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WO2011011494A1 - Composés imidazoazépinones - Google Patents

Composés imidazoazépinones Download PDF

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Publication number
WO2011011494A1
WO2011011494A1 PCT/US2010/042717 US2010042717W WO2011011494A1 WO 2011011494 A1 WO2011011494 A1 WO 2011011494A1 US 2010042717 W US2010042717 W US 2010042717W WO 2011011494 A1 WO2011011494 A1 WO 2011011494A1
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Prior art keywords
alkyl
alkenyl
group
independently selected
hydrogen
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English (en)
Inventor
Mark Spyvee
Qian Chen
Eric Carlson
Kuzutomi Kusano
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Eisai R&D Management Co Ltd
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Eisai R&D Management Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • Thp naive CD4+ T helper precursor
  • ThI Type 1 T helper
  • Th2 Type 2 T helper
  • ThI naive CD4+ T helper precursor
  • Thl7 cells a novel T cell subset, the Thl7 cells, has also been identified and characterized
  • ThI cells produce interferon-gamma, interleukin (IL)-2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are responsible for cell -mediated immunity and phagocyte- dependent protective responses.
  • IL interleukin
  • TNF tumor necrosis factor
  • Th2 cells are known to produce IL-4, IL- 5, IL-6, IL-9, IL-IO and IL-13, which are responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions, thus providing phagocyte-independent protective responses.
  • Th 17 cells mainly produce IL- 17 A, IL- 17F, IL-21, IL-22 & TNF and are required for host defense against extracellular pathogens and are critical mediators of autoimmunity. Accordingly, ThI , Th2, and ThI 7 cells are associated with different immunopathological responses.
  • Th cell development is mediated by a different cytokine pathway. Specifically, it has been shown that IL-4 promotes Th2 differentiation and simultaneously blocks ThI development. In contrast, IL- 12, IL- 18 and IFN-gamma are the cytokines critical for the development of ThI cells. In murine, TGF- ⁇ & IL-6 are critical for the induction of Th 17 cell differentiation, while in human, IL-I, IL-6 & IL-23 are important drivers of Th 17 cell development Accordingly, effective immunologic homeostasis relies on a continual balance between helper T cell activation and regulatory T cell (Treg) suppression.
  • Treg helper T cell activation and regulatory T cell
  • ThI cells are involved in the pathogenesis of a variety of organ- specific autoimmune disorders, Crohn's disease, Helicobacter pylori-induced peptic ulcer, acute kidney allograft rejection, and unexplained recurrent abortions.
  • allergen-specific Th2 responses are responsible for atopic disorders in genetically susceptible individuals.
  • Th2 responses against still unknown antigens predominate in Omenn's syndrome, idiopathic pulmonary fibrosis, and progressive systemic sclerosis.
  • ThI 7 cells cause irnmunopathology in different models of autoimmunity, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease and psoriasis.
  • IL- 17 (the signature Th-17 cytokine) knock-out mice show marked resistance to inflammatory arthritis development. Joint destruction in the CIA model can be ameliorated by the administration of a neutralizing anti-IL-17 antibody.
  • Thl/Th2 and ThI 7 paradigm provides a rationale for the development of strategies for the therapy of allergic and autoimmune disorders.
  • Prostaglandins have been shown to modulate various phases of the immune response.
  • the lipid mediator prostaglandin E2 (PGE2) is an eicasanoid that is well known to suppress CD4 + T cell activation through elevation of intracellular cAMP and inactivation of Ick.
  • PGE2 has been also shown to play a role in regulating ThI responses by suppression of interferon gamma (IFN-gamma) production and T cell proliferation.
  • IFN-gamma interferon gamma
  • PGE2 stimulation via the EP4 subtype of PGE2 receptor can also have the opposite effect, namely to promote ThI differentiation (Prostaglandin E receptor subtypes EP2 and EP4 promote differentiation and expansion of ThI and ThI 7 lymphocytes through different signaling modules, Nature Medicine, 2009, in press) and IL-17 production in activated CD4+ cells.
  • ThI differentiation Prostaglandin E receptor subtypes EP2 and EP4 promote differentiation and expansion of ThI and ThI 7 lymphocytes through different signaling modules, Nature Medicine, 2009, in press
  • IL-17 production in activated CD4+ cells Prostaglandin E2 synergistically with interleukin-23 favors human ThI 7 expansion, Blood, 2008, 112, 3696-3703; Prostaglandin E2 regulates Th 17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling, J. Exp. Med.
  • R 1 is C 1 . 6 alkyl or C 2-6 alkenyl, wherein R] is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkoxy, and CO 2 R 8 , wherein R a is hydrogen, Ci -4 alkyl, or C 2-4 alkenyl;
  • X is absent (i.e., a covalent bond), -NH-, Ci -6 alkylene, or C 2-6 alkenylene;
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C] -3 alkoxy, hydroxyl, C] -3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, -SO 2 NHR b , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, Ci -6 alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between 0 and 5 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, Ci -3 alkylthio, cyclopropylmethyl, and halo; and wherein each occurrence of R c is independently selected from the group consisting of hydrogen, C 1- 6 alkyl, and C2-6 alkenyl;
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I or a subset or example thereof.
  • the invention provides a method of treating rheumatoid arthritis in a subject, comprising the step of administering to the subject a composition comprising a compound of Formula I or a subset or example thereof.
  • the invention provides a method of treating multiple sclerosis in a subject, comprising the step of administering to the subject a composition comprising a compound of Formula I or a subset or example thereof.
  • a further aspect of the invention is the use of a compound of Formula I or a subset or example thereof in the manufacture of a medicament for the treatment of rheumatoid arthritis.
  • Another aspect of the invention is the use of a compound of formula I or a subset or example thereof in the manufacture of a medicament for the treatment of multiple sclerosis.
  • compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • a substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • the term “modulator of ThI differentiation or ThI 7 expansion” or “modulator compound of ThI differentiation or ThI 7 expansion” or “modulator compound” as used herein refers to a compound which suppresses, reduces or inhibits, differentiation of naive CD4+ T cells into ThI cells.
  • the term “modulator of ThI differentiation or ThI 7 expansion” or “modulator compound of ThI differentiation or ThI 7 expansion” as used herein refers to a compound which suppresses, reduces or inhibits, the number of IL-17 producing CD4+ T cells or IL- 17 production in activated CD4+ T cells.
  • “Isomers” refer to compounds having the same number and kind of atoms and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms.
  • Stepoisomers refer to isomers that differ only in the arrangement of the atoms in space.
  • Stereoisomers refer to stereoisomers that are not mirror images of each other.
  • Enantiomers refers to stereoisomers that are non-superimpo sable mirror images of one another.
  • Enantiomers include "enantiomerically pure” isomers that comprise substantially a single enantiomer, for example, greater than or equal to 90%, 92%, 95%, 98%, or 99%, or equal to 100% of a single enantiomer.
  • Enantiomerically pure means a compound, or composition of a compound, that comprises substantially a single enantiomer, for example, greater than or equal to 90%, 92%, 95%, 98%, or 99%, or equal to 100% of a single enantiomer.
  • “Stereomerically pure” as used herein means a compound or composition thereof that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of diastereomers, and substantially free of the enantiomer, of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. See, e.g., US Patent No. 7,189,715.
  • R and S as terms describing isomers are descriptors of the stereochemical configuration at an asymmetrically substituted carbon atom.
  • the designation of an asymmetrically substituted carbon atom as “R” or “S” is done by application of the Cahn-Ingold-Prelog priority rules, as are well known to those skilled in the art, and described in the International Union of Pure and Applied Chemistry (IUPAC) Rules for the Nomenclature of Organic Chemistry. Section E, Stereochemistry.
  • Enantiomeric excess (ee) of an enantiomer is [(the mole fraction of the major enantiomer) minus (the mole fraction of the minor enantiomer)] x 100.
  • “Stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 0 C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • Ar or aryl refer to an aromatic carbocyclic moiety having one or more closed rings. Examples include, without limitation, phenyl, naphthyl, anthracenyl, phenanthracenyl, biphenyl, and pyrenyl.
  • Heteroaryl refers to a cyclic moiety having one or more closed rings, with one or more heteroatoms (for example, oxygen, nitrogen or sulfur) in at least one of the rings, wherein at least one of the rings is aromatic, and wherein the ring or rings may independently be fused, and/or bridged.
  • Examples include without limitation quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, pyrrolyl, indazolyl, thieno[2,3-c]pyrazolyl, benzofuryl, pyrazolo[l,5-a]pyridyl, thiophenylpyrazolyl, benzothienyl, benzothiazolyl, thiazolyl, 2-phenylthiazolyl, and isoxazolyl.
  • Alkyl or "alkyl group,” as used herein, means a straight-chain (i.e., unbranched), branched, or cyclic hydrocarbon chain that is completely saturated.
  • alkyl groups contain 1-6 carbon atoms.
  • alkyl groups contain 1-4 carbon atoms.
  • alkyl groups contain 1-3 carbon atoms.
  • alkyl groups contain 2-3 carbon atoms, and in yet other embodiments alkyl groups contain 1-2 carbon atoms.
  • the term "alkyl” or “alkyl group” refers to a cycloalkyl group, also known as carbocycle.
  • Non-limiting examples of exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl and cyclohexyl.
  • alkenyl or “alkenyl group,” as used herein, refers to a straight-chain (i.e., unbranched), branched, or cyclic hydrocarbon chain that has one or more double bonds.
  • alkenyl groups contain 2-6 carbon atoms hi certain embodiments, alkenyl groups contain 2-4 carbon atoms. In still other embodiments, alkenyl groups contain 3-4 carbon atoms, and in yet other embodiments alkenyl groups contain 2-3 carbon atoms.
  • alkenyl refers to a straight chain hydrocarbon having two double bonds, also referred to as "diene.”
  • alkenyl or “alkenyl group” refers to a cycloalkenyl group.
  • Alkoxy or “alkylthio”, as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“alkylthio”) atom.
  • Methylene”, “ethylene”, and “propylene” as used herein refer to the bivalent moieties -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -, respectively.
  • Alkylidene refers to a bivalent hydrocarbon group formed by mono or dialkyl substitution of methylene.
  • an alkylidene group has 1- 6 carbon atoms.
  • an alkylidene group has 2-6, 1-5, 2-4, or 1-3 carbon atoms.
  • Alkenylidene refers to a bivalent hydrocarbon group having one or more double bonds formed by mono or dialkenyl substitution of methylene.
  • an alkenylidene group has 2-6 carbon atoms.
  • an alkenylidene group has 2-6, 2-5, 2-4, or 2-3 carbon atoms.
  • an alkenylidene has two double bonds.
  • C 1 - O alkyl ester or amide refers to a C 1-6 alkyl ester or a Ci -6 alkyl amide where each C 1 ⁇ alkyl group is as defined above.
  • C 2-6 alkenyl ester or amide refers to a C 2-6 alkenyl ester or a C 2-6 alkenyl amide where each C 2-6 alkenyl group is as defined above.
  • Treatment refers to reversing, alleviating, delaying the onset of, inhibiting the progress of, or preventing a disease or disorder as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • Patient or “subject”, as used herein, means an animal subject, preferably a mammalian subject (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.), and particularly human subjects (including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects).
  • mammalian subject e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.
  • human subjects including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects.
  • “Pharmaceutically acceptable carrier” refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, cyclodextrins, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxyprop
  • “Pharmaceutically acceptable salt” refers to an acid or base salt of a compound of the invention, which salt possesses the desired pharmacological activity and is neither biologically nor otherwise undesirable.
  • the salt can be formed with acids that include without limitation acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate
  • Examples of a base salt include without limitation ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.
  • the basic nitrogen-containing groups can be quartemized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as phenethyl bromides.
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides
  • structures depicted herein are also meant to include all enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • the present invention provides a compound of Formula I:
  • R J is C 1-6 alkyl or C 2-6 alkenyl, wherein R] is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkoxy, and CO 2 R a , wherein R a is hydrogen, C 1-4 alkyl, or C 2-4 alkenyl;
  • X is absent, -NH-, C 1-6 alkylene, or C 2-6 alkenylene
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, Ci -3 alkoxy, hydroxyl, Ci -3 alkylthio, cyclopropylmethyl, halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C ⁇ 6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, C] -6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, -SO 2 NHR b , and - CO 2 R 0 ; wherein each occurrence of R is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between 0 and 5 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy., hydroxyl, Cj -3 alkylthio, cyclopropylmethyl, and halo; and wherein each occurrence of R c is independently selected from the group consisting of hydrogen, C 1- 6 alkyl, and C 2-6 alkenyl;
  • R 1 is methyl, ethyl, -(CHi) 2 OH, -(CH 2 ) 2 OCH 3 , or - CH 2 CO 2 R", wherein R a is hydrogen or Cj -4 alkyl; X is absent, -NH-, C 1-6 alkylene, or C 2-6 alkenylene; R 3 is aryl or heteroaryl and substituted with between O and 5 substituents independently selected from the group consisting of C 1-6 alkyl, of C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, Ci -3 alkylthio, cyclopropylmethyl, and halo; R 4 and R 5 are each independently chosen from the group consisting of hydrogen, methyl, and ethyl; and each of W, X, Y and Z is independently hydrogen or C 1-3 alkoxy.
  • R 1 is methyl, ethyl, -(CH 2 ) 2 OH, -(CHj) 2 OCH 35 or - CH 2 CO 2 R 8 , wherein R a is hydrogen or Q- 4 alkyl; X is absent, -NH-, Ci -6 alkylene, or C 2-6 alkenylene; R 3 is phenyl, quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, naphthyl, pyrrolyl, indazolyl, thieno[2,3-c]pyrazolyl, benzofuryl, pyrazolo[l,5-a]pyridyl, thiophenylpyrazolyl, benzothienyl, benzothiazolyl, thiazolyl, 2-phenylthiazoIyl, or isoxazolyl, and is substituted with between O and 3
  • R 3 is phenyl, quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, naphthyl, pyrrolyl, indazolyl, thieno[2,3-c]pyrazolyl, benzofuryl, pyrazolo[l,5-a]pyridyl, thiophenylpyrazolyl, benzothienyl, benzothiazolyl, thiazolyl, 2-phenylthiazolyl, or isoxazolyl, and is substituted with between O and 3 substituents independently selected from methyl, ethyl, methoxy, hydroxyl, bromo, fluoro, and chloro.
  • W and Y are each methoxy.
  • each of R4 and R 5 is independently selected from hydrogen, methyl, and ethyl. In some embodiments, one of R 4 and R 5 is hydrogen, and the other is methyl or ethyl. In some embodiments, one Of R 4 and R 5 is hydrogen, and the other is methyl. In some embodiments, one OfR 4 and R 5 is hydrogen.
  • the carbon in Formula I denoted with a * has the absolute configuration of S.
  • the invention provides a compound selected from the group consisting of
  • Active compounds of the present invention can be combined with a pharmaceutically acceptable carrier to provide pharmaceutical formulations thereof.
  • a pharmaceutically acceptable carrier to provide pharmaceutical formulations thereof.
  • the particular choice of carrier and formulation will depend upon the particular route of administration for which the composition is intended.
  • compositions of the present invention may be suitable for oral, parenteral, inhalation spray, topical, rectal, nasal, buccal, vaginal or implanted reservoir administration, etc.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • 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 and its glyceride derivatives are useful in the preparation of mjectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
  • the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration.
  • Prostaglandins have been shown to modulate various phases of the immune response.
  • the lipid mediator prostaglandin E2 (PGE2) is an eicasanoid that is well known to suppress CD4 + T cell activation through elevation of intracellular cAMP and inactivation of Ick.
  • PGE2 has been also shown to play a role in regulating ThI responses by suppression of interferon gamma (IFN-gamma) production and T cell proliferation.
  • IFN-gamma interferon gamma
  • PGE2 stimulation via the EP4 subtype of PGE2 receptor can also have the opposite effect, namely to promote ThI differentiation (Prostaglandin E receptor subtypes EP2 and EP4 promote differentiation and expansion of ThI and Thl7 lymphocytes through different signaling modules, Nature Medicine, 2009, in press) and IL- 17 production in activated CD4+ cells (Prostaglandin E2 synergistically with interleukin-23 favors human Th 17 expansion, Blood, 2008, 112, 3696-3703, Prostaglandin E2 regulates ThI 7 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling, J Exp. Med.
  • ThI differentiation Prostaglandin E receptor subtypes EP2 and EP4 promote differentiation and expansion of ThI and Thl7 lymphocytes through different signaling modules, Nature Medicine, 2009, in press
  • IL- 17 production in activated CD4+ cells Prostaglandin E2 synergistically with interleukin-23 favors human Th 17 expansion, Blood, 2008, 112,
  • Prostaglandin E2 enhances Th 17 response via modulation of IL- 17 and IFN- ⁇ production by memory CD4+ T cells, Eur. J. Immunol. 2009, 39, 1301-1312). Consistent with this, antagonism of EP4 with either a novel selective EP4 antagonist or a PGE2- neutralizing antibody suppresses ThI differentiation, ThI 7 expansion, as well as IL- 23 secretion by activated dendritic cells. Induction of ThI differentiation by PGE2 is mediated by PI3 K signaling whereas stimulation of IL- 17 production requires cAMP signaling.
  • Active compounds of the present invention may be administered to patients or subjects to treat a variety of different condition, particularly patients or subjects afflicted with;
  • psoriasis ⁇ see, e.g., A molecule solves psoriasis? Systemic therapies for psoriasis inducing interleukin 4 and Th2 responses, J MoI. Med 2003, 81, 471-80); The IL-23/Thl7 axis in the immunopathogenesis of psoriasis, J Invest Dermatol 2009, doi:10.1038/jid.2009.59;
  • Atherosclerosis ⁇ see, e.g., T-bet deficiency reduces athersclerosis and alters plaque antigen-specific immune responses, Proc. Natl. Acad. ScL USA 2005, 102, 1596-601);
  • neuropathic pain see, e.g., Localisation and modulation of prostanoid receptors EPl and EP4 in the rat chronic constriction injury model of neuropathic pain, Eur. J. Pain 2007, 11, 605-613;
  • Active compounds may be administered to subjects by any suitable route, including orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • the active compounds are administered to the subjects in a treatment effective, or therapeutically effective, amount.
  • the amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, and the particular route of administration.
  • the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • the compositions of the present invention provide a dosage of between 0.01 mg and 50 mg is provided. In other embodiments, a dosage of between 0.1 and 25 mg or between 5 mg and 40 mg is provided.
  • a specific dosage and treatment regimen for any particular patient 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, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • Microwave assisted reactions were carried out using an Emrys Liberator instrument supplied by Biotage Corporation. Solvent removal was carried out using either a Btichi rotary evaporator or a Genevac centrifugal evaporator.
  • Analytical and preparative chromatography was carried out using a Waters autopurification instrument using either normal phase or reverse phase HPLC columns, under either acidic, neutral, or basic conditions. Compounds were estimated to be >90% pure, as determined by area percent of ELSD chromatograms. NMR spectra were recorded using a Varian 300 MHz spectrometer.
  • inerted a reactor (e.g., a reaction vessel, flask, glass reactor, and the like) it is meant that the air hi the reactor has been replaced with an essentially moisture-free or dry, inert gas (such as nitrogen, argon, and the like).
  • inert gas such as nitrogen, argon, and the like
  • ER-811160-00 As depicted in Scheme 1 above, a solution of potassium cyanide (22.5 g, 0.335 mol) in water (5OmL) was added dropwise over 5 minutes to a solution of 1 -Boc-piperidone (32.48 g, 0.1598 mol) and ammonium carbonate (33.8 g, 0.351 mol) in water (9OmL) and methanol (11OmL). An off-white precipitate began to form soon after addition was complete. The reaction flask was sealed and the suspension stirred at room temperature for 72 hours. The resultant pale yellow precipitate was filtered and was washed with small portions of water to give ER- 811160-00 (37.1 g, 86%) as a colorless solid.
  • ER-818039 As depicted in Scheme 2 above, a suspension of ER-811160 (30.0 g, 0.111 mol), 3,5-dimethoxybenzyl bromide (30.9 g, 0.134 mol), and potassium carbonate (18.5 g, 0.134 mol) in acetone (555 mL) was heated under reflux overnight. The reaction solution was cooled to room temperature, filtered and concentrated in vacuo. The crude orange residue was dissolved in a minimal amount of MTBE [TBME?] (250 mL). A small amount of hexanes was added (50 mL) and the product was allowed to precipitate out (over ⁇ 2 hours) as a colorless solid which was isolated by vacuum filtration. The filter cake was washed with small amounts of MTBE, and dried in vacuo to provide ER-818039 (39.6g, 85%) as a colorless solid.
  • ER-824248-00 As depicted in Scheme 3 above, ER-818039-00 (283 g, 0.675 mol) was charged to a dry inerted reactor. Anhydrous THF (1420 mL, 17.4 mol) was charged to the reactor. The solution was heated to 50°C. 2.50M Potassium tert- butoxide in THF (324 mL, 0.810 mol) was added keeping the temperature below 55 0 C. The solution was stirred for 10 min. Iodoethane (64.8 mL, 0.810 mol) was charged to the reactor keeping the temperature below 55 °C. The reaction was stirred at 5O 0 C overnight.
  • ER-824217-01 As depicted in Scheme 4 above, ER-824248-00 (302.Og, 0.6748 mol) was charged to the reactor. Anhydrous methanol (760 mL, 19 mol) was added. While stirring, the reactor was charged with 5-6 M hydrogen chloride in IPA (245 mL, 1.35 mol). The reaction was stirred at room temperature and monitored by TLC (EtOAc) and HPLC. The HCl salt precipitate was collected by filtration to provide ER-824217- 01 (259.1 g, 100%) as a white solid.
  • ER-824217-00 As depicted in Scheme 5 above, ER-824217-01 (259 g, 0.674 mol) was charged to a reactor. Added IN aqueous NaOH. Stirred solution for 20 min. Extracted with toluene and washed out the aqueous. The aqueous layer was back extracted with toluene. The combined organic layers were evaporated in vacuo. Azeotroped with methanol. Added MTBE to the oily material and heated at 55 0 C. Once everything was in solution, the mixture was allowed to cool to room temperature with vigorous stirring to provide ER-824217-00 (184g, 78%) as a white powder.
  • ER-824531-00 As depicted in Scheme 6 above, ER-824217-00 (743.0 g, 2.139 mol) was charged to a reactor. Anhydrous THF (5900 mL) was charged under inert atmosphere. Cooled the reaction mixture to 0-5 0 C. 2.0M Allylmagnesium chloride in THF (2100 mL, 4.3 mol) was added at a rate that the temperature stayed below 15°C. Stirred reaction at 20 0 C for 2 hours. The progress of the reaction was monitored by TLC (10% methanol in DCM) and HPLC. The reaction was quenched with saturated aqueous NH 4 Cl solution and water. Extracted with EtOAc and evaporated to afford the crude product.
  • ER-823917-26 As depicted in Scheme 7 above, ER-824531-00 (439.0 g, 1.1271 mol) was charged to a reactor. Anhydrous acetonitrile (4390 mL) was added. To white slurry mixture was added Trimethylsilyl trifluoromethanesulfonate (214 mL, 1.18 mol) at 20-25 0 C keeping the internal temperature below 50 0 C. The progress of the reaction was monitored by TLC (10% methanol in DCM) and HPLC. After the reaction was complete (10 min), reduced the volume of acetonitrile under vacuo and not exceeding 30 0 C. Added 2-methoxy-2-methylpropane (3510 mL, 29.5 mol) and stirred at room temperature overnight. Filtration followed by MTBE wash afforded ER-823917-26 (295.0 g, 50%).
  • ER-823917-00 As depicted in Scheme 8 above, ER-823917-26 (10.0 g, 0.0191 mol) was transferred to a reactor. Charged reactor with acetonitrile (20.0 mL). While the reaction stirred, charged 0.5M NaOH (20.0 mL, 0.010 mol). Stirred for 10-15 min until solution is clear. Charged the remaining 0.5M NaOH (60.0 mL, 0.030 mol). Stirred the slurry for 1-2 h. Filtered and washed the cake with water. Dried at room temperature using a Buchner funnel under house vacuum to provide ER-823917-00 (6.7 g, 94 %) as a white solid.
  • D-DPTTA Di-p-toluyl-D-tartaric acid
  • ER-824188 D-DPTTA salt in a reactor was stirred with methanol (760 mL) for 5 min.
  • 1 N NaOH aqueous solution (475 mL) was added into the mixture within 1 min with stirring.
  • the mixture was stirred for 10-15 min until there was a clear solution.
  • Water (1900 mL) was added. Crystallization started within the first 2 min of water addition.
  • the mixture was stirred for 4-5 hours then filtered.
  • the cake was washed 3 times with water. The solid was dried under high vacuum until constant weight to provide ER-824188-00 (72.7 g, 43%).
  • the filtrate/mother liquor obtained from the above procedure was concentrated under vacuum to -25% of the initial volume.
  • Methanol (4 volumes) and 1 N NaOH aqueous solution (3.5 volumes) were added to the mixture over 2 min with stirring.
  • the mixture was stirred for 5 min then water (10 volumes) was added over 10 min with stirring. After crystallization had started, the mixture was stirred for an additional 4 hours then filtered.
  • the filter cake was washed 3 times with water (1 volume each time) then dried under high vacuum to provide ER-824220 (75 g, 39 %).
  • ER-814013-00 As depicted in Scheme 10 above, ER-824188-00 (50.0 mg, 0.134 mmol) and pyrazolo[l,5-a]pyridine-3-carbonyl chloride (30.7 mg, 0.170 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-814013-00 (34.9 mg, 50%) as an oil. Scheme 11
  • ER-814020-00 As depicted in Scheme 11 above, ER-824188-00 (50.0 mg, 0.134 mmol) and 1 -Methyl- 1 H-indazole-3-carbonyl chloride (33.0 mg, 0.170 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-814020-00 (28.3 mg, 40%) as an oil.
  • ER-814022-00 As depicted in Scheme 12 above, ER-824188-00 (50.0 mg, 0.134 mmol) and l,3-Dimethyl-lH-thieno[2,3-c]pyrazole-5-carbonyl chloride (46.3 mg, 0.216 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. Heated The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-814022-00 (44.1 mg, 60%) as an oil. Scheme 13
  • ER-814029-00 As depicted in Scheme 13 above, ER-824188-00 (50.0 mg, 0.134 mmol) and 3-(tert-butyl)-l-methyl-lH-pyrazole-5-carbonyl chloride (40.2 mg, 0.200 mmol) were dissolved in NMP (0.500 niL). Triethylamine (0.040 niL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER- 814029-00 (26.0 mg, 36%) as an oil.
  • ER-825382-00 As depicted in Scheme 14 above, ER-824188-00 (50.0 mg, 0.134 mmol) and 3,5-dimethylbenzoyl chloride (51.4 mg, 0.305 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825382-00 (76.5 mg, 73%) as a white powder. Scheme 15
  • ER-825403-00 As depicted in Scheme 15 above, ER-824188-00 (50.0 mg, 0.134 mmol) and 2-thiophenecarboxylic acid chloride (18.0 ⁇ L, 0.168 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825403-00 (47.2 mg, 72%) as a white solid.
  • ER-825405-00 As depicted in Scheme 16 above, ER-824188-00 (50.0 mg, 0.134 mmol) and 2,5-dimethylfuran-3-carbonyl chloride (25.6 mg, 0.162 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825405-00 (58.4 mg, 87%) as a white solid. Scheme 17
  • ER-825411-00 As depicted in Scheme 17 above, ER-824188-00 (50.0 mg, 0.134 mmol) and 3 -methyl- l-benzofuran-2-carbonyl chloride (31.4 mg, 0.162 mmol) were dissolved in NMP (0.500 rnL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. The reaction was not complete by analytical LC/MS. The reaction was re-subjected to heating at 12O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825411-00 (44.9 mg, 63%) as a white solid.
  • ER-825412-00 As depicted in Scheme 18 above, ER-824188-00 (50.0 mg, 0.134 mmol) and benzo[B]thiophene-2-carbonyl chloride (32.6 mg, 0.166 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. The reaction was not complete by analytical LC/MS. The reaction was re-subjected to heating at 12O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825412-00 (45.2 mg, 63%) as a white solid. Scheme 19
  • ER-825414-00 As depicted in Scheme 19 above, ER-824188-00 (50.0 mg, 0.134 mmol) and 3,5-dimethoxybenzoyl chloride (49.6 mg, 0.247 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825414-00 (44.2 mg, 61%) as an oil.
  • ER-825436-00 As depicted in Scheme 20 above, ER-824188-00 (50.0 mg, 0.134 mmol) and m-anisoyl chloride (27.0 mg, 0.158 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825436-00 (36.5 mg, 53%) as an oil. Scheme 21
  • ER-825439-00 As depicted in Scheme 21 above, ER-824188-00 (50.0 mg, 0.134 mmol) and 4-fluoro-3-methylbenzoyl chloride (28.3 mg, 0.164 mtnol) were dissolved in NMP (0.500 niL). Triethylamine (0.040 niL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825439-00 (49.8 mg, 72%) as an oil.
  • ER-825448-00 As depicted in Scheme 22 above, ER-824188-00 (50.0 mg, 0.134 mmol) and 3-dimethylaminobenzoyl chloride (29.0 mg, 0.158 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mmol) was added. The reaction was heated at 8O 0 C for 120 seconds in the microwave. The reaction still contained mainly starting material. The reaction was heated at 15O 0 C for 180 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER-825448-00 (11.3 mg, 16%) as an oil. Scheme 23
  • ER-825469-00 As depicted in Scheme 23 above, ER-824188-00 (50.0 mg, 0.134 mmol) and l ⁇ methyl-3-thien-2-yl-lH-pyrazole-5»carbonyl chloride (43.3 mg, 0.191 mraol) were dissolved in NMP (0.500 mL). Triethylamine (0.040 mL, 0.287 mrnol) was added The reaction was heated at 8O 0 C for 120 seconds in the microwave. Purification by LC/MS followed by evaporation using the genevac provided ER- 825469-00 (50.1 mg, 66%) as an oil.
  • ER-825418-00 As depicted in Scheme 24 above, 3,5-dimethylisoxazole-4-carboxylic acid (17.5 mg, 0.124 mmol) was dissolved in CH 2 Cl 2 (2 mL). O-(Benzotriazol-l-yl)- N,N,N',N'-tetramethyluronrum hexafluorophosphate (47.0 mg, 0.124 mmol) and N,N-diisopropylethylamine (29 ⁇ L, 0.17 mmol) were added. Reaction stirred for 30 minutes. ER-824188-00 (41.9 mg, 0.113 mmol) was added. Reaction stirred overnight. Purification by LC/MS followed by evaporation using the genevac provided ER-825418-00 (29.9 mg, 54%) as a solid.
  • ER-824165-01 As depicted in Scheme 25 above, ER-818039 (10.0 g, 0.0238 mol) was charged to reactor. Anhydrous methanol (25.0 mL) was added. While stirring, charged 5-6 M hydrogen chloride in IPA (10.84 mL, 0.0596 mol). The reaction was stirred at room temperature for 12-16 hrs and monitored by TLC (EtOAc) and HPLC. Once the reaction was complete, added 2-methoxy-2-methylpropane (25.0 mL, 0.2102 mol). Stirred at room temperature for 1-2 hrs. Filtered and washed the cake with MTBE. Dried overnight at room temperature using a Buchner funnel under house vacuum to give ER-824165-01 (8.00 g, 94%) as a fine white powder.
  • ER-824165-00 As depicted in Scheme 26 above, ER-824217-01 (290.0 g 5 0.815 mol) was charged to a reactor. MeOH (580.0 mL) was added. To the stirred slurry was added 1 N NaOH (1160 mL, 64.4 mol). Stirred the mixture until it all became a solution then charged water (1200 mL). Stirred for 2 hr then filtered the white powder. Dried at room temperature using a Buchner funnel under house vacuum for 8-12 h to provide ER-824165-00 (190.0 g, 73.0 %) as a white powder. Scheme 27
  • ER-830322 As depicted in Scheme 27 above, ER-824165-00 (5.0 g, 0.0156 mol) was charged to a reactor. Anhydrous THF (25.0 mL)) was charged under inert atmosphere. Cooled reaction to 0-10 0 C. 2.0M Allylmagnesium chloride in THF (23.5 mL, 0.0470 mol) was added at a rate to keep the temperature below 35°C. The progress of the reaction was monitored by TLC (10% methanol in DCM) and HPLC. After the reaction was complete (1-2 h), charged NH 4 Cl saturated solution (50 mL). Stirred for 1-2 h. Filtered and dried the solid at room temperature using a Buchner funnel under house vacuum to provide ER-830322-00 (5.5 g, 97%) as a white solid.
  • ER-824106-00 As depicted in Scheme 28 above, ER-830322-00 (4.0 g, 0.0110 mol) was charged to a reactor. Methanol (20.0 mL) was added followed by water (20 mL). The slurry was stirred and heated to 35-45 0 C. Trifluormethanesulfonic acid (1.15 mL, 0.0116 mol) was added. The slurry became a clear solution. Checked the progress of the reaction by TLC or HPLC. Once the reaction was complete, cooled to room temperature and charged 1 N NaOH (28.0 mL, 0.0280 mol). Stirred for 1-2 h and then filtered the white solid. Dried at room temperature using a Buchner funnel under house vacuum to provide ER-824106-00 (2.9 g, 76%). Scheme 29
  • ER-848947-00 As depicted in Scheme 30 above, ER-829921-00 (22.3 mg, 0.0649 mmol) was dissolved in methylene chloride (0.500 mL). Triethylamine (0.028 mL, 0.20 mmol) and 3,5-dimethylbenzoyl chloride (17mg, 0.10 mmol) were added. The reaction was stirred at room temperature. The reaction was extracted with ethyl acetate and washed with brine. Purification by silica column followed by evaporation using the rotavap provided ER-848947-00 (15.8 mg, 51%).
  • ER-848957-00 As depicted in Scheme 31 above, ER-848947-00 (5.8 mg, 0.012 mmol) was dissolved in DMF (0.100 mL). The reaction was cooled using an ice/water bath. 60% dispersion of NaH in mineral oil was added. Removed bath and stirred for 25 minute. Added 1 -bromo-2-methoxyethane (1.7 ⁇ L, 0.018 mmol). The reaction was stirred at room temperature. Quenched the reaction using saturated NaHCO 3 (aq). The reaction was extracted with ethyl acetate. Purification by flash chromatography followed by evaporation using the genevac evaporator provided ER-848957-00 (4.1 mg, 63%).
  • ER-876850-00 As depicted in Scheme 32 above, ER-824188-00 (20.0 mg, 0.0538 mmol) and 2-isocyanato-l,4-dimethoxybenzene (89.6 mg, 0.500 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.015 mL, 0.108 mmol) was added The reaction was heated at 120 0 C for 180 seconds in the microwave. The reaction was quenched with 5% aq. DMSO (0.500 mL). Purification by LC/MS followed by evaporation using the genevac provided ER-876850-00 (5 mg, 20%) as a solid.
  • ER-876841-00 As depicted in Scheme 33 above, ER-824188-00 (20.0 mg, 0.0538 mmol) and 2-isocyanato-l,4-dimethylbenzene (73.6 mg, 0.500 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.015 mL, 0.108 mmol) was added. The reaction was heated at 12O 0 C for 180 seconds in the microwave. The reaction was quenched with 5% aq. DMSO (0.500 mL). Purification by LC/MS followed by evaporation using the genevac provided ER-876841-00 (16.4 mg, 58%) as a solid. Scheme 34
  • ER-876849-00 As depicted in Scheme 34 above, ER-824188-00 (20.6 mg, 0.0554 mmol) and 2-isocyanato-2,4-dimethoxybenzene (52.8 mg, 0.295 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.015 mL, 0.108 mmol) was added. The reaction was stirred at room temperature for 54 hours. The reaction was diluted with DMSO. Purification by LC/MS followed by evaporation using the genevac provided ER-876849-00 (19.4 mg, 63%) as a yellow solid.
  • ER-876865-00 As depicted in Scheme 35 above, ER-824188-00 (20.0 mg, 0.0538 mmol) and 2-isocyanatothiophene (62.6 mg, 0.500 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.015 mL, 0.108 mmol) was added. The reaction was heated at 12O 0 C for 180 seconds in the microwave. The reaction was quenched with 5% aq. DMSO (0.500 mL). Purification by LC/MS followed by evaporation using the genevac provided ER-876865-00 (21.6 mg, 80%) as a solid. Scheme 36
  • ER-876845-00 As depicted in Scheme 36 above, ER-824188-00 (20.0 mg, 0.0538 mmol) and 3-methoxylphenyl isocyanate (74.5 mg, 0.500 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.015 mL, 0.108 mmol) was added. The reaction was heated at 12O 0 C for 180 seconds in the microwave. The reaction was quenched with 5% aq. DMSO (0.500 mL). Purification by LC/MS followed by evaporation using the genevac provided ER-876845-00 (5.0 mg, 20%) as a solid.
  • ER-876864-00 As depicted in Scheme 37 above, ER-824188-00 (20.0 mg, 0.0538 mmol) and 3-isocyanato-2-methylfuran (61.6 mg, 0.500 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.015 mL, 0.108 mmol) was added. The reaction was stirred at room temperature for 3 days. The reaction was quenched with 5% aq. DMSO (0.500 mL). Purification by LC/MS followed by evaporation using the genevac provided ER-876864-00 (5.0 mg, 20%) as a solid. Scheme 38
  • ER-876868-00 As depicted in Scheme 38 above, ER-824188-00 (20.0 mg, 0.0538 mmol) and 4-isocyanato-l,3,5-trimethyl-lH-pyrazole (75.6 mg, 0.500 mmol) were dissolved in NMP (0.500 mL). Triethylamine (0.015 mL, 0.108 mmol) was added. The reaction was heated at 12O 0 C for 180 seconds in the microwave. The reaction was quenched with 5% aq. DMSO (0.500 mL). Purification by LC/MS followed by evaporation using the genevac provided ER-876868-00 (18.4 mg, 65%) as a solid.
  • ER-830839-00 As depicted in Scheme 39 above, ER-829921-00 (7.05 g, 0.0205 mol) was dissolved in THF (100.0 mL). Added triethylamine (3.2 mL, 0.0266 mol) followed by di-tert-butyldicarbonate (4.91 g, 0.0218 mol). Stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate. Evaporated the reaction via rotavap. Added ethyl acetate and separated. Extracted the aqueous phase with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate and evaporated via rotavap. Column purification followed by evaporation via rotavap provided ER-830839-00 (7.57 g, 83%). Scheme 40
  • ER-831680-00 As depicted in Scheme 40 above, ER-830839-00 (7.57 g, 0.0171 mol) was dissolved in THF (90.0 mL). Cooled reaction to O 0 C. Added 60% NaH in mineral oil (887 mg). The reaction was stirred at O 0 C for 10 minutes. The reaction was warmed to 2O 0 C for 20 minutes. The reaction was cooled back down to O 0 C. Added methyl bromoacetate (2.2 mL, 0.0222 mol) dropwise. The reaction was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate. Evaporated the THF via rotavap. Added ethyl acetate and separated.
  • ER-877748-01 As depicted in Scheme 41 above, ER-831680-00 (120 mg, 0.23 mmol) was dissolved in 4.0M HCl 1,4-dioxane (0.29 mL). The orange suspension was stirred at room temperature for 3 hours. The reaction was evaporated to give ER- 877748-01 (100 mg, 100%) as a yellow powder.
  • Scheme 42
  • ER-880463-00 As depicted in Scheme 42 above, ER-877748-01 (100 mg, 0.23 mniol) was dissolved in CH 2 Cl 2 (1 mL), The reaction was cooled to O 0 C. Added triethylamine (0.150 mL, 1.1 mmol). Gradually warmed reaction to room temperature and stirred at room temperature for Ih. The reaction was diluted with EtOAc. Added saturated aq NaHCO 3 . The aqueous phase was separated and extracted with EtOAc three times. The organic phases were combined, washed with brine, dried over Na 2 SO 4 , filtered and evaporated. Column purification followed by evaporation via rotavap provided ER-880463-00 (89.6 mg, 70%) as a colorless oil.
  • ER-825462-00 As depicted in Scheme 43 above, ER-880463-00 (89.6 mg, 0.164 mmol) was dissolved in methanol (0.66 mL). Added 1.0M aq NaOH (0.65 mL). The reaction was stirred for Ih at room temperature. The reaction was neutralized using 1.0M aq HCl until the reaction reached pH 3. Evaporated the reaction to give a solid. The solid was re-dissolved in CH2C12. The yellow solution was filtered and the filtrate was concentrated to give ER-825462-00 (70.9 mg, 81%).
  • ER-848938-00 As depicted in Scheme 44 above, ER-824220-00 (50.0 mg, 0.134 mmol) was dissolved in NMP (0.500 mL). Added 1,3 -dimethyl- lH-thieno [2, 3- c]pyrazole-5-carbonyl chloride (46.3 mg, 0.216 mmol). Added triethylamine (0.040 mL, 0.287 mmol). The reaction was heated at 12O 0 C for 180 seconds in the microwave. The reaction was quenched with 5% aq. DMSO (0.500 mL). Purification by LC/MS followed by evaporation using the genevac provided ER-848938-00 (60.9 mg, 82%) as a solid.
  • ER-879069-00 As depicted in Scheme 45 above, ER-824188-00 (20.0 mg, 0.0538 mmol) was dissolved in NMP (0.500 mL). Added 3,5-dimethyl-lH-pyrrole-2- carboxylic acid (42.0 mg, 0.302 mmol). Added N,N,N ⁇ N'-Tetramethyl-O-(7- azabenzotriazoM-yl)uranium hexafiuorophosphate (51.2 mg, 0.134 mmol) in NMP (0.500 niL). The reaction was heated at 100 0 C for 5 minutes in the microwave. The reaction was not complete so it was stirred at room temperature overnight. The mixture was filtered. Purification by LC/MS followed by evaporation using the genevac provided ER-879069-00 (3.6 mg, 14%).
  • ER-879070-00 As depicted in Scheme 46 above, ER-824188-00 (20.0 mg, 0.0538 mmol) was dissolved in NMP (0.500 mL). Added 2, 5 -dimethyl- lH-pyrrole-3- carboxylic acid (42.2 mg, 0.303 mmol). Added N,N,N',N'-Tetramethyl-O-(7- azabenzotriazol-l-yl)uramum hexafluorophosphate (51.2 mg, 0.134 mmol) in NMP (0.500 mL). The reaction was heated at 100 0 C for 5 minutes in the microwave. The reaction was not complete so it was stirred at room temperature overnight. The mixture was filtered. Purification by LC/MS followed by evaporation using the genevac provided ER-879070-00 (2.2 mg, 8%).
  • ER-879054-00 As depicted in Scheme 47 above, ER-824188-00 (20.0 mg, 0.0538 mmol) was dissolved in NMP (0.500 mL). Added Imidazo[l,2-a]pyridine-2- carboxylic acid (49.9 mg, 0.308 mmol). Added N,N,N',N'-Tetramethyl-O-(7- azabenzotriazol-l-yl)uranium hexafluorophosphate (51.2 mg, 0.134 mmol) in NMP (0.500 mL). The reaction was heated at 100 0 C for 5 minutes in the microwave. The reaction was not complete so it was stirred at room temperature overnight. The mixture was filtered. Purification by LC/MS followed by evaporation using the genevac provided ER-879054-00 (8.6 mg, 31%).
  • ER-879073-00 As depicted in Scheme 48 above, ER-824188-00 (22.4 mg, 0.0603 mmol) was dissolved in NMP (1.00 mL). Added pyrrole-2-carboxylic acid (31.9 mg, 0.287 mmol) and N,N 5 N' 5 N'-Tetramethyl-O-(7-azabenzotriazol-l-yl)uranium hexafluorophosphate (59.7 mg, 0.157 mmol). The reaction was heated at 100 0 C for 5 minutes in the microwave followed by stirring at 3O 0 C overnight. The mixture was filtered. Purification by LC/MS followed by evaporation using the genevac provided ER-879073-00 (2.9 mg, 10%).
  • ER-879102-00 As depicted in Scheme 49 above, ER-824188-00 (20.9 mg, 0.0563 mmol) was dissolved hi NMP (1.00 mL). Added pyrrole-3-carboxylic acid (43.4 mg, 0.391 mmol) and N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-l-yl)uranium hexafluorophosphate (50.6 mg, 0.133 mmol). The reaction was heated at 100 0 C for 5 minutes in the microwave followed by stirring at 3O 0 C overnight. The mixture was filtered. Purification by LC/MS followed by evaporation using the genevac provided ER-879102-00 (3.4 mg, 13%).
  • ER-879103-00 As depicted in Scheme 50 above, ER-824188-00 (24.1 mg, 0.0649 mmol) was dissolved in NMP (1.00 mL). Added l,2,5-trimethyl-lH-pyrrole-3- carboxylic acid (44.4 mg, 0.290 mmol) and N,N,N' 5 N'-Tetramethyl-O-(7- azabenzotriazol-l-yl)uranium hexafluorophosphate (52.3 mg, 0.138 mmol). The reaction was heated at 100 0 C for 5 minutes in the microwave followed by stirring at 30 0 C overnight. The mixture was filtered. Purification by LC/MS followed by evaporation using the genevac provided ER-879103-00 (3.0 mg, 9%).
  • Solvent B 0.05% Formic Acid in acetonitrile
  • t M Retention time of compound not retained on column, which is approximately equal to the time required for a molecule of the mobile phase to pass through the column
  • CRE-PLAP reporter assay SE302 is a clone of the HEK/293 cell line that harbors a reporter construct containing a promoter with cAMP response elements (CRE) driving secreted alkaline phosphatase (PLAP), constructed by T. Arai, Eisai Pharamceuticals, Japan. These cells express endogenous EP4 and show induction of PLAP in response to PGE2 and other agonists of EP4, but not of EPl, 2 or 3 (data not shown). Cells were maintained in DMEM/F12 (50:50) (MediaTech) supplemented with 10% FBS (Tissue Culture Biologicals) plus penicillin/streptomycin.
  • CRE cAMP response elements driving secreted alkaline phosphatase
  • cells When used for assays, cells were plated in a 96-well plate at 2x10 4 cells/100 ⁇ L/well in serum-free assay medium (DMEM/F12 supplemented with 0.1% BSA plus penicillin/streptomycin) and incubated for 4-6 h.
  • serum-free assay medium DMEM/F12 supplemented with 0.1% BSA plus penicillin/streptomycin
  • a reference compound (ER-819762) was included in each CRE-PLAP assay run.
  • the un- normalized IC 50 value for a particular test compound was divided by the IC 50 value determined for the reference compound (ER-819762) in the same run, to provide a relative potency value.
  • the relative potency value was then multiplied by a established potency of the reference compound (ER-819762) to provide the normalized CRE-PLAP assay IC5 0 value.
  • the established potency for ER-819762 was 0.043 ⁇ M.
  • the IC50 values provided herein were obtained using this normalization method.
  • Exemplary compounds of the present invention were assayed according to the methods set forth above in the CRE-PLAP reporter assay described above.
  • Table 2 below sets forth exemplary compounds of the present invention having an IC 50 of up to 5.0 ⁇ M as determined by the normalized CRE-PLAP assay described above.
  • ER-824188-01 10 mg was dissolved in approximately 2ml of ca. 3:1 ratio co- solvent of methanol and dichloromethane in a 4ml vial.
  • the vial was placed in a hood and left open in the air at room temperature to allow slow evaporation of solvents and crystallization over two days.
  • a prismatic crystal (ca. 0.3 x 0.2 x 0.2 mm) thus obtained of ER-824188-01 was mounted on a glass capillary.
  • Diffraction data was collected at the room temperature on an R-AXIS RAPID H-R imaging plate detector system (Rigaku, Japan) with ⁇ axis oscillation method using graphite monochromated Cu-Ka radiation.
  • V 2262.20 A 3 Z value 4
  • R 1 is Ci- 6 alkyl or C 2-6 alkenyl, wherein Ri is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkoxy, and C ⁇ 2 R a , wherein R a is hydrogen, C 1-4 alkyl, or C 2-4 alkenyl;
  • X is absent, -NH-, C 1-6 alkylene, or C 2 _ 6 alkenylene;
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting Of Cj -6 alkyl, C 2-6 alkenyl, C] -3 alkoxy, hydroxyl, C]. 3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, Ci -6 alkyl, and C 2-6 alkenyl; each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, Ci -6 alkyl, C 2-6 alkenyl, Ci -3 alkoxy, -SO 2 NHR b , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between 0 and 5 substitu
  • Ri is methyl, ethyl, -(CH 2 ) 2 OH, -(CH 2 ) 2 OCH 3 , Or-CH 2 CO 2 R*, wherein R a is hydrogen or Ci -4 alkyl;
  • X is absent, -NH-, Ci -6 alkylene, or C 2-6 alkenylene;
  • R 3 is aryl or heteroaryl and substituted with between O and 5 substituents independently selected from the group consisting of Ci -6 alkyl, Of C 2-6 alkenyl, Cj -3 alkoxy, hydroxyl, Ci -3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently chosen from the group consisting of hydrogen, methyl, and ethyl;
  • each of W, X, Y and Z is independently hydrogen or Ci -3 alkoxy; or a pharmaceutically acceptable salt thereof.
  • Ri is methyl, ethyl, -(CH 2 ) 2 OH, -(CH 2 ) 2 OCH 3 , or -CH 2 CO 2 R 3 , wherein R a is hydrogen or Ci - 4 alkyl;
  • X is absent, -NH-, C 1-6 alkylene, or C 2 . 6 alkenylene-
  • R 3 is phenyl, quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, naphthyl, pyrrolyl, indazolyl, thieno[2,3-c]pyrazolyl, benzofuryl, pyrazolo[l,5-a]pyridyl, Ihiophenylpyrazolyl, benzothienyl, benzothiazolyl, thiazolyl, 2-phenylthiazolyl, or isoxazolyl, and is substituted with between 0 and 3 substituents independently selected from methyl, ethyl, hydroxyl, methoxy, bromo, fluoro, and chloro;
  • R 4 and R 5 are each independently chosen from the group consisting of hydrogen, methyl, and ethyl;
  • each of W, X, Y and Z is independently hydrogen or Ci -3 alkoxy;
  • R 1 is methyl, ethyl, -(CH 2 ⁇ OH, - (CH 2 ) 2 OCH 3 , or-CH 2 CO 2 R ⁇ wherein R a is hydrogen or Q- 4 alkyl.
  • R 3 is phenyl, quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, naphthyl, pyrrolyl, indazolyl, thieno[2,3-c]pyrazolyl, benzofuryl, pyrazolo[l,5-a]pyridyl, thiophenylpyrazolyl, benzothienyl, benzothiazolyl, thiazolyl, 2-phenylthiazolyl, or isoxazolyl, and is substituted with between 0 and 3 substituents independently selected from methyl, ethyl, methoxy, hydroxyl, bromo, fluoro, and chloro.
  • a pharmaceutical composition comprising a compound of formula I:
  • Ri is C 1-6 alkyl or C 2-6 alkenyl, wherein Ri is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, Ci -3 alkoxy, and CO 2 R 1 *, wherein R a is hydrogen, C] -4 alkyl, or C 2 . 4 alkenyl;
  • X is absent, -NH-, Ci -6 alkylene, or C 2 -6 alkenylene
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting of C] -6 alkyl, C 2 - 6 alkenyl, C 1-3 alkoxy, hydroxyl, Ci -3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, Ci -6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, Ci -6 alkyl, C 2-6 alkenyl, Ci -3 alkoxy, -SO 2 NHR b , and - CO 2 R C ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between 0 and 5 substituents independently selected from the group consisting of Ci -6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropylmethyl, and halo; and wherein each occurrence of R c is independently selected from the group consisting of hydrogen, Ci- 6 alkyl, and C 2-6 alkenyl;
  • a pharmaceutical composition comprising a compound selected from the group consisting of
  • a method of treating multiple sclerosis in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I:
  • R 1 is C j -e alkyl or C 2-6 alkenyl, wherein R 1 is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxy 1, C] -3 alkoxy, and C0 2 R a , wherein R a is hydrogen, C 1-4 alkyl, or C 2-4 alkenyl;
  • X is absent, -NH-, C] -6 alkylene, or C 2-6 alkenylene
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting OfC 1-6 alkyl, C2-6 alkenyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 2 - 6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, -S ⁇ 2 NHR b , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2 .
  • a method of treating multiple sclerosis in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I selected from the group consisting of
  • a method of treating rheumatoid arthritis in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I:
  • R 1 is C 1-6 alkyl or C 2-6 alkenyl, wherein R 1 is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, Ci -3 alkoxy, and CO 2 R 8 , wherein R a is hydrogen, C 1-4 alkyl, or C 2-4 alkenyl;
  • X is absent, -NH-, C 1-6 alkylene, or C 2-6 alkenylene
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting Of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, Cj -3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, Ci -6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, -SO 2 NHR , and - CO 2 R C ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2 .
  • a method of treating rheumatoid arthritis in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I selected from the group consisting of
  • a method of treating systemic lupus erythematosus in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I:
  • R 1 is Cj- 6 alkyl or C 2-6 alkenyl, wherein R 1 is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, Ci- 3 alkoxy, and CO 2 R 8 , wherein R a is hydrogen, C 1-4 alkyl, or C 2-4 alkenyl; X is absent, -NH-, C 1-6 alkylene, or C 2-6 alkenylene;
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting OfC 1-6 alkyl, C 2 - 6 alkenyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropylmethyl, and halo;
  • R and R 5 are each independently selected from the group consisting of hydrogen, Ci -6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, C] -6 alkyl, C 2-6 alkenyl, C] -3 alkoxy, -SO 2 NHR b , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between 0 and 5 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, C] -3 alkylthio, cyclopropylmethyl, and halo; and wherein each occurrence of R c is independently selected from the group consisting of hydrogen, C 1 . 6 alkyl, and C 2 - 6 alkenyl;
  • a method of treating systemic lupus erythematosus in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I selected from the group consisting of
  • a method of treating type 1 diabetes in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of formula I: wherein:
  • Ri is C 1-6 alkyl or C 2-6 alkenyl, wherein Ri is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, Ci -3 alkoxy, and CO 2 R a , wherein R a is hydrogen, Cj -4 alkyl, or C 2-4 alkenyl;
  • X is absent, -NH-, C 1 ⁇ alkylene, or C 2 ⁇ alkenylene
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting Of C 1-6 alkyl, C 2-6 alkenyl, Ci -3 alkoxy, hydroxyl, Cj -3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, Ci -6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, Cj -6 alkyl, C 2-6 alkenyl, C 1 -3 alkoxy, -SO 2 NHR b , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, Ci -6 alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between 0 and 5 substituents independently selected from the group consisting of Ci -6 alkyl, C 2-6 alkenyl, C] -3 alkoxy, hydroxyl, C] -3 alkylthio, cyclopropyhnethyl, and halo; and wherein each occurrence of R c is independently selected from the group consisting of hydrogen, Ci-
  • a method of treating type 1 diabetes in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I selected from the group consisting of
  • a method of treating psoriasis in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I:
  • R 1 is C 1-6 alkyl or C 2 . 6 alkenyl, wherein Ri is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, Ci -3 alkoxy, and CO 2 R a , wherein R a is hydrogen, Cj -4 alkyl, or C 2-4 alkenyl;
  • X is absent, -NH-, C 1-6 alkylene, or C 2 . 6 alkenylene;
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting Of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, Ci -3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, Q -6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, Ci -6 alkyl, C 2-6 alkenyl, Ci -3 alkoxy, -SO 2 NHR , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, Ci -6 alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between O and 5 substituents independently selected from the group consisting of C 1 ⁇ alkyl, C 2 .
  • R c is independently selected from the group consisting of hydrogen, C 1- 6 alkyl, and C 2-6 alkenyl;
  • a method of treating psoriasis in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I selected from the group consisting of
  • a method of treating atherosclerosis in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I: wherein:
  • R] is C 1-6 alkyl or C 2-6 alkenyl, wherein R 1 is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkoxy, and CO 2 R 8 , wherein R a is hydrogen, Cj -4 alkyl, or C 2-4 alkenyl;
  • X is absent, -NH-, C 1-6 alkylene, or C 2 -O alkenylene
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting Of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, Cj . 3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, Cj -6 alkyl, C 2-6 alkenyl, C 1 - 3 alkoxy, -S0 2 NHR b , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, Cj -6 .alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between O and 5 substituents independently selected from the group consisting of C 1 . 6 alkyl, C 2-6 alkenyl, C 1 . 3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropylmethyl, and halo; and wherein each occurrence of R G is independently selected from the group consisting of hydrogen, C 1-
  • a method of treating atherosclerosis in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I selected from the group consisting of
  • a method of treating inflammatory pain in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I:
  • R 1 is C] -6 alkyl or C 2-6 alkenyl, wherein R 1 is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, C 1 . 3 alkoxy, and C0 2 R a , wherein R a is hydrogen, C 1-4 alkyl, or C 2-4 alkenyl;
  • X is absent, -NH-, C 1-6 alkylene, or C 2-6 alkenylene;
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting of Ci -6 alkyl, C 2-6 alkenyl, C] -3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, Ci- ⁇ alkyl, C 2 . 6 alkenyl, Q. 3 alkoxy, -SO 2 NHR , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between 0 and 5 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropylmethyl, and halo; and wherein each occurrence of R c is independently selected from the group consisting of hydrogen, Ci- 6 alkyl, and C 2 - 6 alkenyl;
  • a method of treating inflammatory pain in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I selected from the group consisting of
  • a method of treating neuropathic pain in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I:
  • Ri is C I - 6 alkyl or C 2-6 alkenyl, wherein Ri is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, C 1 ⁇ alkoxy, and CO 2 R a , wherein R a is hydrogen, Ci -4 alkyl, or C 2- 4 alkenyl;
  • X is absent, -NH-, C 1-6 alkylene, or C 2-6 alkenylene
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting of C ⁇ 6 alkyl, C 2 - 6 alkenyl, C 1-3 alkoxy, hydroxyl, C] -3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, Ci -6 alkyl, C 2-6 alkenyl, Cj -3 alkoxy, -SO 2 NHR , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, Ci -6 alkyl, C 2 - 6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between O and 5 substituents independently selected from the group consisting Of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, Ci -3 alkylthio, cyclopropylmethyl, and halo; and wherein each occurrence of R c is independently selected from the group consisting of hydrogen, C 1-
  • a method of treating neuropathic pain in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I selected from the group consisting of
  • a method of treating migraine-associated pain in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I:
  • R 1 is Ci- 6 alkyl or C 2-6 alkenyl, wherein R 1 is substituted with between 0 and 3 substituents independently selected from the group consisting of halo, hydroxyl, C 1 ⁇ alkoxy, and CO 2 R a , wherein R a is hydrogen, C 1 ⁇ alkyl, or C 2-4 alkenyl; X is absent, -NH-, C 1 ⁇ alkylene, or C 2-6 alkenylene;
  • R 3 is aryl or heteroaryl and substituted with between 0 and 5 substituents independently selected from the group consisting Of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropylmethyl, and halo;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 2-6 alkenyl;
  • each of W, X, Y and Z is independently selected from the group consisting of hydrogen, hydroxyl, halo, Cj -6 alkyl, C 2-6 alkenyl, C 3-3 alkoxy, -SO 2 NHR b , and - CO 2 R 0 ; wherein each occurrence of R b is independently selected from the group consisting of hydrogen, Ci -6 alkyl, C 2-6 alkenyl, aryl, and heteroaryl, wherein each occurrence of aryl or heteroaryl is substituted with between 0 and 5 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropylmethyl, and halo; and wherein each occurrence of R G is independently selected from the group consisting of hydrogen, C 1- 6 alkyl, and C 2-6 alkenyl;
  • a method of treating migraine-associated pain in a mammal comprising the step of administering to the mammal a pharmaceutical composition comprising a compound of Formula I selected from the group consisting of

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Abstract

L'invention porte sur des composés de Formule (I) : Formule (I) comprenant leurs sels pharmaceutiquement acceptables, ainsi que sur des formulations pharmaceutiques ou des médicaments à base de ces composés ou de leurs sels, et sur leur utilisation dans le traitement de troubles tels que l'athérosclérose, la sclérose en plaques, le psoriasis et l'arthrite rhumatoïde.
PCT/US2010/042717 2009-07-21 2010-07-21 Composés imidazoazépinones Ceased WO2011011494A1 (fr)

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US7189715B2 (en) 2002-10-24 2007-03-13 Sepracor Inc. Compositions comprising zopiclone derivatives and methods of making and using the same
WO2007139813A1 (fr) * 2006-05-26 2007-12-06 Eisai R&D Management Co., Ltd Imidazoazéphinones
WO2007139948A2 (fr) * 2006-05-26 2007-12-06 Eisai R & D Management Co., Ltd Composés d'imidazo-azépinone
WO2009064431A1 (fr) * 2007-11-15 2009-05-22 Eisai E & D Management Co., Ltd. Procédés d'utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
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