perhaloalkyl, and halogen;
R24 is Ci-6 alkyl optionally substituted with 1-4 groups selected fromhalogen, CN, OH, OCi_6 alkyl, OCi_3 perhaloalkyl, SH, SCi_6 alkyl, NH2, NH(Ci_6 alkyl), and N(Ci_6 alkyl)2;
each R25, R26 and R27 is independently selected from H and Ci-6 alkyl;
each R28 and R29 is independently selected from H, Ci-6 alkyl optionally substituted with 1-4 R36 groups, C(O)R30, C(O)OR30, C(=NR25)NR26R27, C(O)NR26R27, and SO2R30; R30 is selected from Ci-6 alkyl, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1-4 groups selected from Ci-6 alkyl, halogen, CN, OH, OCi_6 alkyl, OCi_3 perhaloalkyl, SH, SCi_6 alkyl, NH2, NH(Ci_6 alkyl), and N(Ci_6 alkyl)2;
each R31 and R32 is independently selected from H, Ci-6 alkyl optionally substituted with 1-4 R36 groups, C3-io cycloalkyl, C(O)R33, C(O)OR33, C(=NR25)NR26R27, C(O)NR34R35, SO2R33, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;
R33 is selected from Ci-6 alkyl optionally substituted with 1-4 R36 groups, C6-Ci0 aryl optionally substituted with 1-4 R37 groups, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-4 R37 groups;
R34 and R35 each independently is selected from H, Ci-6 alkyl optionally substituted with 1-4 R36 groups, C6-Ci0 aryl optionally substituted with 1-4 R37 groups, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-4 R37 groups;
each R36 is independently selected from halogen, CN, OH, Ci-6 alkoxy, Ci-3 perhaloalkoxy, SH, SCi-6 alkyl, NH2, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, C6 or Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;
each R37 is independently selected from Ci-6 alkyl, Ci-3 perhaloalkyl, halogen, CN, OH, Ci-6 alkoxy, Ci-3 perhaloalkoxy, SH, SCi-6 alkyl, NH2, NH(Ci-6 alkyl), and N(Ci-6 alkyl)2;
m is O, 1 2, 3, or 4;
n is O, 1 , 2, 3, 4, 5 or 6; and p is O, 1 , 2, 3, 4, 5 or 6.
In some embodiments, R1 is H.
In some embodiments, R4 is H or C1-6 alkyl.
In some embodiments, m is 0, 1 , 2, or 3. In some embodiments, m is 1 and R5 and R6, are each methyl or H (e.g., both R5 and R6 are H). In some embodiments, m is 2 and R5 and R6, at each occurrence, are each methyl or H (e.g., R5 and R6, at each occurrence, are each H). In some embodiments, m is 3 and R5 and R6, at each occurrence, are each methyl or H (e.g., R5 and R6, at each occurrence, are each H).
In some embodiments, Ar1 is a C6-C10 aryl ring or a 5-14 membered heteroaryl ring, each aryl or heteroaryl ring having at least one substituent selected from Cr6 alkyl, halogen, Cr6 alkoxy, OH, NH2, NH(d_6 alkyl), N(d_6 alkyl)2, NO2, C1-S haloalkyl, d_3 haloalkoxy, SH, SC1^ alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to
4 heteroatoms selected from N, O and S, halogen, wherein the C1-6 alkyl group optionally is substituted with R15 and wherein the 3-10 membered cycloheteroalkyl is optionally substituted with R16.
In some embodiments, Ar1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from Cr6 alkyl, halogen, Cr6 alkoxy, OH, NH2, NH(C^6 alkyl), N(d_6 alkyl)2, NO2, C1-3 haloalkyl, C1-3 haloalkoxy, SH, SC1-6 alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, wherein the C1-6 alkyl group optionally is substituted with R15 and wherein the 3-10 membered cycloheteroalkyl optionally is substituted with R16.
In some embodiments, Ar1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, F, Cl, OH, OCH3, OCF3, SCH3, CH2N(CH3)2, and pyrrolidinyl, piperidinyl, piperazinyl, N- methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl. In some embodiments, Ar1 is para-substituted phenyl (e.g., 4-methoxyphenyl).
In some embodiments, Ar1 is selected from pyridine and pyrimidine, each optionally substituted with 1-5 R11 groups.
In some embodiments, Ar2 is phenyl substituted with 1 , 2, or 3 substituents independently selected from halogen, Cr6 alkyl, C3.10 cycloalkyl, Ci-3 perhaloalkyl, 3-
10 membered cycloheteroalkyl ring containing 1 to 4 heteroatoms selected from N, O and S, and 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from
N, O and S, wherein the Ci-6 alkyl and the C3-I0 cycloalkyl are each optionally substituted with 1-5 R21 groups, and wherein the cycloheteroalkyl and heteroaryl each optionally is substituted with 1-5 R22 groups.
In some embodiments, Ar2 is phenyl substituted with Ci-6 alkyl (e.g., 4-(tert- butyl)phenyl) or C3_i0 cycloalkyl (e.g., 4-cyclopropylphenyl).
In some embodiments, Ar2 is phenyl substituted with 1 , 2 or 3 substitutents independently selected from F, Cl, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyclopropyl, trifluoromethyl, pyrrolidine, piperidine, piperazine N-methylpiperazine, N- ethylpiperazine, morpholine, pyridine, imidazole and 2-methylimidazole. In some embodiments, Ar2 is phenyl substituted with 1 , 2, or 3 OR18 groups. In some embodiments, R18 is selected from H, Ci-6 alkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci-6 alkyl optionally is substituted with 1-4 R23 groups. In some embodiments, R18 is Ci-6 alkyl. In other embodiments, R18 is Ci-6 alkyl substituted with 1-4 groups selected from halogen, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, a C6-Ci0 aryl ring, and a 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O and S. In some embodiments, R18 is Ci-6 alkyl substituted with 1-2 groups selected from F, phenyl, pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl. In some embodiments, Ar2 is phenyl substituted with 1 , 2, or 3 NR19R20 groups. In some embodiments, R19 and R20 are selected from H, Ci-6 alkyl, C(=NR25)NR26R27, and SO2R24. In some embodiments, R19 and R20 are each independently Ci-6 alkyl. Examples of these compounds include those wherein Ar2 is phenyl substituted with NH2, N(CH3)2, N(CH2CHs)2, NHSO2CH3, N(SO2CH3)2, and NH(C=NH)NH2.
In some embodiments, Ar2 is phenyl substituted with two R17 groups, wherein the two R17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring selected from pyrrolidine, 1 ,3-dioxolane, 1 ,4-dioxane, pyrrolidine, piperidine, piperazine and morpholine, each optionally substituted with 1-5 R22 groups. Examples of these compounds include those wherein Ar2 is benzo[d][1 ,3]dioxolyl, 2,2-difluorobenzo[d][1 ,3]dioxolyl, indolinyl, N-methylindolinyl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1 ,4]oxazinyl, N-methyl-3,4- dihydro-2H-benzo[b][1 ,4]oxazinyl, 1 ,2,3,4-tetrahydroquinolinyl, and N-methyl-1 , 2,3,4- tetrahydroquinolinyl.
In some embodiments, Ar2 is para-substituted phenyl.
In some embodiments, Ar2 is 5-10 membered heteroaryl optionally substituted with 1- 5 R17 groups. For example, Ar2 can be selected from furanyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, and quinolinyl, each optionally substituted with 1-5 R17 groups.
In some embodiments, R2 is selected from H, CN, Ci-6 alkyl optionally substituted with 1-5 R15 groups, and C2.6 alkenyl optionally substituted with 1-5 R15 groups.
In some embodiments, R2 is C6-Ci0 aryl (e.g., phenyl) optionally substituted with 1-5 R16 groups.
In some embodiments, R2 is OR18. In some embodiments, R18 is phenyl optionally substituted with 1-4 R23 groups or 5-10 membered heteroaryl optionally substituted with 1-4 R23 groups. In some embodiments, R2 is SO2R30. In some embodiments, R30 is optionally substituted C1-C6 alkyl, or optionally substituted 6-10 membered aryl.
In some embodiments, R2 is 5-10 membered heteroaryl (e.g., pyridinyl, pyrimidinyl, imidazolyl or pyrazolyl) optionally substituted with 1-5 R16 groups
In some embodiments, R2 is C3.10 cycloalkyl (e.g., C3.6 cycloalkyl) optionally substituted with 1-5 R15 groups.
In some embodiments, R2 is 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S (e.g., piperidinyl) optionally substituted with 1- 5 R16 groups.
In some embodiments, R2 is NR28R29. In some embodiments, R28 is H, and R29 is C(O)R30. R30 can be optionally substituted 5-10 membered heteroaryl (e.g., pyridinyl, imidaziolyl, pyrimidinyl or pyrazinyl). In some embodiments, R28 is H, and R29 is C(O)OR30. R30 can be C1-C6 alkyl. In some embodiments, R28 and R29 are each independently H or C1-C6 alkyl. In some embodiments, R28 is H, and R29 is C(O)NR26R27. R28 and R29 can each independently be H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 5-10 membered heteroaryl or 6-10 membered aryl, wherein the 6-10 membered aryl and the 5-10 membered heteroaryl are each optionally and independently substituted with 1-5 R16 groups.
In some embodiments, n is 0, 1 , 2, 3, or 4. In some embodiments, n is 1 and R7 and R8 each is H. In some embodiments, n is 1 and R7 and R8, taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, n is 2 and each R7 and R8, at each occurrence, is H. In some embodiments, n is 2 and one R7 and R8, taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, n is 3 and each R7 and R8, at each occurrence, is H. In some embodiments, n is 3 and one R7 and R8, taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, n is 4 and each R7 and R8, at each occurrence, is H. In some embodiments, n is 4 and one R7 and R8, taken together with the carbon to which they are bound, form a carbonyl.
In some embodiments, p is 0. In some embodiments, p is 0 and R3 is H or C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl or tert-butyl). In some embodiments, R4 is H. In some embodiments, R3 and R4 are each independently H or C1-6 alkyl.
In some embodiments, R3 is C6-C10 aryl (e.g., phenyl) or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., pyrrolyl, imidazolyl, pyridinyl, or pyrimidinyl), each optionally substituted with 1-5 R16 groups.
In some embodiments, R3 is NR31R32. In some embodiments, one of R31 and R32 is H and the other is SO2R33. R33 can be C1-6 alkyl optionally substituted with 1-4 R34 groups (e.g., C6 or C10 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S). In some embodiments, R33 is benzyl or CH2-pyridinyl.
In some embodiments, R3 is NR31R32 and one of R31 and R32 is H and the other is C(O)NR34R35. R34 and R35 can each independently be H or C1-6 alkyl. In some embodiments, one of R34 and R35 is H and the other is C1-6 alkyl. In other embodiments, one of R34 and R35 is H and the other is C6-C10 aryl (e.g., phenyl) or 5- 10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., pyridinyl or pyrimidinyl). In some embodiments, one of R34 and R35 is C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl or tert-butyl) and the other is C6-C10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., phenyl, pyridinyl or pyrimidinyl).
In some embodiments, R3 is NR31R32 and one of R31 and R32 is H and the other is C(O)OR33. R33 can be C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl or tert- butyl) optionally substituted with 1-4 R36 groups (e.g., NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, C6 or C10 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S). In some embodiments, R33 is benzyl. In some embodiments, R3 is NR31R32 and one of R31 and R32 is H and the other is C6 or C10 aryl (e.g., phenyl), or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., pyridinyl or pyrimidinyl).
In some embodiments, R3 is NR31R32 and each of R31 and R32 is H.
In some embodiments, R3 is NR31R32 and each of R31 and R32 independently is Ci-6 alkyl optionally substituted with 1-4 R36 groups. In some embodiments, each of R31 and R32 independently is selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, benzyl and CH2-pyridinyl.
In some embodiments, R3 is OR18. R18 can be H or Ci-6 alkyl optionally is substituted with 1-4 R23 groups (e.g., R18 can be benzyl or CH2-pyridinyl).
In some embodiments, R3 is C6-Ci0 aryl (e.g., phenyl) or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S (e.g., pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl or quinolinyl), each optionally substituted with 1-5 R16 groups.
In some embodiments, p is 1 , 2, 3, or 4. In some embodiments, p is 1 and each of R9 and R10 is H. In some embodiments, p is 1 and R9 and R10, taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, p is 2 and each of R9 and R10, at each occurrence, is H. In some embodiments, p is 2 and one of R9 and R10, taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, p is 3 and each of R9 and R10, at each occurrence, is H. In some embodiments, p is 3 and one of R9 and R10, taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, p is 4 and each of R9 and R10, at each occurrence, is H. In some embodiments, p is 4 and one of R9 and R10, taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, the compounds of the invention have a structure according to Formula (II):
Figure imgf000023_0001
(H)
or a pharmaceutically acceptable salt thereof,
wherein m is 1 , 2 or 3 and Ar1 , Ar2, R1 , R2, R3, R4, R5, R6, R7, R8, R9, R10, n, and p are defined as above.
In some embodiments, m is 1 and R5 and R6 are each H. In some embodiments, m is 1 and one of R5 and R6 is H and the other is Ci-6 alkyl. In some embodiments, m is 1 and R5 and R6, at each occurrence, are each H. In some embodiments, Ar1 is para-substituted phenyl (e.g., 4-methoxyphenyl).
In some embodiments, the compounds of the invention have a structure according to Formula (III):
Figure imgf000024_0001
(III)
or a pharmaceutically acceptable salt thereof,
wherein n is 0, 1 , 2, 3, 4 or 5 and Ar1, Ar2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, m, and p are defined above.
In some embodiments, when m=0, R4 is methyl, (CR9R10)p-R3 forms methyl, (CR7R8)n-R2 forms methyl, Ar2 is phenyl, and R1 is H, then Ar1 cannot be 2,4- dichlorophenyl;
In some embodiments, when m=0, R4 is methyl, and R1 is H, Ar2 is phenyl, and one of (CR9R1VR3 and (CR7R8)n-R2 forms methyl and the other of (CR9R10)p-R3 and (CR7R8)n-R2 forms H, then Ar1 cannot be 2,4-dichlorophenyl;
In some embodiments, when m=0, R4 is methyl, (CR9R10)p-R3 forms methyl, (CR7R8)n-R2 forms t-butyl, Ar2 is phenyl, and R1 is H, then Ar1 cannot be phenyl;
In some embodiments, when m=0, R4 is methyl, (CR9R10)p-R3 forms phenyl, (CR7R8)n-R2 forms t-butyl, Ar2 is phenyl, and R1 is H, then Ar1 cannot be phenyl; In some embodiments, when m=0, R1 is H, Ar2 is phenyl, (CR7R8)n-R2 forms t-butyl, (CR9R10)p-R3 forms methyl, and R4 is methyl, then Ar1 cannot be phenyl, A- methylphenyl, or 4-methoxyphenyl.
In some embodiments, when m=0, R1 is H, Ar2 is phenyl, (CR7R8)n-R2 forms t-butyl, (CR9R1VR3 forms phenyl, and R4 is methyl, then Ar1 cannot be phenyl.
In some embodiments, when m=0, R1 is H, Ar2 is phenyl, (CR7R8)n-R2 forms ethyl, (CR9R10)p-R3 forms H, and R4 is H, then Ar1 cannot be 2-methoxyphenyl.
In some embodiments, when m=0, R1 is H, Ar2 is phenyl, (CR7R8)n-R2 forms methyl, (CR9R1VR3 forms H, and R4 is H, then Ar1 cannot be 4-methoxyphenyl, A- ethoxyphenyl or 4-bromophenyl.
In some embodiments, when m=0, R1 is H, Ar2 is phenyl, (CR7R8)n-R2 forms methyl, (CR9R1VR3 forms butyl, and R4 is H, then Ar1 cannot be phenyl.
In some embodiments, when m=0, R1 is H, Ar2 is phenyl, (CR7R8)n-R2 forms H, (CR9R1VR3 forms methyl, and R4 is H, then Ar1 cannot be 4-chlorophenyl or 2,4,- dichlorophenyl.
In some embodiments, when m=0, R1 is H, Ar2 is phenyl, (CR7R8)n-R2 forms H, (CR9R1VR3 forms methyl, and R4 is H, then Ar1 cannot be 2, 4, -dichlorophenyl.
In some embodiments, when R1 is H, Ar2 is phenyl, n is 0 and R2 is H, p is 1 and R3 is phenyl, and m is 0, then Ar1 cannot be 4-methylphenyl or cyclohexyl. In some embodiments, when R1 is H, Ar2 is phenyl, n is 0 and R2 is H, p is 1 and R3 is phenyl, and m is 1 , then Ar1 cannot be phenyl.
In some embodiments, when p is 0 and R3 is H, R4 is H, n is 1 and R2 is phenyl, m is 1 and Ar1 is phenyl, and R1 is H, then Ar2 cannot be 4-chlorophenyl or A- (dimethylamino)phenyl. In some embodiments, each R17 is independently selected from Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-I0 cycloalkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR18, SR18, NR19R20, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, and C3-I0 cycloalkyl each is optionally substituted with 1-5 R21 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R22 groups;
alternatively, two R17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring containing 1-2 heteroatoms selected from N, O and S, and optionally substituted with 1-5 R22 groups;
Ar2 is selected from C6-Ci0 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1- 5 R17 groups;
each R11 is independently selected from Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-I0 cycloalkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR12, SR12, and NR13R14, wherein the Ci-6 alkyl, the C2.6 alkenyl, the C2.6 alkynyl, and the C3_i0 cycloalkyl each is optionally substituted with 1-5 R15 groups, and wherein the cycloheteroalkyl is optionally substituted with 1-5 R16 groups; and
each R22 is independently is selected from Ci-6 alkyl, Ci-3 perhaloalkyl, halogen, CN, OH, OCi_6 alkyl, Ci_3 perhaloalkoxy, SH, SCi_6 alkyl, NH2, NH(Ci_6 alkyl), and N(Ci_6 alkyl)2.
Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to for example, chiral chromatography, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present invention also includes cis and trans or E/Z isomers of compounds of Formula (I) containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
Pharmaceutically acceptable salts of compounds of the present invention, which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethy l-tert-buty I- , diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic, carbonic, as well as other known pharmaceutically acceptable acids.
The compounds described herein may be administered to humans and other animals orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, intracisternally, intravaginally, intraperitoneal^, bucally, intrathecal^ or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices.
Methods of formulation are well known in the art and are disclosed, for example, in Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 21 st Edition (2005), incorporated herein by reference.
Pharmaceutical compositions for use in the present invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent.
In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
Formulations comprising crystalline forms of the compositions described herein for slow absorption from subcutaneous or intramuscular injection are provided herein. Additionally, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the compounds in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and waxes.
The compounds described herein can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention.
Compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
Effective amounts of the compounds of the invention generally include any amount sufficient to detectably modulate Kv1.5 potassium channel activity, or to alleviate symptoms of diseases associated with Kv1.5 potassium channel activity or susceptible to Kv1.5 potassium channel activity modulation.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician. In another aspect of the invention, kits that include one or more compounds of the invention are provided. Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including directions for treating or preventing atrial arrhythmia, thromboembolism, stroke, or cardiac failure by administering an effective amount of a compound of the present invention.
In another aspect of the invention, kits that include one or more compounds of the invention are provided. Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including directions for inhibiting Kv1.5 potassium channel by administering an effective amount of a compound of the present invention.
In another aspect of the invention, kits that include one or more compounds of the invention are provided. Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including directions for inducing cardioversion by administering an effective amount of a compound of the present invention.
When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(C^6 alkyl)2 , each Ci-6 alkyl may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The Kv1.5 potassium channel inhibitors of the present invention are certain A- imidazolidinones, and include all enantiomeric and diasteriomeric forms and salts of compounds having the formula (I):
Figure imgf000033_0001
(I) wherein the core scaffold is numbered in the following manner,
Figure imgf000033_0002
For the purposes of the present invention, a compound depicted by the racemic formula, for example:
Figure imgf000033_0003
will stand equally well for any of the four stereoisomers having the formula:
Figure imgf000034_0001
Figure imgf000034_0002
or mixtures thereof (or in the case where one or more additional chiral centers are present, all stereoisomers and mixtures thereof).
Compounds of the present invention can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used. Those skilled in the art will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.
The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high-performance liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
Preparation of the compounds can involve protection and deprotection of various chemical groups. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th. Ed. (John Wiley & Sons, 2007), the entire disclosure of which is incorporated by reference herein for all purposes.
The reactions or the processes described herein can be carried out in suitable solvents, which can be readily selected by one skilled in the art. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.
The compounds of these teachings can be prepared by methods known in the art. The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature. For example, compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes:
GENERAL SYNTHETIC SCHEME(S) FOR PREPARATION OF COMPOUNDS.
The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes.
Functionalized amino acid amides (e.g. 1) may be prepared using standard literature procedures. Ring closure to form the 4-imiddazolidinone 3 can be accomplished by heating 1 in the presence of a suitable aldehyde (2) in an appropriate solvent or as a neat mixture of the two. Conventional or microwave heating may be employed.
Figure imgf000036_0001
Alternately, amino acid amide 4 may be cyclized to imidazolidinone 5 by by heating in the presence of a suitable aldehyde (2) in an appropriate solvent or as a neat mixture of the two. Conventional or microwave heating may be employed. Functionalization in the presence of a base and suitable electrophilic (e.g. alkyl halide, alkyl sulfonate, sulfonyl halide, acid halide) agent provides the desired imidazolidinone.
Figure imgf000037_0001
Figure imgf000037_0002
In cases when the amino acid side chain may be modified, such as carboxylic acid side chain examples (e.g. 6) where PG is a suitable protecting group, removal of the protecting group using standard conditions provides imidazolidinone 7. Amide synthesis may then be accomplished using standard literature procedure to provide 8.
Figure imgf000037_0003
Alternatively, imidazolidinone 7 may be converted to suitably protected amines (9) using methods described in the literature, which may be subsequently deprotected under the appropriate conditions to provide the free amine 10. Side chain functionalization may then be accomplished with a suitable electrophile (e.g. carboxylic acid, carboxylic acid halide, sulfonyl halide, isocyanante) in the presence or absence of a suitable coupling agent (e.g. EDCI) or base (e.g. NEt3, DIPEA) to provide 11.
Figure imgf000038_0001
Reduction of 7 with a suitable reducing agent (e.g. borane) may also be employed to provide alcohol 12. Conversion of the alcohol to a leaving group (e.g. halide or sulfonate) using standard literature procedures followed by displacement with a nucleophile provides 13 where Nu is a suitable alcohol or amine.
Figure imgf000038_0002
EXAMPLES
The following non-limiting examples are presented to illustrate the present teachings. The skilled person will understand that there are numerous equivalents and variations not exemplified but which still form part of the present teachings.
CATEGORY I Example 1 : 2-(4-fe/f-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin- 4-one:
Figure imgf000039_0001
Step 1 : 2-Bromo-N-[2-(4-methoxyphenyl)ethyl]acetamide: To 12.9 mL (148.6 mmol) of bromoacetylbromide in 500 mL of anhydrous methylene chloride at room temperature was added 45.7 mL (312.1 mmol) of 4-methoxyphenethyl amine. The resulting solution was stirred for 12 hours and monitored by TLC. 900 mL of 0.1 N HCI was added and the organic layer was separated in a separatory funnel. The remaining aqueous layer was extracted with methylene chloride (3 x 200 mL) and all organic layers were combined. The organic layers were dried over sodium sulfate, filtered, and the solvent was removed in vacuo to provide 40.0 g (94 % yield) of product as a slightly yellow oil. MW = 272.14; 1H NMR (300 MHz, CDCI3)δ 7.20 (d, 2H, J = 6.6 Hz), 6.88 (d, 2H, J = 6.6 Hz), 3.88 (s, 2H), 3.83 (s, 3H), 3.56 (q, 2H, J = 6.7 Hz), 2.81 (t, 2H, J = 6.7 Hz); (MH+) 273;
Step 2: 2-(Benzylmethylamino)-N-[2-(4-methoxyphenyl)ethyl]acetamide: To 40 g (147.1 mmol) of 2-bromo-N-[2-(4-methoxyphenyl)ethyl]acetamide in 200 mL of THF at room temperature was added 36 mL (294.2 mmol) of N-methyl benzyl amine.
The resulting solution was stirred for 12 hours and was monitored by TLC. The THF was removed in vacuo giving 44 g (100 % yield) of a yellow oil. MW = 312.41 ; 1H
NMR (300 MHz, CDCI3) δ 7.33 (m, 5H), 7.14 (d, 2H, J = 8.4 Hz), 6.86 (d, 2H, J = 8.4 Hz), 3.81 (S, 3H), 3.55 (q, 2H, J = 6.7 Hz), 3.52 (s, 2H), 3.03 (s, 2H), 2.80 (t, 2H, J =
6.7 Hz), 2.20 (s, 3H); (MH+) 313;
Step 3: N-[2-(4-Methoxyphenyl)ethyl]-2-methylaminoacetamide: To 44 g of 2- (benzylmethylamino)-N-[2-(4-methoxyphenyl)ethyl]acetamide in ethanol at room temperature was added 5.0 g of 10% Pd/C and the mixture was put on a hydrogen Parr reduction apparatus (40 psi of H2). The resulting mixture was shaken on the Parr reduction machine and recharged with hydrogen gas to maintain the 40 psi of hydrogen gas for 16 hours. The mixture was then filtered through celite, and the solvent removed in vacuo resulting in 31.7 g (100 % yield) of product as a yellow oil. MW = 222.28; 1H NMR (300 MHz, CDCI3): 87.16 (d, 2H, J = 8.2 Hz), 6.86 (d, 2H, J = 8.2 Hz), 3.81 (S, 3H), 3.54 (q, 2H, J = 7.5 Hz), 3.22 (s, 2H), 2.79 (t, 2H, J = 7.5 Hz), 2.37 (s, 3H); (MH+) 223.
Step 4: 2-(4-fe/?-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin-4- one: To 20.0 g (90.1 mmol) of N-[2-(4-methoxyphenyl)ethyl]-2- methylaminoacetamide in 200 ml. of methanol at room temperature was added 13.7 g (99.1 mmol) of potassium carbonate and 13.1 ml. (99.1 mmol) of A-t- butylbenzaldehyde. The resulting mixture was stirred at reflux and monitored by
HPLC. Upon completion, the solvent was removed in vacuo, and the residue was diluted with 300 ml. of methylene chloride, washed with water (3 x 50 ml_), dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by Horizon MPLC in 5 g portions with gradiant solvent eluents of 5 %-
20 % ethyl acetate in hexanes for 1650 mL followed by 20 %-50 % ethyl acetate in hexanes for 1200 mL. The product containing fractions were combined and the solvent removed in vacuo and the remaining solid was recrystallized in ethyl acetate and hexanes to give 20.0 g (60 % yield) of pure product. MW = 366.50, MP = 121.4 or C; Rf: 0.2 (HexΕtOAc 4:1) \.; 1 Η NMR (300 MHz, CDCI3): δ7.43 (m, 2H), 7.26 (m, 2H), 6.96 (m, 2H), 6.81 (m, 2H), 4.41 (s, 1 H), 3.80 (s, 3H), 3.70 (m, 2H), 3.15 (m, 1 H), 2.78 (m, 2H), 2.50 (m, 1 H), 2.26 (s, 3H), 1.36 (m, 9H); 13C NMR (CDCI3) 5171.30, 158.48, 153.05, 134.08, 130.92, 130.04, 128.51 , 125.87, 1 14.10, 84.24, 57.75, 55.51 , 42.20, 39.04, 34.99, 33.00, 31.58; (MH+) 367; Anal. Calcd. for C23H30N2O2 with 0.25 H2O: C, 74.66; H, 8.29; N, 7.55. Found: C, 74.79; H, 8.10; N, 7.26.
Examples 2-48 were prepared according to the procedures described in Example 1 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): Example 2: 2-(4-fe/?-Butylphenyl)-3-[2-(3-methoxyphenyl)ethyl]-1- methylimidazolidin-4-one, 1H NMR (300 MHz, CDCI3) 87.42 (m, 1 H), 7.19 (m, 3H),
6.76 (m, 1 H), 6.60 (m, 2H), 3.75 (s, 3H), 3.71 (m, 2H), 3.08 (m, 1 H), 2.82 (m, 2H), 2.56 (m, 1 H), 2.02 (s, 3H), 1.35 (s, 9H); 13C NMR (CDCI3) δ 170.40, 159.92, 140.50, 129.70, 128.53, 125.87, 121.45, 1 15.52, 1 14.48, 1 12.35, 84.26, 66.1 1 , 60.65, 57.73, 55.39, 41.96, 39.00, 34.99; (MH+) 367; Anal. Calcd. for C23H30N2O2 with 0.6 H2O: C, 67.90; H, 7.53; N, 6.71. Found: C, 67.83; H, 7.53; N, 6.71.
Example 3: 2-(3,4-Dichlorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1- methylimidazolidin-4-one, 1H NMR (300 MHz, CDCI3) § 7.50 (d, 1 H, J = 8.1 Hz), 7.34 (m, 1 H), 7.15 (m, 1 H), 7.02 (d, 2H, J = 8.4 Hz), 6.88 (m, 2H), 4.35 (m, 1 H), 3.85 (s, 3H), 3.74 (m, 2H), 3.14 (m, 1 H), 2.73 (m, 2H), 2.64 (m, 1 H), 2.25 (s, 3H); 13C NMR (CDCI3) δ 171.19, 158.66, 137.92, 134.00, 133.02, 130.96, 130.91 , 130.69, 130.12, 128.06, 1 14.26, 83.30, 57.39, 55.52, 42.28, 38.83, 33.21 ; (MH+) 380; Anal. Calcd. for C19H20CI2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 60.20; H, 5.55; N, 7.24.
Example 4: 2-(4-fe/?-Butylphenyl)-1-ethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin- 4-one, 1H NMR (300 MHz, CDCI3) δ 7.41 (d, 2H, J = 6.6 Hz), 7.27 (d, 2H, J = 6.3 Hz), 6.95 (d, 2H, J = 6.6 Hz), 6.80 (d, 2H, J = 6.6 Hz), 4.56 (s, 1 H), 3.79 (s, 3H), 3.72 (m, 1 H), 3.18 (m, 1 H), 3.09 (m, 1 H), 2.78 (m, 2H), 2.60 (m, 1 H), 2.50 (m, 1 H), 2.31 (m, 1 H), 1.36 (s, 9H), 0.98 (m, 3H); 13C NMR (CDCI3) 8171.28, 158.46, 152.86, 134.81 , 130.99, 130.04, 128.60, 125.74, 1 14.09, 82.85, 55.50, 55.09, 46.76, 42.07, 34.96, 33.04, 31.59, 13.43; (MH+) 381 ; Anal. Calcd. for C24H32N2O2 with 0.35 H2O: C, 74.52; H, 8.52; N, 7.24. Found: C, 74.75; H, 8.13; N, 6.97.
Example 5: 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1- methylimidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 7.21 (d, 2H, J = 7.8 Hz), 7.1 1
(d, 2H, J = 7.8 Hz), 6.97 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.4 Hz), 4.4 (s, 1 H),
3.77 (s, 3H), 3.67 (m, 2H), 3.09 (m, 1 H), 2.75 (m, 2H), 2.85 (m, 1 H), 1.94 (m, 1 H), 1.02 (m, 2H), 0.74 (m, 2H); 13C NMR (CDCI3) δ 171.36, 158.49, 155.51 , 146.08, 130.89, 130.05, 128.81 , 126.07, 1 14.1 1 , 84.27, 57.73, 42.13, 38.87, 33.00, 15.54, 9.92, 9.86; (MH+) 351 ; Anal. Calcd. for C22H26N2O2: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.21 ; H, 7.62; N, 8.03.
Example 6: 3-[2-(4-Methoxyphenyl)ethyl]-1-methyl-2-(4-trifluoromethylphenyl) imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.67 (d, 2H, J = 7.4 Hz), 7.42 (d, 2H, J = 8.4 Hz), 6.97 (d, 2H, J = 8.6 Hz), 6.83 (d, 2H, J = 8.7 Hz), 4.46 (s, 1 H), 3.80 (s, 3H), 3.73 (d, 1 H, J = 15.0 Hz), 3.70 (m, 1 H), 3.15 (d, 1 H, J = 14.2 Hz), 2.73 (m, 2H), 2.57 (m, 1 H), 2.23 (s, 3H); (MH+) 379.
Example 7: 2-(3-Chlorophenyl)-1-ethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4- one trifluoroacetate, 1H-NMR (300 MHz, CDCI3) δ 7.43 (d, 1 H, J = 3.1 Hz), 7.38 (t, 1 H, J = 7.6 Hz), 7.22 (s, 1 H), 7.19 (d, 1 H, J = 7.7 Hz), 7.00 (d, 2H, J = 6.5 Hz), 6.83 (d, 2H, J = 6.5 Hz), 4.93 (s, 1 H), 3.85 (m, 2H), 3.80 (s, 3H), 3.49 (d, 1 H, J = 13.5 Hz), 2.78 (m, 2H), 2.62 (m, 1 H), 2.59 (q, 2H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.5 Hz); (MH+) 359.
Example 8: 2-(3,4-Dichlorophenyl)-1-ethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin- 4-one trifluoroacetate, 1H-NMR (300 MHz, CDCI3) δ 7.48 (d, 1 H, J = 8.21 Hz), 7.3 (d, 1 H, J = 2.0 Hz), 7.13 (dd, 1 H, J = 2.1 , 8.3 Hz), 7.00 (d, 2H, J = 6.6 Hz), 6.85 (d, 2H, J = 6.6 Hz), 4.63 (s, 1 H), 3.81 (s, 3H), 3.78 (m, 2H), 3.27 (d, 1 H, J = 13.0 Hz), 2.75 (m, 2H), 2.48 (m, 3H), 1.02 (t, 3H, J = 7.2 Hz); (MH+) 393.
Example 9: 2-(3,4-Dimethylphenyl)-1-methyl-3-(3-phenylpropyl)imidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 7.16 (m, 1 H), 7.07 (m, 2H), 6.99 (m, 5H), 4.56 (s, 1 H), 3.71 (dd, 1 H, J = 2.1 Hz, 14.1 Hz), 3.49 (m, 1 H), 3.01 (dd, 1 H, J = 2.1 Hz, 14.1 Hz), 2.67 (m, 1 H), 2.45 (t, 2H, J = 14.0 Hz), 2.20 (s, 3H), 1.58 (m, 2H), 1.30 (s, 6H) 13C NMR (CDCI3) δ172.3, 153.1 , 141.7, 138.6, 137.5, 134.7, 134.3, 131.1 , 130.2, 129.9, 128.5, 126.5, 1 14.3, 84.0, 57.9, 40.4, 39.1 , 35.1 , 33.5, 31.7, 29.2; (MH+) 323.
Example 10: 2-(4-fe/?-Butylphenyl)-1-methyl-3-(3-phenylpropyl)imidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 7.36m, 2H), 7.1 1 (m, 5H), 6.99 (m, 2H), 4.66 (s, 1 H), 3.77 (dd, 1 H, J = 2.1 Hz, 14.1 Hz), 3.55 (m, 1 H), 3.1 1 (dd, 1 H, J = 2.1 Hz, 14.1 Hz), 2.55 (m, 1 H), 2.41 (t, 2H, J = 14.0 Hz), 2.26 (s, 3H), 1.55 (m, 2H), 1.27 (s, 9H); 13C NMR (CDCI3) δ 171.2, 153.1 , 141.7, 134.3, 134.1 , 130.0, 128.7, 128.6, 128.5, 126.2, 126.0, 84.0, 57.9, 40.4, 39.1 , 35.1 , 33.5, 31.7, 29.2; (MH+) 351.
Example 11 : 2-(4-fe/?-Butylphenyl)-3-(4-methoxybenzyl)-1-methylimidazolidin-4- one, 1H NMR: (300 MHz, CDCI3) δ 7.5 (d, 2H, J = 8.1 Hz), 7.34 (d, 2H, J = 8.1 Hz), 6.92 (d, 2H, J = 8.1 Hz), 6.80 (d, 2H, J = 8.1 Hz), 4.90 (d, 1 H, J = 14.1 Hz), 4.50 (s, 1 H), 3.81 (s, 3H), 3.44 (d, 1 H, J = 14.1 Hz), 2.90 (d, 1 H, J = 14.1 Hz), 2.30 (s, 2H), 1.44 (S, 9H); 13C NMR (CDCI3) δ 174.0, 159.3, 153.0, 134.1 , 130.2, 128.8, 128.7, 125.9, 1 14.2, 83.1 , 58.0, 55.6, 43.5, 39.1 , 36.9, 35.1 , 31.7; (MH+) 353.
Example 12: 2-(4-fe/?-Butylphenyl)-1-methyl-3-phenethylimidazolidin-4-one, 1H- NMR (300 MHz, CDCI3) δ 7.32 (d, 2H, J = 8.3 Hz), 7.13 (m, 5H), 6.93 (d, 2H, J = 6.4 Hz), 4.31 (s, 1 H), 3.58 (m, 2H), 3.01 (dd, 1 H, J = 2.3, 14.1 Hz), 2.74 (m, 2H), 2.46 (m, 1 H), 2.14 (s, 3H), 1.26 (s, 9H); (MH+) 337.
Example 13: 1-Ethyl-3-phenethyl-2-(4-trifluoromethylphenyl)imidazolidin-4-one, 1H- NMR (300 MHz, CDCI3) δ 7.56 (d, 2H, J = 8.1 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.20 (m, 3H), 6.97 (d, 2H, J = 7.9 Hz), 4.43 (s, 1 H), 3.66 (m, 2H), 3.03 (d, 1 H, J = 16.5 Hz), 2.68 (m, 2H), 2.51 (m, 1 H), 2.40 (m, 1 H), 2.25 (m, 1 H), 0.87 (t, 3H, J = 7.2 Hz); (MH+) 363.
Example 14: 1-Ethyl-3-phenethyl-2-(3-trifluoromethylphenyl)imidazolidin-4-one, 1H- NMR (300 MHz, CDCI3) δ 7.37 (d, 1 H, J = 8.2 Hz), 7.20 (m, 4H), 7.01 (m, 3H), 4.31 (s, 1 H), 3.64 (m, 2H), 3.00 (d, 1 H, J = 16.5 Hz), 2.63 (m, 3H), 2.39 (m, 1 H), 2.24 (m, 1 H), 0.87 (t, 3H, J = 7.2 Hz); (MH+) 363.
Example 15: 1-Ethyl-2-(4-Ethylphenyl)-3-phenethylimidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.04 (m, 7H), 6.88 (d, 2H, J = 8.1 Hz), 4.77 (s, 1 H), 3.60 (m, 2H), 3.23 (d, 1 H, J = 14.6 Hz), 2.64 (m, 2H), 2.50 (m, 3H), 2.36 (q, 2H, J = 7.2 Hz), 1.06 (t, 3H, J = 7.6 Hz), 0.87 (t, 3H, J = 7.2 Hz); (MH+) 323. Example 16: R-3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-methylimidazolidin- 4-one, 1H NMR (300 MHz, CDCI3) 87.43 (m, 2H), 7.26 (m, 2H), 6.96 (m, 2H), 6.81 (m, 2H), 4.41 (s, 1 H), 3.80 (s, 3H), 3.70 (m, 2H), 3.15 (m, 1 H), 2.78 (m, 2H), 2.50 (m, 1 H), 2.26 (s, 3H), 1.36 (m, 9H); (MH+) 367.
Example 17: S-3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-methylimidazolidin- 4-one, 1H NMR (300 MHz, CDCI3) 87.44 (m, 2H), 7.26 (m, 2H), 6.96 (m, 2H), 6.81 (m, 2H), 4.42 (s, 1 H), 3.80 (s, 3H), 3.70 (m, 2H), 3.15 (m, 1 H), 2.79 (m, 2H), 2.50 (m, 1 H), 2.26 (s, 3H), 1.36 (m, 9H); (MH+) 367.
Example 18: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-1 -methyl imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.44 (d, 2H, J = 8.1 Hz), 7.27 (d, 2H, J = 8.4), 7.12 (d, 2H, J = 8.4 Hz), 7.04 (d, 2H, J = 6.6 Hz), 4.14 (s,1 H), 3.75 (dd, 1 H, J = 1.2, 14.1 Hz), 3.62 (m, 2H), 3.14 (dd, 1 H, J = 2.1 , 14.1 Hz), 2.85 (m, 2H), 2.55 (m, 1 H), 2.26 (s, 3H), 1.37 (s, 9H); (MH+) 421.
Example 19: 3-(4-(Trifluoromethoxy)phenethyl)-2-(3,4-dichlorophenyl)-1 -methyl imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.49 (d, 1 H, J = 8.4 Hz), 7.38 (d, 1 H, J = 2.1 Hz), 7.1 1 (m, 5H), 4,34 (s, 1 H), 3.71 (m, 2H), 3.14 (dd, 1 H, J = 2.4, 14.4 Hz), 2.82 (m, 2H), 2.64 (m, 1 H), 2.24 (s, 3H); (MH+) 434.
Example 20: 3-(4-(Trifluoromethoxy)phenethyl)-1-methyl-2-(4-(trifluoromethyl) phenyl)imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.69 (d, 2H, 8.4 Hz), 7.42 (d, 2H, J = 8.4 Hz), 7.16 (d, 2H, J = 7.8 Hz), 7.06 (d, 2H, J = 7.8 Hz), 4.45 (s, 1 H), 3.74 (m, 2H), 3.13 (dd, 1 H, J = 2.4, 14.4 Hz), 2.81 (m, 2H), 2.63 (m, 1 H), 2.45 (s, 3H); (MH+) 433.
Example 21 : 2-(4-ferf-Butylphenyl)-1-methyl-3-(2-phenylpropyl)imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.42 (m, 5H), 7.13 (m,4H), 4.54 (s, 1 H), 3.68 (m, 2H), 3.21 (m, 1 H), 2.50 (m, 3H), 2.24 (s, 3H), 1.36 (s, 9H), 1.22 (d, 3H, J = 6.9 Hz); (MH+) 351 Example 22: 3-(4-Fluorophenethyl)-2-(4-fe/?-butylphenyl)-1-methylimidazolidin-4- one, 1H-NMR (300 MHz, CDCI3) δ 7.44 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4 Hz), 6.97 (m,4H), 4.44 (s, 1 H), 3.68 (m, 2H), 3.18 (m, 2H), 2.95 (m, 2H), 2.26 (s, 3H), 1.37 (s, 9H); (MH+) 355.
Example 23: 3-(4-/so-Propylphenethyl)-2-(4-fe/?-butylphenyl)-1-methylimidazolidin- 4-one, 1H-NMR (300 MHz, CDCI3) δ 7.43 (d, 2H, J = 6.6 Hz) 7.27 (d, 2H, J = 6.6 Hz), 7.14 (d, 2H J = 8.4 Hz), 6.97 (d, 2H. J = 8.4 Hz), 4.42 (s, 1 H), 3.72 (m, 2H), 3.16 (dd, 1 H, J = 2.4, 14.1 Hz), 2.82 (m, 3H), 2.58 (m, 1 H), 2.27 (s, 3H), 1.38 (s, 9H) 1.26 (d, 6H, J = 6.9 Hz); (MH+) 379.
Example 24: 3-(4-(Trifluoromethyl)phenethyl)-2-(4-fe/?-butylphenyl)-1 -methyl imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD) δ 7.49 (dd, 4H, J = 4.8, 13.0 Hz), 7.3 (d, 2H, J = 8.3 Hz), 7.21 (d, 2H, J = 8.0 Hz), 4.61 (s, 1 H), 3.53 (m, 2H), 3.13 (m, 1 H), 2.92 (m, 1 H), 2.78 (m, 1 H), 2.62 (m, 1 H), 2.23 (s, 3H), 1.35 (s, 9H); (MH+) 405.
Example 25: 3-(3,4-Difluorophenethyl)-2-(3,4-dimethylphenyl)-1-methylimidazolidin- 4-one, 1H-NMR (300 MHz, CD3OD) δ 7.21 (m, 1 H), 7.25 (m, 3H), 6.91 (m, 1 H), 6.83 (m, 1 H), 4.59 (s, 1 H), 3.64 (d, 1 H, J = 14.2 Hz), 3.54 (m, 1 H), 3.13 (d, 1 H, J = 14.0, Hz), 2.91 (m, 1 H), 2.68 (m, 1 H), 2.55 (m, 1 H), 2.33 (s, 3H), 2.32 (s, 3H), 2.23 (s, 3H); (MH+) 345.
Example 26: 3-(3,4-difluorophenethyl)-2-(3,4-dichlorophenyl)-1-methylimidazolidin- 4-one: 1H-NMR (300 MHz, CD3OD) δ 7.61 (d, 1 H, J = 7.1 Hz), 7.52 (s, 1 H), 7.33 (dd, 1 H, J = 1.5, 6.8 Hz), 7.13 (q, 1 H, J = 8.1 Hz), 7.01 (m, 1 H), 6.88 (m, 1 H), 4.68 (s, 1 H), 3.66 (d, 1 H, J = 14.1 Hz), 3.58 (m, 1 H), 3.15 (d, 1 H, J = 14.0, Hz), 2.91 (m, 1 H), 2.66 (m, 2H), 2.27 (s, 3H); (MH+) 385.
Example 27: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-1 -ethyl imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.50 (d, 2H, 8.4Hz), 7.22 (d, 2H,
8.2Hz), 7.14 (s, 4H), 5.54 (s, 1 H), 3.94 (m, 1 H), 3.84 (s, 2H), 2.90 (m, 4H), 2.63 (m,
1 H), 1.36 (S, 9H), 1.20 (t, 3H, J = 7.1 Hz); 13C-NMR (CDCI3) δ 166.8, 155.5, 136.7, 130.3, 128.6, 126.9, 121.5, 80.6, 51.1 , 47.9, 42.4, 32.9, 31.4, 1 1.0; (MH+) 435; elemental analysis: theory C26H36N2O2 + 1.05 mol C2HF3O2 C 56.56; H 5.47; N 5.05; found C 56.52, H 5.51 , N 5.07.
Example 28: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-cyclopropylphenyl)-1 -methyl imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.01 (m, 8H), 4.31 (s, 1 H), 3.65 (m, 2H), 3.16 (d, 1 H, J = 14.0 Hz), 2.75 (m, 2H), 2.55 (m, 1 H), 2.17 (s, 3H), 1.90 (m, 1 H), 1.01 (d, 2H, J = 8.4 Hz) 0.68 (d, 2H, J = 8.4 Hz); (MH+) 405.
Example 29: 3-(3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-4-oxoimidazolidin-1- yl)propanenitrile, 1H NMR (300 MHz, CD3OD) δ 7.52 (d, 2H, J = 8.2 Hz), 7.40 (d, 2H, J = 8.2 Hz), 6.95 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.5 Hz), 4.79 (bs, 1 H), 3.81 (bs, 1 H), 3.77 (s, 3H), 3.48 (m, 1 H), 3.24 (m, 1 H), 2.75 (m, 4H), 2.50 (m, 3H), 1.37 (s, 9H); (MH+) 406.
Example 30: 3-(4-Methoxyphenethyl)-1-allyl-2-(4-fe/?-butylphenyl)imidazolidin-4- one, 1H NMR (300 MHz, CD3OD) δ 7.5 (d, 2H, J = 8.3 Hz), 7.32 (d, 2H, J = 8.3 Hz), 6.95 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 5.72 (m, 1 H), 5.20 (m, 2H), 4.74 (s, 1 H), 3.77 (s, 3H), 3.59 (m, 2H), 3.32 (m, 2H), 3.15 (m, 1 H), 2.86 (m, 2H), 2.46 (m, 1 H), 1.36 (S, 9H); (MH+) 393.
Example 31 : 3-(4-Methoxyphenethyl)-2-(4-fe/t-butylphenyl)-1-(3-hydroxypropyl) imidazolidin-4-one, 1H NMR (300 MHz, CD3OD) δ 7.47 (d, 2H, J = 8.1 Hz), 7.25 (d, 2H, J = 8.4 Hz), 6.99 (d, 2H, J = 8.7 Hz), 6.84 (d, 2H, J = 8.7 Hz), 6.25 (bs, 2H), 3.94 (m, 1 H), 3.81 (s, 3H), 3.77 (m, 1 H), 3.61 (m, 2H), 3.46 (m, 1 H), 2.81 (m, 4H), 2.61 (m, 1 H), 1.75 (m, 2H), 1.36 (s, 9H); (MH+) 41 1.
Example 32: 3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-(2-hydroxyethyl) imidazolidin-4-one, 1H NMR (300 MHz, CD3OD) δ 7.38 (d, 2H, J = 8.3 Hz), 7.25 (d, 2H, J = 8.3 Hz), 6.83 (d, 2H, J = 8.6 Hz), 6.70 (d, 2H, J = 8.6 Hz), 4.63 (s, 1 H), 3.65 (m, 4H), 3.38 (m, 3H), 3.21 (m, 1 H), 2.49 (m, 5H), 1.25 (s, 9H); (MH+) 397. Example 33: 3-(4-(trifluoromethyl)phenethyl)-2-(3,4-dimethylphenyl)-1 -methyl imidazolidin-4-one: (1H-NMR, 300 MHz, CD3OD): δ 7.56 (d, 2H, J = 7.1 hz), 7.25 (d, 2H, J = 7.3 hz), 7.22 (m, 1 H), 7.09 (m, 2H), 4.59 (s, 1 H), 3.61 (m, 2H), 3.13 (d, 1 H, J = 14.1 hz), 2.91 (m, 1 H), 2.79 (m, 1 H), 2.66 (m, 1 H), 2.32 (s, 3H), 2.31 (s, 3H), 2.22 (S, 3H). (M+H) 377.
Example 34: (2R,5S)-3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5-isopropyl-1- methylimidazolidin-4-one: (1H-NMR, 300 MHz, CD3OD): δ 7.47 (d, 2H, J = 7.1 hz), 7.14 (d, 2H, J = 6.8 hz), 7.08 (d, 2H, j = 6.7 hz), 6.81 (d, 2H, J = 7.3 hz), 5.19 (s, 1 H), 3.82(m, 1 H), 3.78 (s, 3H), 3.38 (m, 1 H), 2.71 (m, 3H), 2.13 (m, 1 H), 2.07 (s, 3H), 1.36 (s, 9H), 1.06 (d, 3H, J = 6.3 hz), 0.95 (d, 3H, J = 6.5 hz). (M+H) 409.
Example 35: (2S,5S)-3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5-isopropyl-1- methylimidazolidin-4-one: (1H-NMR, 300 MHz, CD3OD): δ 7.48 (d, 2H, J = 7.0 hz), 7.13 (d, 2H, J = 6.9 hz), 7.07 (d, 2H, J = 7.0 hz), 6.82 (d, 2H, J = 7.3 hz), 5.18 (s, 1 H), 3.82(m, 1 H), 3.79 (s, 3H), 3.57 (m, 1 H), 2.69 (m, 3H), 2.08 (s, 3H), 2.07 (m, 1 H), 1.37 (s, 9H), 1.05 (d, 3H, J = 6.3 hz), 0.96 (d, 3H, J = 6.5 hz). (M+H) 409.
Example 36: 1 -Benzyl-2-(4-dimethylamino-phenyl)-3-phenethyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.16 (m, 10H), 6.98 (d, 2H, J = 8.2 Hz), 6.65 (d, 2H, J = 8.8 Hz), 4.55 (s, 1 H), 3.71 (d, 1 H, J = 13.2 Hz), 3.56 (m, 1 H), 3.42 (d, 1 H, J = 15.2 Hz), 3.19 (d, 1 H, J = 13.2 Hz), 2.95 (d, 1 H J = 14.2 Hz), 2.91 (s, 6H), 2.75 (m, 2H), 2.47 (m, 1 H). (M+H) 400.
Example 37: 1 -Benzyl-3-[2-(4-methoxy-phenyl)-ethyl]-2-(3-trifluoromethyl-phenyl)- imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.84 (d, 1 H, J = 7.9 Hz), 7.65 (d, 1 H, J = 8.0 Hz), 7.59 (t, 1 H, J = 7.6 Hz), 7.44 (t, 1 H, J = 7.6 Hz), 7.17 (m, 3H), 7.09 (d, 2H, J = 7.8 Hz), 6.98 (d, 2H, J = 8.6 Hz), 6.70 (d, 2H, J = 8.7 Hz ), 5.47 (s, 1 H), 3.75 (d, 1 H, J = 13.1 Hz), 3.68 (s, 3H), 3.47 (d, 1 H, J = 15.6 Hz), 3.41 (m, 1 H), 3.35 (d, 1 H, J = 13.2 Hz), 3.03 (d, 1 H J = 16.6 Hz), 2.71 (m, 1 H), 2.57 (m, 2H). (M+H) 455. Example 38: 3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2-quinolin-2-yl-imidazolidin-4- one; compound with trifluoro-acetic acid, 1H-NMR (300 MHz, CDCI3): δ 8.28 (d, 1 H, J = 8.5 Hz), 8.22 (d, 1 H, J = 8.4 Hz), 7.90 (d, 1 H, J = 8.1 Hz), 7.83 (t, 1 H, J = 7.7 Hz), 7.67 (t, 1 H, J = 7.5 Hz), 7.62 (d, 1 H, J = 8.5 Hz), 6.96 (d, 2H, J = 9.5 Hz), 6.73 (d, 2H, J = 8.7 Hz), 5.24 (s, 1 H), 3.89 (d, 1 H, J = 14.4 Hz), 3.82 (m, 1 H), 3.75 (s, 3H), 3.34 (d, 1 H, J = 15.9 Hz), 2.83 (m, 2H), 2.63 (m, 1 H), 2.43 (s, 3H). (M+H) 362.
Example 39: 3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1 ,5- dimethylimidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.39 (d, J = 8.2 Hz, 2 H), 7.14 (d, J = 8.2 Hz, 2 H), 7.03 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 4.86 (s, 1 H), 3.82 (m, 1 H), 3.79 (s, 3 H), 3.54 (m, 1 H), 2.78 (m, 2 H), 2.63 (m, 1 H), 2.10 (s, 3 H), 1.34 (s, 9 H), 1.23 (d, J = 6.7 Hz, 3 H); 13C NMR (75 MHz, CDCI3) δ 174.59, 158.62, 152.79, 133.72, 131.05, 130.16, 128.31 , 125.96, 1 14.25, 82.41 , 59.59, 55.64, 42.11 , 35.09, 34.14, 33.28, 31.67, 13.70; (MH+) 381 ; elemental analysis: theory C24H32N2O2 C 75.75; H 8.48; N 7.36; found C 76.02, H 8.15, N 7.06.
Example 40: 5-(S)-/sobutyl-2-(R)-(4-/so-propylphenyl)-3-[2-(4-methoxyphenyl)- ethyl]-1-methylimidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.30 (d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J = 8.1 Hz), 7.06 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.7 Hz), 5.59 (s, 1 H), 3.96 (m, 1 H), 3.79 (s, 3H), 3.49 (t, 1 H, J = 6.3 Hz), 2.95 (m, 1 H), 2.77 (m, 3H), 2.24 (s, 3H), 2.01 (m,1 H), 1.72 (m, 1 H), 1.63 (m, 1 H), 1.27 (d, 6H, J = 6.9 Hz), 0.97 (d, 3H, J = 6.6 Hz), 0.96 (d, 3H, J = 6.5 Hz); (MH+) 409.
Example 41 : 2-(S)-(4-Dimethylaminophenyl)-5-(S)-/so-butyl-3-[2-(4-methoxyphenyl)- ethyl]-1-methylimidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.14 (d, 2H, J = 8.7 Hz), 6.93 (d, 2H, J = 8.6 Hz), 6.83 (d, 2H, J = 8.6 Hz), 6.68 (d, 2H, J = 9.4 Hz), 5.18 (s, 1 H), 3.67 (s, 3H), 3.59 (m, 1 H), 3.03 (m, 1 H), 2.96 (s, 6H), 2.67 (m, 2H), 2.44 (m, 1 H), 2.21 (s, 3H), 1.91 (m, 1 H), 1.69 (m. 1 H), 0.87 (d, 3H, J = 6.6 Hz), 0.84 (d, 3H, J = 6.5 Hz); (MH+) 410.
Example 42: 2-(R)-(4-Ethylphenyl)-5-(S)-/so-butyl-3-[2-(4-methoxyphenyl)-ethyl]-1- methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.27 (d,2H, J = 7.7 Hz), 7.15 (d, 2H, J = 8.1 Hz), 7.06 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.9 Hz), 5.42 (s, 1 H), 3.93 (m, 1 H), 3.79 (s, 3H), 3.74 (d, J = 13.0 Hz, 1 H), 3.48 (m, 1 H), 2.72 (m, 4H), 2.20 (s, 3H), 1.97 (m, 1 H), 1.64 (m, 2H), 1.26 (m, 3H), 0.97 (d, 3H, J = 6.6 Hz), 0.96 (d, 3H, J = 6.6 Hz); (MH+) 395.
Example 43: 5-(S)-Benzyl-2-(R)-(4-ethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1- methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.26 (m, 4H), 7.20 (m, 1 H), 7.14 (d, 2H, J = 8.0 Hz), 6.97 (d, 2H, J = 8.1 Hz), 6.84 (d, 2H, J = 8.7 Hz), 6.72 (d, 2H, J = 8.7 Hz), 5.01 (s, 1 H), 3.77 (m, 1 H), 3.73 (s, 3H), 3.70 (m, 1 H), 3.18 (d, 1 H, J = 14.4 Hz), 3.03 (d, 1 H, J = 14.4 Hz), 2.58 (m, 5H), 1.93 (s, 3H), 1.18 (t, 3H, J = 7.6 Hz); (MH+) 429.
Example 44: 5-(S)-Benzyl-2-(R)-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]- 1-methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.32 (m, 4H), 7.26 (m, 1 H), 7.13 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.85 (m, 2H), 6.78 (d, J = 8.7 Hz, 2H), 5.05 (s, 1 H), 3.87 (m, 1 H), 3.80 (s, 3H), 3.75 (m, 1 H), 3.23 (dd, 1 H, J = 4.3, 14.4 Hz), 3.08 (dd, 1 H, J = 6.3, 14.4 Hz), 2.67 (m, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 2.00 (s, 3H); (MH+) 429.
Example 45: 2-(R)-(4-Chlorophenyl)-5-(S)-/so-butyl-3-[2-(4-methoxyphenyl)-ethyl]-1- methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.32 (d, 2H, J = 8.5 Hz), 7.08 (d, 2H, J = 8.5 Hz), 6.96 (d, 2H, J = 8.6 Hz), 6.74 (d, 2H, J = 8.7 Hz), 5.10 (s, 1 H), 3.85 (m, 1 H), 3.71 (s, 3H), 3.38 (t, 1 H, J = 7.0 Hz), 2.63 (m, 3H), 2.05 (s, 3H), 1.87 (m, 1 H), 1.47 (m, 2H), 0.87 (d, 6H, J = 6.6 Hz); (MH+) 401.
Example 46: 2-(S)-(4-Chlorophenyl)-5-(S)-/so-butyl-3-[2-(4-methoxyphenyl)-ethyl]-1- methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.28 (d, 2H, J = 6.6 Hz), 7.17 (d, 2H, J = 6.6 Hz), 6.87 (d, 2H, J = 6.6 Hz), 6.73 (d, 2H, J = 6.6 Hz), 4.21 (s, 1 H), 3.71 (s, 3H), 2.92 (m, 1 H), 2.66 (m, 2H), 2.41 (m, 1 H), 2.12 (s, 3H), 1.94 (m, 1 H), 1.55 (m, 1 H), 0.91 (d, 3H, J = 6.2 Hz), 0.89 (d, 3H, J = 6.2 Hz); (MH+) 401. Example 47: 2-(S)-(4-Ethylphenyl)-5-(S)-/so-butyl-3-[2-(4-methoxyphenyl)-ethyl]-1- methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.24 (s, 4H), 6.94 (d, 2H, J = 8.7 Hz), 6.79 (d, 2H, J = 8.7 Hz), 4.34 (s, 1 H), 3.78 (s, 3H), 3.56 (m, 1 H), 3.01 (m, 1 H), 2.79 (m, 1 H), 2.69 (q, 3H, J = 7.6 Hz), 2.46 (m, 1 H), 2.23 (s, 3H), 2.03 (m, 1 H), 1.77 (m, 1 H), 1.27 (t, 3H, J = 7.6 Hz), 1.00 (d, 3H, J = 6.5 Hz), 0.98 (d, 3H, J = 6.5 Hz); (MH+) 395.
Example 48: 2-(S)-(4-te/?-Butylphenyl)-5-(S)-/so-butyl-3-[2-(4-methoxyphenyl)- ethyl]-1-methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.33 (d, 2H, J = 8.3 Hz), 7.18 (d, 2H, J = 7.2 Hz), 6.84 (d, 2H, J = 8.6 Hz), 6.71 (d, 2H, J = 8.7 Hz), 4.27 (s, 1 H), 3.70 (s, 3H), 3.45 (m, 1 H), 2.94 (m, 1 H), 2.70 (m, 2H), 2.37 (m, 1 H), 2.16 (s, 3H), 1.96 (m, 1 H), 1.69 (m, 1 H), 1.57 (m, 1 H), 1.26 (s, 9H), 0.92 (d, 3H, J = 6.8 Hz), 0.90 (d, 3H, J = 6.7 Hz); (MH+) 423.
CATEGORY Il
Example 49: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-1- methylimidazolidin-4-one
Amino amides were prepared as indicated previously.
Figure imgf000050_0001
3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-1-methylimidazolidin- 4-one: The starting trifluoromethoxy-phenethyl-amino-amide (523 mg, 1.89 mmol) was added to an Emry's 2 - 5 ml. process vial equipped with a stir bar via pipet. Next, melted 4-diethylaminobenzalde-hdye (2.00 g, 1 1.3 mmol) was added to the reaction in small portions via pipet. The reaction vial was then capped and heated in a Biotage Initiator 60 microwave at 175 0C for 5 minutes. At this time the reaction was cooled to room temperature and de-capped. The material was then purified with flash column chromatography to afford a pale orange viscous syrup, 518 mg, chemical yield 62.9%. 1H-NMR (300 MHz, CDCI3) δ 7.1 1 (m, 6H), 6.67 (d, 2H, J = 7.3 Hz), 4.33 (s, 1 H), 3.71 (d, 1 H, J = 13.9 Hz), 3.62 (m, 1 H), 3.40 (m, 4H), 3.08 (d, 1 H, J = 13.9 Hz), 2.88 (m, 2H), 2.59 (m, 1 H), 2.25 (s, 3H), 1.21 (t, 6H, J = 6.6 Hz); 13C-NMR (CDCI3) δ 171.8, 148.3, 137.9, 136.9, 130.4, 129.9, 122.8, 121.2, 1 1 1.5,
84.5, 57.8, 44.6, 41.8, 38.8, 33.4, 12.8; (MH+) 436.6; elemental analysis: theory C23H28F3N3O2 + 0.16 mol H2O C 63.02; H 6.51 ; N 9.59; found C 63.03, H 6.60, N 9.53.
Examples 50-69 were prepared according to the procedures described in Example 49 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 50: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(dimethylamino)phenyl)-1- methylimidazolidin-4-one, 391 mg, chemical yield 52.4%. 1H-NMR (300 MHz, CDCI3) δ 7.15 (m, 6H), 6.74 (d, 2H, J = 6.9 Hz), 4.37 (s, 1 H), 3.72 (d, 1 H, J = 14.1 Hz), 3.63 (m, 1 H), 3.10 (d, 1 H, J = 14.1 Hz), 3.02 (s, 6H), 2.86 (m, 2H), 2.62 (m, 1 H), 2.25 (s, 3H); 13C-NMR (CDCI3) δ 171.2, 151.8, 137.9, 130.4, 129.8, 121.3, 1 12.3, 84.4, 57.8,
44.6, 41.8, 40.7, 38.7, 33.4; (MH+) 408. Elemental analysis: theory C21H24N3O2 + 0.07 mol H2O C 61.71 ; H 5.95; N 10.28; found C 61.70, H 5.80, N 10.35.
Example 51 : 2-(4-Diethylamino-phenyl)-3-[2-(4-methoxy-phenyl)-ethyl]-1-methyl- imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD) δ 7.17 (d, 2H, J = 8.7 Hz), 6.95 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.6 Hz), 6.73 (d, 2H, J = 8.7 Hz), 4.43 (s, 1 H), 3.74 (s, 3H), 3.60 (d, 1 H, J = 14.3 Hz), 3.50 (m, 1 H), 3.40 (q, 4H, J = 7.0 Hz), 3.07 (dd, 1 H, J = 2.3, 14.2 Hz), 2.82 (m, 1 H), 2.69 (m, 1 H), 2.45 (m, 1 H), 2.21 (s, 3H), 1.17 (t, 6H, J = 7.0 Hz); (MH+) 382.
Example 52: 3-(4-Methoxyphenethyl)-2-(4-(/so-propyl(methyl)amino)phenyl)-1- methylimidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.17 (d, 2H, J = 8.7 Hz), 7.00 (d, 2H, J = 8.7 Hz), 6.80 (m, 4H), 4.37 (s, 1 H), 4.15 (m, 1 H), 3.79 (s, 3H), 3.67 (m, 2H), 3.10 (dd, 1 H, J = 2.1 , 13.8 Hz), 2.82 (m, 3H), 2.78 (s, 3H), 2.56 (m, 3H), 1.22 (d, 6H, J = 6.3 Hz); (MH+) 382.
Example 53: 3-(4-(Methoxy)phenethyl)-2-(4-(diethylamino)benzyl)-1- methylimidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.07 (m, 4H), 6.83 (d, 2H, J = 8.8 Hz), 6.65 (d, 2H, J = 8.4 Hz), 4.07 (t, 1 H, J = 4.8Hz), 3.90 (m, 1 H), 3.79 (s, 3H), 3.52 (d, 1 H, J = 15.6 Hz), 3.37 (q, 4H, J = 6.9 Hz), 3.07 (m, 1 H), 2.95 (d, 1 H, J = 15.2 Hz), 2.79 (d, 2H, J = 4.7 Hz), 2.72 (m, 2H), 2.28 (s, 3H), 1.17 (t, 6H, J = 8.0 Hz); (MH+) 396.
Example 54: 3-(4-Methoxyphenethyl)-2-(4-(dimethylamino)phenyl)-1- methylimidazolidin-4-one, 1H-NMR (300 MHz, CD3OD) δ 7.19 (d, 2H, J = 7.1 Hz), 6.96 (d, 2H, J = 6.9 Hz), 6.81 (d, 4H, J = 7.0 Hz), 4.46 (s, 1 H), 3.60 (d, 1 H, J = 13.9 Hz), 3.52 (m, 1 H), 3.19 (d, 1 H, J = 14.1 Hz), 3.01 (s, 6H), 2.81 (m, 1 H), 2.70 (m, 1 H), 2.48 (m, 1 H), 1.21 (s, 3H); (MH+) 354.
Example 55: 2-(4-Diethylamino-3-fluorophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1- methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD) δ 7.03 (m, 3H), 6.95 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.7 Hz), 4.48 (s, 1 H), 3.74 (s, 3H), 3.61 (dd, 1 H, J = 1.1 , 14.3 Hz), 3.50 (m, 1 H), 3.26 (m, 4H), 3.09 (dd, 1 H, J = 2.3, 14.3 Hz), 2.82 (m, 1 H), 2.68 (m, 1 H), 2.48 (m, 1 H), 2.22 (s, 3H), 1.10 (t, 6H, J = 7.0 Hz); (MH+) 400.
Example 56: 2-(3-Chloro-4-diethylaminophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1- methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD) δ 7.36 (d, 1 H, J = 1.9 Hz), 7.22 (m, 2H), 6.95 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 4.50 (s, 1 H), 3.75 (s, 3H), 3.64 (dd, 1 H, J = 1.2, 14.3 Hz), 3.51 (m, 1 H), 3.15 (q, 4H, J = 7.1 Hz), 3.12 (m, 1 H), 2.82 (m, 1 H), 2.69 (m, 1 H), 2.44 (m, 1 H), 2.24 (s, 3H), 1.05 (t, 6H, J = 7.1 Hz); (MH+) 416.
Example 57: 2-(4-Diethylamino-3,5-difluorophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1- methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD) δ 6.97 (m, 4H), 6.82 (d, 2H, J = 8.7 Hz), 4.54 (s, 1 H), 3.76 (s, 3H), 3.65 (dd, 1 H, J = 14.3, 1.4 Hz), 3.54 (m, 1 H), 3.18 (q, 4H, J = 7.1 Hz), 3.13 (m, 1 H), 2.85 (m, 1 H), 2.70 (m, 1 H), 2.49 (m, 1 H), 2.25 (s, 3H), 1.04 (t, 6H, J = 7.1 Hz); (MH+) 418.
Example 58: 2-(2-Chloro-4-diethylaminophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1- methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD) δ 7.21 (d, 1 H, J = 9.5 Hz), 6.98 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J = 8.7 Hz), 6.69 (m, 2H), 5.20 (s, 1 H), 3.73 (s, 3H), 3.61 (m, 2H), 3.36 (q, 4H, J = 7.1 Hz), 3.09 (dd, 1 H, J = 2.2, 14.2 Hz), 2.74 (m, 2H), 2.51 (m, 1 H), 2.25 (s, 3H), 1.16 (t, 6H, J = 7.1 Hz); (MH+) 416.
Example 59: 2-R-(4-Diethylaminophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1-methyl- imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD) δ 7.17 (d, 2H, J = 8.7 Hz), 6.95 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.6 Hz), 6.71 (d, 2H, J = 8.7 Hz), 4.43 (s, 1 H), 3.72 (s, 3H), 3.60 (d, 1 H, J = 14.3 Hz), 3.51 (m, 1 H), 3.37 (q, 4H, J = 7.0 Hz), 3.06 (dd, 1 H, J = 2.3, 14.2 Hz), 2.82 (m, 1 H), 2.69 (m, 1 H), 2.43 (m, 1 H), 2.19 (s, 3H), 1.15 (t, 6H, J = 7.0 Hz); (MH+) 382.
Example 60: 2-S-(4-Diethylaminophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1-methyl- imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD) δ 7.17 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.7 Hz), 6.71 (d, 2H, J = 8.8 Hz), 4.43 (s, 1 H), 3.73 (s, 3H), 3.60 (d, 1 H, J = 14.2 Hz), 3.50 (m, 1 H), 3.37 (q, 4H, J = 7.1 Hz), 3.06 (dd, 1 H, J = 2.4, 14.1 Hz), 2.82 (m, 1 H), 2.69 (m, 1 H), 2.44 (m, 1 H), 2.19 (s, 3H), 1.15 (t, 6H, J = 7.0 Hz); (MH+) 382.
Example 61 : 5-(S)-lsobutyl-2-(S)-(4-isopropyl-phenyl)-3-[2-(4-methoxy-phenyl)- ethyl]-1-methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD): δ 7.31 (s, 4H), 6.91 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J = 8.7 Hz), 4.42 (d, 1 H, J = 2.3 Hz), 3.74 (s, 3H), 3.44 (m, 1 H), 3.02 (m, 1 H), 2.95 (m, 1 H), 2.82 (m, 1 H), 2.67 (m, 1 H), 2.37 (m, 1 H),
2.19 (s, 3H), 2.01 (m, 1 H), 1.71 (m, 1 H), 1.66 (m, 1 H), 1.29 (s, 3H), 1.26 (s, 3H), 1.01 (d, 3H, J = 6.7 Hz), 0.98 (d, 3H, J = 6.6 Hz). (M+H) 409.
Example 62: 3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2-(4-piperazin-1-yl-phenyl)- imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD): δ 7.27 (d, 2H, J = 8.7 Hz), 7.04 (d, 2H, J = 8.7 Hz), 6.96 (d, 2H, J = 8.7 Hz), 6.83 (d, 2H, J = 8.7 Hz), 4.50 (s, 1 H), 3.77 (s, 3H), 3.62 (dd, 1 H, J = 14.3, 1.0 Hz), 3.54 (m, 1 H), 3.23 (m, 4H), 3.1 1 (dd, 1 H, J = 14.2, 2.4 Hz), 3.01 (m, 4H), 2.74 (m, 3H), 2.48 (m, 1 H), 2.23 (s, 3H). (M+H) 395.
Example 63: 3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2-[4-(pyridin-4-ylmethoxy)- phenyl]-imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD): δ 8.54 (d, 2H, J = 6.1 Hz), 7.54 (d, 2H, J = 5.9 Hz), 7.33 (d, 2H, J = 8.6 Hz), 7.09 (d, 2H, J = 8.6 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 5.25 (s, 2H), 4.53 (s, 1 H), 3.76 (s, 3H), 3.62 (dd, 1 H, J = 14.3, 0.9 Hz), 3.51 (m, 1 H), 3.1 1 (dd, 1 H, J = 14.3, 2.4 Hz), 2.72 (m, 2H), 2.45 (m, 1 H), 2.22 (s, 3H). (M+H) 418.
Example 64: 3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2-[4-(3-methyl-butoxy)- phenyl]-imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD): δ 7.27 (d, 2H, J = 8.4 Hz), 6.95 (m, 4H), 6.80 (d, 2H, J = 8.4 Hz), 4.50 (s, 1 H), 4.03 (t, 2H, J = 6.5 Hz), 3.74 (s, 3H), 3.61 (d, 1 H, J = 14.1 Hz), 3.52 (t, 1 H, J = 5.7 Hz), 3.09 (dd, 1 H, J = 14.3, 2.0 Hz), 2.72 (m, 2H), 2.45 (m, 1 H), 2.20 (s, 3H), 1.85 (m, 1 H), 1.67 (m, 2H), 0.98 (d, 6H, J = 6.6 Hz). (M+H) 397.
Example 65: 5-(S)-Benzyl-2-(R)-(4-tert-butyl-phenyl)-3-[2-(4-methoxy-phenyl)-ethyl]- 1-methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.36 (d, 2H, J = 8.3 Hz), 7.26 (m, 5H), 7.02 (d, 2H, J = 8.3 Hz), 6.88 (d, 2H, J = 8.7 Hz), 6.76 (d, 2h, J = 8.7 Hz), 5.02 (bs, 1 H), 3.85 (m, 1 H), 3.79 (s, 3H), 3.74 (m, 1 H), 3.21 (dd, 1 H, J = 14.3, 4.3 Hz), 3.06 (dd, 1 H, J = 14.3, 6.1 Hz), 2.73 (m, 1 H), 2.57 (m, 2H), 1.99 (s, 3H), 1.31 (S, 9H). (M+H) 457.
Example 66: 2-(R)-(4-tert-Butyl-phenyl)-5-(S)-isobutyl-3-[2-(4-methoxy-phenyl)- ethyl]-1-methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3): δ 7.39 (d, 2H, J = 8.3 Hz), 7.1 1 (d, 2H, J = 8.3 Hz), 7.05 (d, 2H, J = 8.6 Hz), 6.81 (d, 2h, J = 8.6 Hz), 5.08 (bs, 1 H), 3.90 (m, 1 H), 3.78 (s, 3H), 3.44 (dt, 1 H, J = 6.0, 1.6 Hz), 2.76 (m, 2H), 2.65 (m, 1 H), 2.09 (s, 3H), 1.96 (m, 1 H), 1.53 (t, 2H, J = 6.6 Hz), 1.33 (s, 9H), 0.96 (d, 3H, J = 2.8 Hz), 0.93 (d, 3H, J = 2.7 Hz). (M+H) 423. Example 67: (2-{2-(4-Dimethylamino-phenyl)-1-[2-(4-methoxy-phenyl)-ethyl]-3- methyl-5-oxo-imidazolidin-4-(S)-yl}-ethyl)-carbamic acid tert-butyl ester, 1H-NMR (300 MHz, CD3OD): δ 7.30 (d, 2H, J = 8.4 Hz), 6.96 (m, 4H), 6.82 (d, 2H, J = 8.4 Hz), 4.49 (s, 1 H), 3.77 (s, 3H), 3.51 (m, 1 H), 3.20 (m, 2H), 3.06 (s, 6H), 2.85 (m, 2H), 2.69 (m, 1 H), 2.48 (m, 1 H), 2.28 (s, 3H), 2.00 (m, 2H), 1.46 (s, 9H). (M+H) 497.
Example 68: 2-(R)-(4-Dimethylamino-phenyl)-5-(S)-isobutyl-3-[2-(4-methoxy- phenyl)-ethyl]-1-methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD): δ 7.09 (m, 4H), 6.83 (m, 4H), 4.97 (d, 1 H, J = 2.1 Hz), 3.84 (m, 1 H), 3.79 (s, 3H), 3.46 (m, 1 H), 2.99 (s, 6H), 2.77 (m, 2H), 2.61 (m, 1 H), 2.07 (s, 3H), 1.83 (m, 1 H), 1.46 (m, 2H), 0.96 (d, 3H, J = 4.8 Hz), 0.93 (d, 3H, J = 4.8 Hz). (M+H) 410.
Example 69: 5-(S)-Benzyl-2-(S)-(3,4-dimethyl-phenyl)-3-[2-(4-methoxy-phenyl)- ethyl]-1-methyl-imidazolidin-4-one, 1H-NMR (300 MHz, CD3OD): δ 7.28 (m, 5H), 7.03 (d, 1 H, J = 7.5 Hz), 6.91 (d, 2H, J = 9.0 Hz), 6.81 (d, 2H, J = 8.7 Hz), 6.70 (dd, 1 H, J = 7.8, 1.8 Hz), 6.54 (s, 1 H), 4.41 (d, 1 H, J = 2.4 Hz), 3.78 (s, 3H), 3.40 (m, 1 H), 3.12 (m, 2H), 2.68 (m, 2H), 2.33 (m, 2H), 2.25 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H). (M+H) 429.
CATEGORY III
Example 70: 3-(4-Methoxyphenethyl)-1-methyl-2-(1-methyl-1 , 2,3,4- tetrahydroquinolin-6-yl)imidazolidin-4-one
Figure imgf000055_0001
3-(4-Methoxyphenethyl)-1-methyl-2-(1-methyl-1 ,2,3,4-tetrahydroquinolin-6- yl)imidazolidin-4-one: A solution of N-(4-methoxyphenethyl)-2-
(methylamino)acetamide (0.16 g, 0.72 mmol) and 1 -methyl-1 , 2,3,4- tetrahydroquinoline-6-carbaldehyde (0.14 g, 0.78 mmol) in MeCN (1.5 ml.) was irradiated in the microwave (CEM, 150 0C) for 5 min. The crude reaction mixture was purified by reverse phase HPLC to yield 0.09 g of the desired product. 1H NMR (300 MHz, CD3OD) δ 6.99 (m, 3H), 6.85 (m, 3H), 6.62 (d, 2H, J = 8.4 Hz), 4.39 (bs, 1 H), 3.76 (s, 3H), 3.58 (m, 2H), 3.30 (m, 3H), 3.08 (m, 1 H), 2.91 (s, 3H), 2.75 (m, 1 H), 2.20 (s, 3H), 1.97 (m, 2H); (MH+) 380.
Examples 71-74 were prepared according to the procedures described in Example 69 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 71 : 3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2-quinolin-4-yl-imidazolidin-4- one trifluoroacetate, 1H-NMR (300 MHz, CDCI3) δ 9.03 (d, 1 H, J = 4.7 Hz), 8.32 (d, 1 H, J = 8.4 Hz), 8.17 (d, 1 H, J = 8.5 Hz), 7.85 (t, 1 H, J = 7.2 Hz), 7.66 (t, 1 H, J = 7.2 Hz), 7.38 (d, 1 H, J = 4.7 Hz), 6.88 (d, 2H, J = 4.5 Hz), 6.78 (d, 2H, J = 4.5 Hz), 5.07 (s, 1 H), 3.78 (s, 3H), 3.78 (m, 2H), 3.23 (d, 1 H, J = 12.4 Hz), 2.81 (m, 1 H, J = 5.8 Hz), 2.58 (m, 2H), 2.27 (s, 3H); (MH+) 362.
Example 72: 3-[2-(4-Methoxyphenyl)-ethyl]-1-methyl-2-(1 H-pyrrol-2-yl)-imidazolidin- 4-one trifluoroacetate, 1H-NMR (300 MHz, CDCI3) δ 8.79 (bs, 1 H), 6.89 (d, 2H, J = 8.6 Hz), 6.74 (m, 1 H), 6.71 (d, 2H, J = 8.6 Hz), 6.18 (m, 1 H), 6.08 (d, 1 H, J = 8.6 Hz), 4.48 (s, 1 H), 3.68 (s, 3H), 3.54 (d, 1 H, J = 15.0 Hz), 3.34 (m, 1 H), 2.95 (dd, 1 H, J = 2.5, 14.0 Hz), 2.85 (m, 1 H), 2.61 (m, 1 H), 2.28 (m, 1 H), 2.19 (s, 3H); (MH+) 300.
Example 73: 3-[2-(4-Methoxy-phenyl)ethyl]- 1-methyl-2-(1 -methyl- 1 H-pyrrol-2-yl)- imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.00 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 6.45 (t, 1 H, J = 2.2 Hz), 6.17 (q, 1 H, J = 1.8 Hz), 6.07 (t. 1 H, J = 3.1 Hz), 4.59 (s, 1 H), 3.78 (s, 3H), 3.67 (m, 2H), 3.60 (s, 3H), 3.03 (dd, 1 H, J = 2.6, 14.2 Hz), 2.79 (m, 2H), 2.49 (m, 1 H), 2.28 (s, 3H); (MH+) 314. Example 74: 3-(4-Methoxyphenethyl)-1-methyl-2-(4-methyl-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-7-yl)imidazolidin-4-one, 1H NMR (300 MHz, CD3OD) δ 6.97 (d, 2H, J = 8.6 Hz), 6.78 (m, 5H), 4.40 (m, 1 H), 4.28 (m, 2H), 3.76 (s, 3H), 3.55 (m, 2H), 3.30 (m, 3H), 3.07 (m, 1 H), 2.92 (s, 3H), 2.76 (m, 2H), 2.47 (m, 1 H), 2.21 (s, 3H); (MH+) 383.
Category IV
Example 75: 1-(4-Methoxybenzyl)-3-(4-methoxyphenethyl)-2-(4-fe/f- butylphenyl)imidazolidin-4-one
Figure imgf000057_0001
Step 1 : fe/f-Butyl 2-(4-methoxyphenethylamino)-2-oxoethylcarbamate: To a solution of 2-(fe/?-butoxycarbonyl)acetic acid (20.0 g, 1 14.3 mmol) and 2-(4- methoxyphenyl)ethylamine (18.0 ml_, 122.9 mmol) in CH2CI2 (825 ml.) was added EDCI (32.9 g, 171.8 mmol). The reaction mixture was stirred at room temperature for 4 days, washed with 0.1 N HCI (2 x 500 ml_), dried over Na2SO4 and evaporated to yield 32.4 g of the desired product. 1H NMR (300 MHz, CD3OD) δ 7.86 (bs, 1 H), 7.14 (d, 2H, J = 8.5 Hz), 6.9 (d, 2H, J = 8.6 Hz), (s, 3H), 3.66 (s, 2H), 3.39 (m, 2H), 2.74 (t, 2H, J = 7.3 Hz), 1.46 (s, 9H); (MH+) 309. Step 2: N-(4-methoxyphenethyl)-2-aminoacetamide hydrochloride: To a solution of fe/t-butyl 2-(4-methoxyphenethylamino)-2-oxoethylcarbamate (32.39 g, 105.0 mmol) in MeOH (350 ml.) was slowly added a solution of HCI in dioxane (4.0 N, 100 ml_, 400.0 mmol). The reaction mixture was stirred at RT for 16 h and evaporated to yield 24.44 g of the desired product. 1H NMR (CD3OD) δ 7.16 (d, 2H, J = 8.1 Hz), 6.87 (d, 2H, J = 8.1 Hz), 3.78 (s, 3H), 3.64 (s, 2H), 3.46 (t, 2H, J = 6.9 Hz), 2.78 (t, 2H, J = 7.5 Hz); (MH+) 209.
Step 3: 3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)imidazolidin-4-one: To a solution N-(4-methoxyphenethyl)-2-aminoacetamide hydrochloride (5.1 g, 20.7 mmol) and 4-fe/f-butylbenzaldehyde (3.6 ml_, 21.5 mmol) in MeOH (140 ml.) was added Cs2CO3 (7.3 g, 22.2 mmol). The reaction mixture was warmed to 60 0C for 17 h followed by evaporation of the MeOH. The crude residue was dissolved in CH2CI2, washed with H2O and brine, dried over Na2SO4 and evaporated to yield 6.9 g of the desired product. 1H NMR (300 MHz, CD3OD) δ 7.50 (d, 2H, J = 8.3 Hz), 7.26 (d, 2H, J = 8.3 Hz), 7.01 (d, 2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.5 Hz), 5.20 (s, 1 H), 3.84 (s, 3H), 3.45 (m, 3H), 2.79 (m, 2H), 2.57 (m, 1 H), 1.35 (s, 9H); (MH+) 353.
Step 4: 1-(4-Methoxybenzyl)-3-(4-methoxyphenethyl)-2-(4-fe/f- butylphenyl)imidazolidin-4-one, To a solution of 3-(4-methoxyphenethyl)-2-(4-fe/f- butylphenyl)imidazolidin-4-one in 100 ml. DMF (0.5 g 1.4 mmol) sodium hydride (0.04 g 1.6 mmol) was added and stirred for 10 minutes, followed by the addition of p-methoxybenzyl chloride (02 g 1.6 mmol). The new solution was stirred overnight. 400 ml. of water was added and the organic layer was extracted with CH2CI2 (3x100 ml.) and the combined organic layers were dried over MgSO4. The organic solvent was boiled off and the resulting residue was purified by chromatography to produce a white solid, 0.3 g, 55.6 % yield. 1H NMR (300 MHz, CDCI3) δ 7.44 (m, 2 H), 7.31 (m, 3 H), 7.15 (m, 2 H), 6.90 (m, 2 H), 6.82 (m, 3 H), 4.70 (s, 1 H), 3.80 (s, 6 H), 3.61 (m, 4 H), 3.16 (m, 1 H), 2.91 (m, 2 H), 2.50 (m, 1 H), 1.38 (m, 9 H); (MH+) 473.
Examples 76-85 were prepared according to the procedures described in Example 74 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): Example 76: 1 -(4-Methoxybenzyl)-2-(4-chlorophenyl)-3-phenethylimidazolidin-4- one, 1H NMR (300 MHz, CDCI3) δ 7.40 (m, 9 H), 7.06 (m, 2 H), 6.85 (m, 2 H), 4.61 (m, 1 H), 3.81 (s, 3 H), 3.70 (m, 1 H), 3.54 (m, 2 H), 3.30 (m, 1 H), 3.10 (m, 1 H), 2.83 (m, 2 H), 2.61 (m, 1 H); (MH+) 421.
Example 77: 3-(4-Methoxyphenethyl)-2-(benzo[d][1 ,3]dioxol-5-yl)-1- benzylimidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 7.29 (m, 5 H), 7.20 (m, 2 H), 6.98 (m, 2 H), 6.80 (m, 3 H), 3.03 (m, 2 H), 4.64 (m, 1 H), 3.81 (s, 3 H), 3.78 (m, 1 H), 3.63 (m, 1 H), 3.55 (m, 1 H), 3.33 (d, 1 H, J = 13.2 Hz), 3.06 (m, 1 H), 2.80 (m, 2 H), 2.56 (m, 1 H); (MH+) 431
Example 78: 1-Benzyl-3-[2-(4-methoxyphenyl)-ethyl]-2-(4-trifluoromethylphenyl)- imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.57 (d, 2H, J = 8.1 Hz), 7.35 (d, 2H, J = 8.1 Hz), 7.18 (m, 3H), 7.05 (dd, 2H, J = 2.3, 7.6 Hz), 6.88 (d, 2H, J = 8.6 Hz), 6.74 (d, 2H, J = 8.7 Hz), 4.64 (s, 1 H), 3.73 (s, 3H), 3.61 (m, 2H), 3.50 (dd, 1 H, J = 1.4, 14.4 Hz), 3.31 (d, 1 H, J = 13.1 Hz), 3.05 (dd, 1 H, J = 2.1 , 14.4 Hz), 2.65 (m, 2H), 2.48 (m, 1 H); (MH+) 455.
Example 79: 1 -Benzyl-2-(3,4-dichlorophenyl)-3-[2-(4-methoxyphenyl)-ethyl]- imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.38 (d, 1 H, J = 8.2 Hz), 7.19 (m, 4H), 7.06 (m, 3H), 6.90 (d, 2H, J = 8.6 Hz), 6.76 (d, 2H, J = 8.6 Hz), 4.51 (s, 1 H), 3.74 (s, 3H), 3.65 (m, 1 H), 3.47 (dd, 1 H, J = 1.4, 14.5 Hz), 3.30 (d, 1 H, J = 13.1 Hz), 3.03 (dd, 1 H J = 2.2, 14.4 Hz), 2.66 (m, 3H), 2.48 (m, 1 H); (MH+) 455.
Example 80: 1 -Benzyl-2-(3-chlorophenyl)-3-[2-(4-methoxyphenyl)-ethyl]- imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.28 (m, 2H), 7.19 (m, 5H), 7.07 (d, 2H, J = 7.8 Hz), 6.90 (d, 2H, J = 8.6 Hz), 6.75 (d, 2H, J = 8.6 Hz), 4.57 (s, 1 H), 3.73 (s, 3H), 3.65 (d, 1 H, J = 12.7 Hz), 3.61 (m, 1 H), 3.47 (d, 1 H, J = 15.7 Hz), 3.29 (d, 1 H, J = 13.1 Hz), 3.02 (d, 1 H J = 16.5 Hz), 2.67 (m, 2H), 2.44 (m, 1 H); (MH+) 421.
Example 81 : 1-Benzyl-2-(4-/sopropylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]- imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.17 (m, 9H), 6.85 (d, 2H, J = 8.7 Hz), 6.71 (d, 2H, J = 8.7 Hz), 4.63 (s, 1 H), 3.69 (s, 3H), 3.69 (m, 1 H), 3.49 (m, 2H), 3.25 (d, 1 H, J = 13.2 Hz), 2.98 (dd, 1 H, J = 14.3, 2.2 Hz), 2.86 (m, 1 H), 2.70 (m, 2H), 2.38 (m, 1 H), 1.19 (d, 6H, J = 7.1 Hz); (MH+) 429.
Example 82: 1 -Benzyl-2-(4-ethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-imidazolidin- 4-one, 1H-NMR (300 MHz, CDCI3) δ 7.17 (m, 9H), 6.87 (d, 2H, J = 8.6 Hz), 6.71 (d, 2H, J = 1 1.5 Hz), 4.63 (s, 1 H), 3.70 (s, 3H), 3.69 (d, 1 H, J = 12.7 Hz), 3.52 (m, 1 H), 3.44 (d, 1 H, J = 15.5 Hz), 3.24 (d, 1 H, J = 13.2 Hz), 2.98 (d, 1 H, J = 16.5 Hz), 2.64 (m, 4H), 2.39 (m, 1 H), 1.18 (t, 3H, J = 10.6 Hz); (MH+) 415.
Example 83: 1 -Benzyl-2-(4-fe/?-butyl-phenyl)-3-[2-(4-methoxyphenyl)-ethyl]- imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.33 (d, 2H, J = 8.4 Hz), 7.24 (d, 2H, J = 8.4 Hz), 7.15 (m, 5H), 6.85 (d, 2H, J = 8.6 Hz), 6.71 (d, 2H, J = 8.6 Hz), 4.63 (s, 1 H), 3.69 (s, 3H), 3.69 (m, 1 H), 3.47 (m, 2H), 3.25 (d, 1 H, J = 13.2 Hz), 2.98 (dd, 1 H, J = 2.2, 14.3 Hz), 2.71 (m, 2H), 2.38 (m, 1 H), 1.27 (s, 9H); (MH+) 443.
Example 84: 1 -Benzyl-2-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]- imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.12 (m, 8H), 6.88 (d, 2H, J = 8.6 Hz), 6.72 (d, 2H, J = 8.7 Hz), 4.59 (s, 1 H), 3.70 (s, 3H), 3.66 (m, 1 H), 3.56 (m, 1 H), 3.43 (dd, 1 H, J = 1.4, 14.3 Hz), 3.23 (d, 1 H, J = 13.2 Hz), 2.97 (dd, 1 H, J = 13.2 Hz), 2.67 (m, 2H), 2.43 (m, 1 H), 2.20 (s, 6H); (MH+) 415.
Example 85: 1 -Benzyl-2-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)-ethyl]- imidazolidin-4-one, 1H-NMR (300 MHz, CDCI3) δ 7.51 (m, 2H), 7.43 (m, 3H), 7.28 (m, 4H), 7.12 (d, 2H, J = 8.6 Hz), 6.98 (d, 2H, J = 8.6 Hz), 4.86 (s, 1 H), 3.96 (s, 3H), 3.89 (d, 1 H, J = 13.1 Hz), 3.80 (m, 1 H), 3.71 (d, 1 H, J = 15.7 Hz), 3.51 (d, 1 H, J = 13.1 Hz), 3.26 (d, 1 H, J = 14.4 Hz), 2.91 (m, 2H), 2.66 (m, 1 H); (MH+) 405.
CATEGORY V Example 86: 3-(4-Methoxyphenethyl)-1-(2-(benzyloxy)ethyl)-2-(4-te/f- butylphenyl)imidazolidin-4-one
Figure imgf000061_0001
3-(4-Methoxyphenethyl)-1-(2-(benzyloxy)ethyl)-2-(4-fe/?-butylphenyl)imidazolidin-4- one: To a solution of 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)imidazolidin-4- one (0.55 g, 1.57 mmol) and 1-((2-bromoethoxy)methyl)benzene (0.27 ml_, 1.71 mmol) in 1 ,4-dioxane (15.0 ml.) was added Cs2CO3. The reaction mixture was stirred at 65 0C for a total of 3 d followed by filtration and evaporation to yield the crude material. The crude material was purified by reverse phase HPLC to yield 0.18 g of the desired product. 1H NMR (300 MHz, CDCI3) δ 7.45 (d, 2H, J = 8.4 Hz), 7.31 (m, 7H), 6.99 (d, 2H, J = 8.7 Hz), 6.38 (d, 2H, J = 8.7 Hz), 4.94 (s, 1 H), 4.46 (s, 2H), 3.90 (m, 1 H), 3.81 (s, 3H), 3.65 (m, 4H), 2.81 (m, 4H), 2.55 (m, 1 H), 1.37 (s, 9H); (MH+) 487.
Examples 87-88 were prepared according to the procedures described in Example 85 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 87: 3-(4-Methoxyphenethyl)-1-(3-(benzyloxy)propyl)-2-(4-fe/f- butylphenyl)imidazolidin-4-one, 1H NMR (300 MHz, CD3OD) δ 7.72 (d, 2H, J = 8.4 Hz), 7.30 (m, 5H), 7.16 (m, 2H), 6.94 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 4.67 (bs, 1 H), 4.28 (bs, 2H), 3.79 (s, 3H), 3.43 (m, 4H), 3.14 (m, 1 H), 2.70 (m, 3H), 2.43 (m, 2H), 1.66 (m, 2H), 1.32 (s, 9H); (MH+) 501.
Example 88: 3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-(3-(pyridin-2- ylmethoxy)propyl)imidazolidin-4-one trifluroacetate, 1H NMR (300 MHz, CDCI3) δ 8.84 (d, 1 H, J = 5.3 Hz), 8.26 (t, 1 H, J = 7.7 Hz), 7.73 (m, 2H), 7.44 (d, 2H, J = 8.3 Hz), 7.27 (d, 2H, J = 8.3 Hz), 6.96 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.6 Hz), 5.09 (bs, 1 H), 4.80 (bs, 2H), 3.95 (m, 1 H), 3.76 (m, 4H), 3.56 (m, 3H), 2.84 (m, 4H), 2.58 (m, 1 H), 1.86 (m, 2H), 1.31 (s, 9H); (MH+) 502.
CATEGORY Vl
Example 89: 2-(4-fe/?-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-[3-(pyridin-3- ylmethoxy)propyl]imidazolidin-4-one
DMF**
Figure imgf000062_0002
Figure imgf000062_0001
Step 1. 3-(4-methoxyphenethyl)-2-(4-te/?-butylphenyl)-1-(3-(pyridin-3- ylmethoxy)propyl)imidazolidin-4-one: To a solution of 3-(4-methoxyphenethyl)-2-(4- fe/?-butylphenyl)-1-(3-hydroxypropyl)imidazolidin-4-one (0.2 g, 0.6 mmol) in THF (6.0 ml.) was added Et3N (0.2 ml_, 1.2 mmol) followed by methanesulfonyl chloride (0.05 ml_, 0.65 mmol). The reaction mixture was stirred at room temperature for 18 hours followed by evaporation of the THF and dilution in methylene chloride. The methylene chloride was washed with 0.1 N HCI (2x), dried over Na2SO4 and evaporated to yield 0.3 g of the desired product. 1H NMR (300 MHz, CDCI3) δ 7.49 (d, 2H, J = 8.1 Hz), 7.28 (d, 2H, J = 7.8 Hz), 7.01 (d, 2H, J = 8.4 Hz), 6.84 (d, 2H, J = 8.7 Hz), 4.21 (m, 2H), 3.95 (s, 1 H), 3.82 (s, 3H), 3.71 (s, 1 H), 3.03 (m, 1 H), 2.82 (m, 6H), 2.01 (bs, 2 H), 1.39 (m, 9H); (MH+) 489.
Step 2. 3-(4-Methoxyphenethyl)-2-(4-te/?-butylphenyl)-1-(3-(pyridin-3- ylmethoxy)propyl)imidazolidin-4-one: To a solution of 3-(3-(4-methoxyphenethyl)-2- (4-fe/?-butylphenyl)-4-oxoimidazolidin-1-yl)propyl methanesulfonate (0.1 g, 0.3 mmol) in THF (7.5 ml.) was added NaH (60%, 0.02 g, 0.6 mmol) followed by pyridin- 3-ylmethanol (0.04 ml_, 0.4 mmol). The reaction mixture was stirred at room temperature for 17 hours at which time additional NaH (60%, 0.06 g, 1.43 mmol) and pyridin-3-ylmethanol (0.12 ml_, 1.3 mmol) were added. The reaction mixture was warmed to 50 0C for a total reaction time of 41 hours followed by evaporation to yield the crude product. The crude material was purified by reverse phase HPLC to yield 0.06 g of the desired product. 1H NMR (300 MHz, CDCI3) δ 8.79 (bs, 1 H), 8.67 (d, 1 H, J = 5.2 Hz), 8.1 1 (d, 1 H, J = 8.0 Hz), 7.74 (m, 1 H), 7.37 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.6 Hz), 6.72 (d, 2H, J = 8.6 Hz), 5.1 1 (s, 1 H), 4.49 (q, 2 H, J = 9.5, 2.8 Hz), 3.90 (m, 1 H), 3.69 (m, 4H), 3.49 (m, 3H), 2.69 (m, 5H), 1.79 (m, 2H), 1.24 (s, 9H); (MH+) 502.
Example 90 was prepared according to the procedures described in Examples 88 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 90: N-(3-(3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-4-oxoimidazolidin- 1-yl)propyl)nicotinamide, 1H NMR (300 MHz, CDCI3) δ 9.40 (s, 1 H), 8.83 (m, 1 H), 8.51 (m, 1 H), 7.88 (m, 1 H), 7.46 (d, 2H, J = 8.3 Hz), 7.25 (d, 2H, J = 8.3 Hz), 6.97 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.6 Hz), 5.23 (s, 1 H), 4.08 (m, 1 H), 3.81 (m, 2H), 3.75 (s, 3H), 3.43 (m, 3H), 2.73 (m, 5H), 1.95 (t, 2H, J = 6.5 Hz), 1.32 (s, 9H); (MH+) 515.
CATEGORY VII
Example 91 : 3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-(methylsulfonyl) imidazolidin-4-one:
Figure imgf000063_0001
3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-(methylsulfonyl) imidazolidin-4-one:
To a solution of 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl) imidazolidin-4-one (0.2 g 0.6 mmol) sodium hydride (0.02 g (0.7mmol) was added at room temperature in DMF (50 ml.) and stirred for 10 minutes. Mesyl chloride was added in a slow steady stream. The resulting solution was monitored by HPLC and stirred overnight. Water was added (10OmL) and the organic layer was extracted with methylene chloride (3 x 100 mL). The combined organic layers were dried over MgSO4, the organic exract is filtered, and the solvent was boiled off. The residue was purified by chromatography to give 0.08 g of 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1- (methylsulfonyl)imidazolidin-4-one, 31 .7 % yield. 1H NMR (300 MHz, CDCI3) δ 7.45 (d, 2H, J = 8.4 Hz), 7.22 (d, 2H, J = 8.7 Hz), 7.06 (d, 2H, J = 8.4 Hz), 6.86 (d, 2H, J = 8.7 Hz), 5.64 (s, 1 H), 4.20 (m, 1 H), 4.00 (m, 2 H), 3.80 (s, 3 H), 2.85 (m, 2 H), 2.73 (m, 1 H), 2.42 (s, 3 H), 1.34 (s, 9 H); (MH+) 431.
Examples 92-95 were prepared according to the procedures described in Examples 90 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 92: 3-(4-Methoxyphenethyl)-2-(4-te/?-butylphenyl)-1-(3- fluorophenylsulfonyl)imidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 7.08 (m, 12 H), 5.19 (m, 2 H), 3.89 (m, 2 H), 3.81 (s, 3 H), 2.87 (m, 2 H), 2.68 (m, 1 H), 2.28 (s, 3 H); (MH+) 51 1.
Example 93: 3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-tosylimidazolidin-4- one, 1H NMR (300 MHz, CDCI3) δ 7.41 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 7.8 Hz), 7.19 (d, 2H, J = 8.4 Hz), 7.1 1 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.7 Hz), 6.79 (d, 2H, J = 8.7 Hz), 5.77 (s, 1 H), 4.1 1 (m, 2 H), 3.81 (s, 3 H), 3.77 (m, 1 H), 2.71 (m, 2 H), 2.57 (m, 1 H), 2.41 (s, 3 H), 1.34 (s, 9 H); (MH+) 507.
Example 94: 3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1- (ethylsulfonyl)imidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 7.44 (d, 2H, J = 8.4), 7.22 (d, 2H, J = 8.7 Hz), 7.06 (d, 2H, J = 8.4 Hz), 6.86 (d, 2H, J = 8.7 Hz), 5.77 (s, 1 H), 4.30 (m, 1 H), 3.96 (m, 2 H), 3.81 (s, 3 H), 2.82 (m, 1 H), 2.60 (m, 2 H), 2.44 (m, 1 H), 1.36 (s, 9 H), 1.10 (t, 3H, J = 7.5 Hz); (MH+) 445. Example 95: 3-(4-Methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1-(4- ethylphenylsulfonyl)imidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 7.44 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 8.4 Hz), 7.23 (d, 2H, J = 8.7 Hz), 7.1 1 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.7 Hz), 6.81 (d, 2H, J = 8.4 Hz), 5.77 (s, 1 H), 4.09 (m, 2 H), 3.81 (s, 3 H), 3.78 (m, 1 H), 2.73 (m, 4 H), 2.44 (m, 1 H), 1.36 (s, 9 H), 1.25 (t, 3H, J = 6.6 Hz); (MH+) 521.
CATEGORY VIII
Example 96: 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-3-yl)propanamide
ΛF F7iCCIH2CI2, rt,
Figure imgf000065_0001
Step 1 : (S)-benzyl 4-(3-(benzyloxy)-3-oxopropyl)-5-oxooxazolidine-3-carboxylate: The mixture Of Z-GIu(BzI)-OH (3.7 g, 10.0 mmol), p-toluenesulfonic acid (190 mg, 1.0 mmol), and paraformaldehyde (2.5 g) in toluene (120 ml.) was refluxed for 1.5 h. The solution was decanted into a separatory funnel, diluted with ether, washed with 5% NaHCO3 and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product as a colorless oil, which was then purified by column chromatography (silica gel, 4:1 Hexanes/ethyl acetate) to yield a colorless oil (3.5 g, 91 %). 1H NMR (300 MHz, CDCI3) δ 7.36 (m, 10H), 5.53 (bs, 1 H), 5.18 (m, 3H), 5.09 (m, 2H), 4.40 (t, 1 H, J = 5.7 Hz), 2.51 (m, 2H), 2.36 (m, 1 H), 2.24 (m, 1 H); (MH+) 384.
Step2: (S)-5-(benzyloxy)-2-(benzyloxycarbonyl)-5-oxopentanoic acid: To the solution of (S)-benzyl 4-(3-(benzyloxy)-3-oxopropyl)-5-oxooxazolidine-3-carboxylate (3.5 g, 9.1 mmol) in CHCI3 at room temperature was added triethylsilane (4.4 ml_, 27.4 mmol) followed by trifluoroacetic acid (46 ml_). The resultant solution was stirred at room temperature for 2 days. The solvent was removed under reduced pressure to give the crude product as a murky paste, which was purified by HPLC (reversed phase C18, H20/acetonitrile) to give a colorless paste (2.8 g, 81 %). 1H NMR (300 MHz, CDCI3, 2 rotamers) δ 7.36 (m, 10H), 5.12 (4H), 4.75 (m, 1 H), 2.89 (s, 3H), 2.43 (m, 3H), 2.10 (m, 1 H); 13C NMR (75 MHz, CDCI3) δ 175.9, 172.6, 172.5, 157.3, 156.4, 136.4, 136.3, 135.9, 128.8, 128.7, 128.5, 128.3, 128.0, 68.0, 66.7, 60.7, 58.5, 58.3, 32.0, 31.6, 30.9, 30.7, 24.3, 23.9, 21.2, 14.4; (MH+) 385.
Step 3: (S)-benzyl 5-(4-(trifluoromethoxy)phenethylamino)-4-(benzyloxycarbonyl)-5- oxopentanoate: To the solution of (S)-5-(benzyloxy)-2-(benzyloxycarbonyl)-5- oxopentanoic acid (1.4 g, 3.7 mmol) and trifluoromethoxyphenethylamine hydrochloride (0.84 g, 3.5 mmol) in DMF (30 ml.) was added Et3N (1.5 ml_, 4.7 mmol), HOBt (0.71 g, 5.2 mmol), and EDC»HCI (1.0 g, 5.2 mmol). The resultant suspension was stirred at room temperature overnight. The mixture was concentrated to half of the volume and was then partitioned between ethyl acetate and 1 N sodium bisulfate. The layers were separated and the organic solution was washed with water, 5% NaHCO3, water, and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product as a yellowish paste, which was purified by HPLC (C18, H20/acetonitrile) to give a colorless paste (1.73 g, 86%). 1H NMR (300 MHz, CDCI3) δ 7.35 (m, 10H), 7.1 1 (m, 4H), 6.17 (bs, 1 H), 5.1 1 (m, 4H), 4.61 (m, 1 H), 3.53 (m, 1 H), 3.42 (m, 1 H), 2.74 (m, 5H), 2.32 (m, 3H), 1.98 (m, 1 H); (MH+) 573. Step 4: 3-((4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-3-methyl-5- oxoimidazolidin-4-yl)propanoic acid: The mixture of (S)-benzyl 5-(4- (trifluoromethoxy)phenethylamino)-4-(benzyloxycarbonyl)-5-oxopentanoate (1.70 g, 3.0 mmol) and Pd-C (10%, 0.2 g) in 2-propanol (30 ml.) was stirred under hydrogen (1 atm) at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl ether to give a white solid (0.80 g), which was used without further purification. To the mixture of this crude product (4.9 g, 14 mmol), and Cs2CO3 (4.6 g, 14 mmol) in MeOH (70 ml.) was added 4-fe/f-butylbenzaldehyde (4.6 ml_, 27 mmol). The resultant mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the product was purified by HPLC (C18, water/acetonitrile) to give the products as two diastereomers. Major (trans) isomer: 1H NMR (300 MHz, CDCI3) δ 7.43 (d, 2H, J = 8.4 Hz), 7.19 (m, 4H), 7.09 (d, 2H, J = 8.4 Hz), 5.39 (s, 1 H), 4.03 (m, 1 H), 3.58 (m, 1 H), 2.83 (m, 3H), 2.48 (m, 2H), 2.13 (m, 5H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 176.8, 170.9, 154.2, 148.4, 137.1 , 130.4, 130.2,
128.2, 126.6, 121.6, 120.6 (CF3, q, J = 255 Hz), 79.2, 62.7, 42.2, 35.4, 35.2, 33.3, 31.6, 29.9, 23.1 ; (MH+) 493.2313 (calc'd C26H32F3N2O4 493.2314); Minor (cis) isomer: 1H NMR (300 MHz, CDCI3) δ 7.42 (d, 2H, J = 8.4 Hz), 7.22 (d, 2H, J = 8.4 Hz), 7.10 (d, 2H, J = 8.4 Hz), 7.00 (d, 2H, J = 8.4 Hz), 4.39 (d, 1 H, J = 1.5 Hz), 3.55 (m, 1 H), 3.22 (m, 1 H), 2.93 (m, 1 H), 2.76 (m, 1 H), 2.54 (m, 3H), 2.23 (m, 5H), 1.34 (S, 9H); 13C NMR (75 MHz, CDCI3) δ 178.4, 172.1 , 153.6, 148.1 , 137.4, 132.6,
130.3, 128.7, 126.0, 121.3, 120.6 (CF3, q, J = 255 Hz), 82.9, 65.2, 42.2, 36.9, 35.0, 33.1 , 31.5, 29.5, 23.3; (MH+) 493.
Step 5: 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/t-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)-N-(pyridin-3-yl)propanamide: To the solution of 3-((4S)-1-(4-
(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-3-methyl-5-oxoimidazolidin-4- yl)propanoic acid (240 mg, 0.41 mmol) in THF (2 ml.) was added 1 ,1 '- carbonyldiimidazole (264 mg, 1.6 mmol) and the resultant mixture was stirred at room temperature for 30 min. A solution of DBU (183 μl_, 1.2 mmol) and 3- aminopyridine (200 mg, 2.1 mmol) in THF (1.5 ml.) was then added and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the product was purified by HPLC (C18, H20/acetonitrile) to give the major isomer as a yellow amorphous powder (84 mg, 37%). 1H NMR (300 MHz, CDCI3) δ 9.35 (m, 1 H), 8.67 (s, 1 H), 8.28 (m, 2H), 7.38 (d, 2H, J = 8.4 Hz), 7.29 (m, 1 H), 7.10 (m, 6H), 4.99 (d, 1 H, J = 2.1 Hz), 3.93 (m, 1 H), 3.55 (m, 1 H), 2.84 (m, 2H), 2.70 (m, 1 H), 2.43 (m, 2H), 2.21 (m, 1 H), 2.05 (s, 3H), 1.88 (m, 1 H), 1.31 (S, 9H); 13C NMR (75 MHz, CDCI3) δ 173.3, 172.1 , 153.0, 148.1 , 144.1 , 140.6, 137.2, 136.0, 132.5, 130.2, 127.8, 127.6, 126.0, 124.0, 121.2, 120.6 (CF3, q, J = 255 Hz), 80.4, 62.4, 41.3, 34.9, 34.0, 33.2, 32.7, 31.4, 32.7; 19F-NMR (282 MHz, CDCI3) δ104.8; (MH+) 569.
Examples 97-101 were prepared according to the procedures described in Example 95 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 97: 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)-N-(phenylsulfonyl)propanamide, 1H NMR (300 MHz, CDCI3) δ 8.10 (m, 2H), 7.55 (m, 3H), 7.42 (d, 2H, J = 8.4 Hz), 7.20 (d, 2H, J = 8.4 Hz), 7.09 (m, 4H), 5.25 (s, 1 H), 4.07 (m, 1 H), 3.45 (m, 1 H), 2.82 (m, 3H), 2.02 (m, 7H), 1.34 (S, 9H); 13C NMR (75 MHz, CDCI3) δ 171.6, 153.4, 148.2, 140.0, 136.9, 133.5, 131.5, 130.3, 129.0, 128.3, 127.9, 126.2, 121.5, 120.6 (CF3, q, J = 255 Hz), 104.1 , 79.0, 63.1 , 41.3, 35.0, 34.5, 33.4, 33.0, 31.5, 22.8; 19F NMR (282 MHz, CDCI3) 6105.2; (MH+) 632.
Example 98: 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-3-yl)acetamide, 1H NMR (300 MHz, CDCI3) δ 10.10 (s, 1 H), 8.68 (s, 1 H), 8.37 (d, 1 H, J = 4 Hz), 8.25 (d, 1 H, J = 8 Hz), 7.44 (d, 2H, J = 8 Hz), 7.30 (m, 1 H), 7.13 (m, 6H), 5.18 (d, 1 H, J = 2 Hz), 3.94 (m, 1 H), 3.81 (m, 1 H), 2.97 (m, 1 H), 2.8 (m, 4H), 2.14 (s, 3H), 1.35 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 173.3, 169.0, 153.3, 148.2, 144.8, 141.1 , 137.0, 135.6, 131.7, 130.1 , 127.7, 127.3, 126.2, 123.9, 121.4, 120.6 (CF3, q, J = 255 Hz), 80.7, 60.8, 42.2, 38.0, 34.9, 34.7, 33.3, 31.4; 19F NMR (282 MHz, CDCI3) 5105.1 ; (MH+) 555.
Example 99: 2-((2S,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-te/?-butylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-2-yl)acetamide, 1H NMR (300 MHz, CDCI3) δ 9.80 (s, 1 H), 8.19 (d, 1 H, J = 4 Hz), 8.12 (d, 1 H, J = 8 Hz), 7.58 (m, 1 H), 7.26 (d, 2H, J = 8 Hz), 7.13 (d, 2H, J = 8 Hz), 6.88 (m, 5H), 4.28 (d, 1 H, J = 2 Hz), 3.44 (m, 1 H), 3.31 (m, 1 H), 2.83 (m, 2H), 2.69 (m, 2H), 2.38 (m, 1 H), 2.18 (s, 3H), 1.21 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 172.1 , 168.9, 153.5, 151.8, 148.1 , 148.0, 138.5, 137.5, 133.0, 130.3, 128.9, 125.9, 121.3, 120.6 (CF3, q, J = 255 Hz), 1 19.8, 1 14.4, 83.1 , 63.4, 42.3, 38.6, 37.1 , 35.0, 33.2, 31.5; 19F NMR (282 MHz, CDCI3) δ104.8; (MH+) 555.
Example 100: 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/f-butylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-2-ylmethyl)acetamide, 1H NMR (300 MHz, CD3OD) δ 8.50 (d, 1 H, J = 4.5 Hz), 7.81 (dt, 1 H, J = 7.8, 1.6 Hz), 7.48 (m, 3H), 7.31 (dd, 1 H, J = 5.5, 7.1 Hz), 7.17 (m, 6H), 5.16 (d, 1 H, J = 2.2 Hz), 4.54 (dd, 2H, J = 16.0, 28.0), 3.96 (m, 1 H), 3.75 (m, 1 H), 2.79 (m, 5H), 2.10 (s, 3H), 1.34 (s, 9H); 13C NMR (75 MHz, CD3OD) δ 174.5, 173.1 , 159.3, 154.1 , 149.9, 149.2, 139.4, 138.9, 134.2, 131.5, 129.3, 127.0, 123.9, 123.2, 122.2, 122.0 (CF3, q, J = 255 Hz), 82.0, 62.5, 45.7, 43.3, 36.8, 35.7, 34.7, 34.0, 31.8; 19F NMR (282 MHz, CD3OD) 6103.4; (MH+) = 569.
Example 101 : 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/f-butylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-2-ylmethyl)acetamide, 1H NMR (300 MHz, CD3OD) δ 8.55 (d, 1 H, J = 1.8 Hz), 8.44 (dd, 1 H, J = 1.5, 4.8 Hz), 7.84 (m, 1 H), 7.48 (d, 2H, J = 8.4 Hz), 7.41 (m, 1 H), 7.17 (m, 6H), 5.12 (d, 1 H, J = 2.1 Hz), 4.46 (dd, 2H, J = 15.0, 34.0 Hz), 3.93 (m, 1 H), 3.73 (m, 1 H), 2.79 (m, 5H), 2.06 (s, 3H), 1.34 (S, 9H); 13C NMR (75 MHz, CD3OD) δ 174.5, 173.0, 154.1 , 149.6, 149.2, 148.9, 139.5, 137.8, 136.8, 134.3, 131.6, 129.3, 127.0, 125.3, 122.2, 122.0 (CF3, q, J = 255 Hz), 82.0, 62.5, 43.3, 41.7, 36.9, 35.7, 34.7, 34.0, 31.8; 19F NMR (282 MHz, CD3OD) δ103.5; (MH+) = 569.
Category IX
Example 102: benzyl 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-te/f- butylphenyl)-3-methyl-5-oxoimidazolidin-4-yl)ethylcarbamate
Figure imgf000070_0001
A solution of 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-te/?-butylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)propanoic acid (1.86 g, 3.45 mmol), Et3N (2.40 ml_, 17.2 mmol), and diphenylphosphorylazide (1.70 ml_, 7.93 mmol) in toluene (20 ml.) was stirred at 40 0C overnight. Benzyl alcohol (3.20 ml_, 31.0 mmol) was then added and the resultant mixture was stirred at ~105 0C for 12 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and 5% NaHCO3. The layers were separated and the organic solution was washed with another portion of 5% NaHCO3 and brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (silica gel, 4:1 Hexanes/ethyl acetate) to a yellow paste (1.30 g, 63%). 1H NMR (300 MHz, CDCI3) δ 7.28 (m, 7H), 7.03 (m, 4H), 6.94 (d, 2H, J = 8.1 Hz), 5.64 (m, 1 H), 5.03 (s, 2H), 4.91 (s, 1 H), 3.82 (m, 1 H), 3.35 (m, 1 H), 3.28 (m, 1 H), 3.15 (m, 1 H), 2.70 (m, 3H), 1.94 (m, 4H), 1.69 (m, 1 H), 1.24 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 173.1 , 156.6, 152.8, 148.1 , 137.4, 137.0, 132.5, 130.2, 128.6, 128.3, 128.2, 127.7, 125.9, 121.3, 120.7 (CF3, q, J = 255 Hz), 80.4, 66.7, 62.6, 41.8, 37.9, 34.9, 34.6, 33.4, 31.5, 27.9; 19F NMR (282 MHz, CDCI3) δ104.8; (MH+) 598.
Example 103: N-(2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-te/f- butylphenyl)-3-methyl-5-oxoimidazolidin-4-yl)ethyl)picolinamide: A mixture of benzyl 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-3-methyl-5- oxoimidazolidin-4-yl)ethylcarbamate (78 mg, 0.13 mmol) and Pd-C (10%, 5 mg) in MeOH/THF (1 ml_/1 ml_) was stirred under H2 (1 atm) for 2 hours at room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resultant crude amine was dissolved in DMF and to this solution was added Et3N (60 μl_, 0.43 mmol), picolinic acid (24 mg, 0.20 mmol), HOBt (27 mg, 0.20 mmol), and EDOHCI (38 mg, 0.20 mmol). The resultant mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and 5% NaHCO3. The layers were separated and the organic solution was washed with water and brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the product was purified by HPLC (C18, H20/acetonitrile) to give a yellow solid (35 mg, 47%). 1H NMR (300 MHz, CDCI3) δ 8.70 (m, 1 H), 8.58 (d, 1 H, J = 4.2 Hz), 8.21 (d, 1 H, J = 7.8 Hz), 7.84 (dd, 1 H, J = 1.8, 7.8 Hz), 7.40 (m, 3H), 7.07 (m, 6H), 5.05 (d, 1 H, J = 1.8 Hz), 3.94 (m, 1 H), 3.56 (m, 3H), 2.78 (m, 3H), 2.17 (m, 1 H), 2.07 (s, 3H), 1.92 (m, 1 H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 172.8, 164.5, 152.7, 150.4, 148.3, 148.0, 137.5, 137.4, 132.8, 130.2, 127.8, 126.1 , 125.9, 122.4, 121.2, 120.6 (CF3, q, J = 255 Hz), 80.4, 62.4, 41.8, 36.0, 34.9, 34.6, 33.4, 31.5, 27.8; 19F NMR (282 MHz, CDCI3) δ104.8; (MH+) 569.
Examples 104-105 were prepared according to the procedures described in Example 101 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 104: N-(2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-te/f- butylphenyl)-3-methyl-5-oxoimidazolidin-4-yl)ethyl)nicotinamide, 1H NMR (300 MHz, CDCI3) δ 9.10 (d, 1 H, J = 1.8 Hz), 8.72 (dd, 1 H, J = 1.5, 4.8 Hz), 8.46 (m, 1 H), 8.24 (dt, 1 H, J = 8.1 , 2.1 Hz), 7.39 (m, 3H), 7.07 (m, 6H), 5.09 (d, 1 H, J = 2.4 Hz), 3.93 (m, 1 H), 3.83 (m, 1 H), 3.50 (m, 1 H), 3.35 (m, 1 H), 2.79 (m, 3H), 2.12 (m, 1 H), 2.06 (s, 3H), 1.85 (m, 1 H)1.32 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 173.9, 165.3, 153.0, 152.1 , 148.6, 148.1 , 137.2, 135.3, 132.1 , 130.3, 130.1 , 127.7, 126.1 , 123.6, 121.3, 120.6 (CF3, q, J = 255 Hz), 80.7, 64.0, 41.9, 37.8, 34.9, 34.7, 33.3, 31.4, 27.6; 19F NMR (282 MHz, CDCI3) 6105.0; (MH+) 569. Example 105: (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-fe/?-butylphenyl)-1- methyl-5-(2-(pyrimidin-2-ylamino)ethyl)imidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 8.31 (d, 2H, J = 4.4 Hz), 7.38 (d, 2H, J = 8.3 Hz), 7.18 (d, 2H, J = 8.6 Hz), 7.06 (m, 4H), 6.68 (bs, 1 H), 6.55 (t, 1 H, J = 4.8 Hz), 5.22 (s, 1 H), 3.99 (m, 1 H), 3.67 (m, 1 H), 3.53 (m, 1 H), 3.30 (m, 1 H), 2.82 (m, 3H), 2.21 (m, 1 H), 2.07 (s, 3H), 1.91 (m, 1 H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 173.0, 162.1 , 158.1 , 152.8, 148.1 , 137.5, 132.7, 130.2, 127.8, 125.9, 121.2, 120.6 (CF3, q, J = 255 Hz), 114.7, 1 10.3, 80.3, 62.8, 41.7, 38.3, 34.9, 33.3, 31.5, 29.9, 27.5; 19F NMR (282 MHz, CDCI3) 6105.0; (MH+) 542.
Category X
Example 106: (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-te/?-butylphenyl)-5-(2- hydroxyethyl)-1-methylimidazolidin-4-one
Figure imgf000072_0001
To a solution of 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-te/?-butylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)acetic acid (1.0g, 1.7 mmol) in THF (15 ml.) at -78 0C was added BH3»THF (5.1 ml_, 5.1 mmol). The resulting solution was stirred at -78 0C to room temperature overnight. The mixture was diluted with ethyl acetate and washed with 5% NaHCO3 and brine. The organic solution was dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by HPLC to yield a colorless oil (770 mg, 98%). 1H NMR (300 MHz, CDCI3) δ 7.41 (d, 2H, J = 8 Hz), 7.17 (m, 4H), 7.03 (d, 2H, J = 8 Hz), 5.05 (d, 1 H, J = 2 Hz), 4.45 (bs, 1 H), 3.99 (m, 1 H), 3.76 (m, 2H), 3.56 (m, 1 H), 3.80 (m, 3H), 2.06 (s, 3H), 1.98 (m, 2H), 1.34 (s, 9H); 19F NMR (282 MHz, CDCI3) 5105.0; (MH+) 465.
Example 107: (2R,5S)-5-(2-(benzyl(methyl)amino)ethyl)-2-(4-tert-butylphenyl)-1- methyl-3-(4-(trifluoromethoxy)phenethyl)imidazolidin-4-one: To a solution of (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-te/?-butylphenyl)-5-(2-hydroxyethyl)- 1-methylimidazolidin-4-one (130 mg, 0.28 mmol) and Et3N (78 μl_, 0.56 mmol) in THF (3 ml.) was added methanesulfonyl chloride (24 μl_, 0.31 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product as a pale brown oil (157 mg). The crude product (120 mg, 0.22 mmol) was dissolved in THF (1 ml.) and N, N'-benzylmethyl amine (286 μl_, 2.2 mmol) was added. The resultant mixture was stirred at room temperature for 3 days followed by stirring at 60 0C for another day. The solvent was removed under reduced pressure and the product was purified by HPLC to give a colorless oil (106 mg, 85%). 1H NMR (300 MHz, CDCI3) δ 7.43-7.08 (m, 13H), 4.97 (d, 1 H, J = 2 Hz), 3.90 (m, 1 H), 3.54 (m, 3H), 2.83 (m, 2H), 2.69 (m, 2H), 2.44 (m, 1 H), 2.24 (s, 3H), 2.05 (s, 3H), 2.02 (m, 1 H), 1.89 (m, 1 H), 1.36 (S, 9H); 13C NMR (75 MHz, CDCI3) δ 173.4, 152.6, 148.0, 139.3, 137.6, 133.2, 130.2, 129.3, 128.3, 127.8, 127.1 , 125.8, 121.2, 120.6 (CF3, q, J = 255 Hz), 80.6, 62.4, 61.9, 53.3, 42.3, 41.5, 34.8, 34.5, 33.3, 31.4, 26.9; 19F NMR (282 MHz, CDCI3) 6105.2; (MH+) 568.
Category Xl
Example 108: (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)- 1-methyl-5-(2-(pyridin-2-ylmethoxy)ethyl)imidazolidin-4-one:
Figure imgf000074_0001
(2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-1-methyl-5-(2- (pyridin-2-ylmethoxy)ethyl)imidazolidin-4-one: To a solution of (5S)-3-(4- (trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-5-(2-hydroxyethyl)-1- methylimidazolidin-4-one (413 mg, 0.86 mmol) and Et3N (240 μl_, 1.7 mmol) in THF (5 ml.) was added methanesulfonyl chloride (80 μl_, 1.0 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product as light brown oil (478 mg). The crude product (126 mg, 0.23 mmol) was dissolved in dry THF (1 ml_ and 1 ml. wash) and added to the mixture of 2-pyridinemethanol (44 μl_, 0.46 mmol) and NaH (60% dispersion, 18 mg, 0.47 mmol) in THF (1 ml.) at -78 0C (prepared from adding NaH to the solution of 2-pyridinemethanol in THF at -78 0C and stirring it for 20 min). The resultant mixture was stirred at -78 0C to room temperature overnight. The mixture was diluted with ethyl acetate and washed with 5% NaHCO3, water, and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure and the trans-isomer was purified by HPLC (C18, water/acetonitrile) followed by washing with 10% Na2CO3 to give the product as a free base (13 mg). 1H NMR (300 MHz, CD3OD) δ 8.47 (d, 1 H, J = 4.2 Hz), 7.85 (dt, 1 H, J = 7.8, 1.5 Hz), 7.55 (d, 1 H, J = 7.9 Hz), 7.32 (dd, 1 H, J = 5.1 , 6.6 Hz), 7.17 (m, 4H), 7.02 (d, 2H, J = 8.7 Hz), 6.71 (d, 2H, J = 8.7 Hz), 5.01 (d, 1 H, J = 2.1 Hz), 4.59 (s, 2H), 3.77 (m, 1 H), 3.64 (t, 2H, J = 6.6 Hz), 3.56 (m, 1 H), 3.39 (q, 4H, J = 6.9 Hz), 2.82 (m, 2H), 2.65 (m, 1 H), 2.09 (m, 4H), 1.89 (m, 1 H), 1.16 (t, 6H, J = 6.9 Hz); 13C NMR (75 MHz, CD3OD) δ 175.3, 159.8, 150.2, 149.7, 149.3, 139.5, 139.0, 131.6, 130.5, 124.2, 123.4, 122.7, 122.2, 122.0 (CF3, q, J = 255 Hz), 1 12.8,82.1 , 74.3, 68.4, 62.6, 45.5, 42.6, 34.7, 33.9, 29.6, 13.0; 19F NMR (282 MHz, CD3OD) 5103.5; (MH+) 571.
Examples 109-110 were prepared according to the procedures described in Example 108 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 109: (2R,5S)-3-(4-methoxyphenethyl)-5-(benzyloxymethyl)-2-(4- (diethylamino)phenyl)-1-methylimidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 7.35 (m, 5H), 7.05 (d, 2H, J = 8.6 Hz), 6.98 (d, 2H, J = 8.5 Hz), 6.75 d, 2H, J = 8.4 Hz), 6.64 (d, 2H, J = 8.4 Hz), 4.97 (d, 1 H, J = 1.8 Hz), 4.58 (dd, 2H, J = 12.1 , 15.6 Hz), 3.84 (m, 7H), 3.37 (q, 4H, J = 6.9 Hz), 2.71 (m, 3H), 2.29 (s, 3H), 1.18 (t, 6H, J = 6.9 Hz); 13C NMR (75 MHz, CDCI3) δ 171.6, 158.2, 148.7, 138.4, 131.3, 129.9, 129.6, 128.5, 127.8, 127.7, 123.1 , 1 13.9, 1 1 1.4, 82.2, 73.7, 69.5, 64.4, 55.4, 44.5, 42.2, 33.7, 33.1 , 12.7; (MH+) 502.
Example 110: (2S,5S)-3-(4-methoxyphenethyl)-5-(benzyloxymethyl)-2-(4- (diethylamino)phenyl)-1-methylimidazolidin-4-one, 1H NMR (300 MHz, CDCI3) δ 7.36
(m, 5H), 7.19 (d, 2H, J = 8.5 Hz), 7.01 (d, 2H, J = 8.5 Hz), 6.82 d, 2H, J = 8.4 Hz),
6.66 (d, 2H, J = 8.4 Hz), 4.65 (s, 2H), 4.30 (d, 1 H, J = 1.8 Hz), 4.01 (dd, 1 H, J = 2.4,
10.0 Hz), 3.82 (m, 4H), 3.63 (m, 1 H), 3.40 (q, 4H, J = 6.9 Hz), 3.29 (m, 1 H), 2.81 (m,
2H), 2.53 (m, 1 H), 2.39 (s, 3H), 1.21 (t, 6H, J = 6.9 Hz); 13C NMR (75 MHz, CDCI3) δ 170.3, 158.3, 148.8, 138.7, 131.1 , 130.0, 128.5, 127.7, 127.6, 123.4, 114.0, 111.4,
1 10.3, 82.9, 73.6, 71.8, 66.7, 55.4, 44.5, 42.1 , 38.6, 32.9, 12.8; (MH+) 502.
CATEGORY XII
Example 111 : N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-te/?-butylphenyl)-3-methyl-5- oxoimidazolidin-4-yl)methyl)methanesulfonamide
Figure imgf000076_0001
Preparation of N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-te/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)methanesulfonamide and N-(((2S,4S)-1-(4- methoxyphenethyl)-2-(4-fe/?-butylphenyl)-3-methyl-5-oxoimidazolidin-4- yl)methyl)methanesulfonamide: (5S)-3-(4-methoxyphenethyl)-5-(aminomethyl)-2-(4- fe/?-butylphenyl)-1-methylimidazolidin-4-one (105 mg, 0.26 mmol), Et3N (73 μl_, 0.52 mmol), and methanesulfonyl chloride (30 μl_, 0.39 mmol) in THF (2 ml.) were stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by HPLC to give the two diastereomers. Major (trans) diastereomer (38 mg): 1H NMR (300 MHz, CDCI3) δ 7.40 (d, 2H, J = 8.4 Hz), 7.06 (m, 4H), 6.85 (d, 2H, J = 8.5 Hz), 5.1 1 (bs, 1 H), 4.95 (m, 1 H), 3.96 (m, 1 H), 3.80 (s, 3H), 3.51 (m, 2H), 3.89 (m, 1 H), 2.88 (s, 3H), 2.78 (m, 3H), 2.03 (s, 3H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 170.8, 158.6, 153.0, 132.2, 130.3, 129.8, 127.6, 126.1 , 1 14.2, 80.1 , 62.9, 55.4, 42.0, 41.1 , 40.5, 34.9, 34.6, 32.9, 31.4; (MH+) 474. Minor (cis) diastereomer (8 mg): 1H NMR (300 MHz, CDCI3) δ 7.43 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.7 Hz),6.81 (d, 2H, J = 9.0 Hz), 5.26 (m, 1 H), 4.40 (d, 1 H, , J = 1.8 Hz), 3.79 (s, 3H), 3.64 (m, 2H), 3.35 (m, 1 H), 3.18 (m, 1 H), 3.01 (s, 3H), 2.77 (m, 2H), 2.50 (m, 1 H), 2.27 (s, 3H), 1.35 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 170.7, 158.6, 153.5, 133.3, 130.4, 130.0, 128.5, 126.0, 1 14.1 , 82.6, 64.9, 55.5, 42.2, 41.7, 40.7, 37.0, 35.0, 32.8, 31.5; (MH+) 474.
Examples 112-115 were prepared according to the procedures described in Example 1 1 1 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): Example 112: N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)propane-1 -sulfonamide, 1H NMR (300 MHz, CDCI3) δ 7.39 (d, 2H, J = 8.3 Hz), 7.04 (m, 4H), 6.84 (d, 2H, J = 8.6 Hz), 5.09 (bs, 1 H), 4.93 (m, 1 H), 3.91 (m, 1 H), 3.79 (s, 3H), 3.50 (m, 2H), 3.27 (m, 1 H), 2.98 (m, 2H), 2.78 (m, 3H), 2.03 (s, 3H), 1.83 (m, 2H), 1.32 (s, 9H), 1.06 (t, 3H, , J = 7.5 Hz); 13C NMR (75 MHz, CDCI3) δ 171.2, 158.8, 153.1 , 132.5, 130.5, 130.0, 127.8, 126.2, 1 14.4, 80.4, 63.0, 55.6, 54.7, 42.4, 41.4, 35.1 , 34.9, 33.2, 31.6, 17.7, 13.4; (MH+) 502.
Example 113: N-(((2S,4S)-1-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)propane-1 -sulfonamide, 1H NMR (300 MHz, CDCI3) δ 7.43 (d, 2H, J = 8.5 Hz), 7.21 (d, 2H, J = 8.5 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 5.16 (m, 1 H), 4.39 (d, 1 H, , J = 2.1 Hz), 3.79 (s, 3H), 3.62 (m, 2H), 3.33 (m, 1 H), 3.16 (m, 1 H), 3.07 (m, 2H), 2.77 (m, 2H), 2.49 (m, 1 H), 2.26 (s, 3H), 1.86 (m, 2H), 1.35 (s, 9H), 1.07 (t, 3H, , J = 7.5 Hz); 13C NMR (75 MHz, CDCI3) δ 170.7, 158.6, 153.5, 133.2, 130.5, 130.0, 128.5, 126.0, 1 14.1 , 82.6, 65.1 , 55.5, 54.6, 42.2, 41.8, 37.0, 35.0, 32.8, 31.5, 17.6, 13.1 ; (MH+) 502.
Example 114: N-(((2S,4S)-1-(4-methoxyphenethyl)-2-(4-te/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)butane-1-sulfonamide, 1H NMR (300 MHz, CDCI3) δ 7.42 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 5.16 (m, 1 H), 4.39 (d, 1 H, , J = 2.1 Hz), 3.79 (s, 3H), 3.63 (m, 2H), 3.33 (m, 1 H), 3.17 (m, 1 H), 3.09 (m, 2H), 2.76 (m, 2H), 2.50 (m, 1 H), 2.26 (s, 3H), 1.81 (m, 2H), 1.46 (m, 2H), 1.35 (s, 9H), 0.94 (t, 3H, , J = 7.5 Hz); 13C NMR (75 MHz, CDCI3) δ 170.8, 158.6, 153.4, 133.3, 130.5, 130.0, 128.5, 126.0, 1 14.1 , 82.6, 65.1 , 55.5, 52.7, 42.2, 41.8, 37.0, 35.0, 32.8, 31.5, 25.9, 21.7, 13.8; (MH+) 516.
Example 115: N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)(pyridin-3-yl)methanesulfonamide, 1H NMR (300 MHz,
CD3OD) δ 8.57 (d, 1 H, J = 1.8 Hz), 8.52 (dd, 1 H, J = 1.5, 4.8, Hz), 7.91 (dt, 1 H, J =
7.8, 1.8 Hz), 7.46 (m, 3H), 7.12 (d, 2H, J = 8.4 Hz), 7.05 (d, 2H, J = 8.4 Hz), 6.81 (d,
2H, J = 8.4 Hz), 5.19 (d, 1 H, J = 2.4 Hz), 4.30 (m, 2H), 3.82 (m, 1 H), 3.73 (s, 3H),
3.51 (m, 1 H), 3.40 (m, 2H), 2.74 (m, 3H), 2.07 (s, 3H), 1.33 (s, 9H); 13C NMR (75 MHz, CD3OD) δ 173.3, 160.2, 154.3, 152.5, 150.2, 141.1 , 134.5, 132.2, 131.3, 129.4, 129.1 , 127.4, 125.6, 1 15.5, 81.9, 65.8, 57.0, 56.1 , 43.6, 42.9, 36.0, 35.0, 33.9, 32.1 ; (MH+) 551.
Category XIII
Example 116: 1-(((4S)-1-(4-methoxyphenethyl)-2-(4-te/?-butylphenyl)-3-methyl-5- oxoimidazolidin-4-yl)methyl)-3-ethylurea
Figure imgf000078_0001
A mixture of (5S)-3-(4-methoxyphenethyl)-5-(aminomethyl)-2-(4-fe/?-butylphenyl)-1- methylimidazolidin-4-one (98 mg, 0.25 mmol) and ethyl isocyanate (99 μl_, 1.25 mmol) in CH2CI2 (3 ml.) were stirred at room temperature overnight. The solvent was removed under reduced pressure and the products were purified by HPLC (C18, water/acetonitrile) followed by washing with 10% Na2CO3 to give the two diastereomers as free bases. Major diastereomer (trans, 65 mg): 1H NMR (300 MHz, CD3OD) δ 7.44 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H, J = 8.4 Hz), 6.80 (d, 2H, J = 8.4 Hz), 5.15 (d, 1 H, J = 2.1 Hz), 3.73 (s, 3H), 3.68 (m, 2H), 3.49 (m, 1 H), 3.28 (m, 1 H), 3.16 (q, 2H, J = 7.2 Hz), 2.76 (m, 2H), 2.60 (m, 1 H), 2.09 (s, 3H), 1.31 (s, 9H), 1.10 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CD3OD) δ 173.9, 160.9, 159.9, 153.9, 134.4, 131.9, 130.8, 129.1. 126.9, 1 15.1 , 81.9, 65.1 , 55.8, 43.5, 39.8, 35.9, 35.7, 34.7, 33.9, 31.9, 15.9; (MH+) 467. Minor diastereomer (cis, 9 mg): 1H NMR (300 MHz, CD3OD) δ 7.37 (d, 2H, J = 8.4 Hz), 7.23 (d, 2H, J = 8.4 Hz), 6.83 (d, 2H, J = 8.4 Hz), 6.70 (d, 2H, J = 8.4 Hz), 4.39 (d, 1 H, J = 2.1 Hz), 3.65 (s, 3H), 3.42 (m, 3H), 3.04 (m, 3H), 2.63 (m, 2H), 2.32 (m, 1 H), 2.16 (s, 3H), 1.24 (s, 9H), 1.00 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CD3OD) δ 173.4, 161.4, 160.1 , 154.3, 135.5, 131.9, 131.0, 130.0, 126.8, 1 15.1 , 83.7, 67.6, 55.8, 43.5, 40.0, 37.4, 35.9, 35.7, 33.7, 31.9, 15.9; (MH+) 467.
Examples 117-121 were prepared according to the procedures described in Example 1 16 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 117: 1-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)-3-(pyrimidin-4-yl)urea, 1H NMR (300 MHz, CD3OD) δ 8.75 (s, 1 H), 8.41 (d, 1 H, J = 6 Hz), 7.48 (d, 2H, J = 8.4 Hz), 7.24 (d, 1 H, J = 6 Hz), 7.14 (d, 2H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 6.70 (d, 2H, J = 8.4 Hz), 5.21 (d, 1 H, J = 2.1 Hz), 3.78 (m, 3H), 3.69 (s, 3H), 3.61 (m, 1 H), 3.51 (m, 1 H), 2.74 (m, 2H), 2.59 (m, 1 H), 2.14 (s, 3H), 1.33 (s, 9H); 13C NMR (75 MHz, CD3OD) δ 173.6, 160.6, 159.9, 158.4, 157.5, 156.5, 154.0, 134.3, 131.7, 130.7, 129.1 , 127.1 , 1 15.0, 109.9, 81.9, 65.0, 55.7, 43.4, 39.2, 35.7, 34.7, 33.9, 31.8; (MH+) 517.
Example 118: 1-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)urea, 1H NMR (300 MHz, CD3OD) δ 7.46 (d, 2H, J =
8.4 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.4 Hz),
5.12 (d, 1 H, 2.4 Hz), 3.74 (s, 3H), 3.72 (m, 1 H), 3.60 (dd, 1 H, J = 3.3, 13.8 Hz), 3.49
(m, 1 H), 3.30 (m, 1 H), 2.78 (m, 2H), 2.60 (m, 1 H), 2.10 (s, 3H), 1.32 (s, 9H); 13C
NMR (75 MHz, CD3OD) δ 173.9, 162.1 , 160.0, 154.0, 134.4, 131.9, 130.9, 129.2, 127.0, 1 15.1 , 82.0, 65.1 , 55.8, 43.6, 39.8, 35.7, 34.7, 34.0, 31.8; (MH+) 439.
Example 119: 1-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-te/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)-3-methylurea, 1H NMR (300 MHz, CDCI3) δ 7.38 (d, 2H, J = 8.4 Hz), 7.05 (m, 4H), 6.82 (d, 2H, J = 8.4 Hz), 5.27 (bs, 1 H), 5.07 (d, 1 H, J = 1.8 Hz), 3.86 (m, 1 H), 3.78 (s, 3H), 3.72 (m, 1 H), 3.45 (m, 1 H), 3.23 (m, 1 H), 2.79 (m, 2H), 2.77 (d, 3H, J = 4.5 Hz), 2.66 (m, 1 H), 2.1 1 (s, 3H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 172.8, 159.3, 158.5, 152.8, 132.7, 130.5, 129.9, 127.8, 125.9, 1 14.1 , 80.6, 63.4, 55.4, 41.9, 39.6, 34.9, 34.6, 33.0, 31.4, 27.3; (MH+) 453. Example 120: 1-(((2S,4S)-1-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-3-methyl- 5-oxoimidazolidin-4-yl)methyl)-3-methylurea, 1H NMR (300 MHz, CDCI3) δ 7.40 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), , 6.93 (d, 2H, J = 8.4 Hz), 6.80 (d, 2H, J = 8.4 Hz), 5.66 (bs, 1 H), 5.21 (bs, 1 H), 4.50 (s, 1 H), 3.78 (m, 4H), 3.60 (m, 1 H), 3.30 (m, 2H), 2.77 (m, 5H), 2.50 (m, 1 H), 2.36 (s, 3H), 1.34 (s, 9H); 13C NMR (75 MHz, CDCI3) δ 171.8, 160.0, 158.5, 153.4, 130.5, 130.0, 128.6, 125.9, 1 14.1 , 82.6, 66.1 , 55.5, 42.3, 40.5, 37.2, 35.0, 32.8, 31.5, 29.9, 27.4; (MH+) 453.
Example 121 : 1 -(((2S, 4S)- 1 -(4-methoxyphenethyl)-2-(4-cyclopropylphenyl)-3- methyl-5-oxoimidazolidin-4-yl)methyl)-3-methylurea, 1H NMR (300 MHz, CDCI3) δ 7.15 (d, 2H, J = 8.1 Hz), 7.04 (d, 2H, J = 8.1 Hz), 6.92 (d, 2H, J = 8.4 Hz), 6.78 (d, 2H, J = 8.1 Hz), 5.57 (bs, 1 H), 5.23 (bs, 1 H), 4.35 (d, 1 H, J = 2.4 Hz), 3.78 (s, 3H), 3.74 (m, 1 H), 3.58 (m, 1 H), 3.32 (m, 1 H), 3.09 (m, 1 H), 2.76 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1 H), 2.26 (s, 3H), 1.90 (tt, 1 H, J = 3.3, 5.1 Hz), 0.99 (m, 2H), 0.70 (m, 2H); 13C NMR (75 MHz, CDCI3) δ 172.3, 159.7, 158.5, 146.2, 133.8, 130.5, 129.9, 128.8, 126.0, 1 14.1 , 82.6, 66.0, 55.4, 42.0, 40.3, 37.0, 32.8, 27.3, 15.4, 9.9, 9.8; (MH+) 437.
Category XIV
Example 122: 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5- dimethylimidazolidin-4-one
Figure imgf000081_0001
TFA, MeOH, rt, 3 h
Figure imgf000081_0002
Step 1 : Preparation of fe/f-butyl 1-(4-methoxyphenethylamino)-2-methyl-1- oxopropan-2-ylcarbamate: The starting BOC-Aib-OH (5.0 g, 24.6 mmol) was dissolved in methylene chloride (200 ml.) in a single-neck 50OmL flask equipped with a stir bar under an inert N2 atmosphere. Next, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (6.13 g, 32.0 mmol), followed by 1- hydroxybenzotriazole (4.32 g, 32.0 mmol) were added to the mixture and dissolved. 4-methylmorpholine (8.1 1 , 73.8 mmol) was then added to the reaction in one portion via syringe. Lastly, 4-methoxyphenethylamine (3.61 mL, 24.6 mmol) was added to the reaction in one portion also via syringe. The reaction was then vigorously stirred at room temperature for 18 hours then extracted twice with saturated aqueous NaHCO3 (2 x 250 mL) and d.i. H2O (250 mL). The remaining organic layer was then filtered over anhydrous MgSO4, and evaporated to dryness on a rotovap. The product was purified by flash column chromatography using a hexane, HOAc gradient system, whose fractions are concentrated on a roto-evaporator to give a white fluffy powder, 4.71 g, chemical yield 57%. 1H-NMR (300 MHz, CDCI3) δ 7.14 (d, 2H, J = 6.4 Hz), 6.85 (d, 2H, J = 6.4 Hz), 6.46 (bs, 1 H), 4.94 (bs, 1 H), 3.80 (s, 3H), 3.48 (dd, 2H, J = 6.2, 7.0 Hz), 2.77 (t, 2H, J = 7.0), 1.46 (s, 6H), 1.43 (s, 9H); 13C-NMR (75 MHz, CDCI3) δ 174.8, 158.5, 155.0, 131.2, 129.9, 1 14.2, 57.0, 55.5, 41.3, 35.0, 28.6, 26.0; (MH+) 337.1.
Step 2: Preparation of N-(4-methoxyphenethyl)-2-amino-2-methylpropanamide: The fe/t-butyl 1-(4-methoxyphenethylamino)-2-methyl-1-oxopropan-2-ylcarbamate, (4.75 g, 14.1 mmol) was dissolved with stirring in methylene chloride (50 ml.) in a 10OmL single-neck flask equipped with a stir bar under an inert N2 atmosphere. Next, trifluoroacetic acid (10.9 ml_, 141 mmol) was added to the reaction in one portion via syringe increasing the concentration to 25% by volume in acid. The reaction was then vigorously stirred at room temperature for 3 hours. After transferring the mixture to a 500 mL Erlenmeyer flask, the reaction was slowly diluted with saturated aqueous NaHCO3 (100 mL) and d.i. H2O (25 mL). The biphasic mixture was then basified to a constant pH of 9 via the addition of solid KOH. The mixture was separated and the remaining aqueous phase was further extracted with methylene chloride (2 x 100 mL). The combined organic extracts were filtered over anhydrous MgSO4, and evaporated to dryness on a roto-evaporator to give a viscous yellow syrup (3.06 g, chemical yield 92%). 1H-NMR (300 MHz, CDCI3) δ 7.65 (bs, 1 H), 7.09 (d, 2H, J = 8.8 Hz), 6.81 (d, 2H, J = 8.8 Hz), 3.76 (s, 3H), 3.41 (dd, 2H, J = 6.6, 7.3 Hz), 2.73 (t, 2H, J = 7.3 Hz), 1.30 (s, 6H); 13C-NMR (75 MHz, CDCI3) δ 177.7, 158.4, 131.4, 129.9, 1 14.1 , 55.4, 40.8, 35.1 , 29.4; (MH+) 237.1.
Step 3: Preparation of 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5- dimethylimidazolidin-4-one: The N-(4-methoxyphenethyl)-2-amino-2- methylpropanamide (1 g, 4.23 mmol) was dissolved in methanol (25 mL) in single- neck 100 mL flask equipped with a stir bar under an inert N2 atmosphere. Next, K2CO3 (644 mg, 4.66 mmol) was added to the reaction in one portion. Lastly, 4-t- butyl benzaldehyde (0.78 mL, 4.66 mmol) was added to the reaction in one portion via syringe. The reaction was then vigorously stirred at room temperature for 48 hours. The reaction was evaporated to dryness on a roto-evaporator. The resulting residue was re-dissolved in methylene chloride (100 mL) and extracted with saturated aqueous NaHCO3 (3 x 100 mL). The remaining organic layer was filtered over anhydrous MgSO4 and evaporated a second time to dryness. Subsequent flash column chromatography using a hexane, HOAc gradient system affords a white solid (935 mg, chemical yield 58%). 1 H-NMR (300 MHz, CDCI3) δ 7.43 (d, 2H, J =
8.4 Hz), 7.18 (d, 2H, J = 8.4 Hz), 7.04 (d, 2H, J = 8.7 Hz), 6.84 (d, 2H, J = 8.7 Hz),
5.05 (s, 1 H), 3.85 (m, 1 H), 3.80 (s, 3H), 2.87 (m, 2H), 2.64 (m, 1 H), 1.39 (s, 3H), 1.35 (S, 9H), 1.17 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 178.4, 158.6, 152.9, 135.5, 130.7, 130.0, 127.16, 126.3, 1 14.2, 74.2, 59.6, 55.5, 42.0, 35.0, 32.5, 31.5, 25.9, 24.8; (MH+) 381.2; elemental analysis: theory C24H32N2O2 + 0.41 mol H2O C 74.34; H 8.43; N 7.23; found C 74.31 , H 8.15, N 7.37.
Example 123: 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-1 ,5,5- trimethylimidazolidin-4-one: The 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5- dimethylimidazolidin-4-one (200 mg, 0.53 mmol) was dissolved in dry tetrahydrofuran (15ml_) in a single-neck 25 ml. flask equipped with a stir bar under an inert N2 atmosphere. Next, sodium hydride (13 mg, 0.58 mmol) was added to the reaction and allowed to stir for 15 minutes. Lastly, iodomethane (0.06 ml_, 1.16 mmol) was added to the reaction in one portion via syringe. The reaction was vigorously stirred at room for 18 hours. The reaction was evaporated to dryness on a roto-evaporator. The resulting residue was partitioned between methylene chloride (25 mL) and saturated aqueous NaHCO3 (25 mL) and separated. The remaining aqueous layer was further extracted with methylene chloride (2 x 25ml_). The combined organic extracts were then filtered over anhydrous MgSO4 and evaporated to dryness. Subsequent flash column chromatography using a hexane, HOAc gradient system affords a clear, viscous syrup (87 mg, chemical yield 42%). 1H-NMR (300 MHz, CDCI3) δ 7.41 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H, J = 8.8 Hz), 6.83 (d, 2H, J = 8.8 Hz), 4.42 (s, 1 H), 3.80 (s, 3H), 3.72 (m, 1 H), 2.78 (m, 2H), 2.54 (m, 1 H), 2.10 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.5, 158.5, 152.8, 134.5, 130.9, 130.9, 128.6, 125.7, 1 14.1 , 80.2, 61.6, 55.5, 41.4, 35.0, 32.9, 31.6, 30.7, 24.2, 16.7; (MH+) 395.1 ; elemental analysis: theory C25H34N2O2 + 0.3 mol H2O C 75.07; H 8.72; N 7.00; found C 75.30, H 8.78, N 6.69. Examples 124-126 were prepared according to the procedures described in Example 122-123 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 124: 3-(4-Methoxyphenethyl)-2-(4-cyclopropylphenyl)-5,5- dimethylimidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 7.1 1 (m, 4H), 7.06 (m, 2H),
6.82 (m, 2H), 5.00 (s, 1 H), 3.86 (m, 1 H), 3.79 (s, 3H), 2.81 (m, 2H), 2.62 (m, 1 H),
1.91 (m, 1 H), 1.88 (bs, 1 H), 1.38 (s, 3H), 1.16 (s, 3H), 1.02 (m, 2H), 0.73 (m, 2H);
13C-NMR (75 MHz, CDCI3) δ 178.5, 158.6, 146.0, 135.5, 130.7, 130.0, 127.4, 126.5,
1 14.2, 74.3, 59.6, 55.5, 42.0, 32.5, 25.9, 24.8, 15.5, 9.9; (MH+) 365.1 ; elemental analysis: theory C23H28N2O2 + 0.80 mol H2O C 73.30; H 7.38; N 7.43; found C 73.44,
H 7.70, N 7.53.
Example 125: 3-(4-Methoxyphenethyl)-1-benzyl-2-(4-fe/?-butylphenyl)-5,5- dimethylimidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 7.34 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4 Hz), 7.13 (m, 5H), 7.05 (d, 2H, J = 8.5 Hz), 6.85 (d, 2H, J = 6.6 Hz), 4.67 (s, 1 H), 3.82 (s, 3H), 3.77 (m, 1 H), 3.73 (d, 1 H, J = 13.9 Hz), 3.57 (d, 1 H, J = 13.9 Hz), 2.79 (m, 2H), 2.54 (s, 1 H), 1.35 (s, 9H), 1.17 (s, 3H), 1.1 1 (s,3H); 13C- NMR (75 MHz, CDCI3) δ 176.4, 158.5, 152.5, 139.5, 134.8, 130.9, 130.1 , 129.0, 128.0, 127.0, 125.5, 1 14.1 , 79.9, 62.2, 55.6, 50.1 , 41.5, 34.9, 32.9, 31.6, 26.0, 18.2; (MH+) 471.2; elemental analysis: theory C31H38N2O2 + 0.42mol H2O C 77.86; H 8.19; N 5.86; found C 77.86, H 7.98, N 5.71.
Example 126: 3-(4-Methoxyphenethyl)-1-ethyl-2-(4-fe/?-butylphenyl)-5,5- dimethylimidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 7.39 (d, 2H, J = 8.1 Hz), 7.27 (d, 2H, J = 8.4 Hz), 7.00 (d, 2H, J = 8.8 Hz), 6.81 (d, 2H, J = 8.4 Hz), 4.56 (s, 1 H), 3.79 (m, 3H), 3.63 (m, 1 H), 2.73 (m, 3H), 2.46 (m, 2H), 1.42 (s, 3H), 1.36 (s, 9H), 1.09 (S, 3H), 0.78 (t, 3H, J = 7.3 Hz); 13C-NMR (75 MHz, CDCI3) δ 176.3, 158.4, 152.6, 136.1 , 131.0, 130.1 , 128.7, 125.5, 1 14.0, 79.7, 62.0, 55.5, 41.4, 40.5, 34.9, 32.9, 31.6, 26.3, 17.8, 15.9; (MH+) 409; elemental analysis: theory C26H36N2O2 + 0.48 mol H2O C 74.85; H 8.53; N 6.71 ; found C 74.60, H 8.46, N 6.59.
Category XV Example 127: 3-(4-methoxyphenethyl)-2-(4-(diethylamino)phenyl)-1 ,5,5- trimethylimidazolidin-4-one.
Figure imgf000085_0001
Step 1 : fe/t-butyl 1-(4-methoxyphenethylamino)-2-methyl-1-oxopropan-2- yl(methyl)carbamate: The starting N-BOC-α-(methylamino)/so-butryic acid (12.1 g, 55.9 mmol) was dissolved in methylene chloride (300 ml.) in a single-neck 50OmL flask equipped with a stir bar under an inert N2 atmosphere. Next, 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.9 g, 72.7 mmol), followed by 1-hydroxybenzotriazole (9.82 g, 72.7 mmol) were added to the mixture and dissolved. 4-methylmorpholine (18.4 ml_, 168 mmol) was added to the reaction in one portion via syringe. Lastly, 4-methoxyphenethylamine (8.20 mL, 55.9 mmol) was added to the reaction in one portion also via syringe. The reaction was vigorously stirred at room temperature for 18 hours then extracted twice with saturated aqueous NaHCO3 (2 x 250 mL) and d.i. H2O (250 mL). The remaining organic layer was then filtered over anhydrous MgSO4, and evaporated to dryness on a rotovap. The product was purified by flash column chromatography using a hexane, HOAc gradient system, whose fractions are concentrated on a roto- evaporator to give a white fluffy powder, 4.71 g, chemical yield 57%. 1H-NMR (300 MHz, CDCI3) δ 7.14 (d, 2H, J = 8.6 Hz), 6.86 (d, 2H, J = 8.6 Hz), 5.85 (bs, 1 H), 3.82 (s, 3H), 3.75 (m, 2H), 2.89 (s, 3H), 2.77 (t, 2H, J = 7.1), 1.44 (s, 9H), 1.40 (s, 6H); 13C-NMR (75 MHz, CDCI3) δ 176.7, 158.4, 131.4, 129.9, 114.2, 59.2, 55.5, 40.7, 35.1 , 30.2, 25.3; (MH+) 351.0.
Step 2: N-(4-methoxyphenethyl)-2-methyl-2-(methylamino)propanamide: The tert- butyl 1-(4-methoxyphenethylamino)-2-methyl-1-oxopropan-2-yl(methyl)carbamate, (12.9g, 36.8 mmol) was dissolved in methylene chloride (105 ml.) in a single-neck 50OmL flask under an inert N2 atmosphere. Next, trifluoroacetic acid (35 mL) was added to the reaction mixture via syringe to increase the concentration to 25% acid by volume. The reaction was vigorously stirred at room temperature for 3 hours. After transferring the reaction to an Erlenmeyer flask the mixture was slowly diluted with saturated aqueous NaHCO3 (500 mL) and de-ionized water (100 mL). While stirring, this biphasic mixture was basified to a constant pH of 9 via the addition of solid KOH. The mixture was then separated. The remaining aqueous phase was further extracted with methylene chloride (2 x 100 mL). The combined organic layers were filtered over anhydrous MgSO4, and evaporated to dryness on a roto- evaporator to give a viscous yellow syrup, 8.31 g, chemical yield 90%. 1H-NMR (300 MHz, CDCI3) δ 7.41 (bs, 2H), 7.14 (d, 2H, J = 6.4 Hz), 6.86 (d, 2H, J = 6.4 Hz), 3.80 (s, 3H), 3.48 (dd, 2H, J = 6.2, 7.3 Hz), 2.78 (t, 2H, J = 7.0 Hz), 2.22 (s, 3H), 1.27 (s, 6H); 13C-NMR (75 MHz, CDCI3) δ 176.2, 158.4, 131.4, 130.0, 129.9, 1 14.2, 59.1 , 55.6, 55.5, 40.7, 35.2, 30.3, 25.3; (MH+) 251.1.
Step 3: 3-(4-methoxyphenethyl)-2-(4-(diethylamino)phenyl)-1 ,5,5- trimethylimidazolidin-4-one: The N-(4-methoxyphenethyl)-2-methyl-2-
(methylamino)propanamide, (528 mg, 2.1 1 mmol) was added to a 2.0 - 5.0 mL Emry's process vial equipped with a stir bar. Next, melted 4-diethylamino benzaldehyde (2.0 g, 1 1.3 mmol) was added to the reaction via pipet. The reaction was then capped and heated in a Biotage Initiator 60 microwave for 5 minutes at 175 0C with stirring. The reaction was then cooled to room temperature, decapped, diluted with methylene chloride (2 mL) and purified via flash column chromatography whose fractions when evaporated to dryness on a rotovap give a viscous pale beige syrup, 628 mg, chemical yield 73%. 1H-NMR (300 MHz, CDCI3) δ 7.14 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.1 Hz), 6.81 (d, 2H, J = 8.4 Hz), 6.65 (d, 2H, J = 8.4 Hz), 4.35 (s, 1 H, J = ), 3.78 (s, 3H), 3.72 (m, 1 H), 3.38 (q, 4H, J = 7.0 Hz), 2.77 (m, 2H), 2.52 (m, 1 H), 2.09 (s, 3H), 1.33 (s, 3H), 1.19 (t, 6H, J = 7.0), 1.00 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.4, 158.4, 148.9, 131.1 , 130.1 , 130.0, 123.3, 1 14.0, 1 1 1.5, 80.2, 61.5, 55.5, 44.6, 41.3, 33.0, 30.7, 24.1 , 16.4, 12.8; (MH+) 410.1 ; elemental analysis: theory C25H35N3O2 + 1.8 mol H2O C 67.93; H 8.80; N 9.50; found C 67.94, H 8.80, N 9.51.
Examples 128-133 were prepared according to the procedures described in Example 127 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 128: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(dimethylamino)phenyl)-1 ,5,5- trimethylimidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 7.20 (d, 2H, J = 8.8 Hz), 7.14 (s, 4H), 6.75 (d, 2H, J = 8.8 Hz), 4.37 (s, 1 H), 3.77 (m, 1 H), 3.02 (s, 3H), 2.82 (m, 2H), 2.59 (m, 1 H), 2.09 (s, 3H), 1.34 (s, 3H), 0.99 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.6, 151.6, 137.9, 130.5, 129.8, 124.3, 121.3, 1 12.3, 80.2, 61.5, 40.9, 40.7, 33.3, 30.6, 24.1 , 16.3; (MH+) 436.1 ; elemental analysis: theory C23H28F3N3O2 + 0.94 mol H2O C 61.06; H 6.65; N 9.29; found C 61.18, H 6.60, N 9.33.
Example 129: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-1 ,5,5- trimethylimidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 7.15 (d, 2H, J = 8.8 Hz), 7.14 (s, 4H), 6.68 (d, 2H, J = 8.8 Hz), 4.35 (s, 1 H), 3.77 (m, 1 H), 3.39 (dd, 4H, J = 7.1 , 14.3 Hz); 2.83 (m, 2H), 2.60 (m, 1 H), 2.10 (s, 3H), 1.34 (s, 3H), 1.20 (t, 6H, J = 7.0 Hz), 0.97 (S, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.5, 149.0, 148.0, 137.9, 130.5, 130.0, 123.0, 121.2, 1 1 1.5, 80.3, 61.5, 44.6, 40.9, 33.3, 30.6, 24.1 , 16.3, 12.9; (MH+)464.2; elemental analysis: theory C25H32F3N3O2 + 0.63 mol H2O C 63.23; H 7.06; N 8.85; found C 63.23, H 7.22, N 8.91.
Example 130: 3-(4-Methoxyphenethyl)-2-(2-(diethylamino)pyrimidin-5-yl)-1 ,5,5- trimethylimidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 8.16 (s, 2H), 7.05 (d, 2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.6 Hz), 4.20 (s, 1 H), 3.82 (m, 1 H), 3.78 (s, 3H), 3.63 (dd, 4H, J = 7.0, 12.3 Hz), 2.82 (m, 2H), 2.58 (m, 1 H), 2.07 (s, 3H), 1.29 (s, 3H), 1.21 (t,
6H, J = 7.1 Hz), 0.99 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.4, 162.1 , 158.9, 158.6, 130.7, 130.1 , 116.8, 1 14.2, 77.0, 61.4, 55.5, 42.3, 41.3, 33.0, 30.5, 24.1 , 16.7, 13.2; (MH+) 412.4; elemental analysis: theory C23H33N5O2 + 0.50 mol H2O C 65.68; H 8.14; N 16.65; found C 65.68, H 8.34, N 16.68.
Example 131 : 3-(4-Methoxyphenethyl)-2-(4-(dimethylamino)phenyl)-1 ,5,5- trimethylimidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 7.18 (d, 2H, J = 8.8 Hz),
7.03 (d, 2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.6 Hz), 6.72 (d, 2H, J = 8.8 Hz), 4.37 (s,1 H), 3.80 (s, 3H), 3.76 (m, 1 H), 3.00 (s, 6H), 2.76 (m, 2H), 2.53 (m, 1 H), 2.09 (s, 3H), 1.34 (S, 3H), 1.02 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.5, 158.4, 151.5, 131.1 , 130.1 , 129.8, 124.6, 1 14.0, 1 12.3, 80.2, 61.5, 55.5, 41.3, 40.7, 33.0, 30.7, 24.1 , 16.5; (MH+) 382.1 ; elemental analysis: theory C23H31N3O2 + 2.08 mol H2O C 65.93; H 8.46; N 10.03; found C 65.93, H 8.15, N 9.91.
Example 132: 3-(4-Methoxyphenethyl)-1 ,5,5-trimethyl-2-(4-(piperidin-1- yl)phenyl)imidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 7.17 (d, 2H, J = 8.7 Hz), 7.00 (d, 2H, J = 8.6 Hz), 6.92 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 4.36 (s, 1 H), 3.78 (s, 3H), 3.72 (m, 2H), 3.21 (t, 4H, J = 5.1 Hz), 2.75 (m, 2H), 2.54 (m, 1 H), 2.07 (s, 3H), 1.70 (m, 4H), 1.60 (m, 2H), 1.33 (s, 3H), 1.00 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.4, 158.4, 153.2, 131.0, 130.1 , 129.7, 127.2, 1 16.1 , 1 14.0 80.1 , 61.5, 55.5, 50.4, 41.3, 33.0, 30.7, 26.0, 24.6, 24.1 , 16.5; (MH+) 422.1 ; elemental analysis: theory C26H35N3O2 + 3.27 mol H2O C 64.99; H 8.71 ; N 8.75; found C 64.99, H 8.64, N 8.60.
Example 133: 3-(4-Methoxyphenethyl)-2-(4-(/so-propyl(methyl)amino)phenyl)-1 ,5,5- trimethylimidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 7.18 (d, 2H, J = 8.6 Hz),
7.04 (d, 2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J = 8.6 Hz), 4.37 (s, 1 H), 4.16 (m, 1 H), 3.81 (s, 3H), 3.74 (m,1 H), 2.79 (m, 5H), 2.55 (m, 1 H), 2.10 (s, 3H), 1.35 (s, 3H), 1.22 (d, 6H, J = 6.6 Hz), 1.02 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.4, 158.4, 131.3, 130.1 , 129.9, 1 12.8, 80.2, 61.6, 55.5, 49.0, 41.3, 33.0, 30.7, 24.1 , 19.7, 19.6, 16.5; (MH+) 410.2; elemental analysis: theory C25H35N3O2 + 0.35 mol H2O C 72.20; H 8.65; N 10.10; found C 72.20, H 8.33, N 10.07.
Category XVI Example 134: 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5-diethylimidazolidin- 4-one
Figure imgf000089_0001
Figure imgf000089_0002
Step 1 : Preparation of (9H-fluoren-9-yl)methyl)-3-((4- methoxyphenethyl)carbamoyl)pentan-3-ylcarbamate: To a solution of 2-(((9H- fluoren-9-yl)methoxy)carbonyl)-2-ethylbutanoic acid (1.76 g, 5.0 mmole) in DMF (15 ml.) was added PyBOP (2.6 g, 5.0 mmol). After stirring at room temperature for 10 min, 4-methoxyphenethyl amine (0.76 g, 5.0 mmol) was added, and the solution was stirred for a further 5 min. Finally, diisopropyl amine (6 drops) was added, and the solution was stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc and washed with aqueous KHSO4. (5%), saturated NaHCO3, water and dried with Na2SO4. The solvent was removed in vacuo, and the resulting residue was purified by flash silica column chromatography to provide desired product (1.68 g, chemical yield 70%). Step 2: Preparation of N-(4-methoxyphenethyl)-2-amino-2-ethylbutanamide: To a solution of the (9H-fluoren-9-yl)methyl)-3-((4-methoxyphenethyl)carbamoyl)pentan- 3-ylcarbamate (1.40 g, 3.0 mmol) in DMF (10 ml.) was added piperdine (1 ml_). After stirring at room temperature for 2 h, the white ppt was removed and the filtrate was evaporated in vacuo to give desired product (1.7 g). This compound is used for the next step reactions without further purification
Step 3: Preparation of 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5- diethylimidazolidin-4-one: To the solution of the N-(4-methoxyphenethyl)-2-amino-2- ethylbutanamide (530 mg, 2.0 mmol in 5 ml. of methanol) and K2CO3 (276 mg, 2.0 mmol) in a 2.0 - 5.0 ml. Emry's process vial equipped with a stir bar was added A- fe/t-butylbenzaldehyde (356 mg, 2.2 mmol). The reaction mixture was then capped, stirred 30 sec. and heated in a Biotage Initiator 60 microwave for 20 minutes at 120 0C. The reaction was then cooled to room temperature, diluted with ethyl acetate (100 ml_), washed with water, dried over Na2SO4 and purified via flash column chromatography to give desired product (610 mg, chemical yield 74%). 1H-NMR (300 MHz, CDCI3) δ 7.45 (d, 2H, J = 8.0Hz), 7.25 (d, 2H, J = 8.0Hz), 7.05 (d, 2H, J = 8.5Hz), 6.82 (d, 2H, J = 8.8Hz), 5.21 (s, 1 H), 3.82 (m, 1 H), 3.79 (s, 3H), 2.83 (m, 1 H), 2.67 (m, 2H), 1.81 (m, 2H), 1.60 (m, 2H), 1.56 (s 9H), 0.97 (m, 6H); 13C-NMR (75 MHz, CDCI3) δ 175.0, 158.6, 153.0, 136.2, 130.9, 130.0, 127.4, 126.4, 1 14.2, 75.2, 66.5, 55.6, 42.2, 35.1 , 32.8, 31.6, 31.1 , 29.2, 8.9, 8.7; (MH+) 409; elemental analysis: theory C26H36N2O2 + 0.4 H2O C 75.1 1 , H 8.92, N 6.74; found C 75.02, H 9.08, N 6.82.
Example 135: 1-N-methyl-3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5- diethylimidazolidin-4-one: To a solution of 409 mg (1 mmol) of 1-N-methyl-3-(4- methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5-diethylimidazolidin-4-one in 10 ml_ DMF was added 46 mg (2 mmol) of sodium hydride, followed by 710 mg (5 mmol) of iodomethane. The reaction was stirred at room temperature for 2 days and then stripped of solvent. The residue was dissolved in EtOAc, washed with water, dried over Na2SO4, filtered and stripped. The residual material was then purified via flash column chromatography to provide the desired product (350 mg, 82%). 1H-NMR (300 MHz, CDCI3) δ 7.43 (d, 2H, J = 8.5Hz), 7.30 (d, 2H, J = 8.8Hz), 7.00 (d, 2H, J = 8.6Hz), 6.79 (d, 2H, J = 8.8Hz), 4.89 (s, 1 H), 3.79 (s, 3H), 3.73 (m, 1 H), 2.85 (m, 1 H), 2.73 (m, 1 H), 2.57 (m, 1 H), 2.21 (s, 3H), 1.87 (m, 1 H), 1.66 (m, 2H), 1.47 (m, 1 H), 1.37 (s 9H), 0.97 (t, 3H, J = 7.2Hz), 0.91 (t, 3H, J = 7.4Hz); 13C-NMR (75 MHz, CDCI3) δ 175.0, 158.5, 152.7, 135.9, 131.1 , 130.0, 128.7, 125.8, 1 14.1 , 80.9, 68.2, 55.6, 41.8, 35.0, 33.3, 31.7, 29.9, 28.0, 27.8, 9.9, 9.6; MH+) 423.2; elemental analysis: theory C27H38N2O2 + 0.2 H2O C 76.09, H 9.08, N 6.57; found C 75.92, H 9.16, N 6.76.
Category XVII
Example 136: 3-(4-methoxyphenethyl)-1 ,5,5-trimethyl-2-(4-(pyrrolidin-1- yl)phenyl)imidazolidin-4-one
Figure imgf000091_0001
The starting cyclized 4-imidazolidinone (450 mg, 1.14 mmol) was dissolved with stirring in 2 mL of DMF which was then pipetted into an Emry's 2-5 mL process vial equipped with a stir bar. Next, cesium carbonate (746 mg, 2.29 mmol) was added to the reaction vial in one portion. Lastly, iodomethane (0.23 mL, 4.58 mmol) was added to the vial in one portion via syringe. The process vial was then capped and heated in a Biotage Initiator 60 microwave for 5 minutes at 150 0C. The reaction was cooled to room temperature, de-capped, and diluted in a mixture of 30 mL of de-ionized water and 30 mL of methylene chloride. The bi-phasic fluids were then transferred to a separatory funnel and separated. The remaining aqueous layer was extracted with 2 more 30 mL portions of metyhlene chloride. The combined organic extracts were then filtered over anhydrous MgSO4 and evaporated to dryness. Subsequent flash column chromatography affords a clear viscous syrup, 103 mg, chemical yield 22.2%. 1H-NMR (300 MHz, CDCI3) δ 7.17 (d, 2H, J = 8.4Hz), 7.04 (d, 2H, J = 8.4Hz), 6.83 (d, 2H, J = 8.6Hz), 6.56 (d, 2H, J = 8.6Hz), 4.37 (s, 1 H), 3.80 (s, 3H), 3.74 (m, 1 H), 3.33 (t, 4H, J = 6.6Hz), 2.77 (m, 2H), 2.55 (m, 1 H), 2.09 (s, 3H), 2.04 (t, 4H, J = 6.4Hz), 1.34 (s, 3H), 1.01 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.4, 158.4, 148.9, 131.1 , 130.1 , 130.0, 123.4, 1 14.0, 1 1 1.6, 80.3, 61.5, 55.5, 47.8, 41.3, 33.0, 30.6, 25.8, 24.1 , 16.4; (MH+) 408.1 ; elemental analysis: theory C25H33N3O2 + 2.35 mol H2O C 66.74; H 8.44; N 9.34; found C 66.70, H 8.31 , N 9.20.
Category XVIII
Example 137: 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5-dimethyl-1- (pyridin-3-ylmethyl)imidazolidin-4-one:
Figure imgf000092_0001
Preparation of 3-(4-methoxyphenethyl)-2-(4-fe/?-butylphenyl)-5,5-dimethyl-1-(pyridin- 3-ylmethyl)imidazolidin-4-one: The starting 4-imidazolidone (250 mg, 0.92 mmol) was added to an Emry's 2 - 5 mL process vial equipped with a stir bar. Next, cesium carbonate (629 mg, 1.93 mmol) was added in one portion to the reaction vial. This was followed by the addition of picolylbromide hydrogen bromide (232 mg, 0.92 mmol). Lastly, the reactants were submerged via the addition of DMF via syringe (2.0 mL). The reaction vial was then capped and heated in a Biotage Initiator 60 microwave for 8.5 minutes at 200 0C. The reaction was then cooled to room temperature and de-capped. The material was purified by flash column chromatography to afford a clear viscous syrup, 65 mg, chemical yield 15.0%. 1H- NMR (300 MHz, CDCI3) δ 8.28 (d, 2H, J = 7.9Hz), 7.30 (m, 1 H), 7.25 (d, 2H, J = 8.2Hz), 7.12 (d, 2H, J = 8.2Hz), 7.01 (d, 2H, J = 8.4Hz), 6.96 (m, 1 H), 6.83 (d, 2H, J = 8.6Hz) 4.61 (s, 1 H), 3.81 (s, 3H), 3.77 (d, 1 H, J = 14.5Hz) 3.74 (m, 1 H), 3.50 (d, 1 H, J = 14.3Hz), 2.75 (m, 2H), 2.68 (m, 1 H), 1.30 (s, 9H), 1.85 (s, 3H), 1.14 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 175.5, 158.5, 152.6, 150.0, 148.3, 136.6, 134.9, 134.4, 130.8, 130.1 , 128.9, 125.6, 123.0, 1 14.1 , 80.0, 62.2, 55.5, 47.8, 41.3, 34.9, 32.8, 31.5, 25.8, 18.3; (MH+) 472.2; elemental analysis: theory C30H37N3O2 + 1.24 mol C2HF3O2 C 63.64; H 6.29; N 6.85; found C 63.56, H 6.09, N 6.74.
Category XIX
Example 138: 3-(4-methoxyphenethyl)-2,5,5-trimethyl-2-p-tolylimidazolidin-4-one
Figure imgf000093_0001
Figure imgf000093_0002
The starting C-5 geminal dimethyl amino-amide (500 mg, 2.12 mmol) was added to an Emry's 2 - 5 mL process vial equipped with a stir bar. Next, 4- methylacetophenone (5.0 mL, 37.4 mmol) was added to the reaction in one portion via syringe. The reaction vial was then capped and heated in a Biotage Initiator 60 microwave at 220 0C for 5 minutes. The reaction was then cooled to room temperature and de-capped. The material was then purified by flash column chromatography to afford a pale yellow viscous syrup, 488 mg, chemical yield 65.3%. 1H-NMR (300 MHz, CDCI3) δ 7.24 (m, 2H), 7.17 (m, 2H), 7.07 (m, 2H), 6.82 (m, 2H), 3.77 (s, 3H), 3.53 (m, 1 H), 3.00 (m, 1 H), 2.87 (t, 2H, J = 7.3Hz), 2.35 (s, 3H), 2.14 (br, 1 H), 1.71 (s, 3H), 1.42 (s, 3H), 1.29 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 178.0, 158.5, 141.6, 138.4, 131.3, 130.1 , 129.7, 126.0, 1 14.1 , 78.6, 59.0, 55.5, 44.6, 33.7, 28.6, 27.9, 27.0, 21.2; (MH+) 353.1 ; elemental analysis: theory C22H28N2O2 + 0.10 mol H2O C 74.59; H 8.02; N 7.91 ; found C 74.57, H 7.94, N 7.78.
Example 139: 3-(4-methoxyphenethyl)-1 ,2,5,5-tetramethyl-2-p-tolylimidazolidin-4- one: 3-(4-methoxyphenethyl)-2,5,5-trimethyl-2-p-tolylimidazolidin-4-one (301 mg, 0.85 mmol) was added to an Emry's 2 - 5 mL process vial equipped with a stir bar. Next, the material was dissolved in 2 mL of DMF with stirring. This was followed by the addition of cesium carbonate (557 mg, 1.71 mmol). Lastly, iodomethane (0.17 mL, 3.41 mmol) was added to the reaction in one portion via syringe. The reaction vial was then capped and heated in a Biotage Initiator 60 microwave at 150 0C for 5 minutes. The reaction was then cooled to room temperature and de-capped. The reaction mixture was then partitioned between 20 mL of de-ionized water and 20 mL of methylene chloride and separated. The remaining aqueous layer was further extracted with 2 more 20 mL portions of methylene chloride. The combined organic extracts were filtered over anhydrous MgSO4 and evaporated dryness. The resulting material was purified by flash column chromatography to afford a clear viscous syrup, 256 mg, chemical yield 81.9%. 1H-NMR (300 MHz, CDCI3) δ 7.36 (d, 2H, J = 8.0Hz), 7.18 (d, 2H, J = 8.2Hz), 6.97 (d, 2H, J = 8.6Hz), 6.78 (d, 2H, J = 8.4Hz), 3.78 (s, 3H), 3.21 (m, 1 H), 3.06 (m, 1 H), 2.78 (m, 1 H), 2.47 (m, 1 H), 2.38 (s, 3H), 2.18 (s, 3H), 1.64 (S, 3H), 1.36 (s, 3H), 1.34 (s, 3H); 13C-NMR (75 MHz, CDCI3) δ 176.4, 158.3, 139.2, 138.3, 131.5, 130.0, 129.1 , 127.7, 1 14.0, 80.7, 60.8, 55.5, 43.5, 33.8, 27.2, 24.8, 22.7, 21.3, 21.2; (MH+) 367.1 ; elemental analysis: theory C23H30N2O2 C 75.37; H 8.25; N 7.64; found C 75.21 , H 8.09, N 7.65.
Example 140 was prepared according to the procedures described in Example 138- 139 using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents):
Example 140: 3-(4-methoxyphenethyl)-2-(3,4-dimethylphenyl)-1 ,2,5,5- tetramethylimidazolidin-4-one: 1H-NMR (300 MHz, CDCI3) δ 7.15 (m ,4H), 6.99 (d,
2H, J = 8.6Hz), 6.79 (d, 2H, J = 8.4Hz), 3.78 (s, 3H), 3.26 (m, 1 H), 3.03 (m, 1 H), 2.81 (m, 1 H), 2.49 (m, 1 H), 2.29 (s, 6H), 1.64 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H); 13C- NMR (75 MHz, CDCI3) 5176.5, 158.3, 139.6, 136.9, 136.6, 131.6, 130.0, 129.6, 128.9, 125.1 , 1 14.0, 80.8, 60.8, 55.5, 43.6, 33.8, 27.3, 24.7, 22.8, 21.4, 20.3, 19.7; (MH+) 367.1 ; elemental analysis: theory C23H30N2O2 + 0.81 mol H2O C 72.49; H 8.36; N 7.35; found C 72.48, H 8.21 , N 7.23.
CATEGORY XX
Example 141 : 2-(4-tert-butylphenyl)-1-(3-cyclohexylpropanoyl)-3-[2-(4- methoxy phenyl) ethyl]imidazolidin-4-one
Figure imgf000095_0001
Cyclohexaneacetic acid (81 mg, 0.57 mmol) and 2-(4-tert-butylphenyl)-3-(4- methoxyphenethyl)imidazolidin-4-one (158 mg, 0.45 mmol) were dissolved in CH2CI2 (6.0 ml_). After stirring briefly, EDCI (137.7 mg , 72 mmol) was added, and the reaction was stirred at room temperature until the starting material was consumed. The reaction was then stripped of solvent and the crude residue was purified by HPLC (CH3CN/H2O, 0.1% TFA) to provide 38 mg of the desired product.
Examples 142 - 296 were prepared according to the procedures described herein using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents). High-performance liquid chromatography (HPLC) was recorded with Column Aquasil C18 (Aquasil C18 HPLC column, 50 mm length x 2 mm ID, 5 micron particle) using following conditions: Mobile Phase A: 10 mM NH4OAC in 95% water / 5% CAN (Pipette 6.67 mL of 7.5 M NH4OAC solution into 4743 mL H2O, then add 250 mL of ACN to the solution and mixture). Mobile Phase B: 10 mM NH4OAC in 5% water / 95% CAN (Pipette 6.67 mL of 7.5 M NH4OAC solution into 243 mL H2O. Then add 4750 mL of ACN to the solution and mixture). Flow Rate: 0.800 mL/min,
Column Temperature: 4O0C, Injection Volume: 5 mL and UV: monitor 214 nm and
254 nm.
Gradient Table:
Time(min) %B
0.0 0
2.5 100
4.0 100
4.1 0 5.5 0
Mass spectra were recorded using Agilent 1200 HPLC/time-of-flight mass spectrometer 3x50 mm, 1.8 micron stable bond C18 column, T = 70 C, linear gradient from 70/30 (A:B) to 5/95 (A:B) over 1.2 minutes; A) water w/ 0.1% formic acid, B) acetonitrile w/ 0.1% formic acid. Mass spectrometer was scanned from m/z 100-1000.
Table 1
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
KV1.5 PATCH CLAMP EP
Kv1.5 currents are recorded by the whole cell mode of patch clamp electrophysiology. Kv1.5 is stably over expressed in HEK cells. Microelectrodes are pulled from borosilicate glass (TW150) and heat polished (tip resistance, 1.5 to 3 megaohms). The external solution is standard Tyrodes solution. The internal (microelectrode) solution contained: 1 10 mM KCI, 5 mM K2ATP, 5 mM K4BAPTA, 1 mM MgCI2 and 10 mM HEPES, adjusted to pH 7.2 with KOH. Command potentials are applied for 1 second to +6OmV from a holding potential of -70 mV using Axon software (pClamp 8.1) and hardware (Axopatch 1 D, 200B). Compounds are prepared as 10-2OmM DMSO stocks and diluted to appropriate test concentrations. After stable currents are achieved, compounds are perfused onto the cells and the cells are pulsed every 5 seconds until no further changes in current are evident at a given compound concentration. Inhibition is measured at the end of the 1 second pulses and expressed relative to controls. Kv1.5 inhibition is estimated by single point determinations done at 1 μM.
Generally following this procedure, results for representative compounds according to the present invention are listed in Table 2 below.
Table 2
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Variations, modifications, and other implementations of what is described herein will occur to those skilled in the art without departing from the spirit and the essential characteristics of the present teachings. Accordingly, the scope of the present teachings is to be defined not by the preceding illustrative description but instead by the following claims, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
Each of the printed publications, including but not limited to patents, patent applications, books, technical papers, trade publications and journal articles described or referenced in this specification are incorporated by reference herein in their entirety.

Claims

WHAT IS CLAIMED IS:
1. A compound having the Formula (I):
Figure imgf000163_0001
(I) or a pharmaceutically acceptable salt thereof,
wherein:
Ar1 is selected from C6-Ci0 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1- 5 R11 groups;
Ar2 is selected from (CH2)Z-C6-C10 aryl, wherein z = 0 or 1 and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1-5 R17 groups;
R1 is selected from H and Ci-6 alkyl;
R2 is selected from H, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.10 cycloalkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR18, SR18, NR28R29, SO2R30, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, and C3.10 cycloalkyl each is optionally substituted with 1-5 R15 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R16 groups;
R3 is selected from H, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-io cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR18, SR18, NR31R32, SO2R30, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl each is optionally substituted with 1-5 R15 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R16 groups;
R4 is selected from H and C1-6 alkyl;
each R5 and R6 is independently selected from H, C1-6 alkyl, halogen and NHSO2C1-6 alkyl;
or, any two R5 and R6, taken together with the carbon to which they are bound, form a carbonyl group;
each R7 and R8 is independently selected from H, C1-6 alkyl, and halogen;
or, any two R7 and R8, taken together with the carbon to which they are bound, form a carbonyl group;
each R9 and R10 is independently are selected from H, C1-6 alkyl, and halogen;
or, any two R9 and R10 taken together with the carbon to which they are bound, form a carbonyl group;
each R11 is independently selected from Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-i0 cycloalkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR12, SR12, NO2 and NR13R14, wherein the Ci-6 alkyl, the C2_6 alkenyl, the C2_6 alkynyl, and the C3-I0 cycloalkyl each is optionally substituted with 1-5 R15 groups, and wherein the cycloheteroalkyl is optionally substituted with 1-5 R16 groups;
each R12 is independently selected from H, Ci-6 alkyl, and Ci-3 perhaloalkyl;
each Rπj and R14 is independently selected from H and Ci-6 alkyl;
each R15 is independently selected from halogen, CN, OH, Ci-6 alkoxy, Ci-3 perhaloalkoxy, SH, SCi_6 alkyl, NH2, NH(Ci_6 alkyl), and N(Ci_6 alkyl)2;
each R16 is independently selected from Ci-6 alkyl, Ci-3 perhaloalkyl, halogen, CN, OH, OCi-6 alkyl, Od_3 perhaloalkyl, SH, SCi-6 alkyl, NH2, NH(Ci-6 alkyl), and N(Ci-6 alkyl)2;
each R17 is independently selected from Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, NO2, C3. io cycloalkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR18, SR18, NR19R20, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, and C3-I0 cycloalkyl each is optionally substituted with 1-5 R21 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R22 groups;
or, two R17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring containing 1-2 heteroatoms selected from N, O and S, and optionally substituted with 1-5 R22 groups;
each R18 is independently selected from H, Ci-6 alkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the Ci-6 alkyl optionally is substituted with 1-4 R23 groups; each R19 and R20 is independently selected from H, d_6 alkyl, C(O)R24, C(O)OR24, C(=NR25)NR26R27, C(O)NR26R27, and SO2R24;
each R21 is independently selected from halogen, CN, OH, C1-6 alkoxy, SH, SC1-6 alkyl, NH2, NH(C^6 alkyl), N(C^6 alkyl)2, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, a C6-C10 aryl ring, and a 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O and S;
each R22 is independently is selected from C1-6 alkyl, C1-3 perhaloalkyl, halogen, CN, OH, OCi-6 alkyl, Ci-3 perhaloalkoxy, SH, SCi-6 alkyl, NH2, NH(Ci-6 alkyl), -CH2- heteroaryl and N(C1-6 alkyl)2;
each R23 is independently is selected from halogen, CN, OH, OC1-6 alkyl, NH2, NH(C1-S alkyl), N(C1-6 alkyl)2, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the cycloheteroalkyl, aryl , and heteroaryl each is optionally substituted with 1-4 groups selected from C1-6 alkyl, C1-3 perhaloalkyl, and halogen;
R24 is C1-S alkyl optionally substituted with 1-4 groups selected from halogen, CN, OH, OCi-6 alkyl, Od_3 perhaloalkyl, SH, SCi-6 alkyl, NH2, NH(Ci-6 alkyl), and N(Ci-6 alkyl)2;
each R25, R26 and R27 is independently are selected from H and C1-6 alkyl;
each R28 and R29 is independently are selected from H, C1-6 alkyl optionally substituted with 1-4 R36 groups, C(O)R30, C(O)OR30, C(=NR25)NR26R27, C(O)NR26R27, and SO2R30;
R30 is selected from C1-6 alkyl, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1-4 groups selected from Ci-6 alkyl, halogen, CN, OH, OCi_6 alkyl, OCi_3 perhaloalkyl, SH, SCi_6 alkyl, NH2, NH(Ci_6 alkyl), and N(Ci_6 alkyl)2;
each R31 and R32 is independently selected from H, Ci-6 alkyl optionally substituted with 1-4 R36 groups, C3-io cycloalkyl, C(O)R33, C(O)OR33, C(=NR25)NR26R27, C(O)NR34R35, SO2R33, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, C6-Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;
R33 is selected from Ci-6 alkyl optionally substituted with 1-4 R36 groups, C6-Ci0 aryl optionally substituted with 1-4 R37 groups, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-4 R37 groups;
R34 and R35 each independently is selected from H, Ci-6 alkyl optionally substituted with 1-4 R36 groups, C6-Ci0 aryl optionally substituted with 1-4 R37 groups, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-4 R37 groups;
each R36 is independently selected from halogen, CN, OH, Ci-6 alkoxy, Ci-3 perhaloalkoxy, SH, SCi-6 alkyl, NH2, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, C6 or Ci0 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S;
each R37 is independently selected from Ci-6 alkyl, Ci-3 perhaloalkyl, halogen, CN, OH, Ci_6 alkoxy, OCi_3 perhaloalkoxy, SH, SCi_6 alkyl, NH2, NH(Ci_6 alkyl), and N(Ci_6 alkyl)2;
m is O, 1 2, 3, or 4;
n is O, 1 , 2, 3, 4, 5 or 6; and
p is O, 1 , 2, 3, 4, 5 or 6.
2. The compound of claim 1 , wherein R1 is H.
3. The compound of claim 1 or 2, wherein R4 is H.
4. The compound of claim 1 or 2, wherein R4 is C1-6 alkyl.
5. The compound of any one of claims 1 to 4, wherein m is 0 or 1.
6. The compound of any one of claims 1 to 4, wherein m is 2.
7. The compound of any one of claims 1 to 4, wherein m is 3.
8. The compound of any one of claims 1 to 7, wherein R5 and R6, at each occurrence, are each methyl or H.
9. The compound of any one of claims 1 to 8, wherein R5 and R6, at each occurrence, are each H.
10. The compound of any one of claims 1 to 9, wherein Ar1 is a C6-C10 aryl ring or a 5-14 membered heteroaryl ring, each aryl or heteroaryl ring having at least one substituent selected from Cr6 alkyl, halogen, Cr6 alkoxy, OH, NH2, NH(C1^ alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, C1-3 haloalkoxy, SH, SC1-6 alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, wherein the C1-6 alkyl group optionally is substituted with R15 and wherein the 3-10 membered cycloheteroalkyl is optionally substituted with R16.
1 1. The compound of any one of claims 1 to 10, wherein Ar1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from Cr6 alkyl, halogen, Cr6 alkoxy, OH, NH2, NH(d_6 alkyl), N(d_6 alkyl)2, NO2, Ci_3 haloalkyl, d_3 haloalkoxy, SH, SC^6 alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, wherein the Ci-6 alkyl group optionally is substituted with R15 and wherein the 3-10 membered cycloheteroalkyl optionally is substituted with R16.
12. The compound of claim 1 1 , wherein Ar1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, F, Cl, OH, OCH3, OCF3, SCH3, CH2N(CH3)2, and pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl.
13. The compound of any one of claims 1 to 12, wherein Ar1 is para-substituted phenyl.
14. The compound of any one of claims 1 to 13, wherein Ar1 is 4-methoxyphenyl.
15. The compound of any one of claims 1 to 9, wherein Ar1 is selected from pyridinyl and pyrimidinyl, each optionally substituted with 1-5 R11 groups.
16. The compound of any one of claims 1 to 15, wherein Ar2 is phenyl substituted with 1 , 2, or 3 substituents independently selected from halogen, Cr6 alkyl, C3_i0 cycloalkyl, Ci-3 perhaloalkyl, 3-10 membered cycloheteroalkyl ring containing 1 to 4 heteroatoms selected from N, O and S, and 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O and S, wherein the Ci-6 alkyl and the C3-io cycloalkyl are each optionally substituted with 1-5 R21 groups, and wherein the cycloheteroalkyl and heteroaryl each optionally is substituted with 1-5 R22 groups.
17. The compound of claim 16, wherein Ar2 is phenyl substituted with Ci-6 alkyl or C3-io cycloalkyl.
18. The compound of claim 17, wherein Ar2 is 4-(tert-butyl)phenyl or 4- cyclopropylphenyl.
19. The compound of claim 16, wherein Ar2 is phenyl substituted with 1 , 2 or 3 substitutents independently selected from F, Cl, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyclopropyl, trifluoromethyl, pyrrolidinyl, piperidinyl, piperazinyl N- methylpiperazinyl, N-ethylpiperazinyl, morpholinyl, pyridinyl, imidazolyl and 2- methylimidazolyl.
20. The compound of any one of claims 1 to 15, wherein Ar2 is phenyl substituted with 1 , 2, or 3 OR18 groups.
21. The compound of claim 20, wherein R18 is selected from H, C1-6 alkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the C1-6 alkyl optionally is substituted with 1-4 R23 groups.
22. The compound of claim 21 , wherein R18 is C1-6 alkyl.
23. The compound of claim 21 , wherein R18 is C1-6 alkyl substituted with 1-4 groups selected from halogen, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, O and S, a C6-C10 aryl ring, and a 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O and S.
24. The compound of claim 23, wherein R18 is C1-6 alkyl substituted with 1-2 groups selected from F, phenyl, pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, N- methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl.
25. The compound of any one of claims 1 to 15, wherein Ar2 is phenyl substituted with 1 , 2, or 3 NR19R20 groups.
26. The compound of claim 25, wherein R19 and R20 are selected from H, Ci-6 alkyl, C(=NR25)NR26R27, and SO2R24.
27. The compound according to claim 26, wherein R19 and R20 are each independently Ci-6 alkyl.
28. The compound of claim 25, wherein Ar2 is phenyl substituted with NH2, N(CH3)2, N(CH2CHs)2, NHSO2CH3, N(SO2CH3)2, and NH(C=NH)NH2.
29. The compound according to any one of claims 1 to 15, wherein Ar2 is phenyl substituted with two R17 groups, wherein the two R17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring selected from pyrrolidinyl, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, each optionally substituted with 1-5 R22 groups.
30. The compound according to claim 29, wherein Ar2 is benzo[d][1 ,3]dioxolyl, 2,2-difluorobenzo[d][1 ,3]dioxolyl, indolinyl, N-methylindolinyl, 2,3- dihydrobenzo[b][1 ,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1 ,4]oxazinyl, N-methyl-3,4- dihydro-2H-benzo[b][1 ,4]oxazinyl, 1 ,2,3,4-tetrahydroquinolinyl, and N-methyl-1 , 2,3,4- tetrahydroquinolinyl.
31. The compound of any one of claims 1 to 30, wherein Ar2 is para-substituted phenyl.
32. The compound of any one of claims 1 to 15, wherien Ar2 is 5-10 membered heteroaryl optionally substituted with 1-5 R17 groups.
33. The compound of claim 32, wherein Ar2 is selected from furanyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, and quinolinyl, each optionally substituted with 1-5 R17 groups.
34. The compound of any of claims 1 to 33, wherein R2 is selected from H, CN, Ci-6 alkyl optionally substituted with 1-5 R15 groups, and C2.6 alkenyl optionally substituted with 1-5 R15 groups.
35. The compound of any of claims 1 to 33, wherein R2 is C6-Ci0 aryl optionally substituted with 1-5 R16 groups.
36. The compound of claim 35, wherein R2 is phenyl optionally substituted with 1- 5 R16 groups.
37. The compound of any of claims 1 to 33, wherein R2 is OR18.
38. The compound of claim 37, wherein R18 is phenyl optionally substituted with 1-4 R23 groups.
39. The compound of claim 37, wherein R18 is 5-10 membered heteroaryl optionally substituted with 1-4 R23 groups.
40. The compound of any of claims 1 to 33, wherein R2 is SO2R30.
41. The compound of claim 40, wherein R30 is optionally substituted CrC6 alkyl, or optionally substituted 6-10 membered aryl.
42. The compound of any of claims 1 to 33, wherein R2 is 5-10 membered heteroaryl optionally substituted with 1-5 R16 groups.
43. The compound of claim 42, wherein R2 is pyridinyl, pyrimidinyl, imidazolyl or pyrazolyl, each of which is optionally substituted with 1-5 R16 groups.
44. The compound of any of claims 1 to 33, wherein R2 is C3_io cycloalkyl, optionally substituted with 1-5 R15 groups.
45. The compound of claim 44, wherein R2 is C3.6 cycloalkyl, optionally substituted with 1-5 R15 groups.
46. The compound of any of claims 1 to 33, wherein R2 is 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted with 1-5 R16 groups.
47. The compound of claim 46, wherein R2 is piperidinyl optionally substituted with 1-3 R15 groups.
48. The compound of any of claims 1 to 33, wherein R2 is NR28R29.
49. The compound of claim 48, wherein R28 is H, and R29 is C(O)R30.
50. The compound of claim 49, wherein R30 is optionally substituted 5-10 membered heteroaryl.
51. The compound of claim 50, wherein R30 is pyridinyl, imidaziolyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted.
52. The compound of claim 48, wherein R28 is H, and R29 is C(O)OR30.
53. The compound of claim 52, wherein R30 is C1-C6 alkyl.
54. The compound of claim 48, wherein R28 and R29 are each independently H or C1-C6 alkyl.
55. The compound of claim 48, wherein R28 is H, and R29 is C(O)NR26R27.
56. The compound of claim 48, wherein R28 and R29 are each independently H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 5-10 membered heteroaryl or 6-10 membered aryl, wherein the 6-10 membered aryl and the 5-10 membered heteroaryl are each optionally and independently substituted with 1-5 R16 groups.
57. The compound of any one of claims 1 to 56, wherein n is 0.
58. The compound of any one of claims 1 to 56, wherein n is 1.
59. The compound of any one of claims 1 to 56, wherein n is 2.
60. The compound of any one of claims 1 to 56, wherein n is 3.
61. The compound of any one of claims 1 to 56, wherein n is 4.
62. The compound of any one of claims 58 to 61 , wherein R7 and R8, at each occurrence, are each H.
63. The compound of any one of claims 58 to 61 , wherein one R7 and R8, taken together with the carbon to which they are bound, form a carbonyl.
64. The compound of any one of claims 1 to 63, wherein p is 0.
65. The compound of claim 64, wherein R3 is H or Ci-6 alkyl.
66. The compound of claim 65, wherein R3 is selected from methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.
67. The compound of claim 65, wherein R4 is H.
68. The compound of claim 64, wherein R3 and R4 are each H.
69. The compound of claim 64, wherein R3 and R4 are each Ci_6 alkyl.
70. The compound of any one of claims 1 to 64, wherein R3 is C6-C10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each optionally substituted with 1-5 R16 groups.
71. The compound of claim 70, wherein R3 is phenyl.
72. The compound of claim 70, wherein R3 is selected from pyrrolyl, imidazolyl, pyridinyl, and pyrimidinyl.
73. The compound of any one of claims 1 to 64, wherein R3 is NR31R32.
74. The compound of claim 73, wherein one of R31 and R32 is H and the other is SO2R33.
75. The compound of claim 74, wherein R33 is Ci-6 alkyl optionally substituted with 1-4 R34 groups.
76. The compound of claim 75, wherein R33 is Ci-6 alkyl optionally substituted with C6 or Cio aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.
77. The compound of claim 76, wherein R is benzyl or CH2-pyridinyl.
78. The compound of claim 73, wherein one of R31 and R32 is H and the other is C(O)NR34R35.
79. The compound of claim 78, wherein RJ4 and RJD are each H.
80. The compound of claim 78, wherein R and R are each Ci-6 alkyl.
81. The compound of claim 78, wherein one of R34 and R35 is H and the other is C1^ alkyl.
82. The compound of claim 78, wherein one of R34 and R35 is H and the other is C6-C10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.
83. The compound of claim 82, wherein one of R34 and R35 is H and the other is selected from phenyl, pyridinyl and pyrimidinyl.
84. The compound of claim 78, wherein one of R34 and R35 is C1-6 alkyl and the other is C6-C10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.
85. The compound of claim 84, wherein one of R34 and R35 is selected from methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, and the other is selected from phenyl, pyridinyl and pyrimidinyl.
86. The compound of claim 73, wherein one of R31 and R32 is H and the other is C(O)OR33.
87. The compound of claim 86, wherein R33 is Ci-6 alkyl optionally substituted with 1-4 R36 groups.
88. The compound of claim 87, wherein R33 is selected from methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.
89. The compound of claim 87, wherein R33 is Ci-6 alkyl substituted with NH2, NH(Ci_6 alkyl), or N(Ci_6 alkyl)2.
90. The compound of claim 87, wherein R33 is Ci-6 alkyl substituted with C6 or Ci0 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.
91. The compound of claim 90, wherein R33 is benzyl.
92. The compound of claim 73, wherein one of R31 and R32 is H and the other is C6 or Cio aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.
93. The compound of claim 92, wherein one of R31 and R32 is H and the other is selected from phenyl, pyridinyl and pyrimidinyl.
94. The compound of claim 73, wherein each of R31 and R32 is H.
95. The compound of claim 73, wherein each of R31 and R32 independently is Ci-6 alkyl optionally substituted with 1-4 R groups.
96. The compound of claim 95, wherein each of R31 and R32 independently is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl and CH2- pyridinyl.
97. The compound of claim 95, wherein each of R31 and R32 independently is selected from benzyl and CH2-pyridinyl.
98. The compound of any one of claims 1 to 64, wherein R3 is OR 18
99. The compound of claim 98, wherein R18 is H.
100. The compound of claim 98, wherein R18 is Ci-6 alkyl optionally is substituted with 1-4 R23 groups.
101. The compound of claim 100, wherein R18 is benzyl or CH2-pyridinyl.
102. The compound of any one of claims 1 to 64, wherein R3 is C6-C10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each optionally substituted with 1-5 R16 groups.
103. The compound of claim 102, wherein R3 is selected from phenyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl and quinolinyl.
104. The compound of any one of claims 70 to 103, wherein p is 1.
105. The compound of any one of claims 70 to 103, wherein p is 2.
106. The compound of any one of claims 70 to 103, wherein p is 3.
107. The compound of any one of claims 70 to 103, wherein p is 4.
108. The compound of any one of claims 104 to 107, wherein each of R9 and R10, at each occurrence, is H.
109. The compound of any one of claims 104 to 107, wherein one of R9 and R10, taken together with the carbon to which they are bound, form a carbonyl group.
1 10. The compound of claim 1 , having the Formula (II):
Figure imgf000178_0001
(H)
or a pharmaceutically acceptable salt thereof,
wherein m is 1, 2 or 3 and Ar1, Ar2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, n, and p are defined as in claim 1.
111. The compound of claim 110, wherein m is 1 and R5 and R6 are each H.
112. The compound of claim 110, wherein m is 1 and one of R5 and R6 is H and the other is Ci-6 alkyl.
113. The compound of claim 110, wherein m is 1 and R5 and R6, at each occurrence, are each H.
114. The compound of any one of claims 110 to 113, wherein Ar1 is para- substituted phenyl.
115. The compound of claim 114, wherein Ar1 is 4-methoxyphenyl.
116. The compound of claim 1 , having the formula (III):
R~
Figure imgf000179_0001
(III) or a pharmaceutically acceptable salt thereof,
wherein n is 0, 1 , 2, 3, 4 or 5 and Ar1, Ar2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, m, and p are defined as in claim 1.
1 17. A compound of claim 1 that is -(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe, -(4-ferf-butylpheπyl)-3-[2-(3-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,, -(3,4-dιchloropheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe, -(4-ferf-butylpheπyl)-1-ethyl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe, -(4-cyclopropylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[4-(tπfluoromethyl)pheπyl]ιmιdazolιdιπ-4-oπe, -(3-chloropheπyl)-1-ethyl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe, -(3,4-dιchloropheπyl)-1-ethyl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe, -(3,4-dιmethylpheπyl)-1-methyl-3-(3-pheπylpropyl)ιmιdazolιdιπ-4-oπe, -(4-ferf-butylpheπyl)-1-methyl-3-(3-pheπylpropyl)ιmιdazolιdιπ-4-oπe, -(4-ferf-butylpheπyl)-3-(4-methoxybeπzyl)-1-methylιmιdazolιdιπ-4-oπe, 2-(4-ferf-butylpheπyl)-1-methyl-3-(2-pheπylethyl)ιmιdazolιdιπ-4-oπe,
1-ethyl-3-(2-pheπylethyl)-2-[4-(tπfluoromethyl)pheπyl]ιmιdazolιdιπ-4-oπe,
1-ethyl-3-(2-pheπylethyl)-2-[3-(tπfluoromethyl)pheπyl]ιmιdazolιdιπ-4-oπe,
1-ethyl-2-(4-ethylpheπyl)-3-(2-pheπylethyl)ιmιdazolιdιπ-4-oπe,
(2R)-2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
(2S)-2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-methyl-3-{2-[4-(tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
2-(3,4-dιchloropheπyl)-1-methyl-3-{2-[4-(tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
1-methyl-3-{2-[4-(tπfluoromethoxy)pheπyl]ethyl}-2-[4-(tπfluoromethyl)pheπyl]ιmιdazolιdιπ-4- one,
2-(4-ferf-butylpheπyl)-1-methyl-3-(2-pheπylpropyl)ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-fluoropheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-ιsopropylpheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-methyl-3-{2-[4-(tπfluoromethyl)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
3-[2-(3,4-dιfluoropheπyl)ethyl]-2-(3,4-dιmethylpheπyl)-1-methylιmιdazolιdιπ-4-oπe,
2-(3,4-dιchloropheπyl)-3-[2-(3,4-dιfluoropheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe, 2-(4-ferf-butylpheπyl)-1-ethyl-3-{2-[4-(tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
2-(4-cyclopropylpheπyl)-1-methyl-3-{2-[4-(tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
3-{2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-4-oxoιmιdazolιdιπ-1-yl}propaπeπιtπle
1-allyl-2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-(3-hydroxypropyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-(2-hydroxyethyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(3,4-dιmethylpheπyl)-1-methyl-3-{2-[4-(tπfluoromethyl)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
(2R,5S)-2-(4-ferf-butylpheπyl)-5-ιsopropyl-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ- 4-oπe,
(2S,5S)-2-(4-ferf-butylpheπyl)-5-ιsopropyl-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ- 4-oπe,
1-beπzyl-2-[4-(dιmethylamιπo)pheπyl]-3-(2-pheπylethyl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-quιπolιπ-2-ylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1 ,5-dιmethylιmιdazolιdιπ-4-oπe,
(2R,5S)-5-ιsobutyl-2-(4-ιsopropylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4- one,
(2S,5S)-2-[4-(dιmethylamιπo)pheπyl]-5-ιsobutyl-3-[2-(4-methoxypheπyl)ethyl]-1- methylιmιdazolιdιn-4-one, (2R,5S)-2-(4-ethylpheπyl)-5-ιsobutyl-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
(2R,5S)-5-benzyl-2-(4-ethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4-one,
(2R,5S)-5-beπzyl-2-(3,4-dιmethylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4- one,
(2R,5S)-2-(4-chloropheπyl)-5-ιsobutyl-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4- one,
(2S,5S)-2-(4-chlorophenyl)-5-ιsobutyl-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4- one,
(2S,5S)-2-(4-ethylphenyl)-5-ιsobutyl-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4-one,
(2S,5S)-2-(4-ferf-butylphenyl)-5-ιsobutyl-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4- one,
2-[4-(dιethylamιno)phenyl]-1-methyl-3-{2-[4-(trιfluoromethoxy)phenyl]ethyl}ιmιdazolιdιn-4-one,
2-[4-(dιmethylamιno)phenyl]-1-methyl-3-{2-[4-(trιfluoromethoxy)phenyl]ethyl}ιmιdazolιdιn-4- one,
2-[4-(dιethylamιno)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4-one,
2-{4-[ιsopropyl(methyl)amιno]phenyl}-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4- one,
2-[4-(dιethylamιno)benzyl]-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4-one,
2-[4-(dιmethylamιno)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4-one, 2-[4-(dιethylamιπo)-3-fluoropheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-[3-chloro-4-(dιethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-[4-(dιethylamιπo)-3,5-dιfluoropheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4- one,
2-[2-chloro-4-(dιethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
(2R)-2-[4-(dιethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
(2S)-2-[4-(dιethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
(2S,5S)-5-ιsobutyl-2-(4-ιsopropylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4- one,
3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-(4-pιperazιn-1-ylphenyl)ιmιdazolιdιn-4-one,
3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[4-(pyrιdιn-4-ylmethoxy)phenyl]ιmιdazolιdιn-4-one,
3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[4-(3-methylbutoxy)phenyl]ιmιdazolιdιn-4-one,
(2R,5S)-5-benzyl-2-(4-ferf-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4- one,
(2R,5S)-2-(4-ferf-butylphenyl)-5-ιsobutyl-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4- one,
ferf-butyl (2-{(4S)-2-[4-(dιmethylamιno)phenyl]-1-[2-(4-methoxyphenyl)ethyl]-3-methyl-5- oxoιmιdazolιdιn-4-yl}ethyl)carbamate
(2R,5S)-2-[4-(dιmethylamιno)phenyl]-5-ιsobutyl-3-[2-(4-methoxyphenyl)ethyl]-1- methylιmιdazolιdιn-4-one,
(2S,5S)-5-beπzyl-2-(3,4-dιmethylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4- one,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(1-methyl-1 ,2,3,4-tetrahydroquιπolιπ-6- yl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-quιπolιπ-4-ylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(1 /-/-pyrrol-2-yl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(1-methyl-1 /-/-pyrrol-2-yl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(4-methyl-3,4-dιhydro-2/-/-1 ,4-beπzoxazιπ-7- yl)ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-(4-methoxybeπzyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(4-chloropheπyl)-1-(4-methoxybeπzyl)-3-(2-pheπylethyl)ιmιdazolιdιπ-4-oπe,
2-(1 ,3-beπzodιoxol-5-yl)-1-beπzyl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
1-beπzyl-3-[2-(4-methoxypheπyl)ethyl]-2-[4-(tπfluoromethyl)pheπyl]ιmιdazolιdιπ-4-oπe,
1-beπzyl-2-(3,4-dιchloropheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
1-beπzyl-2-(3-chloropheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
1-beπzyl-2-(4-ιsopropylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe, 1-beπzyl-2-(4-ethylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
1-beπzyl-2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
1-beπzyl-2-(3,4-dιmethylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
1-beπzyl-2-(4-fluoropheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
1-[2-(beπzyloxy)ethyl]-2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
1-[3-(beπzyloxy)propyl]-2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-[3-(pyπdιπ-2- ylmethoxy)propyl]ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-[3-(pyπdιπ-3- ylmethoxy)propyl]ιmιdazolιdιπ-4-oπe,
Λ/-(3-{2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-4-oxoιmιdazolιdιπ-1- yl}propyl)πιcotιπamιde
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(methylsulfoπyl)ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-[(3-fluoropheπyl)sulfoπyl]-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4- one,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-[(4-methylpheπyl)sulfoπyl]ιmιdazolιdιπ-4- one,
2-(4-ferf-butylphenyl)-1-(ethylsulfonyl)-3-[2-(4-methoxyphenyl)ethyl]ιmιdazolιdιn-4-one,
2-(4-ferf-butylphenyl)-1-[(4-ethylphenyl)sulfonyl]-3-[2-(4-methoxyphenyl)ethyl]ιmιdazolιdιn-4- one,
3-[(4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]-Λ/-pyπdιπ-3-ylpropaπamιde
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[4-(2-pιpeπdιπ-1-ylethoxy)pheπyl]ιmιdazolιdιπ-4-oπe,
2-[(2R,4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]-Λ/-pyπdιπ-3-ylacetamιde
2-[(2S,4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]-Λ/-pyπdιπ-2-ylacetamιde
2-[(2R,4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]-Λ/-(pyπdιπ-2-ylmethyl)acetamιde
2-[(2R,4S)-2-(4-ferf-butylpheπyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]-Λ/-(pyπdιπ-3-ylmethyl)acetamιde
benzyl {2-[(4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4-
(trιfluoromethoxy)phenyl]ethyl}ιmιdazolιdιn-4-yl]ethyl}carbamate
Λ/-{2-[(4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (trιfluoromethoxy)phenyl]ethyl}ιmιdazolιdιn-4-yl]ethyl}pyrιdιne-2-carboxamιde
Λ/-{2-[(4S)-2-(4-fert-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (trιfluoromethoxy)phenyl]ethyl}ιmιdazolιdιn-4-yl]ethyl}nιcotιnamιde
(5S)-2-(4-ferf-butylphenyl)-1-methyl-5-[2-(pyrιmιdιn-2-ylamιno)ethyl]-3-{2-[4- (trιfluoromethoxy)phenyl]ethyl}ιmιdazolιdιn-4-one,
(2R,5S)-2-(4-ferf-butylphenyl)-5-(2-hydroxyethyl)-1-methyl-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
(2R,5S)-5-{2-[beπzyl(methyl)amιπo]ethyl}-2-(4-ferf-butylpheπyl)-1-methyl-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
(2R,5S)-2-[4-(dιethylamιno)phenyl]-1-methyl-5-[2-(pyπdιn-2-ylmethoxy)ethyl]-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
(2R,5S)-5-[(beπzyloxy)methyl]-2-[4-(dιethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1- methylιmιdazolιdιπ-4-oπe,
(2S,5S)-5-[(beπzyloxy)methyl]-2-[4-(dιethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1- methylιmιdazolιdιπ-4-oπe,
Λ/-({(2S,4S)-2-(4-ferf-butylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ-4- yl}methyl)methaπesulfoπamιde
Λ/-({(2R,4S)-2-(4-ferf-butylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ-4- yl}methyl)propane-1 -sulfonamide
Λ/-({(2S,4S)-2-(4-ferf-butylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ-4- yl}methyl)propaπe-1 -sulfonamide
Λ/-({(2S,4S)-2-(4-ferf-butylphenyl)-1-[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoιmιdazolιdιn-4- yl}methyl)butane-1 -sulfonamide
Λ/-({(2R,4S)-2-(4-ferf-butylphenyl)-1-[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoιmιdazolιdιn-4- yl}methyl)-1-pyrιdιn-3-ylmethanesulfonamιde
1-({(2S,4S)-2-(4-ferf-butylphenyl)-1-[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoιmιdazolιdιn-4- yl}methyl)-3-ethylurea 1-({(2R,4S)-2-(4-ferf-butylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ-4- yl}methyl)-3-pyπmιdιπ-4-ylurea
1-({(2R,4S)-2-(4-ferf-butylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ-4- yl}methyl)urea
1-({(2R,4S)-2-(4-ferf-butylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ-4- yl}methyl)-3-methylurea
1-({(2S,4S)-2-(4-ferf-butylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ-4- yl}methyl)-3-methylurea
1-({(2S,4S)-2-(4-cyclopropylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ- 4-yl}methyl)-3-methylurea
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ-4-oπe,
2-(4-cyclopropylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethylιmιdazolιdιπ-4-oπe,
1-beπzyl-2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-ethyl-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethylιmιdazolιdιπ-4-oπe,
2-[4-(dιethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ-4-oπe,
2-[4-(dιmethylamιπo)pheπyl]-1 ,5,5-tπmethyl-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
2-[4-(dιethylamιπo)pheπyl]-1 ,5,5-tπmethyl-3-{2-[4-(tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ- 4-oπe, 2-[2-(dιethylamιπo)pyrιmιdιπ-5-yl]-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-trιmethylιmιdazolιdιπ-4- one,
2-[4-(dιmethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethyl-2-(4-pιpeπdιπ-1-ylpheπyl)ιmιdazolιdιπ-4-oπe,
2-{4-[ιsopropyl(methyl)amιπo]pheπyl}-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ- 4-oπe,
2-(4-ferf-butylpheπyl)-5,5-dιethyl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-5,5-dιethyl-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethyl-2-(4-pyrrolιdιπ-1-ylpheπyl)ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethyl-1-(pyπdιπ-3- ylmethyl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-2,5,5-tπmethyl-2-(4-methylpheπyl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1 ,2,5,5-tetramethyl-2-(4-methylpheπyl)ιmιdazolιdιπ-4-oπe,
2-(3,4-dιmethylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1 ,2,5,5-tetramethylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-(3-cyclohexylpropaπoyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4- one,
3-[2-(4-methoxyphenyl)ethyl]-5,5-dιmethyl-2-(4-pyrrolιdιn-1-ylphenyl)ιmιdazolιdιn-4-one,
2-(3,4-dιchlorophenyl)-1-methyl-3-{2-[4-(trιfluoromethyl)phenyl]ethyl}ιmιdazolιdιn-4-one, Λ/-({(2R,4S)-2-(4-ferf-butylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ-4- yl}methyl)methaπesulfoπamιde
2-(1-ethyl-1 /-/-ιπdol-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ-4-oπe,
2-{4-[2-(dιmethylamιπo)ethoxy]pheπyl}-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4- one,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[4-(pyπdιπ-2-ylmethoxy)pheπyl]ιmιdazolιdιπ-4-oπe,
Λ/-(4-{3-[2-(4-methoxypheπyl)ethyl]-1-methyl-4-oxoιmιdazolιdιπ-2- yl}pheπyl)methaπesulfoπamιde
2-(2,2-dιfluoro-1 ,3-beπzodιoxol-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ- 4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[4-(2-pyrrolιdιπ-1-ylethoxy)pheπyl]ιmιdazolιdιπ-4-oπe,
2-(4-cyclopropylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(3-pyπdιπ-3-ylpropaπoyl)ιmιdazolιdιπ- 4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(2-pheπyl-1 /-/-ιmιdazol-5-yl)ιmιdazolιdιπ-4-oπe,
Λ/-(2-{2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-4-oxoιmιdazolιdιπ-1- yl}ethyl)ethaπesulfoπamιde
2-(4-ferf-butylpheπyl)-1-butyryl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[4-(2-morpholιπ-4-ylethoxy)pheπyl]ιmιdazolιdιπ-4- one,
2-(4-ferf-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-(3-phenylpropyl)ιmιdazolιdιn-4-one, S-p-t^methoxypheπylJethyll-i-methyl^-^-tpipeπdiπ^-yloxyJpheπyφmidazolidiπ^-oπe,
(5S)-5-(2-amιnoethyl)-2-(4-ferf-butylphenyl)-1-methyl-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-ιsopropyl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[3-(4-fluoropheπyl)propyl]-1-methylιmιdazolιdιπ-4-oπe,
2-{4-[ethyl(ιsopropyl)amιπo]pheπyl}-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
3-[(4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]propaπoιc acid
Λ/-(4-{3-[2-(4-methoxypheπyl)ethyl]-1-methyl-4-oxoιmιdazolιdιπ-2-yl}pheπyl)-Λ/- (methylsulfoπyl)methaπesulfoπamιde
2-(4-ferf-butylpheπyl)-1-methyl-3-{2-[2-(methylthιo)pyπmιdιπ-5-yl]ethyl}ιmιdazolιdιπ-4-oπe,
2-(2,4-dιmethoxypyπmιdιπ-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(pyπdιπ-3-ylacetyl)ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-hexaπoyl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[1-(pyπdιπ-4-ylmethyl)-1 /-/-ιπdol-5-yl]ιmιdazolιdιπ-4- one,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(pyπdιπ-4-ylacetyl)ιmιdazolιdιπ-4-oπe,
2-[2-(dιethylamιπo)pyπmιdιπ-5-yl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe, ferf-butyl (3-{2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-4-oxoιmιdazolιdιπ-1- yl}propyl)carbamate
2-(2-ferf-butyl-1 /-/-ιmιdazol-4-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-cyclopropylpheπyl)-1-methyl-3-(3-pheπylpropyl)ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-[3-(dιιsopropylamιπo)propyl]-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ- 4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[1-(pyπdιπ-2-ylmethyl)-1/-/-ιπdol-5-yl]ιmιdazolιdιπ-4- one,
2-(2-ferf-butylpyπmιdιπ-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[1-(pyπdιπ-3-ylmethyl)-1/-/-ιπdol-5-yl]ιmιdazolιdιπ-4- one,
(2R,5S)-5-{2-[benzyl(pyrιdιn-3-ylmethyl)amιno]ethyl}-2-(4-ferf-butylphenyl)-1-methyl-3-{2-[4- (trιfluoromethoxy)phenyl]ethyl}ιmιdazolιdιn-4-one,
3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-quιnolιn-3-ylιmιdazolιdιn-4-one,
2-(4-ferf-butylphenyl)-1-(cyclohexylacetyl)-3-[2-(4-methoxyphenyl)ethyl]ιmιdazolιdιn-4-one,
Λ/-({(2R,4S)-2-(4-ferf-butylphenyl)-1-[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoιmιdazolιdιn-4- yl}methyl)butane-1 -sulfonamide
1-({(2S,4S)-2-(4-cyclopropylphenyl)-1-[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoιmιdazolιdιn- 4-yl}methyl)urea
3-[(4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]-Λ/-pyπdιπ-2-ylpropaπamιde
2-(1 /-/-ιmιdazol-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(6-ferf-butylpyπdιπ-3-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-pyπdιπ-3-ylιmιdazolιdιπ-4-oπe,
2-(2-furyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(3-pιpeπdιπ-1-ylpropaπoyl)ιmιdazolιdιπ- 4-oπe,
2-(4-ιsobutylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
(5S)-2-(4-ferf-butylpheπyl)-1-methyl-5-[2-(pyπdιπ-2-ylamιπo)ethyl]-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(1-methyl-1 /-/-ιmιdazol-2-yl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(4-morpholιπ-4-ylpheπyl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[4-(4-methylpιperazιπ-1-yl)pheπyl]ιmιdazolιdιπ-4-oπe,
3-[(4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]-Λ/-[2-(dιmethylamιπo)ethyl]propaπamιde
2-[(2R,4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]-Λ/-pyπdιπ-2-ylacetamιde
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(3-pyπmιdιπ-2-ylpropaπoyl)ιmιdazolιdιπ- 4-oπe,
i-tS-IS-p-tΦmethoxypheπylJethyll-i-methyl^-oxoimidazolidiπ^-ylJpheπylJguaπidme
2-(4-cyclopropylpheπyl)-1-methyl-3-(2-pheπoxyethyl)ιmιdazolιdιπ-4-oπe,
2-(4-ethyl-3,4-dιhydro-2H-1 ,4-beπzoxazιπ-7-yl)-3-[2-(4-methoxypheπyl)ethyl]-1- methylιmιdazolιdιπ-4-oπe,
Λ/-{2-[2-(4-ferf-butylpheπyl)-3-methyl-5-oxoιmιdazolιdιπ-1-yl]-1- pheπylethyl}methaπesulfoπamιde
2-(4-ferf-butylpheπyl)-3-[2-(6-methoxypyπdιπ-3-yl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-fluoropheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-amιπopheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(4-pyπdιπ-3-ylpheπyl)ιmιdazolιdιπ-4-oπe,
1-{3-[beπzyl(pyπdιπ-2-ylmethyl)amιπo]propyl}-2-(4-ferf-butylpheπyl)-3-[2-(4- methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-methyl-3-[2-(4-pyrrolιdιπ-1-ylpheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-[4-(dιιsopropylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-[4-(dιethylamιπo)-3-methoxypheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4- one,
Λ/-(2-{2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-4-oxoιmιdazolιdιπ-1- yl}ethyl)methaπesulfoπamιde
3-[2-(4-methoxypheπyl)ethyl]-1 ,5-dιmethyl-2-(4-methylpheπyl)ιmιdazolιdιπ-4-oπe,
1-{2-[(4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]ethyl}-3-pyπdιπ-3-ylurea
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(2-pyπdιπ-2-ylethyl)ιmιdazolιdιπ-4-oπe,
2-[4-(dιethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(4-pyπdιπ-2-ylpheπyl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(4-pyπdιπ-4-ylpheπyl)ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-(3-cyclohexylpropaπoyl)-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4- one,
2-(1-ethyl-1 ,2,3,4-tetrahydroquιπolιπ-6-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ- 4-oπe,
1-beπzyl-3-[2-(4-methoxypheπyl)ethyl]-2-(1 /-/-pyrrol-2-yl)ιmιdazolιdιπ-4-oπe,
2-(2,3-dιhydro-1 ,4-beπzodιoxιπ-6-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-[4-(dιethylamιπo)beπzyl]-3-[2-(4-methoxypheπyl)ethyl]-5,5- dιmethylιmιdazolιdιπ-4-oπe,
2-(5-ferf-butyl-1-methyl-1 /-/-ιmιdazol-2-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ- 4-oπe, 2-(1-ethyl-2,3-dιhydro-1 /-/-ιπdol-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-[2-(dιmethylamιπo)pyπmιdιπ-5-yl]-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ-4- one,
2-(4-ferf-butylpheπyl)-1-cyclopropyl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(1-ethyl-1 /-/-ιπdol-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(2-ferf-butylpyπmιdιπ-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-Λ/-ethyl-3-[2-(4-methoxypheπyl)ethyl]-4-oxoιmιdazolιdιπe-1-carboxamιde
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(4-pyrrolιdιπ-1-ylpheπyl)ιmιdazolιdιπ-4-oπe,
2-[2-(dιmethylamιπo)pyπmιdιπ-5-yl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
(2R,5S)-2-(4-ferf-butylpheπyl)-1-methyl-5-{2-[methyl(pheπyl)amιπo]ethyl}-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
(2R,5S)-2-(4-ferf-butylpheπyl)-5-[2-(dιmethylamιπo)ethyl]-1-methyl-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
(2R,5S)-2-(4-ferf-butylpheπyl)-5-(1 H-ιπdol-3-ylmethyl)-3-[2-(4-methoxypheπyl)ethyl]-1- methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-(1 H-ιmιdazol-2-ylmethyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5- dιmethylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethyl-1-propylιmιdazolιdιπ-4-oπe, 2-(4-chloropheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethyl-1-(pyπdιπ-4- ylmethyl)ιmιdazolιdιn-4-one,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethyl-1-(pyπdιπ-2- ylmethyl)ιmιdazolιdιπ-4-oπe,
(2R,5S)-2-(4-ferf-butylpheπyl)-1-methyl-5-[2-(pyπdιπ-3-ylamιπo)ethyl]-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
2-(3-amιπopheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-(2-{4-[(dιmethylamιπo)methyl]pheπyl}ethyl)-1-methylιmιdazolιdιπ-4- one,
2-[4-(dιιsopropylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(1 /-/-pyrazol-4-ylcarboπyl)ιmιdazolιdιπ-4- one,
2-(4-cyclopropylphenyl)-3-(4-methoxyphenyl)-1-methylιmιdazolιdιn-4-one,
2-[4-(4-hydroxypιperιdιn-1-yl)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4- one,
2-[4-(dιfluoromethoxy)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 ,5,5-trιmethylιmιdazolιdιn-4-one,
2-(4-ferf-butylphenyl)-1-[4-(dιmethylamιno)butanoyl]-3-[2-(4-methoxyphenyl)ethyl]ιmιdazolιdιn- 4-one,
2-[4-(dιmethylamιno)-2-methoxyphenyl]-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4- one,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(pyπdιπ-2-ylacetyl)ιmιdazolιdιπ-4-oπe,
2-[4-(dιethylamιπo)pheπyl]-3-(4-methoxypheπyl)-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylphenyl)-1-(pyπdιn-3-ylmethyl)-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-(4-methoxypheπyl)-1-methylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(4-πιtropheπyl)ιmιdazolιdιπ-4-oπe,
2-(1 /-/-ιπdol-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(3-pyπdιπ-3-ylpropaπoyl)ιmιdazolιdιπ-4- one,
2-(4-ferf-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-(pyrιdιn-3-ylmethyl)ιmιdazolιdιn-4-one,
2-(4-ferf-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-Λ/-pentylιmιdazolιdιne-1- carboxamide
2-[4-(1 /-/-ιmιdazol-1-yl)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1-methylιmιdazolιdιn-4-one,
(2R,5S)-2-(4-ferf-butylphenyl)-5-{2-[ethyl(phenyl)amιno]ethyl}-1-methyl-3-{2-[4- (trιfluoromethoxy)phenyl]ethyl}ιmιdazolιdιn-4-one,
1-cyclopropyl-2-(1 /-/-ιndol-5-yl)-3-[2-(4-methoxyphenyl)ethyl]ιmιdazolιdιn-4-one,
Λ/-{2-[(2R,4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (trifluoromethoxy)phenyl]ethyl}imidazolidin-4-yl]ethyl}-2-methylalaninamide
(2R,5S)-2-(4-ferf-butylpheπyl)-5-[2-(dιethylamιπo)ethyl]-1-methyl-3-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-oπe,
1-beπzyl-3-[2-(4-methoxypheπyl)ethyl]-2-pyπdιπ-2-ylιmιdazolιdιπ-4-oπe,
2-[3-(dιethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-pyπdιπ-2-ylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-hydroxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(2,6-dιmethylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(2-amιπopyπdιπ-3-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-4-oxo-Λ/-pyπmιdιπ-4-ylιmιdazolιdιπe-1- carboxamide
2-(4-ferf-butylpheπyl)-3-{2-[4-(dιmethylamιπo)pheπyl]ethyl}-1-methylιmιdazolιdιπ-4-oπe,
2-[4-(4-ethylpιperazιπ-1-yl)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(3,4-dιmethylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-[4-(dιethylamιπo)-2-(tπfluoromethyl)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]-1- methylιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-(2-pheπylethyl)ιmιdazolιdιπ-4-oπe, 2-(4-cyclopropylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1 ,5,5-tπmethylιmιdazolιdιπ-4-oπe,
2-(4-cyclopropylpheπyl)-3-[3-(4-fluoropheπyl)propyl]-1-methylιmιdazolιdιπ-4-oπe,
1-(2-{2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-4-oxoιmιdazolιdιπ-1-yl}ethyl)-3- ethylurea
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[2-(2-methyl-1 /-/-ιmιdazol-1-yl)pheπyl]ιmιdazolιdιπ-4- one,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethyl-1-(pyπmιdιπ-5- ylmethyl)ιmιdazolιdιn-4-one,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-5,5-dιmethyl-1-[(1-methyl-1 H-ιmιdazol-2- yl)methyl]ιmιdazolιdιπ-4-oπe,
2-(3,4-dιmethylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1 ,5-dιmethylιmιdazolιdιπ-4-oπe,
2-(2-ferf-butyl-1-methyl-1 /-/-ιmιdazol-5-yl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ- 4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(pyrazιπ-2-ylcarboπyl)ιmιdazolιdιπ-4-oπe,
3-[2-(4-methoxypheπyl)ethyl]-1-methyl-2-[4-(pyπdιπ-3-ylmethoxy)pheπyl]ιmιdazolιdιπ-4-oπe,
2-(4-hydroxypheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-methylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-peπtylιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-methyl-3-[2-(4-pιpeπdιπ-1-ylpheπyl)ethyl]ιmιdazolιdιπ-4-oπe, 4-{3-[2-(4-methoxypheπyl)ethyl]-1-methyl-4-oxoιmιdazolιdιπ-2-yl}beπzoπιtπle,
2-(4-ferf-butylpheπyl)-1-ιsoπιcotιπoyl-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-Λ/-methyl-4-oxoιmιdazolιdιπe-1- carboxamide,
2-(4-ferf-butylpheπyl)-1-methyl-3-(2-pheπoxyethyl)ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-1-methyl-3-[2-(4-morpholιπ-4-ylpheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
2-(4-ferf-butylpheπyl)-3-[2-(4-methoxypheπyl)ethyl]-1-(3-pyπdιπ-2-ylpropyl)ιmιdazolιdιπ-4-oπe,
1-beπzyl-2-[4-(dιmethylamιπo)pheπyl]-3-[2-(4-methoxypheπyl)ethyl]ιmιdazolιdιπ-4-oπe,
3-[(4S)-2-(4-ferf-butylphenyl)-3-methyl-5-oxo-1-{2-[4- (tπfluoromethoxy)pheπyl]ethyl}ιmιdazolιdιπ-4-yl]-Λ/-(pheπylsulfoπyl)propaπamιde, and
1-({(2R,4S)-2-(4-ferf-butylpheπyl)-1-[2-(4-methoxypheπyl)ethyl]-3-methyl-5-oxoιmιdazolιdιπ-4- yl}methyl)-3-ethylurea,
or a pharmaceutically acceptable salt thereof.
1 18. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 1 17 and one or more excipients.
1 19. A method for treating or preventing atrial arrhythmia comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 1 17 or a pharmaceutical composition of claim 118 to a subject.
120. The method of claim 1 19, wherein the atrial arrhythmia comprises atrial fibrillation or atrial flutter.
121. A method for or preventing treating thromboembolism, stroke, or cardiac failure comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 1 17 or a pharmaceutical composition of claim 1 18 to a subject.
122. The compound of claim 1 , wherein each R17 is independently selected from C1-S alkyl, C2_6 alkenyl, C2_6 alkynyl, C3.10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR18, SR18, NR19R20, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein the C1-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, and C3-10 cycloalkyl each is optionally substituted with 1-5 R21 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R22 groups;
alternatively, two R17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring containing 1-2 heteroatoms selected from N, O and S, and optionally substituted with 1-5 R22 groups;
Ar2 is selected from C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, each of which is optionally substituted with 1- 5 R17 groups;
each R11 is independently selected from C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S, halogen, CN, OR12, SR12, and NR13R14, wherein the C1-6 alkyl, the C2.6 alkenyl, the C2.6 alkynyl, and the C3-10 cycloalkyl each is optionally substituted with 1-5 R15 groups, and wherein the cycloheteroalkyl is optionally substituted with 1-5 R16 groups; and
each R22 is independently is selected from C1-6 alkyl, C1-3 perhaloalkyl, halogen, CN, OH, OCi-6 alkyl, d_3 perhaloalkoxy, SH, SCi-6 alkyl, NH2, NH(Ci-6 alkyl), and N(Ci-6 alkyl)2.
123. A method for inhibiting Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 1 17 or a pharmaceutical composition of claim 1 18 to a subject.
124. A method for treating or preventing a disorder associated with inhibition of Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 1 17 or a pharmaceutical composition of claim 1 18 to a subject.
125. The method of claim 124, wherein the disorder is selected from the group consisting of atrial arrhythmia, thromboembolism, stroke and cardiac failure.
126. A method for inducing cardioversion, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 1 17 or a pharmaceutical composition of claim 1 18 to a subject.
PCT/US2008/087397 2007-12-19 2008-12-18 4-imidazolidinones as kv1.5 potassium channel inhibitors WO2009079624A1 (en)

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