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US20110269960A1 - Triazole derivative - Google Patents

Triazole derivative Download PDF

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Publication number
US20110269960A1
US20110269960A1 US13/180,011 US201113180011A US2011269960A1 US 20110269960 A1 US20110269960 A1 US 20110269960A1 US 201113180011 A US201113180011 A US 201113180011A US 2011269960 A1 US2011269960 A1 US 2011269960A1
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group
carbon atoms
compound
optionally substituted
substituted
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Inventor
Naoya Ono
Tetsuo Takayama
Fumiyasu Shiozawa
Hironori Katakai
Tetsuya Yabuuchi
Tomomi Ota
Makoto Yagi
Masakazu Sato
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Priority to US13/180,011 priority Critical patent/US20110269960A1/en
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Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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Definitions

  • the present invention relates to novel triazole derivatives which have an inhibitory effect on the binding between sphingosine-1-phosphate having various physiological actions and its receptor Edg-1 (Endothelial differentiation gene receptor type-1, S1P1).
  • the present invention also relates to pharmaceutical preparations comprising these compounds as active ingredients, and synthetic intermediates for these compounds.
  • Sphingosine-1-phosphate (hereinafter referred to as “SIP”) is a physiologically active lipid which is generated when sphingolipids (typified by sphingomyelin) are metabolized in cells.
  • SIP is known to have a wide variety of actions such as cell differentiation induction, cell growth stimulation, cell motility inhibition and apoptosis inhibition, and is also known to show physiological actions such as angiogenesis, bradycardia induction, inflammatory cell activation and platelet activation (Non-patent Document 1).
  • Non-patent Document 2 As SIP receptors, the following 5 subtypes have been reported: Edg-1(S1P1), Edg-3(S1P3), Edg-5(S1P2), Edg-6(S1P4) and Edg-8(S1P5) (Non-patent Document 2).
  • Edg-1(S1P1) is highly expressed in immunocytes (e.g., T cells, dendritic cells) and vascular endothelial cells, suggesting that Edg-1 (S1P1) contributes deeply to SIP-stimulated T cell migration (Non-patent Document 3), mast cell migration (Non-patent Document 4), T and B cell egress from lymphoid organs (Non-patent Document 5) and angiogenesis (Non-patent Document 6), and is involved in autoimmune diseases such as Crohn's disease, irritable colitis, Sjogren's syndrome, multiple sclerosis and systemic lupus erythematosus, as well as other diseases such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis, age-related macular degeneration, etc.
  • autoimmune diseases such as Crohn's disease, irritable colitis, Sjogren'
  • ligands for Edg-1(S1P1) would be effective for treatment or prevention of these diseases.
  • Edg-1(S1P1) ligands previously known include certain types of thiophene derivatives (Non-patent Document 7), phosphoric acid derivatives (Patent Documents 1 and 2, Nonpatent Documents 8 and 9) and thiazolidine derivatives (Patent Document 3), carboxylic acid derivatives (Patent Documents 4, 5, 6 and 8, Non-patent Documents 10 and 11), amino group-containing derivatives (Patent Document 7), and pyrrole derivatives (Patent Document 9).
  • the present invention has as an object to provide a compound with a new skeletal structure, which compound has an action of inhibiting binding between S1P and its receptor Edg-1 (S1P 1 ) and is useful as a pharmaceutical product.
  • the inventors of the present invention have diligently studied in an attempt to find ligand compounds for Edg-1 (S1P 1 ). As a result, they find that the object is attained with a triazole derivative of Formula (I) below or a pharmaceutically acceptable salt thereof (a feature is that R 3 in the formula is an optionally substituted aryl group). This finding has led to the accomplishment of the present invention.
  • the triazole derivative of Formula (I) below with this feature is a completely new compound.
  • compounds having an alkyl group corresponding to R 3 of Formula (I) are commercially available from Bionet as reagents, they differ in structure from that of the compound of the subject application, and pharmaceutical use of the compounds of Bionet has not been known at all.
  • R 1 is:
  • alkyl group having from 1 to 6 carbon atoms and optionally substituted with a halogen atom(s), or
  • a benzyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; and
  • R 1A is a hydrogen atom.
  • R 1 is a methyl group or an ethyl group, and R 1A is a hydrogen atom.
  • R 4 is a hydrogen atom.
  • R 2 is an alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms.
  • a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a methoxycarbonyl group;
  • a furanyl group optionally selected from a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;
  • a thienyl group optionally substituted with a substituent (s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; or
  • a benzothienyl group a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group, a benzoxadiazolyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom.
  • a phenyl group substituted with 1 to 5 substituents selected from the group consisting of a methyl group, a methoxy group, and a halogen atom,
  • a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of:
  • a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms, and a cyano group.
  • R 3 is a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a benzothiazolyl group, a benzothiadiazolyl group, a pyrazolopyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a benzothienyl group, or a dihydroquinolinonyl group, each optionally substituted with 1 to 3 substituents selected from the group consisting of the following substituents:
  • alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of a fluorine atom, a phenyl group, an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and a morpholino group;
  • a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • a 2-naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms,
  • a 3-pyrazolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom, or
  • a 5-benzothiazolyl group a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • phenyl group substituted at 4 position is further optionally substituted at 3 position with a substituent selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having from 1 to 6 carbon atoms;
  • phenyl group substituted at 3 position is further optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or is further optionally substituted at 4 position with a halogen atom;
  • R 7 and R 8 optionally form, together with the nitrogen atom to which said R 7 and R 8 are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  • Embodiment 21 which is for treatment of an autoimmune disease, such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, or age-related macular degeneration.
  • an autoimmune disease such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, or age-related macular degeneration.
  • an autoimmune disease such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, rheumatoi
  • R 1A represents a hydrogen atom
  • R 2 represents:
  • a cycloalkyl group having from 3 to 6 carbon atoms.
  • R 1A represents a hydrogen atom
  • R 2 represents:
  • a cycloalkyl group having from 3 to 6 carbon atoms.
  • R 1 represents an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
  • alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group, and
  • a phenyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;
  • R 1A represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; and R 1 and R 1A optionally form, together with a carbon atom to which said R 1 and R 1A are attached, a cycloalkyl group having from 3 to 6 carbon atoms.
  • R 1 is an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a halogen atom(s), or a benzyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; and R 1A is a hydrogen atom.
  • R 3 is a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a benzothiazolyl group, a benzothiadiazolyl group, a pyrazolopyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a benzothienyl group, or a dihydroquinolinonyl group, each optionally substituted with 1 to 3 substituents selected from the group consisting of the following substituents:
  • alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of a fluorine atom, a phenyl group, an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and a morpholino group, a phenoxy group,
  • a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms;
  • morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • R 7 and R 8 optionally form, together with the nitrogen atom to which said R 7 and R 8 are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  • a 2-naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;
  • a 3-pyrazolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;
  • a 5-benzothiazolyl group a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms;
  • phenyl group substituted at 4 position is further optionally substituted at 3 position with a substituent selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having from 1 to 6 carbon atoms;
  • phenyl group substituted at 3 position is further optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or is further optionally substituted at 4 position with a halogen atom;
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • alkyl group having from 1 to 6 carbon atoms refers to a linear or branched alkyl group containing 1 to 6 carbon atoms. Examples include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, and a n-hexyl group.
  • cycloalkyl group having from 3 to 8 carbon atoms refers to a cycloalkyl group containing 3 to 8 carbon atoms. Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • alkenyl group having from 2 to 8 carbon atoms refers to a linear or branched alkenyl group containing 2 to 8 carbon atoms. Examples include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1,3-butadienyl group, a 2-methylallyl group, a 2-methyl-propenyl group, a 2-pentenyl group, and a 3-methyl-but-2-enyl group.
  • alkynyl group having from 2 to 8 carbon atoms refers to a linear or branched alkynyl group containing 2 to 8 carbon atoms. Examples include an ethynyl group, a 2-propynyl group, a 2-butynyl group, a 1-methyl-prop-2-ynyl group, a 2-pentynyl group, and a 4-pentynyl group.
  • alkoxy group having from 1 to 6 carbon atoms refers to a linear or branched alkoxy group containing 1 to 6 carbon atoms. Examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group.
  • alkyl group having from 1 to 10 carbon atoms refers to a linear or branched alkyl group containing 1 to 10 carbon atoms. Examples include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, and a n-hexadecyl group.
  • alkylthio group having from 1 to 6 carbon atoms refers to a linear or branched alkylthio group containing 1 to 6 carbon atoms. Examples include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a pentylthio group, and a hexylthio group.
  • alkylsulfonyl group having from 1 to 6 carbon atoms refers to a linear or branched alkylsulfonyl group containing 1 to 6 carbon atoms. Examples include a methanesulfonyl group, an ethanesulfonyl group, a propane-2-sulfonyl group, and a hexanesulfonyl group.
  • alkoxycarbonyl group having from 2 to 10 carbon atoms refers to a linear or branched alkoxycarbonyl group containing 2 to 10 carbon atoms. Examples include alkanoyl group having from 2 to 7 carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl group and a t-butoxycarbonyl group, as well as an octyloxycarbonyl group.
  • alkanoyl group having from 2 to 7 carbon atoms refers to a linear or branched alkanoyl group containing 2 to 7 carbon atoms. Examples include an acetyl group, a propanoyl group, a butanoyl group, and a hexanoyl group.
  • alkanoyl group having from 1 to 6 carbon atoms refers to a linear or branched alkanoyl group containing 1 to 6 carbon atoms. Examples include a formyl group, an acetyl group, a propanoyl group, and a butanoyl group.
  • amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms is intended to include, for example, an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a hexylamino group, a dimethylamino group, a diethylamino group, a diisopropylamino group, and a dihexylamino group.
  • aminonosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms is intended to include, for example, a sulfamoyl group, a dimethylaminosulfonyl group, and a diethylaminosulfonyl group.
  • carrier group optionally substituted with an alkyl group(s) having from 1 to 4 carbon atoms
  • carbamoyl group is intended to include a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, and a propylcarbamoyl group.
  • piperazino group which may be substituted or “optionally substituted piperazino group” refers to a piperazino group which may be substituted (preferably on its nitrogen atom) with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (wherein said alkyl group may be substituted with an amino group which may be substituted with one or two alkyl groups each having 1-6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having 1-6 carbon atoms), a formyl group, an alkanoyl group having 2-7 carbon atoms, a carbamoyl group which may be substituted with one or two alkyl groups each having 1-4 carbon atoms, an aminosulfonyl group optionally substituted with one or two alkyl groups each having 1-6 carbon atoms, and an alkylsulfonyl group having 1-6 carbon atoms.
  • Specific examples include a piperazino group
  • monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s) means a 3- to 9-membered monocylic saturated hydrocarbon group containing one or two nitrogen atoms as ring-forming atoms and substituted at a ring carbon atom.
  • monocylic saturated hydrocarbon group include aziridinyl groups, azetidinyl groups, pyrrolidinyl groups, and piperidinyl groups (e.g., 4-piperidinyl groups).
  • nitrogen-containing monocyclic unsaturated hydrocarbon group refers to a 5- or 6-membered unsaturated ring containing 1 to 3 nitrogen atoms as its ring members.
  • examples include a pyrrolyl group (e.g., a pyrrol-1-yl group), an imidazol-1-yl group (e.g., an imidazolyl group), a pyrazolyl group, a triazol-4-yl group (e.g., a [1,2,4]triazol-4-yl group), and a pyridyl group.
  • the 3- to 5-membered saturated hydrocarbon ring formed by R A and R B together with the nitrogen atom to which R A and R B are attached is intended to include an aziridinyl group, an azetidinyl group, and a pyrrolidinyl group.
  • the 3- to 8-membered saturated hydrocarbon ring formed by R 7 and R 8 (or R C and R D ) together with the nitrogen atom to which R 7 and R 8 (or R C and R D ) are attached is intended to include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group.
  • aryl group refers to an aromatic hydrocarbon group, a partially saturated aromatic hydrocarbon group, an aromatic heterocyclic group, or a partially saturated aromatic heterocyclic ring.
  • the aromatic hydrocarbon group refers to, for example, an aromatic hydrocarbon group containing 6-14 carbon atoms, including a phenyl group, a naphthyl group, and an anthryl group.
  • the partially saturated aromatic hydrocarbon group refers to a group obtained by partial saturation of a polycyclic aromatic hydrocarbon group having 6-14 carbon atoms. Examples include a tetrahydronaphthyl group and an indanyl group.
  • the aromatic heterocyclic group refers to a monocylic or polycyclic aromatic heterocyclic group containing 2-13 carbon atoms and having 1-6 hetero atoms (e.g., oxygen, sulfur and/or nitrogen atoms).
  • Examples include a thienyl group, a furanyl group, a pyrrolyl group, an isothiazolyl group, an isoxazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a benzothienyl group, a benzofuranyl group, an indolyl group, a benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group, a quinolinyl group, an isoquinolin
  • the partially saturated aromatic heterocyclic ring refers to a heterocyclic ring obtained by partial saturation of a polycyclic aromatic heterocyclic group. Such a heterocyclic ring may be substituted with an oxo group. Examples include a dihydroquinolinonyl group:
  • a dihydrobenzofuranyl group a dihydrobenzodioxinyl group, a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzoxazolyl group, and a dihydrobenzoxazinyl group.
  • substituents for the aryl group include those listed below and the aryl group can be substituted with 1 to 5 of these substituents:
  • a halogen atom a cyano group, a nitro group, a sulfamoyl group, a hydroxyl group, a carboxyl group, an alkyl group having 1-6 carbon atoms, a trifluoromethyl group, a methoxycarbonylethyl group, an alkoxy group having 1-6 carbon atoms (the alkoxy group is optionally substituted with a phenyl group, an alkylamino group having 1-6 carbon atoms, a dialkylamino group having 2-12 carbon atoms, or a morpholino group), a trifluoromethoxy group, a difluoromethoxy group, a cyanoethoxy group,
  • a phenyl group (the phenyl group is optionally substituted with an alkanoyl group having 2-7 carbon atoms or an alkoxy group having 1-6 carbon atoms),
  • a phenoxy group optionally substituted with an alkoxy group having 1-6 carbon atoms
  • a pyrazolyl group a 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl group, a methylpyrimidinyl group, a 2-methylsulfanyl-pyrimidin-4-yl groups, an oxazolyl group (e.g., oxazol-5-yl group), an isooxazol-5-yl group, a 5-trifluoromethyl-isooxazol-3-yl group, a pyridyloxy group (e.g., 4-pyridyloxy group), a pyridinecarbonyl group, a benzoyl group, a pyrrolyl group (e.g., pyrrol-1-yl group), an imidazolyl group (e.g., imidazol-1-yl group), a thiazolyl group, a [1,2,3]thiadiazol-4-yl group, a triazolyl group (e.g., [1,2,4]tria
  • salts refers to a salt with an alkali metal, an alkaline earth metal, ammonium or an alkylammonium, or a salt with a mineral acid or an organic acid.
  • examples include a sodium salt, a potassium salt, a calcium salt, an ammonium salt, an aluminum salt, a triethylammonium salt, an acetate salt, a propionate salt, a butyrate salt, a formate salt, a trifluoroacetate salt, a maleate salt, a tartrate salt, a citrate salt, a stearate salt, a succinate salt, an ethylsuccinate salt, a lactobionate salt, a gluconate salt, a glucoheptate salt, a benzoate salt, a methanesulfonate salt, an ethanesulfonate salt, a 2-hydroxyethanesulfonate salt, a benzenesulf
  • the compounds of the present invention may have stereoisomers including optical isomers, diastereoisomers and geometrical isomers. All of these stereoisomers and mixtures thereof also fall within the scope of the present invention. Some of the compounds and intermediates of the present invention may also exist, e.g., as keto-enol tautomers.
  • the compounds of the present invention show strong activity in an action of inhibiting binding between SIP and its receptor, Edg-1 (S1P1).
  • the compounds are expected to have preventive or therapeutic effects on autoimmune, diseases, such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, and age-related macular degeneration.
  • a preferred example of A is an oxygen atom or —NR 6 — (it is preferable that R 6 be hydrogen).
  • a more preferred example of A is an oxygen atom.
  • R 1 is an alkyl group having 1-6 carbon atoms which may be substituted with a halogen atom(s), or a benzyl group which may be substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having 1-6 carbon atoms. More preferred is a methyl group, an ethyl group, or a benzyl group which may be substituted with a halogen atom(s), and even more preferred is a methyl group.
  • R 1A is a hydrogen atom.
  • R 2 are an ethyl group and a cyclopropyl group.
  • R 4 is a hydrogen atom.
  • R 3 is: a optionally substituted phenyl group; a 2-naphthyl group (the naphthyl group is optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having 1-6 carbon atoms); a 3-pyrazolyl group (the pyrazolyl group is optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, and a halogen atom); or a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group (preferably a 6-indolyl group), each optionally substituted
  • the “optionally substituted phenyl group” in the preferred embodiment of R 3 includes unsubstituted phenyl groups and substituted phenyl groups (A)-(C) below:
  • R C and R D each represent a hydrogen atom, an alkyl group having 1-6 carbon atoms (the alkyl group is optionally substituted with an amino group optionally substituted with one or two alkyl groups each having 1-4 carbon atoms, a hydroxyl group, or an alkoxy group having 1-4 carbon atoms), a formyl group, an acetyl group, an aminocarbonyl group, a dimethylaminosulfonyl group, or a methylsulfonyl group, or R C and
  • R D optionally form, together with the nitrogen atom to which R C and R D are attached, a 3- to 8-membered saturated hydrocarbon ring, which ring is optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  • R 3 is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom, a 6-indolyl group, and nitrogen-containing groups (i), (iv), and (v) shown in item (C) above, which phenyl group substituted with a substituent selected from the above group is optionally further substituted at 4 position with a halogen atom.
  • R 5 is: an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a cycloalkyl group having 3-8 carbon atoms; an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a phenyl group or a naphthyl group (preferably 2-naphthyl group) each optionally substituted with 1-5 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, an alkoxy group having 1-6 carbon atoms, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms, an alkylsulfonyl group having
  • examples of the “phenyl group which is optionally substituted” include an unsubstituted phenyl group, a phenyl group substituted with 1-5 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), an alkoxy group having 1-6 carbon atoms (preferably a methoxy group), and a halogen atom, and a phenyl group substituted at either 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, an alkoxy group having 1-6 carbon atoms (preferably a methoxy group), a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms, an alkylsulfonyl group having 1-6 carbon atoms (preferably a methyls
  • an example of the “naphthyl group which is optionally substituted” is a naphthyl group optionally substituted with a substituent(s) (preferably 1-3 substituents) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group).
  • it is a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), and a cyano group.
  • a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), and a cyano group.
  • substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), and a cyano group.
  • 2-naphthyl group include an unsubstituted 2-naphthyl group and a 2-naphthyl group substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (substituted at any position, preferably at 5, 7 and/or
  • Examples in a case of a 1-naphthyl group include an unsubstituted 1-naphthyl group and a 1-naphthyl group substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (substituted at any position) and other substituents, preferably a halogen atom (substituted preferably at 4 position).
  • R 5 is a phenyl group substituted at 3 and 4 positions with a halogen atom, an unsubstituted 2-naphthyl group, and a 2-naphthyl group substituted at 5, 7 and/or 8 position with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), and a cyano group.
  • R 3 and R 5 are especially preferred.
  • R 5 is: an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a substituted phenyl group (e.g., a phenyl group substituted with 1-5 methyl groups, a phenyl group substituted at either 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 a carbon atom (preferably a methyl group, an ethyl group, a propyl group), a halogen atom, a methoxy group, a trifluoromethoxy group, a difluorometh
  • R 5 is: an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a phenyl group which is optionally substituted (e.g., an unsubstituted phenyl group, a phenyl group substituted with 1-5 methyl groups, a phenyl group substituted at either 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group, an ethyl group, a propyl group), a halogen atom, a methoxy group, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkeny
  • R 5 is: an alkyl group having 1-6 carbon atoms and substituted with a cycloalkyl group having 3-8 carbon atoms; an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a optionally substituted phenyl group (e.g., an unsubstituted phenyl group, a phenyl group substituted with 1-5 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a halogen atom, a phenyl group substituted at 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms, a hal
  • a preferred optically-active compound of the present compound having R 1A being a hydrogen atom has the structure below.
  • the compound of the present invention can be synthesized by, for instance, the method described below.
  • R 1 , R 1A , R 2 , R 3 , and R 5 are as defined above, R′ represents an alkyl group having 1-6 carbon atoms, R′′ represents a protecting group for an amino group, which protecting group is stable under a basic condition (e.g., a t-butoxycarbonyl group, a benzyloxycarbonyl group), L represents a leaving group (e.g., a halogen atom, such as a chlorine atom, a bromine atom, and an iodine atom, an alkylsulfonyloxy group, such as an a methanesulfonyloxy group and a p-toluenesulfonyloxy group, an arylsulfonyloxy group, a 2-oxo-1-oxazolyl group), and A 1 represents an oxygen atom, a sulfur atom, or a group represented by —NR 6 —, where R 6 represents a hydrogen atom or
  • a compound having A being an oxygen atom, a sulfur atom, or a group represented by —NR 6 — can be synthesized by, for instance, the method shown in Scheme 1.
  • the compound represented by Formula (b) can be obtained by allowing the compound represented by Formula (a) to react with hydrazine in a solvent or in the absence of a solvent.
  • the amount of the hydrazine used is generally 1-30 equivalent weight with respect to Compound (a), preferably 5-30 equivalent weight.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include alcohols such as methanol and ethanol.
  • the reaction temperature is generally a room temperature to a solvent reflux temperature.
  • the reaction time is generally 12-24 hours, but it depends on the reaction temperature and starting compounds.
  • the compound represented by Formula (d) can be obtained by allowing the compound represented by Formula (b) to react with the compound represented by Formula (c) in a solvent or in the absence of a solvent.
  • the amount of the compound represented by Formula (c) to be used is generally 1-3 equivalent weight with respect to the compound represented by Formula (b), preferably 1.1-1.5 equivalent weight.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert. For instance, alcohols, such as methanol and ethanol, and halogenated hydrocarbons, such as dichloromethane and chloroform, are preferably used.
  • the reaction temperature is generally a room temperature to a solvent reflux temperature.
  • the reaction time is generally 30 minutes to 24 hours, but it depends on the reaction temperature and starting compounds.
  • the compound represented by Formula (e) can be obtained by allowing the compound of Formula (d) to react with a base in a solvent or in the absence of a solvent to cyclize.
  • the base to be used includes alkali metal hydroxides such as NaOH and KOH, and alkali metal salts such as NaHCO 3 and K 2 CO 3 .
  • the amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (d), preferably 1.1-1.5 equivalent weight.
  • a solvent is necessary, the following can be used as the solvent: water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran (THF), and mixed solvents thereof.
  • the reaction temperature is generally a room temperature to a solvent reflux temperature.
  • the reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compounds.
  • the compound represented by Formula (g) can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (e) to react with the compound represented by Formula (f) in the presence of a base.
  • the amount of the compound represented by Formula (f) to be used is generally 1-5 equivalent weight, preferably 1.1-1.5 equivalent weight, with respect to the compound represented by Formula (e).
  • the base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO 3 and K 2 CO 3 , and amines, such as triethylamine, diisopropylethylamine, and diisopropylamine.
  • the amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (e), preferably 1.0-3.0 equivalent weight.
  • the reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include water, ethers such as dioxane and THF, dimethylformamide (DMF), N,N′-dimethylacetamide (DMA), N,N′-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), and mixed solvents thereof.
  • the reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compounds.
  • the compound represented by Formula (h) can be obtained by allowing the compound represented by Formula (g) to react with an oxidant in a solvent.
  • the solvent to be used include organic peroxyacids such as m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peroxyacetic acid, and peroxyformic acid, inorganic or organic peroxides such as hydrogen peroxide, hydrogen peroxide urea adduct/phthalic anhydride, tert-butylhydroperoxide, and cumenehydroperoxide, sodium periodate, Oxone (registered trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, hypochlorite tert-butyl, iodobenzene diacetate, and bromine-1,4-diazabicyclo[2,2,2]octane addition complex.
  • organic peroxyacids such as m-chloroperbenzoic acid, magnesium
  • the amount of the oxidant used is 2-10 equivalent weight with respect to the compound represented by Formula (g), preferably 2-3 equivalent weight.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform.
  • the reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C.-40° C.
  • the reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • the compound represented by Formula (i) or a salt of the compound can be obtained by subjecting the compound represented by Formula (h) to deprotection of an amino group in a solvent under a conventional condition, e.g., allowing it to react with an acid.
  • the acid used include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) and organic acids (e.g., trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid).
  • the amount of the acid used is 1-50 equivalent weight with respect to the compound represented by Formula (h).
  • the reaction temperature is 0° C.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert.
  • examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform.
  • the reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • the compound represented by Formula (k) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (i) to react with the compound represented by Formula (j) (where A 1 represents an oxygen atom, a sulfur atom, or a group represented by Formula —NR 6 —, and R 3 is as defined above) in the presence of a base and, when necessary, forming a salt.
  • the amount of the compound of Formula (j) to be used is generally 1-5 equivalent weight with respect to the compound represented by Formula (i), preferably 1-3 equivalent weight.
  • Examples of the base used include alkali metal salts, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, dimsyl sodium, sodium hydride, sodium amide, tert-butoxypotassium, and tert-butoxysodium, amines, such as triethylamine, diisopropylamine, pyrrolidine, and piperidine, sodium acetate, and potassium acetate.
  • the amount of the base used is generally 1-10 equivalent weight with respect to the compound represented by Formula (i), preferably 1-3 equivalent weight.
  • the reaction temperature is 0° C. to a solvent reflux temperature, and it can be carried out under ordinary pressure, increased pressure, microwave irradiation, or the like.
  • the reaction solvent to be used includes ethers such as dioxane and THF, DMF, DMA, DMPU, RMPA, or the like, or mixed solvents thereof.
  • the reaction time is generally a period of 1-12 hours, but it depends on the reaction temperature and starting compound.
  • the compound represented by Formula (m) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (k) to react with the compound represented by Formula (l) in the presence of a base and, when necessary, forming a salt.
  • the amount of the compound represented by Formula (l) used is 1-5 equivalent weight with respect to the compound represented by Formula (k), preferably 1-1.2 equivalent weight.
  • the base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO 3 and K 2 CO 3 , or amines, such as triethylamine, diisopropylethylamine, and diisopropylamine.
  • the amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (k), preferably 1.0-3.0 equivalent weight.
  • the reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as dioxane and THF, and mixed solvents thereof.
  • the reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • R 41 is the same as R 4 excluding the hydrogen atom).
  • the compound represented by Formula (m2), the compound represented by Formula (m3), or pharmaceutically acceptable salts of the compounds can be obtained by allowing, among the compounds obtained in Scheme 1 and represented by Formula (m), the compound represented by Formula (m1) having A 1 being a sulfur atom to react with an oxidant and, when necessary, forming a salt.
  • oxidant to be used examples include organic peroxyacids such as m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peroxyacetic acid, and peroxyformic acid, inorganic or organic peroxides such as hydrogen peroxide, hydrogen peroxide urea adduct/phthalic anhydride, tert-butylhydroperoxide, and cumenehydroperoxide, sodium periodate, Oxone (registered trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, hypochlorite tert-butyl, iodobenzene diacetate, and bromine-1,4-diazabicyclo[2,2,2]octane addition complex.
  • organic peroxyacids such as m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peroxyacetic acid, and peroxyformic acid
  • inorganic or organic peroxides such
  • the amount of the oxidant used is 1-10 equivalent weight with respect to the compound represented by Formula (m1), preferably 1-3 equivalent weight.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform.
  • the reaction temperature is ⁇ 78° C. to a solvent reflux temperature, preferably 0°-40° C.
  • the reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • the compound represented by Formula (o) can be obtained by allowing the compound represented by Formula (a) to react with the compound represented by Formula (n) (R 2 is as defined above) in a solvent or in the absence of a solvent.
  • the amount of the compound represented by Formula (n) to be used is 1-10 equivalent weight with respect to the compound represented by Formula (a), preferably 1-1.2 equivalent weight.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include alcohols such as methanol and ethanol.
  • the reaction temperature is generally a room temperature to a solvent reflux temperature, preferably a room temperature to 50° C.
  • the reaction time is generally a period of 12-24 hours, but it depends on the reaction temperature and starting compound.
  • the compound represented by Formula (p) can be obtained by allowing the compound represented by Formula (o) to react with a Lawesson's reagent in a solvent or in the absence of a solvent.
  • the amount of the Lawesson's reagent used is 1-5 equivalent weight with respect to the compound represented by Formula (o), preferably 1-1.2 equivalent weight.
  • the reaction solvent to be used includes ethers such as dioxane and THF, and mixed solvents thereof.
  • the reaction temperature is a room temperature to a solvent reflux temperature, preferably a room temperature to 50° C.
  • the reaction time is generally 1-12 hours, but it depends on the reaction temperature and starting compounds.
  • the compound represented by Formula (r) can be obtained by allowing the compound represented by Formula (p) to react with the compound represented by Formula (q) in the presence of a mercury compound.
  • the amount of the compound represented by Formula (q) to be used is 1-10 equivalent weight with respect to the compound represented by Formula (p), preferably 1-1.2 equivalent weight.
  • the mercury compound include HgCl 2 and Hg(OAc) 2 .
  • the amount of the mercury compound used is 1-10 equivalent weight with respect to the compound represented by Formula (p), preferably 1-1.2 equivalent weight.
  • the solvent to be used includes acetonitrile, THF, dioxane, and the like.
  • the reaction temperature is a room temperature to a solvent reflux temperature, preferably a room temperature to 50° C.
  • the reaction time is generally a period of 12-48 hours, but it depends on the reaction temperature and starting compound.
  • the compound represented by Formula (k1) or a salt of the compound can be obtained by subjecting the compound represented by Formula (r) to deprotection of an amino group in a solvent under a conventional condition, e.g., allowing it to react with an acid.
  • the acid include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) and organic acids (e.g., trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid).
  • the amount of the acid used is 1-50 equivalent weight with respect to the compound represented by Formula (r).
  • the reaction temperature is 0° C.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert.
  • examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform.
  • the reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • the compound represented by Formula (m4) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (k1) to react with the compound represented by Formula (l) in the presence of a base and, when necessary, forming a salt.
  • the amount of the compound represented by Formula (l) to be used is 1-5 equivalent weight with respect to the compound represented by Formula (k1), preferably 1-1.2 equivalent weight.
  • the base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO 3 and K 2 CO 3 , and amines, such as triethylamine, diisopropylethylamine, and diisopropylamine.
  • the amount of the base is 1-10 equivalent weight, preferably 1.0-3.0 equivalent weight.
  • the reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as dioxane and THF, and mixed solvents thereof.
  • the reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • the compound represented by Formula (u) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (m5) to react with the compound represented by Formula (s) in the presence of a base and, when necessary, forming a salt.
  • the amount of the compound represented by Formula (s) to be used is generally 1-10 equivalent weight with respect to the compound represented by Formula (m5), preferably 1.1-1.5 equivalent weight.
  • the base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO 3 and K 2 CO 3 , and amines, such as triethylamine, diisopropylethylamine, and diisopropylamine.
  • the amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (m5), preferably 1.0-3.0 equivalent weight.
  • the reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature.
  • a solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include water, ethers such as dioxane and THF, dimethylformamide (DMF), N,N′-dimethylacetamide (DMA), N,N′-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), and mixed solvents thereof.
  • the reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • a functional group can be introduced to R 3 by carrying out protection, deprotection, functional group transformation in the process described above.
  • the compounds of the present invention may be supplemented with commonly used excipients, extenders, pH regulators, solubilizers and so on, and then formulated using standard techniques into tablets, granules, pills, capsules, powders, solutions, suspensions, injections, etc.
  • the pharmaceutical preparations thus obtained can be administered as oral or parenteral formulations.
  • the compound of the present invention can be administered to an adult patient at a dose of 1-1000 mg per day in several separated doses. This dosage can be increased or reduced according to a type of a disease, an age, a weight, and a symptom of a patient, or the like.
  • Triethylamine (0.93 mL, 6.64 mmol) and 3,4-dichlorobenzenesulfonyl chloride (0.45 mL, 2.88 mmol) were added at room temperature to a solution of the compound (0.554 g) of Example 1-(7) in THF (10 mL), and the mixture was stirred at room temperature for 2.5 hours. Then, ethyl acetate was added. The organic layer was washed with 1N aqueous hydrochloric acid and thereafter with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
  • Example 3-(1) Starting from the compound obtained in Example 3-(1), the same procedure as used in Example 1-(8) was repeated to give the titled compound.
  • Example 3-(2) To a solution of the compound (0.300 g) of Example 3-(2) in chloroform (6 mL), m-chloroperbenzoic acid (0.329 g) was added, and the mixture was stirred at room temperature for one hour. Then, a further portion of m-chloroperbenzoic acid (0.329 g) was added, and the mixture was stirred at room temperature for 15 hours. Thereafter, a further portion of m-chloroperbenzoic acid (0.329 g) was added, and the mixture was stirred at room temperature for two hours.
  • Triethylamine (0.25 mL) and 3,4-dichlorobenzenesulfonyl chloride (0.707 mL) were added to a solution of the compound (0.144 g) of Example 5-(4) in THF (3 mL), and the mixture was stirred at room temperature for 3.5 hours. Then, 2N aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
  • Example 7-(1) Starting from the compound obtained in Example 7-(1) in place of 4-fluorophenol, the same procedure as used in Example 1-(7) was repeated to give the titled compound (brown oily substance, yield 58%).
  • Example 7-(2) Starting from the compound obtained in Example 7-(2), the same procedure as used in Example 1-(8) was repeated to give the titled compound (colorless powder, yield 64%).
  • Example 7 To a solution of the compound (0.981 g) of Example 7 in THF (10 mL), 2N aqueous hydrochloric acid (8.4 mL) was added, and the mixture was stirred at room temperature for one hour. Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 50° C. for six hours. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and then evaporated under reduced pressure to remove the solvent.
  • Methanesulfonyl chloride (114 mg) was added to a solution of the compound (300 mg) of Example 10-(2) in pyridine (1.32 ml), and the mixture was stirred at room temperature for three hours. Hydrochloric acid (1.0 N) was added, and the mixture was extracted with methanol/chloroform (1/4).
  • Example 18-(1) Starting from the compound obtained in Example 18-(1), the same procedure as used in Example 1-(8) was repeated to give the titled compound (colorless powder, yield 68%).
  • Example 1-(7) To a solution of the compound (12.5 mg) of Example 1-(7) in THF (0.3 ml), triethylamine (25 ⁇ l) was added, and then a solution of 4-methoxybenzenesulfonylchloride (15.5 mg) in THF (0.3 ml) was added. The mixture was stirred at room temperature for two hours. PSA (product name: VARIAN Inc. polymer supported amine, 1.4 meq/g) (75 ⁇ l) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The insoluble matter was filtered off, and the resulting residue was evaporated to remove the solvent.
  • PSA product name: VARIAN Inc. polymer supported amine, 1.4 meq/g
  • N,N′-dimethylpropyleneurea (DMPU) (4.0 ml), 3-(4-methyl-piperazin-1-yl)-phenol (500 mg), and cesium carbonate (2.21 g) were added to the compound (750 mg) obtained in Example 1-(6), and the mixture was stirred at 160° C. for three hours.
  • the mixture was brought to room temperature, and saturated aqueous sodium chloride was added.
  • the mixture was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
  • Triethylamine (0.41 mL) and 3,4-dichlorobenzenesulfonyl chloride (0.232 mL) were added at room temperature to a solution of the compound (427 mg) of Example 21-(1) in THF (8.0 mL), and the mixture was stirred at room temperature overnight.
  • DMPU N,N′′-dimethylpropyleneurea
  • Triethylamine (0.77 mL) and 3,4-dichlorobenzenesulfonyl chloride (1.02 g) were added at room temperature to the compound (748 mg) of Example 22-(1) in THF (10.0 mL), and the mixture was stirred at room temperature overnight.
  • the resulting solid was washed with a mixed solution of hexane/AcOEt (1/1) and dried, and the resulting white powder (55.30 g) was added to an aqueous solution (228 ml) of NaOH (913 mg). The mixture was stirred at 70° C. for four hours, at room temperature overnight, and then at 100° C. for seven hours. The reaction mixture was concentrated to approximately 1 ⁇ 3, and then a saturated aqueous NH 4 Cl solution (300 ml) was added. The resulting white precipitate was filtered and dried to give the titled compound (15.06 g) as a colorless powder.
  • Example 26-(1) (2) Starting from the compound obtained in Example 26-(1), the same procedure as used in Example 1-(4) was repeated to give the titled compound as a light yellow solid (yield 84%).
  • Example 26-(2) Starting from the compound obtained in Example 26-(2), the same procedure as used in Example 1-(5) was repeated to give the titled compound as a light yellow solid (yield 84%).
  • Example 26-(8) Starting from the compound (79 mg) obtained in Example 26-(8), the same procedure as used in Example 1-(8) was repeated to give the titled compound (3 mg) as a light yellow oily substance.
  • the membrane fraction was obtained by treating the cells with a solubilizing buffer (1 mM Tris/HCl, pH 7.2) for 10 minutes on ice, centrifuging at 1000 ⁇ g for 5 minutes to remove insoluble fractions, and then centrifuging at 40000 ⁇ g for 30 minutes at 4° C.
  • the resulting membrane fraction was dissolved in a binding buffer (20 mM Tris-HCl, pH 7.4, 100 mM NaCl, 15 mM NaF, 2 mM deoxypyridoxine, 4 mg/mL fatty acid-free BSA), and then [ 33 P]-S1P (manufactured by ARC, final concentration 0.1 nM) and a DMSO solution (final concentration of the compound 10 ⁇ 5 M, final concentration of DMSO 0.1%) of the test compound were added. Thereafter, the mixture was stirred and then treated for one hour at 30° C.
  • a binding buffer (20 mM Tris-HCl, pH 7.4, 100 mM NaCl, 15 mM NaF, 2 mM deoxypyridoxine, 4 mg/mL fatty acid-free BSA
  • [ 33 P]-S1P manufactured by ARC, final concentration 0.1 nM
  • a DMSO solution final concentration of the compound 10 ⁇ 5 M, final concentration of DMSO 0.1%)
  • the membrane fraction was harvested onto unifilter-96 GF/C filter (manufactured by Perkin Elmer), washing was carried out four times with the binding buffer, and the filter was dried. Twenty five ⁇ L Microscint 0 (manufactured by Perkin Elmer) was added, and radioactivity was measured using Top Count NXT (manufactured by Packard) to calculate the amount (A) of [ 33 P]-S1P bound to the membrane fraction at the time when the compound was added.
  • Inhibition rate(%) [1 ⁇ ( A ⁇ C )/( B ⁇ C )] ⁇ 100
  • IC 50 concentrations at the time when binding in the absence of the test compound was inhibited by 50% were calculated.
  • the membrane system binding assay was carried out in the presence of test compounds with various concentrations, and the Edg-1 (S1P 1 ) binding inhibition rates were calculated using the equation above. Then, IC 50 values were calculated using Origin (Lightstone Corp.), a software for data analysis.
  • the compounds below each had an IC 50 value of 35 nM or lower and showed particularly strong activity.
  • the following compounds had an IC 50 value of 10 nM or below, and showed even stronger activity.
  • IC 50 values of the individual compounds are as follows (unit: nM).
  • Compound 3 4.2. Compound 7: 35.5. Compound 8: 18.5. Compound 10: 17.5. Compound 11: 8.9. Compound 12: 20.0. Compound 14: 6.4. Compound 15: 32.5. Compound 22: 14.0. Compound 28: 3.1. Compound 34: 2.0. Compound 36: 17.5. Compound 38: 11.7. Compound 42: 22.0. Compound 45: 4.2. Compound 46: 28.5. Compound 49: 6.0. Compound 61: 39.0. Compound 73: 2.2. Compound 74: 15.0. Compound 83: 8.1. Compound 88: 5.4. Compound 99: 25.0. Compound 100: 18.5. Compound 105: 2.9. Compound 108: 18.0. Compound 120:1.7.
  • Example 7-(1) Starting from the corresponding amine in place of 1,4-dioxa-8-azaspiro[4,5]decane used in Example 7-(1), the same procedure as used in Example 7-(1) was repeated to give the titled compounds.
  • the compounds of the present invention are excellent Edg-1 (S1P 1 ) ligands, they are useful as agents for treating or preventing autoimmune diseases, such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, and age-related macular degeneration.
  • autoimmune diseases such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus
  • diseases such as rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, and age-related macular degeneration.

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Abstract

An object of the present invention is to provide a compound having an action of inhibiting binding between S1P and its receptor, Edg-1 (S1P1), and is useful as a pharmaceutical compound. A compound or a pharmaceutically acceptable salt thereof, which compound is represented by the formula below
Figure US20110269960A1-20111103-C00001
(where A represents an oxygen atom, a sulfur atom, a group represented by Formula —SO—, a group represented by Formula —SO2—, or the like, R1 represents a hydrogen atom, an alkyl group having 1-6 carbon atoms, or the like, R1A represents a hydrogen atom or the like, R2 represents an alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, or the like, R3 represents an aryl group, R4 represents a hydrogen atom or an alkyl group having 1-6 carbon atoms and optionally substituted with a carboxyl group, and R5 represents an alkyl group having 1-10 carbon atoms, a cycloalkyl group having 3-8 carbon atoms, an aryl group which is optionally substituted, or the like).

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This is a divisional application of U.S. application Ser. No. 12/278,054 filed Aug. 1, 2008, which is a National Stage of International Application No. PCT/JP2007/051951 filed Feb. 5, 2007, which claims priority to Japanese Application No. 2006/027799, filed Feb. 3, 2006. The contents of all of the prior applications are incorporated herein by reference in their entirety.
    • TECHNICAL FIELD
  • The present invention relates to novel triazole derivatives which have an inhibitory effect on the binding between sphingosine-1-phosphate having various physiological actions and its receptor Edg-1 (Endothelial differentiation gene receptor type-1, S1P1). The present invention also relates to pharmaceutical preparations comprising these compounds as active ingredients, and synthetic intermediates for these compounds.
    • BACKGROUND ART
  • Sphingosine-1-phosphate (hereinafter referred to as “SIP”) is a physiologically active lipid which is generated when sphingolipids (typified by sphingomyelin) are metabolized in cells. SIP is known to have a wide variety of actions such as cell differentiation induction, cell growth stimulation, cell motility inhibition and apoptosis inhibition, and is also known to show physiological actions such as angiogenesis, bradycardia induction, inflammatory cell activation and platelet activation (Non-patent Document 1).
  • As SIP receptors, the following 5 subtypes have been reported: Edg-1(S1P1), Edg-3(S1P3), Edg-5(S1P2), Edg-6(S1P4) and Edg-8(S1P5) (Non-patent Document 2).
  • Among these subtypes, Edg-1(S1P1) is highly expressed in immunocytes (e.g., T cells, dendritic cells) and vascular endothelial cells, suggesting that Edg-1 (S1P1) contributes deeply to SIP-stimulated T cell migration (Non-patent Document 3), mast cell migration (Non-patent Document 4), T and B cell egress from lymphoid organs (Non-patent Document 5) and angiogenesis (Non-patent Document 6), and is involved in autoimmune diseases such as Crohn's disease, irritable colitis, Sjogren's syndrome, multiple sclerosis and systemic lupus erythematosus, as well as other diseases such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis, age-related macular degeneration, etc.
  • Thus, ligands for Edg-1(S1P1) would be effective for treatment or prevention of these diseases.
  • Edg-1(S1P1) ligands previously known include certain types of thiophene derivatives (Non-patent Document 7), phosphoric acid derivatives (Patent Documents 1 and 2, Nonpatent Documents 8 and 9) and thiazolidine derivatives (Patent Document 3), carboxylic acid derivatives (Patent Documents 4, 5, 6 and 8, Non-patent Documents 10 and 11), amino group-containing derivatives (Patent Document 7), and pyrrole derivatives (Patent Document 9).
    • Patent Document 1: WO2002-18395
    • Patent Document 2: JP 2003-137894 A
    • Patent Document 3: JP 2002-332278 A
    • Patent Document 4: WO2002-092068
    • Patent Document 5: WO2003-105771
    • Patent Document 6: WO2004-058149
    • Patent Document 7: WO2004-103279
    • Patent Document 8: WO2005-058848
    • Patent Document 9: WO2005-123677
    • Non-patent Document 1: J Biol Chem. 2004, 279: 20555, FASEB J 2002, 16: 625, Proceedings of the Japanese Society for Immunology 2003, 33: 2-J-W30-20-P
    • Non-patent Document 2: Pharmacol Res 2003, 47: 401
    • Non-patent Document 3: FASEB J 2002, 16:1874
    • Non-patent Document 4: J Exp Med 2004, 199: 959
    • Non-patent Document 5: Nature 2004, 427: 355
    • Non-patent Document 6: J Clin Invest 2000, 106: 951, Biocchim Biophys Acta 2002, 1582: 222
    • Non-patent Document 7: J Biol Chem 2004, 279: 13839
    • Non-patent Document 8: Bioorg Med Chem Lett 2003, 13: 3401
    • Non-patent Document 9: J Med Chem. 2004, 47: 6662
    • Non-patent Document 10: J Med Chem. 2005, 48: 6169
    • Non-patent Document 11: J Biol Chem. 2005; 280: 9833
    DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
  • The present invention has as an object to provide a compound with a new skeletal structure, which compound has an action of inhibiting binding between S1P and its receptor Edg-1 (S1P1) and is useful as a pharmaceutical product.
    • Means for Solving the Problems
  • The inventors of the present invention have diligently studied in an attempt to find ligand compounds for Edg-1 (S1P1). As a result, they find that the object is attained with a triazole derivative of Formula (I) below or a pharmaceutically acceptable salt thereof (a feature is that R3 in the formula is an optionally substituted aryl group). This finding has led to the accomplishment of the present invention. The triazole derivative of Formula (I) below with this feature is a completely new compound. Although compounds having an alkyl group corresponding to R3 of Formula (I) are commercially available from Bionet as reagents, they differ in structure from that of the compound of the subject application, and pharmaceutical use of the compounds of Bionet has not been known at all.
  • The following are embodiments of the triazole derivatives of Formula (I) and compounds of Formula (II), which are intermediates of the triazole derivatives (hereinafter, all of them will be referred to as “compounds of the present invention”).
  • 1. A compound represented by Formula (I)
  • Figure US20110269960A1-20111103-C00002
  • or a pharmaceutically acceptable salt thereof, wherein
    A represents:
      • an oxygen atom,
      • a sulfur atom,
      • a group represented by Formula —SO—,
      • a group represented by Formula —SO2—,
      • a group represented by Formula —CH2—, or
      • a group represented by Formula —NR6—, wherein R6 represents
        a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
        R1 represents:
      • a hydrogen atom,
      • an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
        • a hydroxyl group,
        • a halogen atom,
        • an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group, and
        • a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms,
      • a cycloalkyl group having from 3 to 8 carbon atoms,
      • an alkenyl group having from 2 to 8 carbon atoms,
      • an alkynyl group having from 2 to 8 carbon atoms, or a phenyl group;
        R1A represents:
      • a hydrogen atom or
      • an alkyl group having from 1 to 6 carbon atoms;
        R1 and R1A optionally form, together with a carbon atom to which said R1 and R1A are attached, a cycloalkyl group having from 3 to 6 carbon atoms;
        R2 represents:
      • a hydrogen atom,
      • an alkyl group having from 1 to 6 carbon atoms,
      • an alkenyl group having from 2 to 8 carbon atoms,
      • an alkynyl group having from 2 to 8 carbon atoms, or
      • a cycloalkyl group having from 3 to 6 carbon atoms;
        R3 represents an optionally substituted aryl group;
        R4 represents:
      • a hydrogen atom or
      • an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a carboxyl group;
        R5 represents:
      • (i) an alkyl group having from 1 to 10 carbon atoms,
      • (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
        • a cycloalkyl group having from 3 to 8 carbon atoms, a pyridyl group, and
        • a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms,
      • (iii) a cycloalkyl group having from 3 to 8 carbon atoms,
      • (iv) an alkenyl group having from 2 to 8 carbon atoms,
      • (v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,
      • (vi) an alkynyl group having from 2 to 8 carbon atoms,
      • (vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or
      • (viii) an optionally substituted aryl group.
        2. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein, in Formula (I):
        R1 represents:
      • a hydrogen atom,
      • an alkyl group having from 1 to 6 carbon atoms,
      • an alkyl group having from 1 to 6 carbon atoms and substituted with a phenyl group,
      • a cycloalkyl group having from 3 to 8 carbon atoms,
      • an alkenyl group having from 2 to 8 carbon atoms,
      • an alkynyl group having from 2 to 8 carbon atoms, or
      • a phenyl group;
        R1A represents a hydrogen atom;
        R2 represents:
      • an alkyl group having from 1 to 6 carbon atoms,
      • an alkenyl group having from 2 to 8 carbon atoms,
      • an alkynyl group having from 2 to 8 carbon atoms, or
      • a cycloalkyl group having from 3 to 6 carbon atoms;
        R4 represents:
      • a hydrogen atom, or
      • an alkyl group having from 1 to 6 carbon atoms;
        R5 represents:
      • (i) an alkyl group having from 1 to 10 carbon atoms,
      • (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
        • a cycloalkyl group having from 3 to 8 carbon atoms, a phenyl group,
        • a naphthyl group,
        • a pyridyl group, and
        • a phenyl group substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms,
      • (iii) a cycloalkyl group having from 3 to 8 carbon atoms,
      • (iv) an alkenyl group having from 2 to 8 carbon atoms,
      • (v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,
      • (vi) an alkynyl group having from 2 to 8 carbon atoms,
      • (vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or
      • (viii) an optionally substituted aryl group.
        3. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is an oxygen atom or a group represented by Formula —NR6—.
        4. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is an oxygen atom.
        5. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is a group represented by Formula —NH—.
        6. The compound of any one of Embodiments 1 and 3-5, or a pharmaceutically acceptable salt thereof, wherein:
        R1 represents an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
      • a hydroxyl group,
      • a halogen atom,
      • an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group; and
      • a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;
        R1A represents:
      • a hydrogen atom; or
      • an alkyl group having from 1 to 6 carbon atoms; and
        R1 and R1A optionally form, together with a carbon atom to which said R1 and R1A are attached, a cycloalkyl group having from 3 to 6 carbon atoms.
        7. The compound of any one of Embodiments 1 and 3-5, or a pharmaceutically acceptable salt thereof, wherein:
    R1 is:
  • an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a halogen atom(s), or
  • a benzyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; and
  • R1A is a hydrogen atom.
    8. The compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is a methyl group or an ethyl group, and R1A is a hydrogen atom.
    9. The compound of any one of Embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R4 is a hydrogen atom.
    10. The compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R2 is an alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms.
    11. The compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R2 is an ethyl group or a cyclopropyl group.
    12. The compound of any one of Embodiments 1 and 3-11, or a pharmaceutically acceptable salt thereof, wherein R5 is:
      • (i) an alkyl group having from 1 to 10 carbon atoms,
      • (ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
        • a cycloalkyl group having from 3 to 8 carbon atoms, a pyridyl group, and
        • a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms;
      • (iii) an alkenyl group having from 2 to 8 carbon atoms and optionally substituted with a phenyl group, or
      • (iv) a phenyl group, a naphthyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group, a pyridyl group, a furanyl group, a benzothienyl group, an isoquinolinyl, an isoxazolyl group, a thiazolyl group, a benzothiadiazolyl group, a benzoxadiazolyl group, a dihydrobenzodioxepinyl group, a dihydrobenzodioxynyl group, a benzodioxolyl group, a dihydrobenzofuranyl group, an indanyl group, an uracil group, a coumaryl group, a chromanyl group, a dihydroindolyl group, a tetrahydronaphthyl group, or a tetrahydroisoquinolinyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of:
        • an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),
        • an alkenyl group having from 2 to 8 carbon atoms, a halogen atom,
        • an alkoxy group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),
        • a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiadiazolyl group, and a pyrimidinyl group, each optionally substituted with a substituent(s) selected from Group X consisting of a methyl group, a trifluoromethyl group, a halogen atom, and a methylsulfanyl group,
        • an alkylthio group having from 1 to 6 carbon atoms,
        • an alkylsulfonyl group having from 1 to 6 carbon atoms,
        • a benzenesulfonyl group,
        • a morpholinosulfonyl group,
        • a morpholinocarbonylamino group,
        • an aminosulfonyl group,
        • an alkoxycarbonyl group having from 2 to 10 carbon atoms,
        • a morpholino group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms
        • a phenyl group optionally substituted with an alkoxy group(s) having from 1 to 6 carbon atoms,
        • a phenoxy group,
        • a pyridinecarbonyl group,
        • a pyridineoxy group,
        • a cyano group,
        • an alkanoyl group having from 2 to 7 carbon atoms and optionally substituted with a fluorine atom(s), and
        • an alkanoylamino group having from 2 to 7 carbon atoms.
          13. The compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein R5 is:
  • an alkyl group having from 1 to 10 carbon atoms and substituted with a cycloalkyl group having from 3 to 8 carbon atoms,
  • an alkyl group having from 1 to 10 carbon atoms and substituted with a naphthyl group,
  • an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,
  • a phenyl group or a naphthyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of:
      • an alkyl group having from 1 to 6 carbon atoms;
      • a halogen atom,
      • an alkoxy group having from 1 to 6 carbon atoms;
      • a trifluoromethoxy group,
      • a difluoromethoxy group,
      • a trifluoromethyl group,
      • an alkenyl group having from 1 to 6 carbon atoms,
      • an alkylsulfonyl group having from 1 to 6 carbon atoms,
      • an alkanoyl group having from 2 to 7 carbon atoms,
      • an alkoxycarbonyl group having from 2 to 7 carbon atoms, and
      • a cyano group,
  • a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a methoxycarbonyl group;
  • a furanyl group optionally selected from a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;
  • a thienyl group optionally substituted with a substituent (s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; or
  • a benzothienyl group, a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group, a benzoxadiazolyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom.
  • 14. The compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein R5 is:
  • an alkyl group having from 1 to 6 carbon atoms and substituted with a naphthyl group,
  • an alkenyl group having from 2 to 6 carbon atoms and substituted with a phenyl group;
  • an unsubstituted phenyl group,
  • a phenyl group substituted with 1 to 5 substituents selected from the group consisting of a methyl group, a methoxy group, and a halogen atom,
  • a phenyl group substituted with 1 to 3 substituents selected from the group consisting of:
      • an alkyl group having from 1 to 6 carbon atoms,
      • a halogen atom,
      • a methoxy group,
      • a trifluoromethoxy group,
      • a difluoromethoxy group,
      • a trifluoromethyl group,
      • an alkenyl group having from 1 to 6 carbon atoms,
      • a methylsulfonyl group,
      • an acetyl group,
      • a methoxycarbonyl group, and
      • a cyano group,
      • said phenyl group substituted at either 3 or 4 position or both;
  • a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of:
      • a halogen atom,
      • an alkyl group having from 1 to 6 carbon atoms,
      • a cyano group, and
      • an alkylsulfonyl group having from 1 to 6 carbon atoms, or
  • a benzothienyl group, a benzoxadiazolyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, an indanyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom. 15. The compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein R5 is:
  • a phenyl group substituted at 3 and 4 positions each with a halogen atom, or
  • a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms, and a cyano group.
  • 16. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R3 is a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a benzothiazolyl group, a benzothiadiazolyl group, a pyrazolopyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a benzothienyl group, or a dihydroquinolinonyl group, each optionally substituted with 1 to 3 substituents selected from the group consisting of the following substituents:
  • an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),
  • a cycloalkyl group having from 3 to 8 carbon atoms,
  • a halogen atom,
  • an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of a fluorine atom, a phenyl group, an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and a morpholino group;
  • a phenoxy group,
  • a phenyl group,
  • a carboxyl group,
  • an alkoxycarbonyl group having from 2 to 10 carbon atoms,
  • a hydroxyl group,
  • a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • a nitrogen-containing monocylic unsaturated hydrocarbon group,
  • a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • a piperazino group optionally substituted with a substituent(s) selected from the group consisting of:
      • an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
      • a formyl group,
      • an alkanoyl group having from 2 to 7 carbon atoms,
      • a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
      • an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, and
      • an alkylsulfonyl group having from 1 to 6 carbon atoms, and
  • Formula —NR7R8, wherein:
      • R7 and R8 each represent:
      • a hydrogen atom,
      • an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
      • an alkanoyl group having from 1 to 6 carbon atoms,
      • a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
      • a morpholinocarbonyl group,
      • an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
      • an alkylsulfonyl group having from 1 to 6 carbon atoms, or
      • R7 and R8 optionally form, together with the nitrogen atom to which said R7 and R8 are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
        17. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R3 is:
  • a 2-naphthyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms,
  • a 3-pyrazolyl group, optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom, or
  • a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • an unsubstituted phenyl group, or
  • a substituted phenyl group (A), (B), or (C) below:
  • (A) a phenyl group substituted at 4 position with a substituent selected from the group consisting of:
      • an alkyl group having from 1 to 6 carbon atoms,
      • a cycloalkyl group having from 3 to 8 carbon atoms,
      • an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,
      • a halogen atom,
      • a trifluoromethoxy group,
      • a phenoxy group,
      • a phenyl group,
      • a 1-pyrrolyl group, and
      • —NRARB, wherein each of RA and RB is an alkyl group having from 1 to 6 carbon atoms, or RA and RB optionally form, together with the nitrogen atom to which said RA and RB are attached, a 3- to 5-membered saturated hydrocarbon ring,
  • wherein said phenyl group substituted at 4 position is further optionally substituted at 3 position with a substituent selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having from 1 to 6 carbon atoms;
  • (B) a phenyl group substituted at 3 position with a substituent selected from the group consisting of:
      • a hydroxyl group,
      • an alkyl group having from 1 to 6 carbon atoms, and
      • an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,
  • wherein said phenyl group substituted at 3 position is further optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or is further optionally substituted at 4 position with a halogen atom; and
  • (C) a phenyl group substituted at 3 position with a substituent selected from the group consisting of nitrogen-containing groups (i)-(v) below, said phenyl group further optionally substituted at 4 position with a halogen atom:
      • (i) a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
      • (ii) a nitrogen-containing monocylic unsaturated hydrocarbon group,
      • (iii) a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
      • (iv) a piperazino group, optionally substituted with an alkanoyl group having from 2 to 7 carbon atoms or an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
        • an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and
        • a morpholino group, and
      • (v) Formula —NR7R8, wherein:
        • R7 and R8 each represent:
        • a hydrogen atom,
        • an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms, an alkanoyl group having from 1 to 6 carbon atoms,
        • a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
        • a morpholinocarbonyl group,
        • an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
        • an alkylsulfonyl group having from 1 to 6 carbon atoms, or
      • R7 and R8 optionally form, together with the nitrogen atom to which said R7 and R8 are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
        18. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R3 is a phenyl group substituted at 3 position with a substituent selected from the group consisting of nitrogen-containing groups (i)-(v) below, said phenyl group further optionally substituted at 4 position with a halogen atom:
  • (i) a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • (ii) a nitrogen-containing monocylic unsaturated hydrocarbon group,
  • (iii) a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • (iv) a piperazino group, optionally substituted with an alkanoyl group having from 2 to 7 carbon atoms or an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
      • an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and
      • a morpholino group, and
  • (v) Formula —NR7R8, wherein:
      • R7 and R8 each represent:
      • a hydrogen atom,
      • an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
      • an alkanoyl group having from 1 to 6 carbon atoms,
      • a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
      • a morpholinocarbonyl group,
      • an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
      • an alkylsulfonyl group having from 1 to 6 carbon atoms, or
  • R7 and R8 optionally form, together with the nitrogen atom to which said R7 and R8 are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  • 19. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R3 is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom.
    20. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R3 is a 6-indolyl group.
    21. A pharmaceutical preparation, comprising the compound of any one of Embodiments 1-20 or a pharmaceutically acceptable salt thereof.
    22. The pharmaceutical preparation of Embodiment 21, which is for treatment of an autoimmune disease, such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, or age-related macular degeneration.
    23. A compound represented by Formula (II)
  • Figure US20110269960A1-20111103-C00003
  • or a salt thereof, wherein R1, R1A, R2, and R3 are as defined in Embodiment 1, and A′ represents an oxygen atom or NH.
    24. The compound of Embodiment 23, or a salt thereof, wherein, in Formula (II):
    A′ represents an oxygen atom;
    R1 represents:
  • a hydrogen atom,
  • an alkyl group having from 1 to 6 carbon atoms,
  • an alkyl group having from 1 to 6 carbon atoms and substituted with a phenyl group,
  • a cycloalkyl group having from 3 to 8 carbon atoms,
  • an alkenyl group having from 2 to 8 carbon atoms,
  • an alkynyl group having from 2 to 8 carbon atoms, or
  • a phenyl group;
  • R1A represents a hydrogen atom; and
    R2 represents:
  • an alkyl group having from 1 to 6 carbon atoms,
  • an alkenyl group having from 2 to 8 carbon atoms,
  • an alkynyl group having from 2 to 8 carbon atoms, or
  • a cycloalkyl group having from 3 to 6 carbon atoms.
  • 25. The compound of Embodiment 23, or a salt thereof, wherein, in Formula (II):
    A′ represents NH;
    R1 represents:
  • a hydrogen atom,
  • an alkyl group having from 1 to 6 carbon atoms,
  • an alkyl group having from 1 to 6 carbon atoms and substituted with a phenyl group,
  • a cycloalkyl group having from 3 to 8 carbon atoms,
  • an alkenyl group having from 2 to 8 carbon atoms,
  • an alkynyl group having from 2 to 8 carbon atoms, or
  • a phenyl group;
  • R1A represents a hydrogen atom; and
    R2 represents:
  • an alkyl group having from 1 to 6 carbon atoms,
  • an alkenyl group having from 2 to 8 carbon atoms,
  • an alkynyl group having from 2 to 8 carbon atoms, or
  • a cycloalkyl group having from 3 to 6 carbon atoms.
  • 26. The compound of Embodiment 23, or a salt thereof, wherein:
    R1 represents an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
  • a hydroxyl group,
  • a halogen atom,
  • an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group, and
  • a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;
  • R1A represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; and
    R1 and R1A optionally form, together with a carbon atom to which said R1 and R1A are attached, a cycloalkyl group having from 3 to 6 carbon atoms.
    27. The compound of Embodiment 23, or a salt thereof, wherein:
    R1 is an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a halogen atom(s), or a benzyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; and
    R1A is a hydrogen atom.
    28. The compound of any one of Embodiments 23-25, or a salt thereof, wherein R1 is a methyl group or an ethyl group, and R1A is a hydrogen atom.
    29. The compound of any one of Embodiments 23-28, or a salt thereof, wherein R2 is an alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group having from 3 to 8 carbon atoms.
    30. The compound of any one of Embodiments 23-28, or a salt thereof, wherein R2 is an ethyl group or a cyclopropyl group.
    31. The compound of any one of Embodiments 23-30, or a salt thereof, wherein:
  • R3 is a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a benzothiazolyl group, a benzothiadiazolyl group, a pyrazolopyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a benzothienyl group, or a dihydroquinolinonyl group, each optionally substituted with 1 to 3 substituents selected from the group consisting of the following substituents:
  • an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),
  • a cycloalkyl group having from 3 to 8 carbon atoms,
  • a halogen atom,
  • an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of a fluorine atom, a phenyl group, an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, and a morpholino group, a phenoxy group,
  • a phenyl group,
  • a carboxyl group,
  • an alkoxycarbonyl group having from 2 to 10 carbon atoms,
  • a hydroxyl group,
  • a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms;
  • a nitrogen-containing monocylic unsaturated hydrocarbon group,
  • a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
  • a piperazino group optionally substituted with a substituent(s) selected from the group consisting of:
      • an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
      • a formyl group,
      • an alkanoyl group having from 2 to 7 carbon atoms,
      • a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
      • an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, and
      • an alkylsulfonyl group having from 1 to 6 carbon atoms; and
  • Formula —NR7R8, wherein:
      • R7 and R8 each represent:
      • a hydrogen atom,
      • an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms,
      • an alkanoyl group having from 1 to 6 carbon atoms,
      • a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
      • a morpholinocarbonyl group,
      • an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
      • an alkylsulfonyl group having from 1 to 6 carbon atoms, or
  • R7 and R8 optionally form, together with the nitrogen atom to which said R7 and R8 are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  • 32. The compound of any one of Embodiments 23-30, or a salt thereof, wherein R3 is:
  • a 2-naphthyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;
  • a 3-pyrazolyl group, optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;
  • a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms;
  • an unsubstituted phenyl group; or
  • a substituted phenyl group (A), (B), or (C) below:
  • (A) a phenyl group substituted at 4 position with a substituent selected from the group consisting of:
      • an alkyl group having from 1 to 6 carbon atoms,
      • a cycloalkyl group having from 3 to 8 carbon atoms,
      • an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,
      • a halogen atom,
      • a trifluoromethoxy group,
      • a phenoxy group,
      • a phenyl group,
      • a 1-pyrrolyl group, and
      • —NRARB, wherein each of RA and RB is an alkyl group having from 1 to 6 carbon atoms, or RA and RB optionally form, together with the nitrogen atom to which said RA and RB are attached, a 3- to 5-membered saturated hydrocarbon ring,
  • wherein said phenyl group substituted at 4 position is further optionally substituted at 3 position with a substituent selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having from 1 to 6 carbon atoms;
  • (B) a phenyl group substituted at 3 position with a substituent selected from the group consisting of:
      • a hydroxyl group,
      • an alkyl group having from 1 to 6 carbon atoms, and
      • an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,
  • wherein said phenyl group substituted at 3 position is further optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or is further optionally substituted at 4 position with a halogen atom; and
  • (C) a phenyl group substituted at 3 position with a substituent selected from the group consisting of nitrogen-containing groups (i)-(v) below, said phenyl group further optionally substituted at 4 position with a halogen atom:
      • (i) a monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s), said saturated hydrocarbon group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
      • (ii) a nitrogen-containing monocylic unsaturated hydrocarbon group,
      • (iii) a morpholinyl group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
      • (iv) a piperazino group, optionally substituted with an alkanoyl group having from 2 to 7 carbon atoms or an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
        • an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms; and
        • a morpholino group, and
      • (v) Formula —NR7R8, wherein:
        • R7 and R8 each represent:
          • a hydrogen atom,
          • an alkyl group having from 1 to 6 carbon atoms, said alkyl group optionally substituted with an amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having from 1 to 6 carbon atoms;
          • an alkanoyl group having from 1 to 6 carbon atoms,
          • a carbamoyl group optionally substituted with one or two alkyl groups each having from 1 to 4 carbon atoms,
          • a morpholinocarbonyl group,
          • an aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or
          • an alkylsulfonyl group having from 1 to 6 carbon atoms, or
        • R7 and R8 optionally form, together with the nitrogen atom to which said R7 and R8 are attached, a 3- to 8-membered saturated hydrocarbon ring, said ring optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  • The present invention is described in detail as follows.
  • The term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • The term “alkyl group having from 1 to 6 carbon atoms” refers to a linear or branched alkyl group containing 1 to 6 carbon atoms. Examples include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, and a n-hexyl group.
  • The term “cycloalkyl group having from 3 to 8 carbon atoms” refers to a cycloalkyl group containing 3 to 8 carbon atoms. Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • The term “alkenyl group having from 2 to 8 carbon atoms” refers to a linear or branched alkenyl group containing 2 to 8 carbon atoms. Examples include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1,3-butadienyl group, a 2-methylallyl group, a 2-methyl-propenyl group, a 2-pentenyl group, and a 3-methyl-but-2-enyl group.
  • The term “alkynyl group having from 2 to 8 carbon atoms” refers to a linear or branched alkynyl group containing 2 to 8 carbon atoms. Examples include an ethynyl group, a 2-propynyl group, a 2-butynyl group, a 1-methyl-prop-2-ynyl group, a 2-pentynyl group, and a 4-pentynyl group.
  • The term “alkoxy group having from 1 to 6 carbon atoms” refers to a linear or branched alkoxy group containing 1 to 6 carbon atoms. Examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group.
  • The term “alkyl group having from 1 to 10 carbon atoms” refers to a linear or branched alkyl group containing 1 to 10 carbon atoms. Examples include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, and a n-hexadecyl group.
  • The term “alkylthio group having from 1 to 6 carbon atoms” refers to a linear or branched alkylthio group containing 1 to 6 carbon atoms. Examples include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a pentylthio group, and a hexylthio group.
  • The term “alkylsulfonyl group having from 1 to 6 carbon atoms” refers to a linear or branched alkylsulfonyl group containing 1 to 6 carbon atoms. Examples include a methanesulfonyl group, an ethanesulfonyl group, a propane-2-sulfonyl group, and a hexanesulfonyl group.
  • The term “alkoxycarbonyl group having from 2 to 10 carbon atoms” refers to a linear or branched alkoxycarbonyl group containing 2 to 10 carbon atoms. Examples include alkanoyl group having from 2 to 7 carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl group and a t-butoxycarbonyl group, as well as an octyloxycarbonyl group.
  • The term “alkanoyl group having from 2 to 7 carbon atoms” refers to a linear or branched alkanoyl group containing 2 to 7 carbon atoms. Examples include an acetyl group, a propanoyl group, a butanoyl group, and a hexanoyl group.
  • The term “alkanoyl group having from 1 to 6 carbon atoms” refers to a linear or branched alkanoyl group containing 1 to 6 carbon atoms. Examples include a formyl group, an acetyl group, a propanoyl group, and a butanoyl group.
  • The phrase “amino group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms” is intended to include, for example, an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a hexylamino group, a dimethylamino group, a diethylamino group, a diisopropylamino group, and a dihexylamino group.
  • The phrase “aminosulfonyl group optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms” is intended to include, for example, a sulfamoyl group, a dimethylaminosulfonyl group, and a diethylaminosulfonyl group.
  • The phrase “carbamoyl group optionally substituted with an alkyl group(s) having from 1 to 4 carbon atoms” is intended to include a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, and a propylcarbamoyl group.
  • The phrase “piperazino group which may be substituted” or “optionally substituted piperazino group” refers to a piperazino group which may be substituted (preferably on its nitrogen atom) with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (wherein said alkyl group may be substituted with an amino group which may be substituted with one or two alkyl groups each having 1-6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having 1-6 carbon atoms), a formyl group, an alkanoyl group having 2-7 carbon atoms, a carbamoyl group which may be substituted with one or two alkyl groups each having 1-4 carbon atoms, an aminosulfonyl group optionally substituted with one or two alkyl groups each having 1-6 carbon atoms, and an alkylsulfonyl group having 1-6 carbon atoms. Specific examples include a piperazino group, a methylpiperazino group, an isopropylpiperazino group, a dimethylaminoethylpiperazino group, and an acetylpiperazino group.
  • The term “monocylic saturated hydrocarbon group having from 2 to 7 carbon atoms and having a nitrogen atom(s) as a ring atom(s)” means a 3- to 9-membered monocylic saturated hydrocarbon group containing one or two nitrogen atoms as ring-forming atoms and substituted at a ring carbon atom. Examples of the monocylic saturated hydrocarbon group include aziridinyl groups, azetidinyl groups, pyrrolidinyl groups, and piperidinyl groups (e.g., 4-piperidinyl groups).
  • The term “nitrogen-containing monocyclic unsaturated hydrocarbon group” refers to a 5- or 6-membered unsaturated ring containing 1 to 3 nitrogen atoms as its ring members. Examples include a pyrrolyl group (e.g., a pyrrol-1-yl group), an imidazol-1-yl group (e.g., an imidazolyl group), a pyrazolyl group, a triazol-4-yl group (e.g., a [1,2,4]triazol-4-yl group), and a pyridyl group.
  • The 3- to 5-membered saturated hydrocarbon ring formed by RA and RB together with the nitrogen atom to which RA and RB are attached is intended to include an aziridinyl group, an azetidinyl group, and a pyrrolidinyl group.
  • The 3- to 8-membered saturated hydrocarbon ring formed by R7 and R8 (or RC and RD) together with the nitrogen atom to which R7 and R8 (or RC and RD) are attached is intended to include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group.
  • The term “aryl group” as used herein refers to an aromatic hydrocarbon group, a partially saturated aromatic hydrocarbon group, an aromatic heterocyclic group, or a partially saturated aromatic heterocyclic ring. The aromatic hydrocarbon group refers to, for example, an aromatic hydrocarbon group containing 6-14 carbon atoms, including a phenyl group, a naphthyl group, and an anthryl group.
  • The partially saturated aromatic hydrocarbon group refers to a group obtained by partial saturation of a polycyclic aromatic hydrocarbon group having 6-14 carbon atoms. Examples include a tetrahydronaphthyl group and an indanyl group.
  • The aromatic heterocyclic group refers to a monocylic or polycyclic aromatic heterocyclic group containing 2-13 carbon atoms and having 1-6 hetero atoms (e.g., oxygen, sulfur and/or nitrogen atoms). Examples include a thienyl group, a furanyl group, a pyrrolyl group, an isothiazolyl group, an isoxazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a benzothienyl group, a benzofuranyl group, an indolyl group, a benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group, a quinolinyl group, an isoquinolinyl group, a benzoxadiazolyl group, a benzothiadiazolyl group, and a pyrazolopyrimidinyl group (e.g., a 5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl group).
  • The partially saturated aromatic heterocyclic ring refers to a heterocyclic ring obtained by partial saturation of a polycyclic aromatic heterocyclic group. Such a heterocyclic ring may be substituted with an oxo group. Examples include a dihydroquinolinonyl group:
  • Figure US20110269960A1-20111103-C00004
  • a dihydrobenzofuranyl group, a dihydrobenzodioxinyl group, a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzoxazolyl group, and a dihydrobenzoxazinyl group.
  • In a case where such an aryl group is substituted, substituents for the aryl group include those listed below and the aryl group can be substituted with 1 to 5 of these substituents:
  • a halogen atom, a cyano group, a nitro group, a sulfamoyl group, a hydroxyl group, a carboxyl group, an alkyl group having 1-6 carbon atoms, a trifluoromethyl group, a methoxycarbonylethyl group, an alkoxy group having 1-6 carbon atoms (the alkoxy group is optionally substituted with a phenyl group, an alkylamino group having 1-6 carbon atoms, a dialkylamino group having 2-12 carbon atoms, or a morpholino group), a trifluoromethoxy group, a difluoromethoxy group, a cyanoethoxy group,
  • an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms,
  • a cycloalkyl group having 3-8 carbon atoms, an alkanoyl group having 2-7 carbon atoms, a trifluoroacetyl group, an alkoxycarbonyl group having 2-10 carbon atoms,
  • a phenyl group (the phenyl group is optionally substituted with an alkanoyl group having 2-7 carbon atoms or an alkoxy group having 1-6 carbon atoms),
  • a phenoxy group optionally substituted with an alkoxy group having 1-6 carbon atoms,
  • a pyrazolyl group, a 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl group, a methylpyrimidinyl group, a 2-methylsulfanyl-pyrimidin-4-yl groups, an oxazolyl group (e.g., oxazol-5-yl group), an isooxazol-5-yl group, a 5-trifluoromethyl-isooxazol-3-yl group, a pyridyloxy group (e.g., 4-pyridyloxy group), a pyridinecarbonyl group, a benzoyl group, a pyrrolyl group (e.g., pyrrol-1-yl group), an imidazolyl group (e.g., imidazol-1-yl group), a thiazolyl group, a [1,2,3]thiadiazol-4-yl group, a triazolyl group (e.g., [1,2,4]triazol-4-yl group), an alkylthio group having 1-6 carbon atoms (e.g., methylthio group), an alkylsulfonyl group having 1-6 carbon atoms (e.g., methanesulfonyl group), a benzenesulfonyl group, a pyrrolidinesulfonyl group, a morpholinylsulfonyl group, a 4-piperidinyl group optionally substituted with an alkyl group having 1-6 carbon atoms, a morpholino group optionally substituted with an alkyl group having 1-6 carbon atoms, a piperazino group substituted with an alkyl group having 1-6 carbon atoms or an alkyl group having 1-6 carbon atoms and substituted with a dimethylamino group, or a group represented by Formula —NR7R8, where R7 and R8 each represent a hydrogen atom, an alkyl group having 1-6 carbon atoms (the alkyl group is optionally substituted with an alkoxy group having 1-6 carbon atoms or a dimethylamino group), an alkanoyl group having 1-6 carbon atoms, a carbamoyl group, a carbamoyl group substituted with an alkyl group(s) having 1-4 carbon atoms, a morpholinocarbonyl group, a dimethylaminosulfonyl group, or an alkylsulfonyl group having 1-6 carbon atoms, or R7 and R8 optionally form, together with the nitrogen atom to which R7 and R8 are attached, to form a 3- to 8-membered saturated hydrocarbon ring, which ring is optionally substituted with a dimethylenedioxy group, an oxo group, or a hydroxyl group, (e.g., acetamide groups, dimethylamino groups, methylureido groups, butylureido groups, trimethylureido groups, morpholinylcarbonylamino), a methoxyethylureido group, a pyridylethoxycarbonylamino group.
  • The term “pharmaceutically acceptable salt” refers to a salt with an alkali metal, an alkaline earth metal, ammonium or an alkylammonium, or a salt with a mineral acid or an organic acid. Examples include a sodium salt, a potassium salt, a calcium salt, an ammonium salt, an aluminum salt, a triethylammonium salt, an acetate salt, a propionate salt, a butyrate salt, a formate salt, a trifluoroacetate salt, a maleate salt, a tartrate salt, a citrate salt, a stearate salt, a succinate salt, an ethylsuccinate salt, a lactobionate salt, a gluconate salt, a glucoheptate salt, a benzoate salt, a methanesulfonate salt, an ethanesulfonate salt, a 2-hydroxyethanesulfonate salt, a benzenesulfonate salt, a paratoluenesulfonate salt, a lauryl sulfate salt, a malate salt, an aspartate salt, a glutamate salt, an adipate salt, a salt with cysteine, a salt with N-acetylcysteine, a hydrochloride salt, a hydrobromide salt, a phosphate salt, a sulfate salt, a hydroiodide salt, a nicotinate salt, an oxalate salt, a picrate salt, a thiocyanate salt, an undecanoate salt, a salt with an acrylate polymer, and a salt with a carboxyvinyl polymer.
  • The compounds of the present invention may have stereoisomers including optical isomers, diastereoisomers and geometrical isomers. All of these stereoisomers and mixtures thereof also fall within the scope of the present invention. Some of the compounds and intermediates of the present invention may also exist, e.g., as keto-enol tautomers.
  • As shown in Test Example below, the compounds of the present invention show strong activity in an action of inhibiting binding between SIP and its receptor, Edg-1 (S1P1). Thus, the compounds are expected to have preventive or therapeutic effects on autoimmune, diseases, such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, and age-related macular degeneration.
  • Preferred embodiments of the compound of the present invention are described as follows.
  • A preferred example of A is an oxygen atom or —NR6— (it is preferable that R6 be hydrogen). A more preferred example of A is an oxygen atom.
  • A preferred example of R1 is an alkyl group having 1-6 carbon atoms which may be substituted with a halogen atom(s), or a benzyl group which may be substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having 1-6 carbon atoms. More preferred is a methyl group, an ethyl group, or a benzyl group which may be substituted with a halogen atom(s), and even more preferred is a methyl group.
  • A preferred example of R1A is a hydrogen atom.
  • Preferred examples of R2 are an ethyl group and a cyclopropyl group.
  • A preferred example of R4 is a hydrogen atom.
  • In a preferred embodiment, R3 is: a optionally substituted phenyl group; a 2-naphthyl group (the naphthyl group is optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having 1-6 carbon atoms); a 3-pyrazolyl group (the pyrazolyl group is optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, and a halogen atom); or a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group (preferably a 6-indolyl group), each optionally substituted with an alkyl group(s) having 1-6 carbon atoms (preferably a methyl group).
  • The “optionally substituted phenyl group” in the preferred embodiment of R3 includes unsubstituted phenyl groups and substituted phenyl groups (A)-(C) below:
  • (A) a phenyl group substituted at 4 position with a substituent selected from the group consisting of an alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-8 carbon atoms, an alkoxy group having 1-6 carbon atoms (the alkoxy group is optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having 1-4 carbon atoms, a morpholino group, and a phenyl group), a halogen atom, a trifluoromethoxy group, a phenoxy group, a phenyl group, a 1-pyrrolyl group, and —NRARB (RA and RB are alkyl groups each having 1-6 carbon atoms, or RA and RB optionally form, together with the nitrogen atom to which RA and RB are attached, a 3- to 5-membered saturated hydrocarbon ring), which phenyl group substituted at 4 position is optionally further substituted at 3 position with a substituent selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, and an alkoxy group having 1-6 carbon atoms;
    (B) a phenyl group substituted at 3 position with a substituent selected from the group consisting of a hydroxyl group, an alkyl group having 1-6 carbon atoms, and an alkoxy group having 1-6 carbon atoms (the alkoxy group is optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having 1-4 carbon atoms, a morpholino group, and a phenyl group), which phenyl group substituted at 3 position is optionally further substituted with one or two alkyl groups each having 1-6 carbon atoms, or is optionally further substituted at 4 position with a halogen atom; and
    (C) a phenyl group substituted at 3 position with a substituent selected from the group consisting of nitrogen-containing groups (i)-(v) below and, in some cases, optionally further substituted at 4 position with a halogen atom, which nitrogen-containing groups preferably have a tertiary nitrogen and are attached to the phenyl group at a nitrogen atom:
      • (i) a monocylic saturated hydrocarbon group having 2-7 carbon atoms, having a nitrogen atom(s) as a ring atom(s), and substituted with a phenyl group at a carbon atom (the saturated hydrocarbon group is optionally substituted with an alkyl group(s) having 1-6 carbon atoms) (e.g., a piperidinyl group optionally substituted with an alkyl group(s) having 1-6 carbon atoms, such as a 4-piperidinyl group);
      • (ii) a nitrogen-containing monocylic unsaturated hydrocarbon group (e.g., a pyrrolyl group, an imidazolyl group);
      • (iii) a morpholinyl group optionally substituted with an alkyl group(s) having 1-6 carbon atoms, such as a morpholino group;
      • (iv) an optionally substituted piperazino group (e.g., a piperazino group optionally substituted (preferably on a nitrogen atom constituting a ring) with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (the alkyl group is optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having 1-4 carbon atoms, and a morpholino group), and an alkanoyl group having 2-7 carbon atoms); and
      • (v) Formula —NR7R8, in which R7 and R8 each represent a hydrogen atom, an alkyl group having 1-6 carbon atoms (the alkyl group is optionally substituted with an amino group optionally substituted with one or two alkyl groups each having 1-6 carbon atoms, a morpholino group, a hydroxyl group, or an alkoxy group having 1-6 carbon atoms), an alkanoyl group having 1-6 carbon atoms, a carbamoyl group optionally substituted with one or two alkyl groups each having 1-4 carbon atoms, a morpholinocarbonyl group, an aminosulfonyl group optionally substituted with one or two alkyl groups each having 1-6 carbon atoms, or an alkylsulfonyl group having 1-6 carbon atoms, or R7 and R8 optionally form, together with the nitrogen atom to which R7 and R8 are attached, a 3- to 8-membered saturated hydrocarbon ring, which ring is optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  • It is preferable that Formula —NR7R8 in item (v) above be —NRCRD as defined below.
  • RC and RD each represent a hydrogen atom, an alkyl group having 1-6 carbon atoms (the alkyl group is optionally substituted with an amino group optionally substituted with one or two alkyl groups each having 1-4 carbon atoms, a hydroxyl group, or an alkoxy group having 1-4 carbon atoms), a formyl group, an acetyl group, an aminocarbonyl group, a dimethylaminosulfonyl group, or a methylsulfonyl group, or RC and
  • RD optionally form, together with the nitrogen atom to which RC and RD are attached, a 3- to 8-membered saturated hydrocarbon ring, which ring is optionally substituted with a substituent(s) selected from the group consisting of a dimethylenedioxy group, an oxo group, and a hydroxyl group.
  • In an especially preferred embodiment, R3 is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom, a 6-indolyl group, and nitrogen-containing groups (i), (iv), and (v) shown in item (C) above, which phenyl group substituted with a substituent selected from the above group is optionally further substituted at 4 position with a halogen atom.
  • In a preferred embodiment, R5 is: an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a cycloalkyl group having 3-8 carbon atoms; an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a phenyl group or a naphthyl group (preferably 2-naphthyl group) each optionally substituted with 1-5 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, an alkoxy group having 1-6 carbon atoms, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms, an alkylsulfonyl group having 1-6 carbon atoms, an alkanoyl group having 2-7 carbon atoms, an alkoxycarbonyl group having 2-7 carbon atoms, and a cyano group; a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a methoxycarbonyl group; a furanyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, and a halogen atom; a thienyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; or a benzothienyl group (preferably a 2-benzothienyl group), a phenyl group condensed with a 5- to 7-membered saturated hydrocarbon ring which may contain one or two oxygen atoms as ring-forming atoms (e.g., a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group), a thiadiazolyl group, a benzoxadiazolyl group, or a benzothiadiazolyl group (preferably 5-benzothiadiazolyl groups), each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a halogen atom.
  • In a preferred embodiment of R5, examples of the “phenyl group which is optionally substituted” include an unsubstituted phenyl group, a phenyl group substituted with 1-5 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), an alkoxy group having 1-6 carbon atoms (preferably a methoxy group), and a halogen atom, and a phenyl group substituted at either 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, an alkoxy group having 1-6 carbon atoms (preferably a methoxy group), a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms, an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group), a methoxycarbonyl group, an acetyl group, and a cyano group, preferably a halogen atom, a methyl group, and a methoxy group, and more preferably a halogen atom.
  • In a preferred embodiment of R5, an example of the “naphthyl group which is optionally substituted” is a naphthyl group optionally substituted with a substituent(s) (preferably 1-3 substituents) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group). More preferably, it is a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), and a cyano group. Examples in a case of a 2-naphthyl group include an unsubstituted 2-naphthyl group and a 2-naphthyl group substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (substituted at any position, preferably at 5, 7 and/or 8 position) and other substituents (substituted at 5, 7 and/or 8 position). Examples in a case of a 1-naphthyl group include an unsubstituted 1-naphthyl group and a 1-naphthyl group substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (substituted at any position) and other substituents, preferably a halogen atom (substituted preferably at 4 position).
  • In an especially preferred embodiment, R5 is a phenyl group substituted at 3 and 4 positions with a halogen atom, an unsubstituted 2-naphthyl group, and a 2-naphthyl group substituted at 5, 7 and/or 8 position with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), and a cyano group.
  • The following are combinations of R3 and R5 that are especially preferred. In a case in which R3 is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom, R5 is: an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a substituted phenyl group (e.g., a phenyl group substituted with 1-5 methyl groups, a phenyl group substituted at either 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 a carbon atom (preferably a methyl group, an ethyl group, a propyl group), a halogen atom, a methoxy group, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms (preferably a vinyl group), a methoxycarbonyl group, an acetyl group, and a cyano group; a benzothienyl group; a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group); a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of a methyl group and a methoxycarbonyl group; a thienyl group substituted with an alkyl group(s) having 1-6 carbon atoms (preferably a methyl group); a benzodioxolyl group; a dihydrobenzodioxynyl group; a dihydrobenzofuranyl group; a tetrahydronaphthyl group; an indanyl group; or a benzothiadiazolyl group (preferably a 5-benzothiadiazolyl group).
  • In a case in which R3 is a 6-indolyl group, R5 is: an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a phenyl group which is optionally substituted (e.g., an unsubstituted phenyl group, a phenyl group substituted with 1-5 methyl groups, a phenyl group substituted at either 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group, an ethyl group, a propyl group), a halogen atom, a methoxy group, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms (preferably a vinyl group), a methoxycarbonyl group, an acetyl group, and a cyano group); a benzothienyl group; a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group); a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a methoxycarbonyl group; or a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, or a benzothiadiazolyl group (preferably, 5-benzothiadiazolyl group), each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a halogen atom.
  • In a case in which R3 is of the embodiment shown in item (C) above, R5 is: an alkyl group having 1-6 carbon atoms and substituted with a cycloalkyl group having 3-8 carbon atoms; an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted with a naphthyl group; an alkenyl group having 2-8 carbon atoms (preferably 2-6 carbon atoms) and substituted with a phenyl group; a optionally substituted phenyl group (e.g., an unsubstituted phenyl group, a phenyl group substituted with 1-5 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a halogen atom, a phenyl group substituted at 3 or 4 position or both and substituted with 1-3 substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms, a halogen atom, a methoxy group, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkenyl group having 1-6 carbon atoms, an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group), a methoxycarbonyl group, an acetyl group, and a cyano group; a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having 1-6 carbon atoms (preferably a methyl group), a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms (preferably a methylsulfonyl group); a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a methoxycarbonyl group; a thienyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; a furanyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group), a trifluoromethyl group, and a halogen atom; or a benzothienyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group (preferably a 5-thiadiazolyl group), a benzoxadiazolyl group, or a benzothiadiazolyl group (preferably a 5-benzothiadiazolyl group), each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having 1-6 carbon atoms (preferably a methyl group) and a halogen atom.
  • A preferred optically-active compound of the present compound having R1A being a hydrogen atom has the structure below.
  • Figure US20110269960A1-20111103-C00005
  • The compound of the present invention can be synthesized by, for instance, the method described below.
  • Figure US20110269960A1-20111103-C00006
  • (where R1, R1A, R2, R3, and R5 are as defined above, R′ represents an alkyl group having 1-6 carbon atoms, R″ represents a protecting group for an amino group, which protecting group is stable under a basic condition (e.g., a t-butoxycarbonyl group, a benzyloxycarbonyl group), L represents a leaving group (e.g., a halogen atom, such as a chlorine atom, a bromine atom, and an iodine atom, an alkylsulfonyloxy group, such as an a methanesulfonyloxy group and a p-toluenesulfonyloxy group, an arylsulfonyloxy group, a 2-oxo-1-oxazolyl group), and A1 represents an oxygen atom, a sulfur atom, or a group represented by —NR6—, where R6 represents a hydrogen atom or an alkyl group having 1-6 carbon atoms.)
  • In the present invention, a compound having A being an oxygen atom, a sulfur atom, or a group represented by —NR6— can be synthesized by, for instance, the method shown in Scheme 1.
  • The compound represented by Formula (b) can be obtained by allowing the compound represented by Formula (a) to react with hydrazine in a solvent or in the absence of a solvent. The amount of the hydrazine used is generally 1-30 equivalent weight with respect to Compound (a), preferably 5-30 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include alcohols such as methanol and ethanol. The reaction temperature is generally a room temperature to a solvent reflux temperature. The reaction time is generally 12-24 hours, but it depends on the reaction temperature and starting compounds.
  • The compound represented by Formula (d) can be obtained by allowing the compound represented by Formula (b) to react with the compound represented by Formula (c) in a solvent or in the absence of a solvent. The amount of the compound represented by Formula (c) to be used is generally 1-3 equivalent weight with respect to the compound represented by Formula (b), preferably 1.1-1.5 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. For instance, alcohols, such as methanol and ethanol, and halogenated hydrocarbons, such as dichloromethane and chloroform, are preferably used. The reaction temperature is generally a room temperature to a solvent reflux temperature. The reaction time is generally 30 minutes to 24 hours, but it depends on the reaction temperature and starting compounds.
  • The compound represented by Formula (e) can be obtained by allowing the compound of Formula (d) to react with a base in a solvent or in the absence of a solvent to cyclize. The base to be used includes alkali metal hydroxides such as NaOH and KOH, and alkali metal salts such as NaHCO3 and K2CO3. The amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (d), preferably 1.1-1.5 equivalent weight. If a solvent is necessary, the following can be used as the solvent: water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran (THF), and mixed solvents thereof. The reaction temperature is generally a room temperature to a solvent reflux temperature. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compounds.
  • The compound represented by Formula (g) can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (e) to react with the compound represented by Formula (f) in the presence of a base. The amount of the compound represented by Formula (f) to be used is generally 1-5 equivalent weight, preferably 1.1-1.5 equivalent weight, with respect to the compound represented by Formula (e). The base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO3 and K2CO3, and amines, such as triethylamine, diisopropylethylamine, and diisopropylamine. The amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (e), preferably 1.0-3.0 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include water, ethers such as dioxane and THF, dimethylformamide (DMF), N,N′-dimethylacetamide (DMA), N,N′-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), and mixed solvents thereof. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compounds.
  • The compound represented by Formula (h) can be obtained by allowing the compound represented by Formula (g) to react with an oxidant in a solvent. Examples of the solvent to be used include organic peroxyacids such as m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peroxyacetic acid, and peroxyformic acid, inorganic or organic peroxides such as hydrogen peroxide, hydrogen peroxide urea adduct/phthalic anhydride, tert-butylhydroperoxide, and cumenehydroperoxide, sodium periodate, Oxone (registered trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, hypochlorite tert-butyl, iodobenzene diacetate, and bromine-1,4-diazabicyclo[2,2,2]octane addition complex. The amount of the oxidant used is 2-10 equivalent weight with respect to the compound represented by Formula (g), preferably 2-3 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C.-40° C. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • The compound represented by Formula (i) or a salt of the compound can be obtained by subjecting the compound represented by Formula (h) to deprotection of an amino group in a solvent under a conventional condition, e.g., allowing it to react with an acid. Examples of the acid used include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) and organic acids (e.g., trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid). The amount of the acid used is 1-50 equivalent weight with respect to the compound represented by Formula (h). The reaction temperature is 0° C. to a solvent reflux temperature, preferably a room temperature to 40° C. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • The compound represented by Formula (k) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (i) to react with the compound represented by Formula (j) (where A1 represents an oxygen atom, a sulfur atom, or a group represented by Formula —NR6—, and R3 is as defined above) in the presence of a base and, when necessary, forming a salt. The amount of the compound of Formula (j) to be used is generally 1-5 equivalent weight with respect to the compound represented by Formula (i), preferably 1-3 equivalent weight. Examples of the base used include alkali metal salts, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, dimsyl sodium, sodium hydride, sodium amide, tert-butoxypotassium, and tert-butoxysodium, amines, such as triethylamine, diisopropylamine, pyrrolidine, and piperidine, sodium acetate, and potassium acetate. The amount of the base used is generally 1-10 equivalent weight with respect to the compound represented by Formula (i), preferably 1-3 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, and it can be carried out under ordinary pressure, increased pressure, microwave irradiation, or the like. The reaction solvent to be used includes ethers such as dioxane and THF, DMF, DMA, DMPU, RMPA, or the like, or mixed solvents thereof. The reaction time is generally a period of 1-12 hours, but it depends on the reaction temperature and starting compound.
  • The compound represented by Formula (m) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (k) to react with the compound represented by Formula (l) in the presence of a base and, when necessary, forming a salt. The amount of the compound represented by Formula (l) used is 1-5 equivalent weight with respect to the compound represented by Formula (k), preferably 1-1.2 equivalent weight. The base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO3 and K2CO3, or amines, such as triethylamine, diisopropylethylamine, and diisopropylamine. The amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (k), preferably 1.0-3.0 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as dioxane and THF, and mixed solvents thereof. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • Figure US20110269960A1-20111103-C00007
    Figure US20110269960A1-20111103-C00008
  • (where R1, R1A, R2, R3, R4, R5, R′, R″, A, and L are as defined above, R41 is the same as R4 excluding the hydrogen atom).
  • In the present invention, a compound having A represented by Formula —SO— or Formula —SO2— can be synthesized by the method shown in Scheme 2.
  • The compound represented by Formula (m2), the compound represented by Formula (m3), or pharmaceutically acceptable salts of the compounds can be obtained by allowing, among the compounds obtained in Scheme 1 and represented by Formula (m), the compound represented by Formula (m1) having A1 being a sulfur atom to react with an oxidant and, when necessary, forming a salt. Examples of the oxidant to be used include organic peroxyacids such as m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peroxyacetic acid, and peroxyformic acid, inorganic or organic peroxides such as hydrogen peroxide, hydrogen peroxide urea adduct/phthalic anhydride, tert-butylhydroperoxide, and cumenehydroperoxide, sodium periodate, Oxone (registered trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, hypochlorite tert-butyl, iodobenzene diacetate, and bromine-1,4-diazabicyclo[2,2,2]octane addition complex. The amount of the oxidant used is 1-10 equivalent weight with respect to the compound represented by Formula (m1), preferably 1-3 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is −78° C. to a solvent reflux temperature, preferably 0°-40° C. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • In the present invention, a compound having A represented by —CH2— can be synthesized by the method shown in Scheme 3.
  • The compound represented by Formula (o) can be obtained by allowing the compound represented by Formula (a) to react with the compound represented by Formula (n) (R2 is as defined above) in a solvent or in the absence of a solvent. The amount of the compound represented by Formula (n) to be used is 1-10 equivalent weight with respect to the compound represented by Formula (a), preferably 1-1.2 equivalent weight. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include alcohols such as methanol and ethanol. The reaction temperature is generally a room temperature to a solvent reflux temperature, preferably a room temperature to 50° C. The reaction time is generally a period of 12-24 hours, but it depends on the reaction temperature and starting compound.
  • The compound represented by Formula (p) can be obtained by allowing the compound represented by Formula (o) to react with a Lawesson's reagent in a solvent or in the absence of a solvent. The amount of the Lawesson's reagent used is 1-5 equivalent weight with respect to the compound represented by Formula (o), preferably 1-1.2 equivalent weight. The reaction solvent to be used includes ethers such as dioxane and THF, and mixed solvents thereof. The reaction temperature is a room temperature to a solvent reflux temperature, preferably a room temperature to 50° C. The reaction time is generally 1-12 hours, but it depends on the reaction temperature and starting compounds.
  • The compound represented by Formula (r) can be obtained by allowing the compound represented by Formula (p) to react with the compound represented by Formula (q) in the presence of a mercury compound. The amount of the compound represented by Formula (q) to be used is 1-10 equivalent weight with respect to the compound represented by Formula (p), preferably 1-1.2 equivalent weight. Examples of the mercury compound include HgCl2 and Hg(OAc)2. The amount of the mercury compound used is 1-10 equivalent weight with respect to the compound represented by Formula (p), preferably 1-1.2 equivalent weight. The solvent to be used includes acetonitrile, THF, dioxane, and the like. The reaction temperature is a room temperature to a solvent reflux temperature, preferably a room temperature to 50° C. The reaction time is generally a period of 12-48 hours, but it depends on the reaction temperature and starting compound.
  • The compound represented by Formula (k1) or a salt of the compound can be obtained by subjecting the compound represented by Formula (r) to deprotection of an amino group in a solvent under a conventional condition, e.g., allowing it to react with an acid. Examples of the acid include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) and organic acids (e.g., trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid). The amount of the acid used is 1-50 equivalent weight with respect to the compound represented by Formula (r). The reaction temperature is 0° C. to a solvent reflux temperature, preferably a room temperature to 40° C. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • The compound represented by Formula (m4) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (k1) to react with the compound represented by Formula (l) in the presence of a base and, when necessary, forming a salt. The amount of the compound represented by Formula (l) to be used is 1-5 equivalent weight with respect to the compound represented by Formula (k1), preferably 1-1.2 equivalent weight. The base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO3 and K2CO3, and amines, such as triethylamine, diisopropylethylamine, and diisopropylamine. The amount of the base is 1-10 equivalent weight, preferably 1.0-3.0 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as dioxane and THF, and mixed solvents thereof. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • The compound represented by Formula (u) or a pharmaceutically acceptable salt of the compound can be obtained by allowing, in a solvent or in the absence of a solvent, the compound represented by Formula (m5) to react with the compound represented by Formula (s) in the presence of a base and, when necessary, forming a salt. The amount of the compound represented by Formula (s) to be used is generally 1-10 equivalent weight with respect to the compound represented by Formula (m5), preferably 1.1-1.5 equivalent weight. The base to be used includes alkali metal hydroxides, such as NaOH and KOH, alkali metal salts, such as NaHCO3 and K2CO3, and amines, such as triethylamine, diisopropylethylamine, and diisopropylamine. The amount of the base used is 1-10 equivalent weight with respect to the compound represented by Formula (m5), preferably 1.0-3.0 equivalent weight. The reaction temperature is 0° C. to a solvent reflux temperature, preferably 0° C. to a room temperature. A solvent to be used when it is necessary is not particularly limited, as long as it is inert. Examples of the solvent to be used include water, ethers such as dioxane and THF, dimethylformamide (DMF), N,N′-dimethylacetamide (DMA), N,N′-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), and mixed solvents thereof. The reaction time is generally a period of 30 minutes to 24 hours, but it depends on the reaction temperature and starting compound.
  • Further, a functional group can be introduced to R3 by carrying out protection, deprotection, functional group transformation in the process described above.
  • For use as pharmaceutical preparations, the compounds of the present invention may be supplemented with commonly used excipients, extenders, pH regulators, solubilizers and so on, and then formulated using standard techniques into tablets, granules, pills, capsules, powders, solutions, suspensions, injections, etc. The pharmaceutical preparations thus obtained can be administered as oral or parenteral formulations.
  • The compound of the present invention can be administered to an adult patient at a dose of 1-1000 mg per day in several separated doses. This dosage can be increased or reduced according to a type of a disease, an age, a weight, and a symptom of a patient, or the like.
    • Advantageous Effect of the Invention
  • As the Test Example described below shows, it is found that the compounds of the present invention are strong Edg-1 (S1P1) ligands.
    • BEST MODE FOR CARRYING OUT THE INVENTION
  • The following describes the present invention in more detail, with reference to Examples and the Test Example.
    • Example 1 3,4-Dichloro-N—{(R)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl]ethyl}benzenesulfonamide (Compound 12)
  • Figure US20110269960A1-20111103-C00009
    • (R)-(1-Hydrazinocarbonyl-2-ethyl)carbamic acid t-butyl ester
  • Figure US20110269960A1-20111103-C00010
  • (1) Hydrazine monohydrate (30 ml) was added to a solution of N-(t-butoxycarbonyl)-D-alanine methyl ester (41.8 g) in methanol (180 ml), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the resulting crude crystal was washed with a mixed solvent of hexane and ethyl acetate (1:1, 300 ml) and then dried to give the titled compound as a colorless powder (32.6 g).
  • 1H NMR (300 MHz, DMDO-d6) δ ppm: 1.14 (d, J=7.2 Hz, 3H), 1.37 (s, 9H), 3.30-4.09 (m, 3H), 6.70-6.90 (m, 1H), 8.96 (br s, 1H)
    • (R)-2-(N-(t-Butoxycarbonyl)amino)propionyl)-N-ethylhydrazinecarbothioamide
  • Figure US20110269960A1-20111103-C00011
  • (2) Ethyl isothiocyanate (14.6 ml) was added to a solution of the compound (30.8 g) of Example 1-(1) in ethanol (152 ml), and the mixture was heated under reflux for two hours. Then, the mixture was cooled to room temperature, and the resulting crystal was filtered. The filtrate was concentrated, and the resulting residue was purified by silica-gel chromatography with a mixed solvent of ethyl acetate and chloroform to give the titled compound as a colorless amorphous substance (43.2 g).
  • 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98-1.28 (m, 6H), 1.40 (s, 9H), 3.25-3.65 (m, 2H), 3.77-3.95 (m, 1H), 7.20-7.39 (m, 1H), 7.45-7.60 (m, 1H), 9.25 (s, 1H), 10.00 (s, 1H)
    • [(R)-1-(4-Ethyl-5-mercapto-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester
  • Figure US20110269960A1-20111103-C00012
  • (3) One mol/l aqueous sodium hydroxide (218 ml) was added to a mixed solution of the compound (42.1 g) of Example 1-(2) in methanol (120 ml) and dioxane (240 ml), and the mixture was heated under reflux for three hours. The reaction solution was concentrated, and an aqueous hydrochloric acid (2N, 100 ml) was added. The mixture was extracted with a mixed solution of ethyl acetate, chloroform, and methanol (10:10:1, 500 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The resulting residue was washed with a mixed solvent of hexane and ethyl acetate (1:1, 300 ml) and then dried to give the titled compound as a white solid (29.22 g).
  • 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.21 (t, J=7.1 Hz, 3H), 1.30-1.50 (m, 3H), 1.39 (s, 9H), 3.82-4.05 (m, 2H), 4.72-4.88 (m, 1H), 7.58 (d, J=8.5 Hz, 1H), 13.60 (br s, 1H
    • [(R)-1-(4-Ethyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester
  • Figure US20110269960A1-20111103-C00013
  • (4) Diisopropylamine (17.4 ml) and MeI (7.7 ml) were added to a solution of the compound (28.12 g) of Example 1-(3) in THF (200 ml), and the mixture was stirred at room temperature for one hour. Thereafter, the resulting crystal was filtered. The filtrate was concentrated, and the resulting crude crystal was washed with a mixed solvent of hexane and ethyl acetate (3:1, 200 ml) and then dried to give the titled compound as a white powder (29.5 g).
  • 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.21 (t, J=7.0 Hz, 3H), 1.38 (s, 9H), 1.45 (t, J=7.0 Hz, 3H), 2.62 (s, 3H), 3.80-4.00 (m, 2H), 4.85-4.92 (m, 1H), 7.52 (d, J=8.5 Hz, 1H)
    • [(R)-1-(4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester
  • Figure US20110269960A1-20111103-C00014
  • (5) With ice cooling, m-chloroperbenzoic acid (43.0 g) was added in four portions to a solution of the compound (21.0 g) of Example 1-(4) in chloroform (293 ml), and the mixture was stirred at room temperature for three hours and thereafter at 40° C. for one hour. Na2S2O3 (12.9 g) and 1 mol/l aqueous sodium hydroxide (300 ml) were added to the reaction solution to separate the organic layer, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica-gel flush column chromatography with a mixed solvent of hexane and ethyl acetate, and then recrystallized with hexane and chloroform to give the titled compound as a white powder (17.2 g).
  • 1H NMR (300 MHz, CDCl3) δ ppm: 1.44 (s, 9H), 1.49 (t, J=7.1 Hz, 3H), 1.67 (t, J=6.8 Hz, 3H), 3.53 (s, 3H), 4.25-4.59 (m, 2H), 4.92-5.20 (m, 2H)
    • (R)-1-(4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethylamine trifluoroacetic acid salts
  • Figure US20110269960A1-20111103-C00015
  • (6) Trifluoroacetic acid (121 ml) was added to the compound (100.0 g) obtained in Example 1-(5), and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to give the titled compound as a white powder (103.8 g).
  • 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J=7.2 Hz, 3H), 1.59 (d, J=6.8 Hz, 3H), 3.65 (s, 3H), 4.21-4.50 (m, 2H), 4.72-4.90 (m, 1H), 8.69 (br s, 3H)
    • (1R)-1-(4-Ethyl-5(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl)ethylamine
  • Figure US20110269960A1-20111103-C00016
  • (7) In a pressure-resistant screw cap test tube,
    • N,N′-dimethylpropyleneurea (DMPU) (5 mL), 4-fluorophenol (1.01 g) and cesium carbonate (2.94 g) were added to the compound (1.00 g) obtained in Example 1-(6), and the mixture was stirred at 200° C. for one hour. The mixture was brought to room temperature, and saturated aqueous sodium chloride was added. The mixture was extracted with ethyl acetate (100 ml×5). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH SiO2, hexane/ethyl acetate=50/50 to 20/80, chloroform/methanol=30/1) to give the titled compound (brown oil compound, 0.586 g).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.41 (t, J=7.3 Hz, 3H), 1.58 (d, J=6.4 Hz, 3H), 3.95-4.23 (m, 3H), 6.90-7.15 (m, 2H), 7.30-7.44 (m, 2H)
    • 3,4-Dichloro-N-{(R)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl]ethyl}benzenesulfonamide (Compound 12)
  • Figure US20110269960A1-20111103-C00017
  • (8) Triethylamine (0.93 mL, 6.64 mmol) and 3,4-dichlorobenzenesulfonyl chloride (0.45 mL, 2.88 mmol) were added at room temperature to a solution of the compound (0.554 g) of Example 1-(7) in THF (10 mL), and the mixture was stirred at room temperature for 2.5 hours. Then, ethyl acetate was added. The organic layer was washed with 1N aqueous hydrochloric acid and thereafter with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH SiO2, hexane/ethyl acetate=50/50 to 10/90) and then recrystallized (ethyl acetate-hexane) to give 0.447 g of the titled compound (Compound 12) as a colorless powder.
  • Melting point: 190.0° C. to 192.0° C.
    • Example 2 N-[(1R)-1-(4-Ethyl-5(4-methylphenylamino)-4H-[1,2,4]triazol-3-yl)ethyl]3,4-dichlorobenzenesulfonamide (Compound 61)
  • Figure US20110269960A1-20111103-C00018
    • (R)-1-(4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethylamine
  • Figure US20110269960A1-20111103-C00019
  • (1) To the compound (4.30 g) obtained in Example 1-(6), n-BuNH2 (20 ml) was added, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, and the resulting crude product was purified by NH silica-gel chromatography with a mixed solvent of methanol and chloroform (methanol/chloroform=10%) to give the titled compound as a colorless crystal (2.737 g).
  • 1H NMR (200 MHz, CDCl3) δ ppm: 1.53 (t, J=7.3 Hz, 3H), 1.65 (d, J=6.8 Hz, 3H), 3.53 (s, 3H), 4.14-4.58 (m, 3H)
    • [5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-4-methylphenylamine
  • Figure US20110269960A1-20111103-C00020
  • (2) The compound (437 mg) obtained in Example 2-(1), DMPU (2.0 mL), 4-toluidine (257 mg), and NaH (240 mg, 60-72 wt % oily) were put in a pressure-resistant screw cap test tube. The mixture was stirred at 200° C. for 1.0 hour and then brought to room temperature, and 10% methanol/chloroform was added to the reaction solution. The reaction solution was filtered through NH silica gel and then concentrated, and the resulting brown oily substance was purified by column chromatography (NH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=5%) to give the titled compound (brown oil compound, 224 mg).
  • 1H NMR (200 MHz, CDCl3) δ ppm: 1.31 (t, J=7.3 Hz, 3H), 1.60 (d, J=6.6 Hz, 3H), 2.28 (s, 3H), 3.60-4.30 (m, 3H), 6.96-7.02 (m, 4H)
    • N-[(1R)-1-(4-Ethyl-5(4-methylphenylamino)-4H-[1,2,4]triazol-3-yl)ethyl]3,4-dichlorobenzenesulfonamide (Compound 61)
  • Figure US20110269960A1-20111103-C00021
  • A solution of 3,4-dichlorobenzenesulfonyl chloride (154 μl) in THF (2.0 ml) was added at room temperature to a solution of the compound (220 mg) of Example 2-(2) and triethylamine (0.249 ml) in THF (9.0 ml), and the mixture was stirred at room temperature for five hours. The insoluble matter was filtered off, and the resulting residue was concentrated. The resulting crude product was purified by OH silica-gel column chromatography (elution solvent: ethyl acetate/hexane=50-99%) and then recrystallized (ethyl acetate-hexane) to give 160 mg of the titled compound (Compound 61) as a pale yellow powder.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.1 Hz, 3H), 1.30 (d, J=6.9 Hz, 3H), 2.23 (s, 3H), 3.87-4.03 (m, 2H), 4.63-4.72 (m, 1H), 7.00-7.12 (m, 2H), 7.35-7.45 (m, 2H), 7.74 (dd, J=8.6, 1.9 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.96 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 8.57-8.66 (m, 1H)
  • Melting point: 93.0° C. to 99.0° C.
    • Example 3 3,4-Dichloro-N—[(R)-1-(4-ethyl-5(4-methylbenzenesulfenyl)-4H-[1,2,4]triazol-3-yl)-ethyl]-benzenesulfonamide (Compound 55)
  • Figure US20110269960A1-20111103-C00022
    • (R)-1-(4-Ethyl-5(4-methylphenylsulfanyl)-4H-[1,2,4]triazol-3-yl)-ethylamine
  • Figure US20110269960A1-20111103-C00023
  • (1) The compound (5.00 g, 15.1 mmol) obtained in Example 1-(6), DMF (50 mL), 4-methylbenzenethiol (3.74 g, 30.1 mmol), and cesium carbonate (14.7 g, 45.1 mmol) were put in a pressure-resistant screw cap test tube. The mixture was stirred at 150° C. for four hours and thereafter brought back to room temperature, and a mixed solvent of chloroform/methanol (10/1) was added. The insoluble matter was filtered off. The filtrate was removed by evaporation under reduced pressure, and the resulting crude product was purified by column chromatography (NH SiO2, hexane/ethyl acetate=50/50 to 10/90, chloroform/methanol=40/1) to give 3.01 g of the titled compound (colorless oily compound).
  • 1H NMR (600 MHz, CDCl3) δ ppm 1.21 (t, J=7.3 Hz, 3H), 1.59 (d, J=6.4 Hz, 3H), 2.31 (s, 3H), 4.00-4.18 (m, 3H), 7.06-7.14 (m, 2H), 7.26-7.30 (m, 2H)
    • 3,4-Dichloro-N—[(R)-1-(4-ethyl-5(4-methylbenzenesulfanyl)-4H-[1,2,4]triazol-3-yl)-ethyl]-benzenesulfonamide (Compound 55)
  • Figure US20110269960A1-20111103-C00024
  • (2) Starting from the compound obtained in Example 3-(1), the same procedure as used in Example 1-(8) was repeated to give the titled compound.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 1.08 (t, J=7.3 Hz, 3H), 1.32 (d, J=6.9 Hz, 3H), 2.28 (s, 3H), 3.90-4.11 (m, 2H), 4.78 (q, J=6.9 Hz, 1H), 7.17-7.23 (m, 4H), 7.67-7.74 (m, 1H), 7.81-7.88 (m, 1H), 7.92-7.94 (m, 1H), 8.77 (s, 1H)
  • Yield: 46%, Melting point: 141.0° C. to 143.0° C.
    • Example 4 3,4-Dichloro-N—[(R)-1-[4-ethyl-5(4-methylbenzenesulfonyl)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 57)
  • Figure US20110269960A1-20111103-C00025
  • To a solution of the compound (0.300 g) of Example 3-(2) in chloroform (6 mL), m-chloroperbenzoic acid (0.329 g) was added, and the mixture was stirred at room temperature for one hour. Then, a further portion of m-chloroperbenzoic acid (0.329 g) was added, and the mixture was stirred at room temperature for 15 hours. Thereafter, a further portion of m-chloroperbenzoic acid (0.329 g) was added, and the mixture was stirred at room temperature for two hours. Then, ethyl acetate was added, and the organic layer was washed with 5% aqueous Na2S2O3 solution and thereafter with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO2, hexane/ethyl acetate=70/30 to 40/60) and then recrystallized (ethyl acetate-hexane) to give 0.196 g of the titled compound (Compound 57) (colorless powdered compound). 1H NMR (600 MHz, DMSO-d6) δ ppm 1.25-1.35 (m, 6H), 2.45 (s, 3H), 4.23-4.40 (m, 2H), 4.78-4.86 (m, 1H), 7.52-7.56 (m, 2H), 7.62-7.67 (m, 1H), 7.78-7.82 (m, 1H), 7.86-7.94 (m, 3H)
  • Melting point: 164.0° C. to 165.0° C.
    • Example 5 3,4-Dichloro-N—[(R)-1-[4-ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 56)
  • Figure US20110269960A1-20111103-C00026
    • ((R)-1-Ethylcarbamoyl-ethyl)-carbamic acid t-butyl ester
  • Figure US20110269960A1-20111103-C00027
  • (1) EtNH2 (10 ml, 70% aqueous solution) was added to N-(t-butoxycarbonyl)-D-alanine methyl ester (4.76 g) in methanol (20 ml), and the mixture was stirred at room temperature for 19 hours. The reaction solution was concentrated, and the resulting crude product was purified by column chromatography (acidic OH SiO2, chloroform/ethyl acetate=10-50%) to give 3.96 g of the titled compound (colorless amorphous substance).
  • 1H NMR (200 MHz, CDCl3) δ ppm: 1.12 (t, J=7.2 Hz, 3H), 1.35 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 3.18-3.37 (m, 2H), 4.00-4.20 (m, 1H), 4.90-5.10 (m, 1H), 6.04-6.22 (m, 1H)
    • ((R)-1-Ethylthiocarbamoyl-ethyl)-carbamic acid t-butyl ester
  • Figure US20110269960A1-20111103-C00028
  • (2) A Lawesson's reagent (8.89 g) was added to a solution of the compound (3.96 g) of Example 5-(1) in THF (92 ml), and the mixture was stirred at room temperature for one hour and thereafter at 50° C. for 30 minutes. The reaction solution was cooled to room temperature, and the insoluble matter was filtered off. Then, the resulting residue was concentrated. The resulting crude product was purified by column chromatography (acidic OH SiO2, chloroform/ethyl acetate=10-50%) and thereafter by NH silica-gel column chromatography (ethyl acetate/hexane=50%) to give the titled compound (3.75 g) as a colorless powder.
  • 1H NMR (200 MHz, CDCl3) δ ppm: 1.26 (t, J=7.2 Hz, 3H), 1.38-1.52 (m, 3H), 1.45 (s, 9H), 3.60-3.77 (m, 2H), 4.36-4.53 (m, 1H), 5.10-5.32 (m, 1H), 7.99-8.24 (m, 1H)
    • [(R)-1-[4-Ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethyl]-carbamic acid t-butyl ester
  • Figure US20110269960A1-20111103-C00029
  • (3) Hg (OAc)2 (2.43 g) was added to a solution of the compound (1.61 g) obtained in Example 5-(2) and 4-methylphenylacetic acid hydrazide (1.25 g) in CH3CN (30 mL), and the mixture was stirred at room temperature for 42 hours. Ethyl acetate was added to the reaction solution, and the insoluble matter was filtered off through celite. The filtrate was washed with 1N aqueous KHSO4 solution and thereafter with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH SiO2, ethyl acetate/hexane=50-100%, methanol/chloroform=1/1) (neutral OH SiO2, methanol/chloroform=1/10) to give 0.530 g of the titled compound (colorless amorphous substance).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.04 (t, J=7.3 Hz, 3H), 1.41 (s, 9H), 1.61 (d, J=6.9 Hz, 3H), 2.30 (s, 3H), 3.73-3.90 (m, 2H), 4.06-4.20 (m, 2H), 4.85-4.94 (m, 1H), 5.11-5.17 (m, 1H), 7.09 (s, 4H)
    • (R)-1-[4-Ethyl-5-(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethylamine
  • Figure US20110269960A1-20111103-C00030
  • (4) Trifluoroacetic acid (5 mL) was added to a solution of the compound (0.496 g) of Example 5-(3) in chloroform (5 mL), and the mixture was stirred at room temperature for 18 hours. Aqueous sodium hydroxide (1.0N) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent, whereby 0.148 g of the titled compound was obtained as a colorless oily compound.
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.09 (t, J=7.3 Hz, 3H), 1.57 (d, J=6.9 Hz, 3H), 2.30 (s, 3H), 3.74-3.94 (m, 2H), 4.01-4.20 (m, 3H), 7.10 (s, 4H)
    • 3,4-Dichloro-N—[(R)-1-[4-ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 56)
  • Figure US20110269960A1-20111103-C00031
  • (5) Triethylamine (0.25 mL) and 3,4-dichlorobenzenesulfonyl chloride (0.707 mL) were added to a solution of the compound (0.144 g) of Example 5-(4) in THF (3 mL), and the mixture was stirred at room temperature for 3.5 hours. Then, 2N aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO2, chloroform/methanol=50/1 to 10/1) and then recrystallized (ethyl acetate-hexane) to give 0.100 g of the titled compound (Compound 56) as a colorless powdered compound.
  • 1H NMR (600 MHz, DMSO-D6) δ ppm: 0.91 (t, J=7.1 Hz, 3H), 1.26 (d, J=6.9 Hz, 3H), 2.23 (s, 3H), 3.77-3.92 (m, 2H), 4.00 (s, 2H), 4.60-4.70 (m, 1H), 7.03-7.12 (m, 4H), 7.64-7.68 (m, 1H), 7.79-7.82 (m, 1H), 7.89-7.91 (m, 1H), 8.64 (s, 1H)
  • Melting point: 189.0° C. to 191.0° C.
    • Example 6 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-N-methyl-benzenesulfonamide (Compound 115)
  • Figure US20110269960A1-20111103-C00032
  • K2CO3 (78 mg) and MeI (0.022 ml) were added at room temperature to a solution of Compound 12 (150 mg) of Example 1 in dimethylformamide (2.0 ml), and the mixture was stirred at room temperature for three hours. Water was added to the reaction solution, and the mixture was extracted with a mixed solution of methanol/chloroform (methanol/chloroform=1/4). The resulting organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered, and evaporated under reduced pressure to remove the solvent. After eluting the residue with a mixed solvent of ethyl acetate and hexane, the resulting elute was purified by column chromatography (acidic OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-10%) and then recrystallized (ethyl acetate-hexane) to give 111 mg of the titled compound as a colorless powdered compound.
  • Melting point: 125.5° C. to 126.5° C.
    • Example 7 3,4-Dichloro-N—((R)-1-[5-[3-(1,4-dioxa-8-aza-spiro[4.5]decan-8-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 87)
  • Figure US20110269960A1-20111103-C00033
    • 3-(1,4-Dioxa-8-aza-spiro[4.5]decen-8-yl)-phenol
  • Figure US20110269960A1-20111103-C00034
  • (1) In a pressure-resistant screw cap test tube, 3-bromophenol (1.50 g), 1,4-dioxa-8-azaspiro[4,5]decan (1.49 g), Pd2(dba)3 (0.079 g), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.082 g), and LiN(TMS)2 (20% in THF, 18 mL) were put, and the mixture was stirred at 65° C. for 7.5 hours. Ethyl acetate was added, and the organic layer was washed with 1N aqueous hydrochloric acid and thereafter with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO2, hexane/ethyl acetate=70/30 to 60/40) to give 1.96 g of the titled compound (brown oil).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.79-1.83 (m, 4H), 3.27-3.35 (m, 4H), 3.98 (s, 4H), 4.86 (s, 1H), 6.28 (dd, J=8.0, 2.5 Hz, 1H), 6.41 (t, J=2.3 Hz, 1H), 6.51 (dd, J=8.5, 2.5 Hz, 1H), 7.08 (t, J=8.3 Hz, 1H)
    • (R)-1-[5-[3-(1,4-Dioxa-8-aza-spiro[4.5]decan-8-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethylamine
  • Figure US20110269960A1-20111103-C00035
  • (2) Starting from the compound obtained in Example 7-(1) in place of 4-fluorophenol, the same procedure as used in Example 1-(7) was repeated to give the titled compound (brown oily substance, yield 58%).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.38 (t, J=7.3 Hz, 3H), 1.57 (d, J=6.9 Hz, 3H), 1.77-1.83 (m, 4H), 3.27-3.36 (m, 4H), 3.95-4.06 (m, 6H), 4.14 (q, J=6.9 Hz, 1H), 6.70-6.75 (m, 2H), 6.97 (t, J=2.3 Hz, 1H), 7.20 (t, J=8.3 Hz, 1H)
    • 3,4-Dichloro-N—((R)-1-[5-[3-(1,4-dioxa-8-aza-spiro[4.5]decan-8-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 87)
  • Figure US20110269960A1-20111103-C00036
  • (3) Starting from the compound obtained in Example 7-(2), the same procedure as used in Example 1-(8) was repeated to give the titled compound (colorless powder, yield 64%).
  • Melting point: 174.0° C. to 179.0° C.
    • Example 8 3,4-Dichloro-N—((R)-1-[4-ethyl-5-[3-(4-oxo-piperidin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 88)
  • Figure US20110269960A1-20111103-C00037
  • To a solution of the compound (0.981 g) of Example 7 in THF (10 mL), 2N aqueous hydrochloric acid (8.4 mL) was added, and the mixture was stirred at room temperature for one hour. Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 50° C. for six hours. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO2, ethyl acetate) and then recrystallized (chloroform-hexane) to give the titled compound (0.572 g, colorless powder).
  • Melting point: 188.5° C. to 190.5° C.
    • Example 9 3,4-Dichloro-N—((R)-1-[4-ethyl-5-[3-(4-hydroxy-piperidin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 93)
  • Figure US20110269960A1-20111103-C00038
  • NaBH4 (0.021 g) was added at 0° C. to a solution of the compound (0.150 g) of Example 8 in methanol (3.0 ml), and the mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over MgSO4, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH SiO2, methanol/chloroform=1/50 to 1/10) and then recrystallized (ethyl acetate-hexane) to give 0.113 g of the titled compound (Compound 93) as a colorless powder.
  • Melting point: 167.5° C. to 169.5° C.
    • Example 10 N—[(R)-1-[5-(3-Amino-phenoxy)-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl]-3,4-dichlorobenzenesulfonamide (Compound 82)
  • Figure US20110269960A1-20111103-C00039
    • 3-[5-((R)-1-Amino-ethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl amine
  • Figure US20110269960A1-20111103-C00040
  • (1) Starting from 3-aminophenol in place of 4-fluorophenol, the same procedure as used in Example 1-(7) was repeated to give the titled compound (brown oily substance, yield 99%). 1H NMR (600 MHz, CDCl3) δ ppm: 1.37 (t, J=7.1 Hz, 3H), 1.58 (d, J=6.9 Hz, 3H), 3.96-4.05 (m, 2H), 4.15 (q, J=6.7 Hz, 1H), 6.45-6.50 (m, 1H), 6.62-6.67 (m, 1H), 6.71-6.75 (m, 1H), 7.11 (t, J=8.0 Hz, 1H)
    • N—[(R)-1-[5-(3-Amino-phenoxy)-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl]-3,4-dichlorobenzenesulfonamide (Compound 82)
  • Figure US20110269960A1-20111103-C00041
  • (2) Triethylamine (4.16 ml) and 3,4-dichlorobenzenesulfonyl chloride (3.73 g) were added to a solution of the compound (3.69 g) of Example 10-(1) in THF (15 ml), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the resulting crude product was purified by column chromatography (NH SiO2, methanol/chloroform) and recrystallized (ethyl acetate/hexane) to give 3.60 g of the titled compound (Compound 82) (colorless powdered compound).
  • Melting point: 142.0° C. to 145.0° C.
    • Example 11 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-pyrrol-1-yl-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 86)
  • Figure US20110269960A1-20111103-C00042
  • To a solution of the compound (700 mg) of Example 10 in AcOH (4.6 ml), 2,5-dimethoxy-tetrahydrofuran (375 μl) was added, and the mixture was stirred at 130° C. for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Thereafter, water was added, and the mixture was extracted with methanol/chloroform (1/4). Then, the organic layer was washed with saturated aqueous sodium chloride, dried over MgSO4, filtered, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO2, ethyl acetate/hexane=33-100%, methanol/chloroform=5%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 86) (173 mg, colorless powdered compound).
  • Melting point: 176.0° C. to 177.0° C.
    • Example 12 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-formylamino-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 90)
  • Figure US20110269960A1-20111103-C00043
  • A mixture of the compound (300 mg) obtained in Example 10-(2) and ethyl formate (1.1 ml) was stirred at 105° C. for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (acidic OH SiO2, ethyl acetate/hexane=50-100%, methanol/chloroform=5%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 90) (81 mg, colorless powder).
  • Melting point: 168.0° C. to 170.0° C.
    • Example 13 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-ureido-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 91)
  • Figure US20110269960A1-20111103-C00044
  • A mixture of the compound (300 mg) obtained in Example 10-(2), potassium cyanate (65 mg), AcOH (1.0 ml), and water (0.5 ml) was stirred at room temperature for one hour. Water was added, and the mixture was extracted with methanol/chloroform (1/4). The organic layer was dried over MgSO4, filtered, and evaporated to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-3%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 91) (273 mg, colorless powder).
  • Melting point: 137.0° C. to 138.0° C.
    • Example 14 3,4-Dichloro-N—((R)-1-[5-[3-(3,3-dimethylureido)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 97)
  • Figure US20110269960A1-20111103-C00045
  • Dimethylcarbamyl chloride (146 μl) was added to a solution of the compound (300 mg) of Example 10-(2) and triethylamine (368 μl) in chloroform (1.1 ml), and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-3%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 97) (93 mg, colorless powder).
  • Melting point: 158.0° C. to 159.0° C.
    • Example 15 3,4-Dichloro-N—((R)-1-[4-ethyl-5-[3-(3-ethylureido)-phenoxy]4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 92)
  • Figure US20110269960A1-20111103-C00046
  • Ethyl isocyanate (63 μl) was added to a solution of the compound (300 mg) of Example 10-(2) in chloroform (1.1 ml), and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-3%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 92) (228 mg, colorless powder).
  • Melting point: 118.0° C. to 120.0° C.
    • Example 16 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-methanesulfonylamino-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 102)
  • Figure US20110269960A1-20111103-C00047
  • Methanesulfonyl chloride (114 mg) was added to a solution of the compound (300 mg) of Example 10-(2) in pyridine (1.32 ml), and the mixture was stirred at room temperature for three hours. Hydrochloric acid (1.0 N) was added, and the mixture was extracted with methanol/chloroform (1/4). The organic layer was dried over Na2SO4, filtered, and concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-5%) and then recrystallized (ethyl acetate-hexane) to give the titled compound (Compound 102) (281 mg, colorless powder).
  • Melting point: 117.0° C. to 118.0° C.
    • Example 17 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-hydroxyphenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 114)
  • Figure US20110269960A1-20111103-C00048
    • (R)-1-[5-(3-Benzyloxy-phenoxy)-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethylamine
  • Figure US20110269960A1-20111103-C00049
  • (1) Starting from 3-benzyloxyphenol in place of 4-fluorophenol, the same procedure as used in Example 1-(7) was repeated to give the titled compound (brown oily substance, yield 84%).
  • 1H NMR (600 MHz, CDCl3), δ ppm: 1.39 (t, J=7.3 Hz, 3H), 1.60 (d, J=6.4 Hz, 3H), 3.96-4.09 (m, 2H), 4.17 (q, J=6.9 Hz, 1H), 5.06 (s, 2H), 6.79-6.84 (m, 1H), 6.91-6.96 (m, 1H), 7.04-7.08 (m, 1H), 7.22-7.46 (m, 6H)
    • 3-[5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenol
  • Figure US20110269960A1-20111103-C00050
  • (2) A suspension of the compound (1.5 g) of Example 17-(1) and Pd(OH)2/C (150 mg, Pd 20 wt %) in methanol (4.0 ml) was stirred at room temperature for a day under a hydrogen atmosphere (approximately 1 atmospheric pressure). The reaction mixture was filtered through celite and evaporated to remove the solvent. The resulting crude product was purified by column chromatography (NH SiO2, methanol/chloroform=0-25%) to give the titled compound (gray amorphous substance, 323 mg).
  • 1H NMR (600 MHz, DMSO-d6), 8 ppm: 1.23 (t, J=7.3 Hz, 3H), 1.54 (d, J=6.9 Hz, 3H), 3.82-4.09 (m, 2H), 4.60 (q, J=6.0 Hz, 1H), 6.61-6.69 (m, 2H), 6.70-6.77 (m, 1H), 7.14-7.21 (m, 1H), 8.28-9.11 (m, 2H), 9.43-10.55 (m, 1H)
    • 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-hydroxyphenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 114)
  • Figure US20110269960A1-20111103-C00051
  • (3) Triethylamine (0.225 ml) and 3,4-dichlorobenzenesulfonyl chloride (198 mg) were added at room temperature to a solution of the compound (200 mg) of Example 17-(2) in THF (2.0 ml), and the mixture was stirred at room temperature for 12 hours. The mixture was evaporated to remove the solvent, and KOH (104 mg), ethanol (4.0 ml), and water (4.0 ml) were added to the resulting crude product. The mixture was stirred at 120° C. for 40 minutes, and then cooled to room temperature. HCl (1.0 N) was added, and the mixture was extracted with a mixed solution of methanol/chloroform (methanol/chloroform=1/4), dried (MgSO4), filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH SiO2, ethyl acetate/hexane=30-70%) and then recrystallized (methanol/chloroform/hexane) to give 37 mg of the titled compound (Compound 114) as a colorless powder.
  • Melting point: 185.0° C. to 186.0° C.
    • Example 18 3-[5-[(R)-1-(3,4-Dichlorobenzenesulfonylamino)-ethyl]-4-ethyl-4H-[1,2,4]triazol-3-yloxy]benzoic acid t-butyl ester (Compound 118)
  • Figure US20110269960A1-20111103-C00052
    • 3-[(5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-benzoic acid t-butyl ester
  • Figure US20110269960A1-20111103-C00053
  • (1) Starting from 3-hydroxybenzoic acid t-butyl ester in place of 4-fluorophenol, the same procedure as used in Example 1-(7) was repeated to give the titled compound (colorless and oily, yield 24%).
  • 1H NMR (600 MHz, CDCl3), 8 ppm: 1.43 (t, J=7.1 Hz, 3H), 1.58-1.62 (m, 12H), 4.01-4.13 (m, 2H), 4.18 (q, J=6.6 Hz, 1H), 7.42-7.46 (m, 1H), 7.61-7.65 (m, 1H), 7.82-7.85 (m, 1H), 7.87-7.91 (m, 1H)
    • 3-[5-[(R)-1-(3,4-Dichlorobenzenesulfonylamino)-ethyl]-4-ethyl-4H-[1,2,4]triazol-3-yloxy]benzoic acid t-butyl ester (Compound 118)
  • Figure US20110269960A1-20111103-C00054
  • (2) Starting from the compound obtained in Example 18-(1), the same procedure as used in Example 1-(8) was repeated to give the titled compound (colorless powder, yield 68%).
  • 1H NMR (600 MHz, CDCl3), 8 ppm: 1.38 (t, J=7.3 Hz, 3H), 1.51 (d, J=6.9 Hz, 3H), 1.58 (s, 9H), 3.93-4.01 (m, 2H), 4.29-4.35 (m, 1H), 7.43-7.48 (m, 1H), 7.50-7.60 (m, 3H), 7.64-7.69 (m, 1H), 7.81-7.89 (m, 2H), 7.90-7.94 (m, 1H)
    • Example 19 3-[5-[(R)-1-(3,4-Dichlorobenzenesulfonylamino)-ethyl]-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-benzoic acid (Compound 113)
  • Figure US20110269960A1-20111103-C00055
  • Trifluoroacetic acid (0.12 ml) was added to a solution of the compound (260 mg) of Example 18 in chloroform (12.0 ml), and the mixture was stirred at room temperature for five days. The mixture was evaporated to remove the solvent, and the resulting crude product was purified by column chromatography (neutral OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-20%) and then recrystallized (methanol/chloroform/hexane) to give the titled compound (Compound 113) (101 mg, colorless powder).
  • Melting point: 183.0° C. to 185.0° C.
    • N—[(R)-1-[4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-4-methoxybenzenesulfonamide (Compound 175)
  • Figure US20110269960A1-20111103-C00056
  • To a solution of the compound (12.5 mg) of Example 1-(7) in THF (0.3 ml), triethylamine (25 μl) was added, and then a solution of 4-methoxybenzenesulfonylchloride (15.5 mg) in THF (0.3 ml) was added. The mixture was stirred at room temperature for two hours. PSA (product name: VARIAN Inc. polymer supported amine, 1.4 meq/g) (75 μl) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The insoluble matter was filtered off, and the resulting residue was evaporated to remove the solvent. The resulting crude product was purified by silica-gel column chromatography (acidic OH SiO2, ethyl acetate/hexane=50-100%, methanol/chloroform=10%) to give 10.7 mg of the titled compound (Compound 175) as a colorless powder.
  • APCI MS (M−H)−: 419, APCI MS (M+H)+: 421
    • Example 21 3,4-Dichloro-N-((R)-1-[4-ethyl-5-[3-(4-methyl-piperazin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 45)
  • Figure US20110269960A1-20111103-C00057
  • (1) The following compound was obtained by the same procedure as used in Example 1-(7) (the procedure will be specifically described below).
    • (R)-1-[4-Ethyl-5-[3-(4-methyl-piperazin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethylamine
  • Figure US20110269960A1-20111103-C00058
  • In a pressure-resistant screw cap test tube, N,N′-dimethylpropyleneurea (DMPU) (4.0 ml), 3-(4-methyl-piperazin-1-yl)-phenol (500 mg), and cesium carbonate (2.21 g) were added to the compound (750 mg) obtained in Example 1-(6), and the mixture was stirred at 160° C. for three hours. The mixture was brought to room temperature, and saturated aqueous sodium chloride was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH SiO2, chloroform/methanol=50/1-30/1) to give the titled compound (yellow oily compound, 427 mg).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.40 (t, J=7.3 Hz, 3H), 1.59 (d, J=6.9 Hz, 3H), 2.35 (s, 3H), 2.52-2.61 (m, 4H), 3.22-3.27 (m, 4H), 3.97-4.08 (m, 2H), 4.15 (q, J=6.9 Hz, 1H), 6.71-6.80 (m, 2H), 6.99-7.03 (m, 1H), 7.20-7.25 (m, 1H)
  • (2) The following compound was obtained by the same procedure as used in Example 1-(8) (the procedure will be specifically described below).
    • 3,4-Dichloro-N-((R)-1-[4-ethyl-5-[3-(4-methyl-piperazin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 45)
  • Figure US20110269960A1-20111103-C00059
  • Triethylamine (0.41 mL) and 3,4-dichlorobenzenesulfonyl chloride (0.232 mL) were added at room temperature to a solution of the compound (427 mg) of Example 21-(1) in THF (8.0 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (NH SiO2, chloroform/methanol=50/1-30/1) and then recrystallized (ethyl acetate-hexane) to give 280 mg of the titled compound (Compound 45) as a colorless powder.
  • Melting point: 194.0° C. to 196.0° C.
    • Example 22 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(1H-indol-6-yloxy)-4H-1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 64)
  • Figure US20110269960A1-20111103-C00060
  • (1) The following compound was obtained by the same procedure as used in Example 1-(7) (the procedure will be specifically described below).
    • (R)-1-[4-Ethyl-5-(1H-indol-6-yloxy)-4H-[1,2,4]triazol-3-yl]-ethylamine
  • Figure US20110269960A1-20111103-C00061
  • In a pressure-resistant screw cap test tube, N,N″-dimethylpropyleneurea (DMPU) (5.0 ml), 1H-indol-6-ol (601 mg), and cesium carbonate (2.94 g) were added to the compound (1.00 g) obtained in Example 1-(6), and the mixture was stirred at 200° C. for one hour and then brought to room temperature. Saturated aqueous sodium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated under reduced pressure to remove the solvent. Then, the resulting crude product was purified by column chromatography (NH SiO2, chloroform/methanol=50/1-30/1) to give the titled compound (yellow oily compound, 750 mg).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.42 (t, J=7.1 Hz, 3H), 1.58 (d, J=6.4 Hz, 3H), 3.98-4.10 (m, 2H), 4.15 (q, J=6.7 Hz, 1H), 6.30-6.39 (m, 1H), 6.87-7.00 (m, 2H), 7.39-7.52 (m, 2H), 9.55 (s, 1H)
  • (2) The following compound was obtained by the same procedure as used in Example 1-(8) (the procedure will be specifically described below).
    • 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(1H-indol-6-yloxy)-4H-1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 64)
  • Figure US20110269960A1-20111103-C00062
  • Triethylamine (0.77 mL) and 3,4-dichlorobenzenesulfonyl chloride (1.02 g) were added at room temperature to the compound (748 mg) of Example 22-(1) in THF (10.0 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (NH SiO2,chloroform/methanol=30/1) and then recrystallized (CHCl3/MeOH/hexane) to give 815 mg of the titled compound (Compound 64) as a colorless powder.
  • Melting point: 223.0° C. to 224.0° C.
    • Example 23 N—[(S)-2-Benzyloxy-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-3,4-dichlorobenzenesulfonamide (Compound 695)
  • Figure US20110269960A1-20111103-C00063
  • Starting from (R)-2-amino-3-benzyloxy-propionic acid methyl ester in place of N-(t-butoxycarbonyl)-D-alanine methyl ester used in Example 1-(1), the same procedure as used in Example 1 was repeated to give the titled compound (Compound 695) as a colorless powder.
  • 1H NMR (200 MHz, CDCl3) δ ppm: 1.31 (t, J=7.3 Hz, 3H), 3.65-4.03 (m, 4H), 4.35 (s, 2H), 4.67 (q, J=7.9 Hz, 1H), 7.03-7.39 (m, 10H), 7.68 (dd, J=8.8, 2.2 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H)
    • Example 24 3,4-Dichloro-N—[(S)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2-hydroxyethyl]-benzenesulfonamide (Compound 696)
  • Figure US20110269960A1-20111103-C00064
  • AlCl3 (49 mg) and PhNMe2 (148 mg) were added to a solution of the compound (69 mg) of Example 23 in CH2Cl2 (2.0 ml), and the mixture was stirred at room temperature for one hour. Then, AcOEt was added, and the mixture was washed with 1N hydrochloric acid and thereafter with saturated aqueous sodium chloride. The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to remove the solvent. Then, the resulting crude product was purified by column chromatography (OH SiO2, AcOEt/hexane=2/1) to give 54 mg of the titled compound (Compound 696) as a colorless powder.
  • 1H NMR (200 MHz, CDCl3) δ ppm: 1.41 (t, J=7.5 Hz, 3H), 3.62 (dd, J=4.8, 11.8 Hz, 1H), 3.88 (dd, J=4.8, 11.8 Hz, 1H), 4.05 (q, J=7.5 Hz, 2H), 4.51-4.60 (m, 1H), 7.04-7.13 (m, 2H), 7.23-7.31 (m, 3H), 7.53 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.8, 2.2 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H)
    • Example 25 3,4-Dichloro-N—[(S)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2-fluoroethyl]-benzenesulfonamide (Compound 689)
  • Figure US20110269960A1-20111103-C00065
  • A solution of diethylaminosulfurtrifluoride (DAST) (16 mg) in CH2Cl2 (1.0 ml) was added at 0° C. to a solution of the compound (45 mg) of Example 24 in CH2Cl2 (2.0 ml), and the mixture was stirred at the same temperature for one hour. The reaction solution was added to saturated aqueous sodium bicarbonate, and the mixture was extracted with AcOEt. The organic layer was dried (Na2SO4) and filtered evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (OH SiO2, AcOEt/hexane=30-50%) to give 6 mg of the titled compound (Compound 696) as a pale yellow powder.
  • 1H NMR (200 MHz, CDCl3) δ ppm 1.39 (t, J=7.5 Hz, 3H), 4.01 (q, J=7.5 Hz, 2H), 4.45-4.86 (m, 3H), 6.98 (br, 1H), 7.05-7.36 (m, 4H), 7.48 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.5, 2.2 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H)
    • Example 26 3,4-Dichloro-N-[1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl]-2,2,2-trifluoroethyl]-benzenesulfonamide (Compound 687)
  • Figure US20110269960A1-20111103-C00066
    • 4-Ethyl-5-mercapto-4H-[1,2,4]triazol-3-carboxylic acid ethyl ester
  • Figure US20110269960A1-20111103-C00067
  • (1) To a solution of diethyl formate (48.64 g) in MeOH (100 ml), a solution of hydrazine monohydrate (16.33 g) in MeOH (100 ml) was added dropwise at −5° C. over 1.5 hours, and ethylisothiocyanate (29.00 g) was added at the same temperature. The mixture was warmed to room temperature and stirred overnight. The insoluble matter was filtered off, and the resulting residue was evaporated to remove the solvent. The resulting solid was washed with a mixed solution of hexane/AcOEt (1/1) and dried, and the resulting white powder (55.30 g) was added to an aqueous solution (228 ml) of NaOH (913 mg). The mixture was stirred at 70° C. for four hours, at room temperature overnight, and then at 100° C. for seven hours. The reaction mixture was concentrated to approximately ⅓, and then a saturated aqueous NH4Cl solution (300 ml) was added. The resulting white precipitate was filtered and dried to give the titled compound (15.06 g) as a colorless powder.
  • 1H NMR (200 MHz, CDCl3) δ ppm 1.38 (t, J=6.6 Hz, 3H), 1.45 (t, J=6.5 Hz, 3H), 4.40-4.57 (m, 4H), 11.58-11.84 (m, 1H)
    • 4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-carboxylic acid ethyl ester
  • Figure US20110269960A1-20111103-C00068
  • (2) Starting from the compound obtained in Example 26-(1), the same procedure as used in Example 1-(4) was repeated to give the titled compound as a light yellow solid (yield 84%).
  • 1H NMR (200 MHz, CDCl3) δ ppm 1.31-1.50 (m, 6H), 2.80 (s, 3H), 4.31 (q, J=7.2 Hz, 2H), 4.47 (q, J=7.1 Hz, 2H)
    • 4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-carboxylic acid ethyl ester
  • Figure US20110269960A1-20111103-C00069
  • (3) Starting from the compound obtained in Example 26-(2), the same procedure as used in Example 1-(5) was repeated to give the titled compound as a light yellow solid (yield 84%).
  • 1H NMR (200 MHz, CDCl3) δ ppm 1.48 (t, J=7.1 Hz, 3H), 1.53 (t, J=7.2 Hz, 3H), 3.60 (s, 3H), 4.53 (q, J=7.1 Hz, 2H), 4.75 (q, J=7.2 Hz, 2H)
    • 4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-carboxylic acid ethyl ester
  • Figure US20110269960A1-20111103-C00070
  • (4) To a suspension of NaH (1.236 g, oil free) in THF (68 ml), 4-fluorophenol (4.62 g) was added at 0° C., and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0° C., and a solution of the compound (8.49 g) of Example 26-(3) in THF (20 ml) was added. The mixture was stirred at room temperature for 30 minutes and thereafter at 70° C. for 1.5 hours. The temperature was cooled to room temperature, and then the reaction mixture was added to a saturated aqueous NH4Cl solution (500 ml). The mixture was extracted with AcOEt (500 ml) and washed with saturated aqueous sodium chloride. The organic layer was dried (MgSO4), filtered, and concentrated, and the resulting crude product was purified by column chromatography (OH acid SiO2, AcOEt/hexane=10-99%) to give the titled compound (5.144 g, light yellow solid).
  • 1H NMR (200 MHz, CDCl3) δ ppm 1.35-1.52 (m, 6H), 4.36 (q, J=7.2 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 7.02-7.18 (m, 2H), 7.28-7.48 (m, 2H)
    • 4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-carbaldehyde
  • Figure US20110269960A1-20111103-C00071
  • (5) DiBAl—H (0.99 M, toluene solution, 36.1 ml) was added at −5° C. to a solution of the compound (5.00 g) of Example 26-(4) in THF (50 ml), and the mixture was stirred at the same temperature for three hours. Then, 1N-hydrochloric acid was added to the reaction solution, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO2, AcOEt/hexane=5-40%) to give the titled compound (2.22 g, colorless and oily).
  • 1H NMR (600 MHz, CDCl3) δ ppm ppm 1.44 (t, J=7.3 Hz, 3H), 4.37 (J=7.3 Hz, 2H), 7.10-7.17 (m, 2H), 7.36-7.40 (m, 2H)
    • 4-Methylbenzene sulfonic acid 4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-ylmethyleneamide
  • Figure US20110269960A1-20111103-C00072
  • (6) A solution of the compound (1.00 g) obtained in Example 26-(5), 4-methylbenzene sulfonic acid amide (660 mg), and cesium carbonate (1.39 g) in chloroform (21 ml) was stirred at 45° C. for nine hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The resulting residue was purified by silica-gel chromatography (neutral OH silica gel, elution solvent: AcOEt/hexane 0-30%) to give the titled compound (630 mg) as a pale yellow solid.
  • 1H NMR (600 MHz, CDCl3) δ ppm 1.30 (t, J=7.1 Hz, 3H), 2.42 (s, 3H), 4.27-4.43 (m, 2H), 7.07-7.15 (m, 2H), 7.31-7.39 (m, 4H), 7.57-7.62 (m, 2H), 8.85 (s, 1H)
    • N-[1-[4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]2,2,2-trifluoroethyl]-4-methylbenzamide
  • Figure US20110269960A1-20111103-C00073
  • (7) Under an argon atmosphere, a solution of (trifluoromethyl)trimethyl silane (120 μl) in THF (5.0 ml) was added at −35° C. to a suspension of the compound (200 mg) of Example 26-(6) and tetramethylfluoride (60 mg) in THF (5.0 ml), and the mixture was stirred at the same temperature for an hour and a half. A further portion of tetramethylfluoride (60 mg) and thereafter a further portion of (trifluoromethyl)trimethyl silane (60 mg) were added to the reaction solution at the same temperature, and the mixture was stirred at the same temperature for two hours and warmed to −10° C., and a saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by silica-gel column chromatography (neutral —OH silica gel, AcOEt/hexane 0-40%) to give the titled compound (219 mg) as a pale yellow oily substance.
  • 1H NMR (600 MHz, CDCl3) δ ppm 1.32 (t, J=7.3 Hz, 3H), 2.40 (s, 3H), 3.80-3.87 (m, 2H), 4.86-4.92 (m, 1H), 5.59 (d, J=8.3 Hz, 1H), 7.06-7.13 (m, 2H), 7.27-7.31 (m, 2H), 7.32-7.37 (m, 2H), 7.53-7.59 (m, 2H)
    • 1-[4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2,2,2,-trifluoroethylamine
  • Figure US20110269960A1-20111103-C00074
  • (8) HCl (4N, dioxane solution, 1.25 ml) was added at room temperature to a solution of the compound (215 mg) of Example 26-(7) in methanol (5.0 ml), and the mixture was stirred at 85° C. for two hours. The reaction solution was concentrated, and the resulting residue was purified by silica-gel column chromatography (NH SiO2, AcOEt/hexane 0-50%) to give the titled compound (82 mg) as a colorless oily substance.
  • (600 MHz, CDCl3) δ ppm: 1.43 (t, J=7.3 Hz, 3H), 3.97-4.11 (m, 2H), 4.47-4.54 (m, 1H), 7.06-7.12 (m, 2H), 7.35-7.40 (m, 2H)
    • 3,4-Dichloro-N-[1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2,2,2-trifluoroethyl]-benzenesulfonamide (Compound 687)
  • Figure US20110269960A1-20111103-C00075
  • (9) Starting from the compound (79 mg) obtained in Example 26-(8), the same procedure as used in Example 1-(8) was repeated to give the titled compound (3 mg) as a light yellow oily substance.
  • (600 MHz, CDCl3) δ ppm: 1.43 (t, J=7.1 Hz, 3H), 3.91-4.07 (m, 2H), 5.06-5.13 (m, 1H), 7.07-7.16 (m, 2H), 7.29-7.35 (m, 2H), 7.50-7.57 (m, 1H), 7.67-7.74 (m, 1H), 7.90 (s, 1H)
    • Example 27 N—((R)-1-[5-[3-(4-Acetylpiperazin-1-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-3,4-dichlorobenzenesulfonamide (Compound 697)
  • Figure US20110269960A1-20111103-C00076
    • (R)-1-[4-Ethyl-5-(3-piperazin-1-yl-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethylamine
  • Figure US20110269960A1-20111103-C00077
  • (1) In a pressure-resistant screw cap test tube, DMPU (10 ml), 3-piperazinylphenol (1.34 g), and Cs2CO3 (6.13 g) were added to the compound (2.08 g) obtained in Example 1-(6), and the mixture was stirred at 200° C. for 40 minutes. It was cooled to room temperature and then concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (NH SiO2, AcOEt to MeOH/CHCl2=1/50) to give the titled compound (yellow oily compound, 1.17 g).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.40 (t, J=7.1 Hz, 3H), 1.59 (d, J=6.9 Hz, 3H), 2.98-3.04 (m, 4H), 3.14-3.19 (m, 4H), 3.97-4.09 (m, 2H), 4.13-4.18 (m, 1H), 6.70-6.80 (m, 2H), 6.97-7.03 (m, 1H), 7.21-7.26 (m, 1H)
    • 1-(4-[3-[5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl]-piperazin-1-yl)-ethanone
  • Figure US20110269960A1-20111103-C00078
  • (2) AcCl (0.24 ml) was added at −30° C. to a solution of the compound (1.06 g) of Example 27-(1) and Et3N (1.4 ml) in THF (20 ml), and the mixture was stirred at the same temperature for two hours. Then, the mixture was warmed to room temperature and then stirred for another five hours. The reaction mixture was concentrated, and the resulting crude product was purified by column chromatography (neutral OH SiO2, MeOH/CHCl3=1/5) to give a mixture (315 mg, colorless solid) of the titled compound and triethylamine hydrochloride.
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.35 (t, J=7.3 Hz, 3H), 1.72 (d, J=6.4 Hz, 3H), 2.12 (s, 3H), 3.14-3.23 (m, 4H), 3.57-3.64 (m, 2H), 3.71-3.77 (m, 2H), 3.87-4.10 (m, 2H), 4.57-4.66 (m, 1H), 6.70-6.81 (m, 2H), 6.95-6.99 (m, 1H), 7.21-7.26 (m, 1H)
    • N—((R)-1-[5-[3-(4-Acetylpiperazin-1-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-3,4-dichlorobenzenesulfonamide (Compound 697)
  • Figure US20110269960A1-20111103-C00079
  • (3) Water was added to a mixture (307 mg) of 1-(4-[3-[5-((R)-1-aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl]-piperazin-1-yl)-ethanone obtained in Example 27-(2) and triethylamine hydrochloride, 3,4-dichlorobenzenesulfonyl chloride (0.13 ml), and K2CO3 (355 mg). The mixture was stirred at room temperature for 15 hours. The precipitated solid was filtered and purified by column chromatography (NH SiO2, MeOH/CHCl3=1/50) to give the titled compound (Compound 697) (117 mg, colorless syrup).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.38 (t, J=7.3 Hz, 3H), 1.52 (d, J=6.9 Hz, 3H), 2.14 (s, 3H), 3.14-3.27 (m, 4H), 3.56-3.64 (m, 2H), 3.72-3.80 (m, 2H), 3.88-4.01 (m, 2H), 4.58-4.68 (m, 1H), 5.98-6.06 (m, 1H), 6.72-6.82 (m, 2H), 6.95-7.01 (m, 1H), 7.25-7.30 (m, 1H), 7.51-7.57 (m, 1H), 7.65-7.73 (m, 1H), 7.89-7.97 (m, 1H)
    • Example 28 3,4-Dichloro-N—[(R)-1-[4-ethyl-5-(3-piperazin-1-yl-phenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 683),
  • Figure US20110269960A1-20111103-C00080
  • A mixture of the compound (107 mg) obtained in Example 27-(3), NaOH (105 mg), water (2.0 ml), and EtOH (4.0 ml) was stirred at 80° C. for one hour and then stirred at 100° C. for 18 hours. The mixture was cooled to room temperature and then extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated. The resulting crude product was purified by column chromatography (NH SiO2, MeOH/CHCl2=1/30) and then recrystallized (AcOEt/hexane) to give the titled compound (Compound 683) (55 mg, colorless powder).
  • 1H NMR (600 MHz, DMSO-d6) δ ppm: 1.24 (t, J=7.3 Hz, 3H), 1.31 (d, J=6.9 Hz, 3H), 2.77-2.86 (m, 4H), 3.03-3.10 (m, 4H), 3.81-3.99 (m, 2H), 4.67-4.75 (m, 1H), 6.56-6.62 (m, 1H), 6.76-6.85 (m, 2H), 7.19-7.27 (m, 1H), 7.69-7.77 (m, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.93-7.97 (m, 1H)
  • Melting point: 175.0° C. to 178.0° C.
  • The compounds shown in Table 1 were obtained using the corresponding starting compounds and the procedures shown in Examples 1 to 28.
  • The compounds obtained in the Examples above are also shown in Table 1 together with the other compounds.
    • Test Example 1 (S1P1 Binding Assay
  • Using a human Edg-1 (S1P1) gene transferred HEK-293 cell strain membrane fraction, the Edg-1 (S1P1) binding inhibiting action of the compounds of the present invention was determined in accordance with the method described in the literature (Science. 2002, 296: 346) (showing a binding of Kd=0.15 nM, Bmax=2.5 fmol/μg to [33P]-S1P). The membrane fraction was obtained by treating the cells with a solubilizing buffer (1 mM Tris/HCl, pH 7.2) for 10 minutes on ice, centrifuging at 1000×g for 5 minutes to remove insoluble fractions, and then centrifuging at 40000×g for 30 minutes at 4° C. The resulting membrane fraction was dissolved in a binding buffer (20 mM Tris-HCl, pH 7.4, 100 mM NaCl, 15 mM NaF, 2 mM deoxypyridoxine, 4 mg/mL fatty acid-free BSA), and then [33P]-S1P (manufactured by ARC, final concentration 0.1 nM) and a DMSO solution (final concentration of the compound 10−5M, final concentration of DMSO 0.1%) of the test compound were added. Thereafter, the mixture was stirred and then treated for one hour at 30° C. Using a harvester, the membrane fraction was harvested onto unifilter-96 GF/C filter (manufactured by Perkin Elmer), washing was carried out four times with the binding buffer, and the filter was dried. Twenty five μL Microscint 0 (manufactured by Perkin Elmer) was added, and radioactivity was measured using Top Count NXT (manufactured by Packard) to calculate the amount (A) of [33P]-S1P bound to the membrane fraction at the time when the compound was added.
  • The same procedure was carried out in the absence of the test compound, and the amount (B) of [33P]-S1P bound was calculated. Further, the same procedure was carried out in the absence of the test compound by use of HEK-293 cells to which no Edg-1 (S1P1) gene was introduced, and the background amount (C) of [33P]-S1P bound was calculated.
  • The Edg-1 (S1P1) binding inhibition rates of the compound calculated using the following equation are shown in Table 1.

  • Inhibition rate(%)=[1−(A−C)/(B−C)]×100
  • Further, concentrations (IC50) at the time when binding in the absence of the test compound was inhibited by 50% were calculated. The membrane system binding assay was carried out in the presence of test compounds with various concentrations, and the Edg-1 (S1P1) binding inhibition rates were calculated using the equation above. Then, IC50 values were calculated using Origin (Lightstone Corp.), a software for data analysis.
  • The compounds below each had an IC50 value of 35 nM or lower and showed particularly strong activity.
  • Compounds 5, 13, 16, 18, 21, 23, 25, 26, 32, 35, 37, 43, 46, 64, 69, 76, 101, 102, 109, 122, 123, 125, 131, 134, 141, 142, 145, 665.
  • The following compounds had an IC50 value of 10 nM or below, and showed even stronger activity.
  • Compounds 24, 39, 40, 70, 75, 87, 93, 94, 107, 111, 112, 121, 132, 133, 137, 138, 139, 140, 147, 151, 663, 666, 667, 669, 671, 681, 683, 690.
  • Specific IC50 values of the individual compounds are as follows (unit: nM).
  • Compound 3: 4.2. Compound 7: 35.5. Compound 8: 18.5. Compound 10: 17.5. Compound 11: 8.9. Compound 12: 20.0. Compound 14: 6.4. Compound 15: 32.5. Compound 22: 14.0. Compound 28: 3.1. Compound 34: 2.0. Compound 36: 17.5. Compound 38: 11.7. Compound 42: 22.0. Compound 45: 4.2. Compound 46: 28.5. Compound 49: 6.0. Compound 61: 39.0. Compound 73: 2.2. Compound 74: 15.0. Compound 83: 8.1. Compound 88: 5.4. Compound 99: 25.0. Compound 100: 18.5. Compound 105: 2.9. Compound 108: 18.0. Compound 120:1.7. Compound 129: 20.0. Compound 130: 2.9. Compound 136: 8.1. Compound 143: 7.3. Compound 144: 7.9. Compound 146: 12.0. Compound 148: 1.9. Compound 149: 7.8. Compound 670: 5.2. Compound 678: 10.2. Compound 680:1.4. Compound 688: 1.5. Compound 691: 2.6. Compound 692: 5.1. Compound 694: 2.9. Compound 698: 2.3.
  • TABLE 1
    Binding assay
    (membrane)
    Compound Melting % inhibition
    number Chemical structure point (° C.) (10 μM)
    Compound  1
    Figure US20110269960A1-20111103-C00081
         		182.0-184.0 100.8
    Compound  2
    Figure US20110269960A1-20111103-C00082
         		134.0-138.0 97.8
    Compound  3
    Figure US20110269960A1-20111103-C00083
         		183.5-187.5 98.7
    Compound  4
    Figure US20110269960A1-20111103-C00084
         		198.5-200.5 95.7
    Compound  5
    Figure US20110269960A1-20111103-C00085
         		160.0-161.0 97.3
    Compound  6
    Figure US20110269960A1-20111103-C00086
         		180.0-190.0 98.2
    Compound  7
    Figure US20110269960A1-20111103-C00087
         		159.5-161.5 99.4
    Compound  8
    Figure US20110269960A1-20111103-C00088
         		179.0-179.5 100.1
    Compound  9
    Figure US20110269960A1-20111103-C00089
         		145.0-148.0 100.3
    Compound  10
    Figure US20110269960A1-20111103-C00090
         		182.5-184.5 99.8
    Compound  11
    Figure US20110269960A1-20111103-C00091
         		155.0-160.0 98.5
    Compound  12
    Figure US20110269960A1-20111103-C00092
         		190.0-192.0 99.2
    Compound  13
    Figure US20110269960A1-20111103-C00093
         		152.0-156.0 102.0
    Compound  14
    Figure US20110269960A1-20111103-C00094
         		161.0-162.5 99.5
    Compound  15
    Figure US20110269960A1-20111103-C00095
         		200.0-205.0 102.7
    Compound  16
    Figure US20110269960A1-20111103-C00096
         		125.0-127.0 101.3
    Compound  17
    Figure US20110269960A1-20111103-C00097
         		129.5-131.5 95.4
    Compound  18
    Figure US20110269960A1-20111103-C00098
         		189.0-194.0 102.1
    Compound  19
    Figure US20110269960A1-20111103-C00099
         		145.0-150.0 97.9
    Compound  20
    Figure US20110269960A1-20111103-C00100
         		118.0-120.0 97.4
    Compound  21
    Figure US20110269960A1-20111103-C00101
         		146.5-149.5 96.7
    Compound  22
    Figure US20110269960A1-20111103-C00102
         		163.0-167.5 95.4
    Compound  23
    Figure US20110269960A1-20111103-C00103
         		173.0-176.0 96.7
    Compound  24
    Figure US20110269960A1-20111103-C00104
         		172.5-173.0 101.0
    Compound  25
    Figure US20110269960A1-20111103-C00105
         		155.0-156.0 97.5
    Compound  26
    Figure US20110269960A1-20111103-C00106
         		159.0-164.0 97.9
    Compound  27
    Figure US20110269960A1-20111103-C00107
         		163.0-168.0 100.1
    Compound  28
    Figure US20110269960A1-20111103-C00108
         		165.0-170.0 104.4
    Compound  29
    Figure US20110269960A1-20111103-C00109
         		177.0-178.5 101.4
    Compound  30
    Figure US20110269960A1-20111103-C00110
         		212.0-216.0 100.4
    Compound  31
    Figure US20110269960A1-20111103-C00111
         		143.0-146.0 101.2
    Compound  32
    Figure US20110269960A1-20111103-C00112
         		147.0-148.0 104.1
    Compound  33
    Figure US20110269960A1-20111103-C00113
         		173.5-174.5 100.8
    Compound  34
    Figure US20110269960A1-20111103-C00114
         		192.5-195.5 106.1
    Compound  35
    Figure US20110269960A1-20111103-C00115
         		156.0-159.0 100.4
    Compound  36
    Figure US20110269960A1-20111103-C00116
         		125.0-130.0 102.2
    Compound  37
    Figure US20110269960A1-20111103-C00117
         		145.0-147.0 100.3
    Compound  38
    Figure US20110269960A1-20111103-C00118
         		148.5-150.0 104.8
    Compound  39
    Figure US20110269960A1-20111103-C00119
         		176.0-178.0 98.5
    Compound  40
    Figure US20110269960A1-20111103-C00120
         		155.5-156.5 105.6
    Compound  41
    Figure US20110269960A1-20111103-C00121
         		166.0-170.0 92.0
    Compound  42
    Figure US20110269960A1-20111103-C00122
         		176.5-179.5 102.4
    Compound  43
    Figure US20110269960A1-20111103-C00123
         		182.5-185.0 99.8
    Compound  44
    Figure US20110269960A1-20111103-C00124
         		140.0-145.5 100.1
    Compound  45
    Figure US20110269960A1-20111103-C00125
         		194.0-196.0 106.0
    Compound  46
    Figure US20110269960A1-20111103-C00126
         		247.0-250.0 94.6
    Compound  47
    Figure US20110269960A1-20111103-C00127
         		191.0-192.0 102.3
    Compound  48
    Figure US20110269960A1-20111103-C00128
         		195.5-196.5 96.7
    Compound  49
    Figure US20110269960A1-20111103-C00129
         		198.0-199.0 102.5
    Compound  50
    Figure US20110269960A1-20111103-C00130
         		129.0-130.0 92.9
    Compound  51
    Figure US20110269960A1-20111103-C00131
         		148.5-150.5 99.9
    Compound  52
    Figure US20110269960A1-20111103-C00132
         		203.0-205.0 100.2
    Compound  53
    Figure US20110269960A1-20111103-C00133
         		172.0-173.0 86.8
    Compound  54
    Figure US20110269960A1-20111103-C00134
         		192.0-193.0 104.1
    Compound  55
    Figure US20110269960A1-20111103-C00135
         		141.0-143.0 80.6
    Compound  56
    Figure US20110269960A1-20111103-C00136
         		189.0-191.0 88.3
    Compound  57
    Figure US20110269960A1-20111103-C00137
         		164.0-165.0
    Compound  58
    Figure US20110269960A1-20111103-C00138
         		181.0-183.0 99.7
    Compound  59
    Figure US20110269960A1-20111103-C00139
         		169.5-170.5 94.3
    Compound  60
    Figure US20110269960A1-20111103-C00140
         		192.5-195.0 98.9
    Compound  61
    Figure US20110269960A1-20111103-C00141
         		93.0-99.0 102.2
    Compound  62
    Figure US20110269960A1-20111103-C00142
         		186.0-188.5 83.5
    Compound  63
    Figure US20110269960A1-20111103-C00143
         		216.5-217.5 104.7
    Compound  64
    Figure US20110269960A1-20111103-C00144
         		223.0-224.0 100.8
    Compound  65
    Figure US20110269960A1-20111103-C00145
         		201.0-202.0 105.3
    Compound  66
    Figure US20110269960A1-20111103-C00146
         		183.0-190.0 93.4
    Compound  67
    Figure US20110269960A1-20111103-C00147
         		182.0-188.0 95.5
    Compound  68
    Figure US20110269960A1-20111103-C00148
         		212.0-223.0 100.9
    Compound  69
    Figure US20110269960A1-20111103-C00149
         		119.0-120.5 103.2
    Compound  70
    Figure US20110269960A1-20111103-C00150
         		144.0-146.0 96.5
    Compound  71
    Figure US20110269960A1-20111103-C00151
         		126.0-135.0 99.3
    Compound  72
    Figure US20110269960A1-20111103-C00152
         		198.0-200.5 99.0
    Compound  73
    Figure US20110269960A1-20111103-C00153
         		185.0-187.0 103.3
    Compound  74
    Figure US20110269960A1-20111103-C00154
         		218.5-227.0 104.9
    Compound  75
    Figure US20110269960A1-20111103-C00155
         		177.0-179.0 95.0
    Compound  76
    Figure US20110269960A1-20111103-C00156
         		151.5-153.5 99.2
    Compound  77
    Figure US20110269960A1-20111103-C00157
         		123.0-127.0 99.7
    Compound  78
    Figure US20110269960A1-20111103-C00158
         		178.0-179.0 90.7
    Compound  79
    Figure US20110269960A1-20111103-C00159
         		190.0-195.0 103.7
    Compound  80
    Figure US20110269960A1-20111103-C00160
         		164.0-165.0 87.6
    Compound  81
    Figure US20110269960A1-20111103-C00161
         		160.0-165.0 93.2
    Compound  82
    Figure US20110269960A1-20111103-C00162
         		142.0-145.0 100.8
    Compound  83
    Figure US20110269960A1-20111103-C00163
         		170.0-173.0 100.7
    Compound  84
    Figure US20110269960A1-20111103-C00164
         		160.0-165.0 100.5
    Compound  85
    Figure US20110269960A1-20111103-C00165
         		133.0-134.0 100.0
    Compound  86
    Figure US20110269960A1-20111103-C00166
         		176.0-177.0 106.7
    Compound  87
    Figure US20110269960A1-20111103-C00167
         		174.0-179.0 99.9
    Compound  88
    Figure US20110269960A1-20111103-C00168
         		188.5-190.5 99.5
    Compound  89
    Figure US20110269960A1-20111103-C00169
         		101.0-103.0 90.3
    Compound  90
    Figure US20110269960A1-20111103-C00170
         		168.0-170.0 99.0
    Compound  91
    Figure US20110269960A1-20111103-C00171
         		137.0-138.0 90.6
    Compound  92
    Figure US20110269960A1-20111103-C00172
         		118.0-120.0 92.1
    Compound  93
    Figure US20110269960A1-20111103-C00173
         		167.5-169.5 99.9
    Compound  94
    Figure US20110269960A1-20111103-C00174
         		190.0-192.0 106.4
    Compound  95
    Figure US20110269960A1-20111103-C00175
         		205.0-208.5 92.4
    Compound  96
    Figure US20110269960A1-20111103-C00176
         		191.0-194.0 78.7
    Compound  97
    Figure US20110269960A1-20111103-C00177
         		158.0-159.0 93.0
    Compound  98
    Figure US20110269960A1-20111103-C00178
         		143.0-144.0 100.4
    Compound  99
    Figure US20110269960A1-20111103-C00179
         		103.0-105.5 102.4
    Compound 100
    Figure US20110269960A1-20111103-C00180
         		109.9
    Compound 101
    Figure US20110269960A1-20111103-C00181
         		142.0-143.0 100.9
    Compound 102
    Figure US20110269960A1-20111103-C00182
         		117.0-118.0 104.2
    Compound 103
    Figure US20110269960A1-20111103-C00183
         		146.5-147.5 91.2
    Compound 104
    Figure US20110269960A1-20111103-C00184
         		187.0-187.5 95.2
    Compound 105
    Figure US20110269960A1-20111103-C00185
         		121.0-123.0 104.4
    Compound 106
    Figure US20110269960A1-20111103-C00186
         		132.0-134.0 110.2
    Compound 107
    Figure US20110269960A1-20111103-C00187
         		159.0-162.0 103.8
    Compound 108
    Figure US20110269960A1-20111103-C00188
         		175.0-180.0 101.3
    Compound 109
    Figure US20110269960A1-20111103-C00189
         		152.0-153.0 103.5
    Compound 110
    Figure US20110269960A1-20111103-C00190
         		187.5-188.5 103.6
    Compound 111
    Figure US20110269960A1-20111103-C00191
         		204.0-205.0 108.7
    Compound 112
    Figure US20110269960A1-20111103-C00192
         		171.0-173.0 99.2
    Compound 113
    Figure US20110269960A1-20111103-C00193
         		183.0-185.0 74.2
    Compound 114
    Figure US20110269960A1-20111103-C00194
         		185.0-186.0 94.5
    Compound 115
    Figure US20110269960A1-20111103-C00195
         		125.5-126.5 81.8
    Compound 116
    Figure US20110269960A1-20111103-C00196
         		192.0-195.0 83.1
    Compound 117
    Figure US20110269960A1-20111103-C00197
         		153.5-155.5 87.1
    Compound 118
    Figure US20110269960A1-20111103-C00198
    Compound 119
    Figure US20110269960A1-20111103-C00199
    Compound 120
    Figure US20110269960A1-20111103-C00200
         		211.5-216.5 93.03
    Compound 121
    Figure US20110269960A1-20111103-C00201
         		195.5-198.5 103.45
    Compound 122
    Figure US20110269960A1-20111103-C00202
         		167.0-170.0 81.93
    Compound 123
    Figure US20110269960A1-20111103-C00203
         		162.0-165.0 97.12
    Compound 124
    Figure US20110269960A1-20111103-C00204
         		178.5-180.0 97.44
    Compound 125
    Figure US20110269960A1-20111103-C00205
         		253.5-254.5 94.28
    Compound 126
    Figure US20110269960A1-20111103-C00206
         		176.5-178.0 91.80
    Compound 127
    Figure US20110269960A1-20111103-C00207
         		94.44
    Compound 128
    Figure US20110269960A1-20111103-C00208
         		182.5-183.5 90.70
    Compound 129
    Figure US20110269960A1-20111103-C00209
         		96.0-104.0 96.79
    Compound 130
    Figure US20110269960A1-20111103-C00210
         		107.0-114.0 98.87
    Compound 131
    Figure US20110269960A1-20111103-C00211
         		102.0-110.5 97.35
    Compound 132
    Figure US20110269960A1-20111103-C00212
         		95.0-104.0 99.52
    Compound 133
    Figure US20110269960A1-20111103-C00213
         		164.0-169.5 101.11
    Compound 134
    Figure US20110269960A1-20111103-C00214
         		108.5-114.5 101.47
    Compound 135
    Figure US20110269960A1-20111103-C00215
         		188.5-192.0 100.63
    Compound 136
    Figure US20110269960A1-20111103-C00216
         		100.0-106.0 96.51
    Compound 137
    Figure US20110269960A1-20111103-C00217
         		173.5-177.0 101.74
    Compound 138
    Figure US20110269960A1-20111103-C00218
         		167.5-169.0 99.58
    Compound 139
    Figure US20110269960A1-20111103-C00219
         		174.0-177.0 101.46
    Compound 140
    Figure US20110269960A1-20111103-C00220
         		110.0-119.0 101.57
    Compound 141
    Figure US20110269960A1-20111103-C00221
         		169.0-173.0 104.70
    Compound 142
    Figure US20110269960A1-20111103-C00222
         		183.0-184.0 98.11
    Compound 143
    Figure US20110269960A1-20111103-C00223
         		144.0-145.0 99.89
    Compound 144
    Figure US20110269960A1-20111103-C00224
         		187.0-188.0 99.38
    Compound 145
    Figure US20110269960A1-20111103-C00225
         		150.0-152.0 101.30
    Compound 146
    Figure US20110269960A1-20111103-C00226
         		121.0-122.0 101.65
    Compound 147
    Figure US20110269960A1-20111103-C00227
         		141.0-143.0 102.74
    Compound 148
    Figure US20110269960A1-20111103-C00228
         		154.5-155.5 102.47
    Compound 149
    Figure US20110269960A1-20111103-C00229
         		212.0-214.5 100.70
    Compound  1
    Figure US20110269960A1-20111103-C00230
         		191.5-196.0 93.40
    Compound  2
    Figure US20110269960A1-20111103-C00231
         		252.0-255.0 102.84
    Binding assay
    APCI APCI (membrane)
    Compound MS MS % inhibition
    number Chemical Structure (M − H)− (M + H)+ (10 μM)
    Compound 152
    Figure US20110269960A1-20111103-C00232
         		467 469
    Compound 153
    Figure US20110269960A1-20111103-C00233
         		446 448
    Compound 154
    Figure US20110269960A1-20111103-C00234
         		431 433 92.3
    Compound 155
    Figure US20110269960A1-20111103-C00235
         		389 391 59.9
    Compound 156
    Figure US20110269960A1-20111103-C00236
         		467, 469  469, 471  106.6
    Compound 157
    Figure US20110269960A1-20111103-C00237
         		445 447 74.6
    Compound 158
    Figure US20110269960A1-20111103-C00238
         		467, 469  469, 471 
    Compound 159
    Figure US20110269960A1-20111103-C00239
         		461 463
    Compound 160
    Figure US20110269960A1-20111103-C00240
         		467, 469  469, 471  96.9
    Compound 161
    Figure US20110269960A1-20111103-C00241
         		551, 553  553, 554 
    Compound 162
    Figure US20110269960A1-20111103-C00242
         		423 425 109.3
    Compound 163
    Figure US20110269960A1-20111103-C00243
         		414 416
    Compound 164
    Figure US20110269960A1-20111103-C00244
         		465 467
    Compound 165
    Figure US20110269960A1-20111103-C00245
         		414 416 72.9
    Compound 166
    Figure US20110269960A1-20111103-C00246
         		493 495
    Compound 167
    Figure US20110269960A1-20111103-C00247
         		451 453 113.3
    Compound 168
    Figure US20110269960A1-20111103-C00248
         		457 459 68.4
    Compound 169
    Figure US20110269960A1-20111103-C00249
         		457 459
    Compound 170
    Figure US20110269960A1-20111103-C00250
         		449 451 76.0
    Compound 171
    Figure US20110269960A1-20111103-C00251
         		341 343
    Compound 172
    Figure US20110269960A1-20111103-C00252
         		417 419 92.0
    Compound 173
    Figure US20110269960A1-20111103-C00253
         		407 409 97.2
    Compound 174
    Figure US20110269960A1-20111103-C00254
         		431 433 52.5
    Compound 175
    Figure US20110269960A1-20111103-C00255
         		419 421 102.7
    Compound 176
    Figure US20110269960A1-20111103-C00256
         		327 329
    Compound 177
    Figure US20110269960A1-20111103-C00257
         		467 469 55.3
    Compound 178
    Figure US20110269960A1-20111103-C00258
         		467 469
    Compound 179
    Figure US20110269960A1-20111103-C00259
         		439 441 83.0
    Compound 180
    Figure US20110269960A1-20111103-C00260
         		467 469 94.6
    Compound 181
    Figure US20110269960A1-20111103-C00261
         		479 481 50.4
    Compound 182
    Figure US20110269960A1-20111103-C00262
         		514 517 109.3
    Compound 183
    Figure US20110269960A1-20111103-C00263
         		415 417 92.8
    Compound 184
    Figure US20110269960A1-20111103-C00264
         		491, 493  493, 495  97.3
    Compound 185
    Figure US20110269960A1-20111103-C00265
         		515 517
    Compound 186
    Figure US20110269960A1-20111103-C00266
         		403 405 86.8
    Compound 187
    Figure US20110269960A1-20111103-C00267
         		403 405
    Compound 188
    Figure US20110269960A1-20111103-C00268
         		457 459 106.6
    Compound 189
    Figure US20110269960A1-20111103-C00269
         		403 405 99.7
    Compound 190
    Figure US20110269960A1-20111103-C00270
         		473 475 87.9
    Compound 191
    Figure US20110269960A1-20111103-C00271
         		415 417 96.9
    Compound 192
    Figure US20110269960A1-20111103-C00272
         		403 405 95.2
    Compound 193
    Figure US20110269960A1-20111103-C00273
         		530 532
    Compound 194
    Figure US20110269960A1-20111103-C00274
         		540 542 80.7
    Compound 195
    Figure US20110269960A1-20111103-C00275
         		417 419 90.1
    Compound 196
    Figure US20110269960A1-20111103-C00276
         		479 481 65.6
    Compound 197
    Figure US20110269960A1-20111103-C00277
         		535 537
    Compound 198
    Figure US20110269960A1-20111103-C00278
         		441 443
    Compound 199
    Figure US20110269960A1-20111103-C00279
         		408 410
    Compound 200
    Figure US20110269960A1-20111103-C00280
         		465 467
    Compound 201
    Figure US20110269960A1-20111103-C00281
         		450 452 84.3
    Compound 202
    Figure US20110269960A1-20111103-C00282
         		421 423
    Compound 203
    Figure US20110269960A1-20111103-C00283
         		447 449
    Compound 204
    Figure US20110269960A1-20111103-C00284
         		457 459
    Compound 205
    Figure US20110269960A1-20111103-C00285
         		465 467
    Compound 206
    Figure US20110269960A1-20111103-C00286
         		431 433 85.4
    Compound 207
    Figure US20110269960A1-20111103-C00287
         		491, 493  493, 495  107.7
    Compound 208
    Figure US20110269960A1-20111103-C00288
         		445 447 80.2
    Compound 209
    Figure US20110269960A1-20111103-C00289
         		457 459 91.4
    Compound 210
    Figure US20110269960A1-20111103-C00290
         		437 439
    Compound 211
    Figure US20110269960A1-20111103-C00291
         		423 425
    Compound 212
    Figure US20110269960A1-20111103-C00292
         		525 527 69.7
    Compound 213
    Figure US20110269960A1-20111103-C00293
         		457 459 101.9
    Compound 214
    Figure US20110269960A1-20111103-C00294
         		437 439 102.1
    Compound 215
    Figure US20110269960A1-20111103-C00295
         		419 421 91.4
    Compound 216
    Figure US20110269960A1-20111103-C00296
         		503, 505  505, 507  88.9
    Compound 217
    Figure US20110269960A1-20111103-C00297
         		461 463 57.5
    Compound 218
    Figure US20110269960A1-20111103-C00298
         		497, 499  499, 501  74.7
    Compound 219
    Figure US20110269960A1-20111103-C00299
         		421 423 70.8
    Compound 220
    Figure US20110269960A1-20111103-C00300
         		459 461 93.7
    Compound 221
    Figure US20110269960A1-20111103-C00301
         		433 435 69.2
    Compound 222
    Figure US20110269960A1-20111103-C00302
         		473 475
    Compound 223
    Figure US20110269960A1-20111103-C00303
         		414 416 90.8
    Compound 224
    Figure US20110269960A1-20111103-C00304
         		481 483
    Compound 225
    Figure US20110269960A1-20111103-C00305
         		491, 493  493, 495 
    Compound 226
    Figure US20110269960A1-20111103-C00306
         		457 459 80.4
    Compound 227
    Figure US20110269960A1-20111103-C00307
         		425 427 51.4
    Compound 228
    Figure US20110269960A1-20111103-C00308
         		449 451 53.9
    Compound 229
    Figure US20110269960A1-20111103-C00309
         		441 443
    Compound 230
    Figure US20110269960A1-20111103-C00310
         		407 409
    Compound 231
    Figure US20110269960A1-20111103-C00311
         		423 425 65.1
    Compound 232
    Figure US20110269960A1-20111103-C00312
         		431 433 68.7
    Compound 233
    Figure US20110269960A1-20111103-C00313
         		455 457 87.1
    Compound 234
    Figure US20110269960A1-20111103-C00314
         		495, 497  497, 499  50.6
    Compound 235
    Figure US20110269960A1-20111103-C00315
         		481, 483  483, 485  82.9
    Compound 236
    Figure US20110269960A1-20111103-C00316
         		448 450
    Compound 237
    Figure US20110269960A1-20111103-C00317
         		443 445 64.8
    Compound 238
    Figure US20110269960A1-20111103-C00318
         		425 427
    Compound 239
    Figure US20110269960A1-20111103-C00319
         		525 527
    Compound 240
    Figure US20110269960A1-20111103-C00320
         		459 461 82.5
    Compound 241
    Figure US20110269960A1-20111103-C00321
         		425 427 95.8
    Compound 242
    Figure US20110269960A1-20111103-C00322
         		485, 487  487, 489  85.9
    Compound 243
    Figure US20110269960A1-20111103-C00323
         		459 461 90.0
    Compound 244
    Figure US20110269960A1-20111103-C00324
         		503, 505  505, 507  94.6
    Compound 245
    Figure US20110269960A1-20111103-C00325
         		459 461 89.3
    Compound 246
    Figure US20110269960A1-20111103-C00326
         		471 473
    Compound 247
    Figure US20110269960A1-20111103-C00327
         		493 495
    Compound 248
    Figure US20110269960A1-20111103-C00328
         		471 473 104.9
    Compound 249
    Figure US20110269960A1-20111103-C00329
         		581, 583  583, 585 
    Compound 250
    Figure US20110269960A1-20111103-C00330
         		425 427
    Compound 251
    Figure US20110269960A1-20111103-C00331
         		491 493 59.0
    Compound 252
    Figure US20110269960A1-20111103-C00332
         		407 409 82.8
    Compound 253
    Figure US20110269960A1-20111103-C00333
         		480 482
    Compound 254
    Figure US20110269960A1-20111103-C00334
         		453 455 75.1
    Compound 255
    Figure US20110269960A1-20111103-C00335
         		471 473 86.4
    Compound 256
    Figure US20110269960A1-20111103-C00336
         		443 445 85.2
    Compound 257
    Figure US20110269960A1-20111103-C00337
         		545, 547  547, 549  78.2
    Compound 258
    Figure US20110269960A1-20111103-C00338
         		462 464 67.9
    Compound 259
    Figure US20110269960A1-20111103-C00339
         		437 439
    Compound 260
    Figure US20110269960A1-20111103-C00340
         		545, 547  547, 549  74.1
    Compound 261
    Figure US20110269960A1-20111103-C00341
         		432 434 73.6
    Compound 262
    Figure US20110269960A1-20111103-C00342
         		417 419 79.6
    Compound 263
    Figure US20110269960A1-20111103-C00343
         		455 457 82.6
    Compound 264
    Figure US20110269960A1-20111103-C00344
         		455 457 95.9
    Compound 265
    Figure US20110269960A1-20111103-C00345
         		503, 505  505, 507  59.1
    Compound 266
    Figure US20110269960A1-20111103-C00346
         		425 427 99.0
    Compound 267
    Figure US20110269960A1-20111103-C00347
         		441 443 89.6
    Compound 268
    Figure US20110269960A1-20111103-C00348
         		443 445 99.9
    Compound 269
    Figure US20110269960A1-20111103-C00349
         		485, 487  487, 489  91.5
    Compound 270
    Figure US20110269960A1-20111103-C00350
         		535, 537  537, 539  73.0
    Compound 271
    Figure US20110269960A1-20111103-C00351
         		535, 537  537, 539  57.1
    Compound 272
    Figure US20110269960A1-20111103-C00352
         		421 423 104.3
    Compound 273
    Figure US20110269960A1-20111103-C00353
         		421 423 71.6
    Compound 274
    Figure US20110269960A1-20111103-C00354
         		441 443 53.5
    Compound 275
    Figure US20110269960A1-20111103-C00355
         		485, 487  487, 489  107.1
    Compound 276
    Figure US20110269960A1-20111103-C00356
         		501, 503  503, 505  94.4
    Compound 277
    Figure US20110269960A1-20111103-C00357
         		535, 537  537, 539 
    Compound 278
    Figure US20110269960A1-20111103-C00358
         		477 479
    Compound 279
    Figure US20110269960A1-20111103-C00359
         		421 423 79.6
    Compound 280
    Figure US20110269960A1-20111103-C00360
         		441 443 87.3
    Compound 281
    Figure US20110269960A1-20111103-C00361
         		475 477
    Compound 282
    Figure US20110269960A1-20111103-C00362
         		495 497
    Compound 283
    Figure US20110269960A1-20111103-C00363
         		482 484
    Compound 284
    Figure US20110269960A1-20111103-C00364
         		404 406
    Compound 285
    Figure US20110269960A1-20111103-C00365
         		419 421
    Compound 286
    Figure US20110269960A1-20111103-C00366
         		409 411 60.6
    Compound 287
    Figure US20110269960A1-20111103-C00367
         		456 455
    Compound 288
    Figure US20110269960A1-20111103-C00368
         		394 396
    Compound 289
    Figure US20110269960A1-20111103-C00369
         		447 449 105.6
    Compound 290
    Figure US20110269960A1-20111103-C00370
         		424 426
    Compound 291
    Figure US20110269960A1-20111103-C00371
         		447 449
    Compound 292
    Figure US20110269960A1-20111103-C00372
         		447 449 106.9
    Compound 293
    Figure US20110269960A1-20111103-C00373
         		431 433
    Compound 294
    Figure US20110269960A1-20111103-C00374
         		395 397 50.8
    Compound 295
    Figure US20110269960A1-20111103-C00375
         		462 464
    Compound 296
    Figure US20110269960A1-20111103-C00376
         		469 471
    Compound 297
    Figure US20110269960A1-20111103-C00377
         		478 480
    Compound 298
    Figure US20110269960A1-20111103-C00378
         		543 545
    Compound 299
    Figure US20110269960A1-20111103-C00379
         		519 521
    Compound 300
    Figure US20110269960A1-20111103-C00380
         		423 425 82.1
    Compound 301
    Figure US20110269960A1-20111103-C00381
         		449 451 78.8
    Compound 302
    Figure US20110269960A1-20111103-C00382
         		538 540
    Compound 303
    Figure US20110269960A1-20111103-C00383
         		491 493 77.4
    Compound 304
    Figure US20110269960A1-20111103-C00384
         		517 519
    Compound 305
    Figure US20110269960A1-20111103-C00385
         		561 563
    Compound 306
    Figure US20110269960A1-20111103-C00386
         		431 433 60.2
    Compound 307
    Figure US20110269960A1-20111103-C00387
         		457 459 94.4
    Compound 308
    Figure US20110269960A1-20111103-C00388
         		490 492
    Compound 309
    Figure US20110269960A1-20111103-C00389
         		490 492
    Compound 310
    Figure US20110269960A1-20111103-C00390
         		494 496
    Compound 311
    Figure US20110269960A1-20111103-C00391
         		447 449 76.5
    Compound 312
    Figure US20110269960A1-20111103-C00392
         		461 463
    Compound 313
    Figure US20110269960A1-20111103-C00393
         		437 439
    Compound 314
    Figure US20110269960A1-20111103-C00394
         		502 504 52.2
    Compound 315
    Figure US20110269960A1-20111103-C00395
         		440 442
    Compound 316
    Figure US20110269960A1-20111103-C00396
         		525 527
    Compound 317
    Figure US20110269960A1-20111103-C00397
         		535, 537  537, 539 
    Compound 318
    Figure US20110269960A1-20111103-C00398
         		535, 537  537, 539  78.9
    Compound 319
    Figure US20110269960A1-20111103-C00399
         		535, 537  537, 539  61.7
    Compound 320
    Figure US20110269960A1-20111103-C00400
         		390 392
    Compound 321
    Figure US20110269960A1-20111103-C00401
         		475 477
    Compound 322
    Figure US20110269960A1-20111103-C00402
         		539 541
    Compound 323
    Figure US20110269960A1-20111103-C00403
         		445 447 77.9
    Compound 324
    Figure US20110269960A1-20111103-C00404
         		445 447 81.8
    Compound 325
    Figure US20110269960A1-20111103-C00405
         		488 490
    Compound 326
    Figure US20110269960A1-20111103-C00406
         		487 469
    Compound 327
    Figure US20110269960A1-20111103-C00407
         		452 454 92.3
    Compound 328
    Figure US20110269960A1-20111103-C00408
         		410 412 85.2
    Compound 329
    Figure US20110269960A1-20111103-C00409
         		488, 490  490, 492  100.8
    Compound 330
    Figure US20110269960A1-20111103-C00410
         		466 468 81.6
    Compound 331
    Figure US20110269960A1-20111103-C00411
         		488, 490  490, 492  59.8
    Compound 332
    Figure US20110269960A1-20111103-C00412
         		482 484
    Compound 333
    Figure US20110269960A1-20111103-C00413
         		488, 490  490, 492  102.2
    Compound 334
    Figure US20110269960A1-20111103-C00414
         		572, 574  574, 576 
    Compound 335
    Figure US20110269960A1-20111103-C00415
         		444 446 106.1
    Compound 336
    Figure US20110269960A1-20111103-C00416
         		435 437 56.8
    Compound 337
    Figure US20110269960A1-20111103-C00417
         		486 488
    Compound 338
    Figure US20110269960A1-20111103-C00418
         		435 437 69.2
    Compound 339
    Figure US20110269960A1-20111103-C00419
         		514 516 62.8
    Compound 340
    Figure US20110269960A1-20111103-C00420
         		472 474 100.0
    Compound 341
    Figure US20110269960A1-20111103-C00421
         		478 480 92.8
    Compound 342
    Figure US20110269960A1-20111103-C00422
         		478 480 53.6
    Compound 343
    Figure US20110269960A1-20111103-C00423
         		470 472 86.5
    Compound 344
    Figure US20110269960A1-20111103-C00424
         		362 364
    Compound 345
    Figure US20110269960A1-20111103-C00425
         		438 440 90.4
    Compound 346
    Figure US20110269960A1-20111103-C00426
         		428 430 89.2
    Compound 347
    Figure US20110269960A1-20111103-C00427
         		452 454 50.1
    Compound 348
    Figure US20110269960A1-20111103-C00428
         		440 442 109.1
    Compound 349
    Figure US20110269960A1-20111103-C00429
         		348 350
    Compound 350
    Figure US20110269960A1-20111103-C00430
         		488 490 75.0
    Compound 351
    Figure US20110269960A1-20111103-C00431
         		488 490
    Compound 352
    Figure US20110269960A1-20111103-C00432
         		460 462 88.5
    Compound 353
    Figure US20110269960A1-20111103-C00433
         		488 490 92.3
    Compound 354
    Figure US20110269960A1-20111103-C00434
         		500 502
    Compound 355
    Figure US20110269960A1-20111103-C00435
         		536 538 98.8
    Compound 356
    Figure US20110269960A1-20111103-C00436
         		436 438 95.6
    Compound 357
    Figure US20110269960A1-20111103-C00437
         		512, 514  514, 516  106.1
    Compound 358
    Figure US20110269960A1-20111103-C00438
         		536 538
    Compound 359
    Figure US20110269960A1-20111103-C00439
         		424 426 95.7
    Compound 360
    Figure US20110269960A1-20111103-C00440
         		424 426
    Compound 361
    Figure US20110269960A1-20111103-C00441
         		424 426 96.9
    Compound 362
    Figure US20110269960A1-20111103-C00442
         		494 496 95.1
    Compound 363
    Figure US20110269960A1-20111103-C00443
         		436 438 96.2
    Compound 364
    Figure US20110269960A1-20111103-C00444
         		424 426 87.5
    Compound 365
    Figure US20110269960A1-20111103-C00445
         		551 553
    Compound 366
    Figure US20110269960A1-20111103-C00446
         		561 563 63.2
    Compound 367
    Figure US20110269960A1-20111103-C00447
         		438 440 94.3
    Compound 368
    Figure US20110269960A1-20111103-C00448
         		500 502 60.5
    Compound 369
    Figure US20110269960A1-20111103-C00449
         		556 558
    Compound 370
    Figure US20110269960A1-20111103-C00450
         		462 464
    Compound 371
    Figure US20110269960A1-20111103-C00451
         		429 431
    Compound 372
    Figure US20110269960A1-20111103-C00452
         		471 473 106.3
    Compound 373
    Figure US20110269960A1-20111103-C00453
         		442 444
    Compound 374
    Figure US20110269960A1-20111103-C00454
         		468 470
    Compound 375
    Figure US20110269960A1-20111103-C00455
         		478 480
    Compound 376
    Figure US20110269960A1-20111103-C00456
         		486 488
    Compound 377
    Figure US20110269960A1-20111103-C00457
         		452 454 73.9
    Compound 378
    Figure US20110269960A1-20111103-C00458
         		466 468 71.6
    Compound 379
    Figure US20110269960A1-20111103-C00459
         		478 480 89.2
    Compound 380
    Figure US20110269960A1-20111103-C00460
         		458 460
    Compound 381
    Figure US20110269960A1-20111103-C00461
         		444 446
    Compound 382
    Figure US20110269960A1-20111103-C00462
         		546 548 66.9
    Compound 383
    Figure US20110269960A1-20111103-C00463
         		478 480 83.6
    Compound 384
    Figure US20110269960A1-20111103-C00464
         		458 460 88.1
    Compound 385
    Figure US20110269960A1-20111103-C00465
         		462 464 98.0
    Compound 386
    Figure US20110269960A1-20111103-C00466
         		440 442 84.0
    Compound 387
    Figure US20110269960A1-20111103-C00467
         		524, 526  526, 528  63.5
    Compound 388
    Figure US20110269960A1-20111103-C00468
         		482 484 65.8
    Compound 389
    Figure US20110269960A1-20111103-C00469
         		518, 520  520, 522  88.0
    Compound 390
    Figure US20110269960A1-20111103-C00470
         		442 444 65.9
    Compound 391
    Figure US20110269960A1-20111103-C00471
         		480 482 80.4
    Compound 392
    Figure US20110269960A1-20111103-C00472
         		566, 568  568, 570  73.6
    Compound 393
    Figure US20110269960A1-20111103-C00473
         		454 456 79.7
    Compound 394
    Figure US20110269960A1-20111103-C00474
         		494 496
    Compound 395
    Figure US20110269960A1-20111103-C00475
         		435 437 79.1
    Compound 396
    Figure US20110269960A1-20111103-C00476
         		502 504
    Compound 397
    Figure US20110269960A1-20111103-C00477
         		512, 514  514, 516 
    Compound 398
    Figure US20110269960A1-20111103-C00478
         		478 480 84.7
    Compound 399
    Figure US20110269960A1-20111103-C00479
         		446 448
    Compound 400
    Figure US20110269960A1-20111103-C00480
         		470 472 75.3
    Compound 401
    Figure US20110269960A1-20111103-C00481
         		462 464
    Compound 402
    Figure US20110269960A1-20111103-C00482
         		428 430
    Compound 403
    Figure US20110269960A1-20111103-C00483
         		444 446 72.5
    Compound 404
    Figure US20110269960A1-20111103-C00484
         		452 454 60.2
    Compound 405
    Figure US20110269960A1-20111103-C00485
         		476 478 61.4
    Compound 406
    Figure US20110269960A1-20111103-C00486
         		516, 518  518, 520  56.3
    Compound 407
    Figure US20110269960A1-20111103-C00487
         		502, 504  504, 506  68.2
    Compound 408
    Figure US20110269960A1-20111103-C00488
         		469 471
    Compound 409
    Figure US20110269960A1-20111103-C00489
         		464 466 74.7
    Compound 410
    Figure US20110269960A1-20111103-C00490
         		446 448
    Compound 411
    Figure US20110269960A1-20111103-C00491
         		546 548
    Compound 412
    Figure US20110269960A1-20111103-C00492
         		480 482 82.5
    Compound 413
    Figure US20110269960A1-20111103-C00493
         		446 448 95.3
    Compound 414
    Figure US20110269960A1-20111103-C00494
         		506, 508  508, 510  92.5
    Compound 415
    Figure US20110269960A1-20111103-C00495
         		480 482 91.5
    Compound 416
    Figure US20110269960A1-20111103-C00496
         		524, 526  526, 528  83.2
    Compound 417
    Figure US20110269960A1-20111103-C00497
         		480 482 90.8
    Compound 418
    Figure US20110269960A1-20111103-C00498
         		492 494
    Compound 419
    Figure US20110269960A1-20111103-C00499
         		514 516
    Compound 420
    Figure US20110269960A1-20111103-C00500
         		602, 604  604, 606  61.0
    Compound 421
    Figure US20110269960A1-20111103-C00501
         		446 448
    Compound 422
    Figure US20110269960A1-20111103-C00502
         		512 514 83.1
    Compound 423
    Figure US20110269960A1-20111103-C00503
         		428 430 87.8
    Compound 424
    Figure US20110269960A1-20111103-C00504
         		501 503
    Compound 425
    Figure US20110269960A1-20111103-C00505
         		474 476 90.1
    Compound 426
    Figure US20110269960A1-20111103-C00506
         		492 494 92.3
    Compound 427
    Figure US20110269960A1-20111103-C00507
         		464 466 86.5
    Compound 428
    Figure US20110269960A1-20111103-C00508
         		566, 568  568, 570  81.4
    Compound 429
    Figure US20110269960A1-20111103-C00509
         		483 485 71.1
    Compound 430
    Figure US20110269960A1-20111103-C00510
         		458 460 50.0
    Compound 431
    Figure US20110269960A1-20111103-C00511
         		566, 568  568, 570  80.5
    Compound 432
    Figure US20110269960A1-20111103-C00512
         		453 455 84.2
    Compound 433
    Figure US20110269960A1-20111103-C00513
         		438 440 93.8
    Compound 434
    Figure US20110269960A1-20111103-C00514
         		476 478 79.5
    Compound 435
    Figure US20110269960A1-20111103-C00515
         		476 478 94.6
    Compound 436
    Figure US20110269960A1-20111103-C00516
         		524, 526  526, 528  67.5
    Compound 437
    Figure US20110269960A1-20111103-C00517
         		446 448 97.3
    Compound 438
    Figure US20110269960A1-20111103-C00518
         		462 464 71.6
    Compound 439
    Figure US20110269960A1-20111103-C00519
         		464 466 98.1
    Compound 440
    Figure US20110269960A1-20111103-C00520
         		502, 504  504, 506  88.4
    Compound 441
    Figure US20110269960A1-20111103-C00521
         		506, 508  508, 510  63.0
    Compound 442
    Figure US20110269960A1-20111103-C00522
         		556, 558  558, 560  70.1
    Compound 443
    Figure US20110269960A1-20111103-C00523
         		556, 558  558, 560  55.7
    Compound 444
    Figure US20110269960A1-20111103-C00524
         		442 444 100.2
    Compound 445
    Figure US20110269960A1-20111103-C00525
         		442 444 55.6
    Compound 446
    Figure US20110269960A1-20111103-C00526
         		462 464 75.8
    Compound 447
    Figure US20110269960A1-20111103-C00527
         		506, 508  508, 510  95.5
    Compound 448
    Figure US20110269960A1-20111103-C00528
         		522, 524  524, 526  81.1
    Compound 449
    Figure US20110269960A1-20111103-C00529
         		556, 558  558, 560 
    Compound 450
    Figure US20110269960A1-20111103-C00530
         		498 500
    Compound 451
    Figure US20110269960A1-20111103-C00531
         		442 444 76.8
    Compound 452
    Figure US20110269960A1-20111103-C00532
         		462 464 68.9
    Compound 453
    Figure US20110269960A1-20111103-C00533
         		496 498
    Compound 454
    Figure US20110269960A1-20111103-C00534
         		516 518
    Compound 455
    Figure US20110269960A1-20111103-C00535
         		503 505
    Compound 456
    Figure US20110269960A1-20111103-C00536
         		425 427
    Compound 457
    Figure US20110269960A1-20111103-C00537
         		440 442
    Compound 458
    Figure US20110269960A1-20111103-C00538
         		430 432 83.8
    Compound 459
    Figure US20110269960A1-20111103-C00539
         		474 476
    Compound 460
    Figure US20110269960A1-20111103-C00540
         		482 484 53.2
    Compound 461
    Figure US20110269960A1-20111103-C00541
         		468 470 99.7
    Compound 462
    Figure US20110269960A1-20111103-C00542
         		445 447
    Compound 463
    Figure US20110269960A1-20111103-C00543
         		468 470
    Compound 464
    Figure US20110269960A1-20111103-C00544
         		468 470 87.9
    Compound 465
    Figure US20110269960A1-20111103-C00545
         		452 454
    Compound 466
    Figure US20110269960A1-20111103-C00546
         		416 418 51.1
    Compound 467
    Figure US20110269960A1-20111103-C00547
         		483 485 59.9
    Compound 468
    Figure US20110269960A1-20111103-C00548
         		490 492 56.2
    Compound 469
    Figure US20110269960A1-20111103-C00549
         		499 501
    Compound 470
    Figure US20110269960A1-20111103-C00550
         		564 566
    Compound 471
    Figure US20110269960A1-20111103-C00551
         		540 542
    Compound 472
    Figure US20110269960A1-20111103-C00552
         		444 446 55.3
    Compound 473
    Figure US20110269960A1-20111103-C00553
         		470 472 74.5
    Compound 474
    Figure US20110269960A1-20111103-C00554
         		559 561
    Compound 475
    Figure US20110269960A1-20111103-C00555
         		512 514 51.8
    Compound 476
    Figure US20110269960A1-20111103-C00556
         		482 484
    Compound 477
    Figure US20110269960A1-20111103-C00557
         		452 454 58.1
    Compound 478
    Figure US20110269960A1-20111103-C00558
         		478 480 87.0
    Compound 479
    Figure US20110269960A1-20111103-C00559
         		511 513
    Compound 480
    Figure US20110269960A1-20111103-C00560
         		511 513
    Compound 481
    Figure US20110269960A1-20111103-C00561
         		515 517
    Compound 482
    Figure US20110269960A1-20111103-C00562
         		468 470 87.4
    Compound 483
    Figure US20110269960A1-20111103-C00563
         		482 484
    Compound 484
    Figure US20110269960A1-20111103-C00564
         		523 525 65.3
    Compound 485
    Figure US20110269960A1-20111103-C00565
         		461 463
    Compound 486
    Figure US20110269960A1-20111103-C00566
         		546 548
    Compound 487
    Figure US20110269960A1-20111103-C00567
         		556, 558  558, 560 
    Compound 488
    Figure US20110269960A1-20111103-C00568
         		556, 558  558, 560  62.5
    Compound 489
    Figure US20110269960A1-20111103-C00569
         		556, 558  558, 560 
    Compound 490
    Figure US20110269960A1-20111103-C00570
         		411 413
    Compound 491
    Figure US20110269960A1-20111103-C00571
         		496 498
    Compound 492
    Figure US20110269960A1-20111103-C00572
         		560 562
    Compound 493
    Figure US20110269960A1-20111103-C00573
         		466 468 83.1
    Compound 494
    Figure US20110269960A1-20111103-C00574
         		466 468 66.0
    Compound 495
    Figure US20110269960A1-20111103-C00575
         		547 549
    Compound 496
    Figure US20110269960A1-20111103-C00576
         		526 528
    Compound 497
    Figure US20110269960A1-20111103-C00577
         		511 513 103.6
    Compound 498
    Figure US20110269960A1-20111103-C00578
         		469 471 84.0
    Compound 499
    Figure US20110269960A1-20111103-C00579
         		547, 549  549, 551  108.9
    Compound 500
    Figure US20110269960A1-20111103-C00580
         		525 527 90.2
    Compound 501
    Figure US20110269960A1-20111103-C00581
         		547, 549  549, 551  61.7
    Compound 502
    Figure US20110269960A1-20111103-C00582
         		541 543 75.5
    Compound 503
    Figure US20110269960A1-20111103-C00583
         		547, 549  549, 551  116.0
    Compound 504
    Figure US20110269960A1-20111103-C00584
         		631, 633  633, 635  53.5
    Compound 505
    Figure US20110269960A1-20111103-C00585
         		503 505 108.0
    Compound 506
    Figure US20110269960A1-20111103-C00586
         		494 496 83.2
    Compound 507
    Figure US20110269960A1-20111103-C00587
         		545 547 84.8
    Compound 508
    Figure US20110269960A1-20111103-C00588
         		494 496
    Compound 509
    Figure US20110269960A1-20111103-C00589
         		573 575 87.0
    Compound 510
    Figure US20110269960A1-20111103-C00590
         		531 533 113.5
    Compound 511
    Figure US20110269960A1-20111103-C00591
         		537 539 98.6
    Compound 512
    Figure US20110269960A1-20111103-C00592
         		537 539 60.7
    Compound 513
    Figure US20110269960A1-20111103-C00593
         		529 531 96.6
    Compound 514
    Figure US20110269960A1-20111103-C00594
         		421 423
    Compound 515
    Figure US20110269960A1-20111103-C00595
         		497 499 108.9
    Compound 516
    Figure US20110269960A1-20111103-C00596
         		487 489 106.7
    Compound 517
    Figure US20110269960A1-20111103-C00597
         		511 513 69.6
    Compound 518
    Figure US20110269960A1-20111103-C00598
         		499 501 110.8
    Compound 519
    Figure US20110269960A1-20111103-C00599
         		407 409
    Compound 520
    Figure US20110269960A1-20111103-C00600
         		547 549 69.9
    Compound 521
    Figure US20110269960A1-20111103-C00601
         		547 549
    Compound 522
    Figure US20110269960A1-20111103-C00602
         		519 521 98.4
    Compound 523
    Figure US20110269960A1-20111103-C00603
         		547 549 113.5
    Compound 524
    Figure US20110269960A1-20111103-C00604
         		559 561 83.0
    Compound 525
    Figure US20110269960A1-20111103-C00605
         		595 597 110.9
    Compound 526
    Figure US20110269960A1-20111103-C00606
         		571, 573  573, 575  111.8
    Compound 527
    Figure US20110269960A1-20111103-C00607
         		595 597 52.1
    Compound 528
    Figure US20110269960A1-20111103-C00608
         		483 485 106.2
    Compound 529
    Figure US20110269960A1-20111103-C00609
         		483 485
    Compound 530
    Figure US20110269960A1-20111103-C00610
         		537 539 114.7
    Compound 531
    Figure US20110269960A1-20111103-C00611
         		483 485 100.1
    Compound 532
    Figure US20110269960A1-20111103-C00612
         		553 555 99.2
    Compound 533
    Figure US20110269960A1-20111103-C00613
         		495 497
    Compound 534
    Figure US20110269960A1-20111103-C00614
         		483 485 100.8
    Compound 535
    Figure US20110269960A1-20111103-C00615
         		610 612
    Compound 536
    Figure US20110269960A1-20111103-C00616
         		620 622 50.3
    Compound 537
    Figure US20110269960A1-20111103-C00617
         		497 499 96.7
    Compound 538
    Figure US20110269960A1-20111103-C00618
         		559 561 97.1
    Compound 539
    Figure US20110269960A1-20111103-C00619
         		615 617
    Compound 540
    Figure US20110269960A1-20111103-C00620
         		521 523 64.3
    Compound 541
    Figure US20110269960A1-20111103-C00621
         		488 490 65.5
    Compound 542
    Figure US20110269960A1-20111103-C00622
         		545 547 50.1
    Compound 543
    Figure US20110269960A1-20111103-C00623
         		530 532 111.8
    Compound 544
    Figure US20110269960A1-20111103-C00624
         		501 503 53.9
    Compound 545
    Figure US20110269960A1-20111103-C00625
         		527 529 50.7
    Compound 546
    Figure US20110269960A1-20111103-C00626
         		537 539 55.8
    Compound 547
    Figure US20110269960A1-20111103-C00627
         		545 547
    Compound 548
    Figure US20110269960A1-20111103-C00628
         		511 513 96.7
    Compound 549
    Figure US20110269960A1-20111103-C00629
         		525 527 89.2
    Compound 550
    Figure US20110269960A1-20111103-C00630
         		537 539 103.6
    Compound 551
    Figure US20110269960A1-20111103-C00631
         		517 519 76.1
    Compound 552
    Figure US20110269960A1-20111103-C00632
         		503 505 67.2
    Compound 553
    Figure US20110269960A1-20111103-C00633
         		605 607 106.6
    Compound 554
    Figure US20110269960A1-20111103-C00634
         		537 539 116.5
    Compound 555
    Figure US20110269960A1-20111103-C00635
         		517 519 102.0
    Compound 556
    Figure US20110269960A1-20111103-C00636
         		499 501 104.8
    Compound 557
    Figure US20110269960A1-20111103-C00637
         		583, 585  585, 587  107.3
    Compound 558
    Figure US20110269960A1-20111103-C00638
         		541 543 64.8
    Compound 559
    Figure US20110269960A1-20111103-C00639
         		577, 579  579, 581  79.3
    Compound 560
    Figure US20110269960A1-20111103-C00640
         		501 503 74.4
    Compound 561
    Figure US20110269960A1-20111103-C00641
         		539 541 92.4
    Compound 562
    Figure US20110269960A1-20111103-C00642
         		513 515 93.3
    Compound 563
    Figure US20110269960A1-20111103-C00643
         		553 555 64.1
    Compound 564
    Figure US20110269960A1-20111103-C00644
         		494 496 105.4
    Compound 565
    Figure US20110269960A1-20111103-C00645
         		561 563
    Compound 566
    Figure US20110269960A1-20111103-C00646
         		571, 573  573, 575  88.7
    Compound 567
    Figure US20110269960A1-20111103-C00647
         		537 539 101.6
    Compound 568
    Figure US20110269960A1-20111103-C00648
         		505 507 71.1
    Compound 569
    Figure US20110269960A1-20111103-C00649
         		529 531 75.0
    Compound 570
    Figure US20110269960A1-20111103-C00650
         		521 523 77.4
    Compound 571
    Figure US20110269960A1-20111103-C00651
         		487 489 55.7
    Compound 572
    Figure US20110269960A1-20111103-C00652
         		503 505 96.5
    Compound 573
    Figure US20110269960A1-20111103-C00653
         		511 513 86.3
    Compound 574
    Figure US20110269960A1-20111103-C00654
         		575, 577  577, 579  86.9
    Compound 575
    Figure US20110269960A1-20111103-C00655
         		561, 563  563, 565  103.7
    Compound 576
    Figure US20110269960A1-20111103-C00656
         		528 530 81.4
    Compound 577
    Figure US20110269960A1-20111103-C00657
         		523 525 92.4
    Compound 578
    Figure US20110269960A1-20111103-C00658
         		505 507
    Compound 579
    Figure US20110269960A1-20111103-C00659
         		605 607 87.6
    Compound 580
    Figure US20110269960A1-20111103-C00660
         		539 541 89.2
    Compound 581
    Figure US20110269960A1-20111103-C00661
         		505 507 99.9
    Compound 582
    Figure US20110269960A1-20111103-C00662
         		565, 567  567, 569  106.0
    Compound 583
    Figure US20110269960A1-20111103-C00663
         		539 541 108.9
    Compound 584
    Figure US20110269960A1-20111103-C00664
         		583, 585  585, 587  96.2
    Compound 585
    Figure US20110269960A1-20111103-C00665
         		539 541 103.0
    Compound 586
    Figure US20110269960A1-20111103-C00666
         		551 553 87.9
    Compound 587
    Figure US20110269960A1-20111103-C00667
         		573 575 60.0
    Compound 588
    Figure US20110269960A1-20111103-C00668
         		551 553 109.3
    Compound 589
    Figure US20110269960A1-20111103-C00669
         		661, 663  663, 665  80.2
    Compound 590
    Figure US20110269960A1-20111103-C00670
         		505 507 62.3
    Compound 591
    Figure US20110269960A1-20111103-C00671
         		571 573 77.5
    Compound 592
    Figure US20110269960A1-20111103-C00672
         		487 489 95.8
    Compound 593
    Figure US20110269960A1-20111103-C00673
         		560 562 65.9
    Compound 594
    Figure US20110269960A1-20111103-C00674
         		533 535 84.0
    Compound 595
    Figure US20110269960A1-20111103-C00675
         		551 553 93.7
    Compound 596
    Figure US20110269960A1-20111103-C00676
         		523 525 100.3
    Compound 597
    Figure US20110269960A1-20111103-C00677
         		625, 627  627, 629  97.3
    Compound 598
    Figure US20110269960A1-20111103-C00678
         		542 544 89.5
    Compound 599
    Figure US20110269960A1-20111103-C00679
         		517 519 80.6
    Compound 600
    Figure US20110269960A1-20111103-C00680
         		625, 627  627, 629  100.5
    Compound 601
    Figure US20110269960A1-20111103-C00681
         		512 514 100.4
    Compound 602
    Figure US20110269960A1-20111103-C00682
         		497 499 106.7
    Compound 603
    Figure US20110269960A1-20111103-C00683
         		535 537 106.8
    Compound 604
    Figure US20110269960A1-20111103-C00684
         		535 537 109.4
    Compound 605
    Figure US20110269960A1-20111103-C00685
         		583, 585  535, 587  83.4
    Compound 606
    Figure US20110269960A1-20111103-C00686
         		505 507 107.8
    Compound 607
    Figure US20110269960A1-20111103-C00687
         		521 523
    Compound 608
    Figure US20110269960A1-20111103-C00688
         		523 525 108.6
    Compound 609
    Figure US20110269960A1-20111103-C00689
         		565, 567  567, 569  93.1
    Compound 610
    Figure US20110269960A1-20111103-C00690
         		615, 617  617, 619  91.2
    Compound 611
    Figure US20110269960A1-20111103-C00691
         		615, 617  617, 619  63.9
    Compound 612
    Figure US20110269960A1-20111103-C00692
         		501 503 114.0
    Compound 613
    Figure US20110269960A1-20111103-C00693
         		501 503 90.9
    Compound 614
    Figure US20110269960A1-20111103-C00694
         		521 523 77.8
    Compound 615
    Figure US20110269960A1-20111103-C00695
         		565, 567  567, 569  110.3
    Compound 616
    Figure US20110269960A1-20111103-C00696
         		581, 583  583, 585  99.9
    Compound 617
    Figure US20110269960A1-20111103-C00697
         		615, 617  617, 619  77.5
    Compound 618
    Figure US20110269960A1-20111103-C00698
         		557 559 65.4
    Compound 619
    Figure US20110269960A1-20111103-C00699
         		497 499 114.2
    Compound 620
    Figure US20110269960A1-20111103-C00700
         		501 503 88.4
    Compound 621
    Figure US20110269960A1-20111103-C00701
         		521 523 95.4
    Compound 622
    Figure US20110269960A1-20111103-C00702
         		555 557 58.9
    Compound 623
    Figure US20110269960A1-20111103-C00703
         		575 577
    Compound 624
    Figure US20110269960A1-20111103-C00704
         		562 564
    Compound 625
    Figure US20110269960A1-20111103-C00705
         		484 486
    Compound 626
    Figure US20110269960A1-20111103-C00706
         		499 501 61.1
    Compound 627
    Figure US20110269960A1-20111103-C00707
         		489 491 90.0
    Compound 628
    Figure US20110269960A1-20111103-C00708
         		533 535 64.4
    Compound 629
    Figure US20110269960A1-20111103-C00709
         		541 543 101.1
    Compound 630
    Figure US20110269960A1-20111103-C00710
         		527 529 107.4
    Compound 631
    Figure US20110269960A1-20111103-C00711
         		504 506 95.2
    Compound 632
    Figure US20110269960A1-20111103-C00712
         		527 529 59.9
    Compound 633
    Figure US20110269960A1-20111103-C00713
         		527 529 111.2
    Compound 634
    Figure US20110269960A1-20111103-C00714
         		511 513 51.0
    Compound 635
    Figure US20110269960A1-20111103-C00715
         		475 477 68.7
    Compound 636
    Figure US20110269960A1-20111103-C00716
         		542 544 85.7
    Compound 637
    Figure US20110269960A1-20111103-C00717
         		549 551 50.6
    Compound 638
    Figure US20110269960A1-20111103-C00718
         		558 560
    Compound 639
    Figure US20110269960A1-20111103-C00719
         		623 625
    Compound 640
    Figure US20110269960A1-20111103-C00720
         		599 601 59.5
    Compound 641
    Figure US20110269960A1-20111103-C00721
         		503 505 85.2
    Compound 642
    Figure US20110269960A1-20111103-C00722
         		529 531 85.5
    Compound 643
    Figure US20110269960A1-20111103-C00723
         		618 620
    Compound 644
    Figure US20110269960A1-20111103-C00724
         		571 573 93.0
    Compound 645
    Figure US20110269960A1-20111103-C00725
         		597 599
    Compound 646
    Figure US20110269960A1-20111103-C00726
         		641 643
    Compound 647
    Figure US20110269960A1-20111103-C00727
         		511 513 99.0
    Compound 648
    Figure US20110269960A1-20111103-C00728
         		537 539 107.8
    Compound 649
    Figure US20110269960A1-20111103-C00729
         		570 572 64.7
    Compound 650
    Figure US20110269960A1-20111103-C00730
         		570 572
    Compound 651
    Figure US20110269960A1-20111103-C00731
         		574 576
    Compound 652
    Figure US20110269960A1-20111103-C00732
         		527 529 91.9
    Compound 653
    Figure US20110269960A1-20111103-C00733
         		541 543
    Compound 654
    Figure US20110269960A1-20111103-C00734
         		582 584 71.7
    Compound 655
    Figure US20110269960A1-20111103-C00735
         		605 607
    Compound 656
    Figure US20110269960A1-20111103-C00736
         		615, 617  617, 619 
    Compound 657
    Figure US20110269960A1-20111103-C00737
         		615, 617  617, 619  94.9
    Compound 658
    Figure US20110269960A1-20111103-C00738
         		615, 617  617, 619  80.4
    Compound 659
    Figure US20110269960A1-20111103-C00739
         		470 472
    Compound 660
    Figure US20110269960A1-20111103-C00740
         		555 557
    Compound 661
    Figure US20110269960A1-20111103-C00741
         		619 621
    Compound 662
    Figure US20110269960A1-20111103-C00742
         		525 527 95.4
    Binding assay
    (membrane)
    Compound Melting % inhibition
    number Chemical structure point (° C.) (10 μM)
    Compound 663
    Figure US20110269960A1-20111103-C00743
         		210.0-217.0 99.5
    Compound 664
    Figure US20110269960A1-20111103-C00744
         		218.0-221.5 85.4
    Compound 665
    Figure US20110269960A1-20111103-C00745
         		197.0-201.0 100.3
    Compound 666
    Figure US20110269960A1-20111103-C00746
         		143.5-144.5 97.9
    Compound 667
    Figure US20110269960A1-20111103-C00747
         		207.0-208.0 99.2
    Compound 668
    Figure US20110269960A1-20111103-C00748
         		98.6
    Compound 669
    Figure US20110269960A1-20111103-C00749
         		131.5-132.5 100.3
    Compound 670
    Figure US20110269960A1-20111103-C00750
         		214.5-218.0 100.8
    Compound 671
    Figure US20110269960A1-20111103-C00751
         		100.6
    Compound 672
    Figure US20110269960A1-20111103-C00752
         		102.7
    Compound 673
    Figure US20110269960A1-20111103-C00753
         		62.0
    Compound 674
    Figure US20110269960A1-20111103-C00754
         		97.0
    Compound 675
    Figure US20110269960A1-20111103-C00755
         		96.6
    Compound 676
    Figure US20110269960A1-20111103-C00756
         		92.6
    Compound 677
    Figure US20110269960A1-20111103-C00757
         		60.8
    Compound 678
    Figure US20110269960A1-20111103-C00758
         		97.4
    Compound 679
    Figure US20110269960A1-20111103-C00759
         		104.0
    Compound 680
    Figure US20110269960A1-20111103-C00760
         		169.5-170.5 100.1
    Compound 681
    Figure US20110269960A1-20111103-C00761
         		189.0-189.5 100.2
    Compound 682
    Figure US20110269960A1-20111103-C00762
         		228.0-228.5 76.6
    Compound 683
    Figure US20110269960A1-20111103-C00763
         		175.0-178.0 100.5
    Compound 684
    Figure US20110269960A1-20111103-C00764
         		169.5-171.5
    Compound 685
    Figure US20110269960A1-20111103-C00765
         		255.0-260.0 65.1
    Compound 686
    Figure US20110269960A1-20111103-C00766
         		220.5-221.0 92.7
    Compound 687
    Figure US20110269960A1-20111103-C00767
         		80.1
    Compound 688
    Figure US20110269960A1-20111103-C00768
         		192.0-193.0 100.5
    Compound 689
    Figure US20110269960A1-20111103-C00769
         		92.7
    Compound 690
    Figure US20110269960A1-20111103-C00770
         		198.0-200.0 102.2
    Compound 691
    Figure US20110269960A1-20111103-C00771
         		180.0-182.0 98.5
    Compound 692
    Figure US20110269960A1-20111103-C00772
         		227.0-229.0 98.5
    Compound 693
    Figure US20110269960A1-20111103-C00773
         		158.0-161.0 97.7
    Compound 694
    Figure US20110269960A1-20111103-C00774
         		189.0-191.0 106.0
    Compound 695
    Figure US20110269960A1-20111103-C00775
    Compound 696
    Figure US20110269960A1-20111103-C00776
    Compound 697
    Figure US20110269960A1-20111103-C00777
    Compound 698
    Figure US20110269960A1-20111103-C00778
         		99.8
  • In Table 1, some of the compounds have two data on APCI MS (M−H)− and APCI MS (M+H)+, because two peaks were detected due to isotopes of a chlorine atom or a bromine atom.
  • For the compounds listed below, 1H-NMR data is shown.
  • Compound 100: (600 MHz, DMSO-d6) δ ppm: 1.21 (t, J=7.1 Hz, 3H) 1.27 (d, J=6.9 Hz, 3H) 3.22 (s, 6H) 3.40-3.50 (m, 8H) 3.77-3.93 (m, 2H) 4.68 (q, J=6.9 Hz, 1H) 6.34 (dd, J=7.3, 2.29 Hz, 1H) 6.52 (dd, J=8.3, 2.29 Hz, 1H) 6.56 (t, J=2.3 Hz, 1H) 7.12 (t, J=8.3 Hz, 1H) 7.70 (dd, J=8.3, 2.3 Hz, 1H) 7.85 (d, J=8.3 Hz, 1H) 7.92 (d, J=1.8 Hz, 1H) 8.66 (s, 1H).
  • Compound 119: (600 MHz, CDCl3) δ ppm: 1.34 (t, J=7.3 Hz, 3H), 1.50 (d, J=7.3 Hz, 3H), 3.89-3.98 (m, 2H), 4.59-4.65 (m, 1H), 5.06 (s, 2H) 6.37-6.42 (m, 1H), 6.80-6.95 (m, 2H), 7.01-7.04 (m, 1H), 7.24-7.36 (m, 2H), 7.36-7.44 (m, 4H), 7.49-7.53 (m, 1H), 7.67-7.73 (m, 1H), 7.93-7.96 (m, 1H).
  • Compound 127: (600 MHz, CDCl3) δ ppm: 1.38 (t, J=7.1 Hz, 3H), 1.49 (d, J=6.9 Hz, 3H), 2.41 (s, 3H), 3.93-4.02 (m, 2H), 4.59-4.65 (m, 1H), 5.47 (d, J=9.6 Hz, 1H), 7.05-7.10 (m, 2H), 7.31-7.37 (m, 3H), 7.61-7.64 (m, 1H), 7.80-7.82 (m, 1H).
  • Compound 129: (600 MHz, DMSO-d6) δ ppm: 1.21-1.29 (m, 6H), 2.29 (s, 6H), 3.83-4.01 (m, 2H), 4.61 (q, J=6.4 Hz, 1H), 6.43-6.47 (m, 1H), 6.89-6.93 (m, 1H), 7.34-7.40 (m, 3H), 7.52-7.60 (m, 3H), 8.24 (s, 1H), 11.18 (s, 1H).
  • Compound 130: (600 MHz, DMSO-d6) δ ppm: 1.22 (d, J=6.8 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H), 3.87-4.02 (m, 2H), 4.70 (q, J=6.8 Hz, 1H), 6.43-6.45 (m, 1H), 6.77-6.80 (m, 1H), 7.28-7.30 (m, 1H), 7.36-7.38 (m, 1H), 7.50-7.53 (m, 1H), 7.67-7.75 (m, 2H), 7.83-7.86 (m, 1H), 8.04-8.07 (m, 1H), 8.12-8.19 (m, 2H), 8.45-8.47 (m, 1H), 8.52 (s, 1H), 11.16 (s, 1H).
  • Compound 131: (600 MHz, DMSO-d6) δ ppm: 1.28 (t, J=7.1 Hz, 3H), 1.35 (d, J=6.9 Hz, 3H), 2.36 (s, 3H), 3.89-4.03 (m, 2H), 4.64-4.72 (m, 1H), 6.44-6.46 (m, 1H), 6.87-6.90 (m, 1H), 7.36-7.38 (m, 2H), 7.53-7.57 (m, 1H), 7.82-7.84 (m, 1H), 7.88-7.91 (m, 1H), 8.77 (s, 1H), 11.18 (s, 1H).
  • Compound 132: (600 MHz, DMSO-d6) δ ppm: 1.23-1.31 (m, 6H), 2.39 (s, 3H), 3.85-4.02 (m, 2H), 4.69 (q, J=6.9 Hz, 1H), 6.43-6.47 (m, 1H), 6.88-6.92 (m, 1H), 7.36-7.39 (m, 2H), 7.53-7.60 (m, 2H), 7.64-7.68 (m, 1H), 7.77-7.80 (m, 1H), 8.51 (s, 1H), 11.18 (s, 1H).
  • Compound 134: (600 MHz, DMSO-d6) δ ppm: 1.29 (t, J=7.3 Hz, 3H), 1.36 (d, J=6.9 Hz, 3H), 3.89-4.05 (m, 2H), 4.67-4.73 (m, 1H), 6.44-6.46 (m, 1H), 6.86-6.90 (m, 1H), 7.35-7.39 (m, 2H), 7.54-7.57 (m, 1H), 7.83-7.88 (m, 1H), 7.91-7.94 (m, 1H), 9.01 (s, 1H), 11.17 (s, 1H).
  • Compound 136: (600 MHz, DMSO-d6) δ ppm: 1.23-1.31 (m, 6H), 3.85-4.02 (m, 2H), 4.72 (q, J=6.9 Hz, 1H), 6.44-6.47 (m, 1H), 6.87-6.91 (m, 1H), 7.34-7.39 (m, 2H), 7.52-7.57 (m, 1H), 7.97-8.05 (m, 4H), 8.74 (s, 1H), 11.17 (s, 1H).
  • Compound 150: (200 MHz, CDCl3) δ ppm: 0.94 (d, J=6.4 Hz, 3H), 0.97 (d, J=6.4 Hz, 3H), 1.30 (t, J=7.3 Hz, 3H), 2.00-2.20 (m, 1H), 2.37 (s, 3H), 3.70-3.88 (m, 2H), 4.10 (dd, J=6.9, 9.4 Hz, 1H), 6.71 (d, J=9.4 Hz, 2H), 7.12-7.22 (m, 4H), 7.40 (d, J=8.4 Hz, 1H), 7.65 (dd, J=2.2, 8.4 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H).
  • Compound 668: (600 MHz, DMSO-d6) ppm: 1.19-1.25 (m, 6H), 2.22 (s, 3H), 2.41-2.46 (m, 4H), 2.49-2.54 (m, 3H), 3.11-3.17 (m, 4H), 3.83-3.99 (m, 2H), 4.65-4.71 (m, 1H), 6.47-6.51 (m, 1H), 6.77-6.82 (m, 2H), 7.17-7.22 (m, 1H), 7.51-7.55 (m, 1H), 7.77-7.84 (m, 2H), 8.01-8.10 (m, 2H), 8.38-8.51 (m, 2H).
  • Compound 671: (200 MHz, CDCl3) δ ppm: 0.89 (t, J=7.5 Hz, 3H), 1.23 (t, J=7.3 Hz, 3H), 1.70-2.06 (m, 2H), 2.42 (s, 3H), 2.66 (bs, 4H), 3.29 (t, J=5.1 Hz, 4H), 3.68-3.92 (m, 2H), 4.38 (dd, J=7.0, 15.4 Hz, 1H), 6.50 (bs, 1H), 6.56 (dd, J=2.0, 8.1 Hz, 1H), 6.72 (dd, J=2.0, 8.4 Hz, 1H), 6.89 (t, J=2.0 Hz, 1H), 7.20 (t, J=8.4 Hz, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.94 (d, J=2.0, 9.0 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.4 (d, J=2.0 Hz, 1H).
  • Compound 672: (200 MHz, CDCl3) δ ppm: 1.33 (t, J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.41 (s, 3H), 2.57-2.70 (m, 4H), 3.16-3.33 (m, 6H), 3.91 (q, J=7.3 Hz, 2H), 4.52-4.69 (m, 3H), 5.08 (d, J=9.0 Hz, 1H), 6.73 (dd, J=2.2, 8.6 Hz, 2H), 6.81 (d, J=9.0 Hz, 1H), 6.97 (t, J=2.2 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.62-7.68 (m, 2H).
  • Compound 673: (200 MHz, CDCl3) δ ppm: 1.31 (t, J=7.0 Hz, 3H), 1.33 (s, 6H), 1.49 (d, J=7.0 Hz, 3H), 1.80 (t, J=6.6 Hz, 2H), 2.39 (s, 3H), 2.59 (t, J=5.0 Hz, 4H), 2.79 (t, J=7.0 Hz, 2H), 3.25 (t, J=5.0 Hz, 4H), 3.90 (q, J=7.0 Hz, 2H), 4.48-4.65 (m, 1H), 5.07 (d, J=9.5 Hz, 1H), 6.73 (dd, J=2.4, 8.1 Hz, 2H), 6.82 (d, J=9.2 Hz, 1H), 6.97 (t, J=2.4 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.51-7.57 (m, 2H).
  • Compound 674: (200 MHz, CDCl3) δ ppm: 1.34 (t, J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.21 (quint, J=6.0 Hz, 2H), 2.37 (s, 3H), 2.59 (t, J=4.6 Hz, 4H), 3.25 (t, J=4.6 Hz, 4H), 3.93 (q, J=7.3 Hz, 2H), 4.27 (dd, J=6.0, 11.6 Hz, 4H) 4.51-4.66 (m, 1H), 5.15 (d, J=9.5 Hz, 1H), 6.74 (dd, J=2.2, 8.4 Hz, 1H), 7.07-7.13 (m, 2H), 7.23 (t, J=8.1 Hz, 1H), 7.38 (dd, J=2.4, 8.1 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H).
  • Compound 675: (200 MHz, CDCl3) δ ppm: 1.36 (t, J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.39 (s, 3H), 2.59 (t, J=5.0 Hz, 4H), 3.26 (t, J=5.0 Hz, 4H), 3.95 (q, J=7.3 Hz, 2H), 4.50-4.68 (m, 1H), 5.18 (d, J=9.5 Hz, 1H), 6.05 (s, 2H), 6.74 (dd, J=2.4, 8.1 Hz, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.98 (t, J=2.4 Hz, 1H), 7.19-7.27 (m, 2H), 7.42 (dd, J=1.8, 8.1 Hz, 1H).
  • Compound 676: (200 MHz, CDCl3) δ ppm: 1.27-1.33 (m, 15H), 1.47 (d, J=6.8 Hz, 3H), 2.43 (s, 3H), 2.61-2.72 (m, 4H), 3.25-3.33 (m, 4H), 3.90 (q, J=7.5 Hz, 2H), 4.57 (dd, J=6.8, 9.2 Hz, 1H), 5.13 (d, J=9.2 Hz, 1H), 6.70-6.79 (m, 2H), 6.99 (t, J=2.2 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.57 (dd, J=2.0, 8.1 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H).
  • Compound 677: (200 MHz, CDCl3) δ ppm: 1.32 (t, J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.22 (s, 3H), 2.38 (s, 3H), 2.56-2.63 (m, 4H), 3.14-3.30 (m, 6H), 3.84-4.10 (m, 4H), 4.53-4.64 (m, 1H), 5.25 (d, J=9.5 Hz, 1H), 6.71-6.79 (m, 2H), 7.01 (t, J=2.4 Hz, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.69 (dd, J=2.0, 8.4 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H).
  • Compound 678: (200 MHz, CDCl3) δ ppm: 1.32 (t, J=7.3 Hz, 3H), 1.46 (d, J=6.8 Hz, 3H), 2.11 (quint, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.58 (t, J=5.0 Hz, 4H), 2.94 (t, J=7.5 Hz, 4H), 3.25 (t, J=5.0 Hz, 4H), 3.92 (q, J=7.3 Hz, 2H), 4.52-4.67 (m, 1H), 5.15 (d, J=10.0 Hz, 1H), 6.73 (dd, J=2.2, 8.1 Hz, 2H), 6.98 (t, J=2.2 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.62 (dd, J=2.2, 7.9 Hz, 1H), 7.67 (s, 1H).
  • Compound 679: (600 MHz, DMSO-d6) δ ppm: 1.24 (t, J=7.1 Hz, 3H), 1.29 (d, J=6.9 Hz, 3H), 2.22 (s, 3H), 2.40-2.46 (m, 4H), 3.12-3.16 (m, 4H), 3.81-3.97 (m, 2H), 4.64-4.72 (m, 1H), 6.53-6.58 (m, 1H), 6.60-6.65 (m, 1H), 6.77-6.82 (m, 2H), 7.20 (t, J=8.3 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.94-7.99 (m, 1H), 8.17-8.23 (m, 2H), 8.54-8.61 (m, 1H).
  • Compound 698: (600 MHz, CDCl3) δ ppm: 1.33 (t, J=7.1 Hz, 3H), 1.43 (d, J=6.9 Hz, 3H), 2.11 (s, 3H), 3.10-3.20 (m, 4H), 3.53-3.59 (m, 2H), 3.67-3.74 (m, 2H), 3.89-4.00 (m, 2H), 4.67 (q, J=7.1 Hz, 1H), 6.65-6.75 (m, 2H), 6.94-6.97 (m, 1H), 7.21-7.25 (m, 1H), 7.46-7.50 (m, 1H), 7.69-7.73 (m, 1H), 7.80-7.84 (m, 1H), 7.95-7.99 (m, 1H), 8.29-8.34 (m, 1H), 8.45-8.47 (m, 1H).
  • The following describes exemplary methods of preparing starting materials used to produce the compounds of the present application.
    • Reference Examples 1-3
  • Starting from the corresponding amine in place of 1,4-dioxa-8-azaspiro[4,5]decane used in Example 7-(1), the same procedure as used in Example 7-(1) was repeated to give the titled compounds.
    • Reference Example 1 3-((2R,6S)-2,6-Dimethylmorpholine-4-yl)-phenol
  • Figure US20110269960A1-20111103-C00779
  • Brown oily substance, yield 71%
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.24 (d, J=6.0 Hz, 6H), 2.36-2.45 (m, 2H), 3.37-3.46 (m, 2H), 3.73-3.83 (m, 2H), 5.01 (s, 1H), 6.28-6.33 (m, 1H), 6.36-6.38 (m, 1H), 6.46-6.51 (m, 1H), 7.10 (t, J=8.0 Hz, 1H)
    • Reference Example 2 3-[4-(2-Dimethylaminoethyl)-piperazin-1-yl]-phenol
  • Figure US20110269960A1-20111103-C00780
  • Yellow oily substance, yield 12%
  • 1H NMR (600 MHz, CDCl3) δ ppm: 2.29 (s, 6H), 2.48-2.57 (m, 4H), 2.57-2.64 (m, 4H), 3.11-3.16 (m, 4H), 6.24-6.30 (m, 1H), 6.32-6.37 (m, 1H), 6.42-6.49 (m, 1H), 7.04-7.09 (m, 1H)
    • Reference Example 3 3-[(2-Dimethylaminoethyl)-methyl-amino]-phenol
  • Figure US20110269960A1-20111103-C00781
  • Brown oily substance, yield 42%
  • 1H NMR (600 MHz, CDCl3) δ ppm: 2.27 (s, 6H), 2.44-2.50 (m, 2H), 2.87 (s, 3H), 3.37-3.44 (m, 2H), 6.09-6.16 (m, 2H), 6.19-6.24 (m, 1H), 7.01 (t, J=8.0 Hz, 1H)
    • Reference Example 4 3-(4-Isopropyl-piperazin-1-yl)-phenol
  • Figure US20110269960A1-20111103-C00782
  • Acetone (1.95 g) and NaBH(OAc)3 (7.12 g) were added to a solution of 3-piperazin-1-yl-phenol (2.00 g) in THF (40 ml), and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and filtered to give the titled compound (1.48 g, colorless powder).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.11 (d, J=6.4 Hz, 6H), 2.68-2.72 (m, 4H), 2.71-2.78 (m, 1H), 3.15-3.23 (m, 4H), 6.28-6.32 (m, 1H), 6.36 (t, J=2.3 Hz, 1H), 6.50 (dd, J=8.3, 2.3 Hz, 1H), 7.09 (t, J=8.3 Hz, 1H)
    • Reference Example 5 3-(1-Isopropylpiperidin-4-yl)-phenol
  • Figure US20110269960A1-20111103-C00783
  • Starting from 3-piperidin-4-yl-phenol in place of 3-piperazin-1-yl-phenol used in Reference Example 4, the same procedure as used in Reference Example 4 was repeated to give the titled compound (yield 31%, colorless powder).
  • 1H NMR (600 MHz, CDCl3) δ ppm: 1.16 (d, J=6.4 Hz, 6H), 1.76-1.86 (m, 2H), 1.91-2.01 (m, 2H), 2.31-2.50 (m, 3H), 2.92-3.02 (m, 1H), 3.08-3.19 (m, 2H), 6.66-6.72 (m, 2H), 6.74-6.79 (m, 1H), 7.11 (t, J=7.8 Hz, 1H)
    • Reference Example 6 4-Fluoro-3-(4-methyl-piperazin-1-yl)-phenol
  • Figure US20110269960A1-20111103-C00784
    • 4-Benzyloxy-2-chloro-1-fluorobenzene
  • Figure US20110269960A1-20111103-C00785
  • (1) A suspension of 3-chloro-4-fluorophenol (2.00 g), benzyl chloride (1.88 ml), and potassium carbonate (2.82 g) in dimethylformamide (10 ml) was stirred at room temperature for three hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated, and the resulting residue was purified by silica-gel column chromatography (OH SiO2, AcOEt/hexane=0-10%) to give the titled compound (2.00 g) as a light yellow oily substance.
  • 1H NMR (600 MHz, CDCl3) δ ppm: 5.01 (s, 2H), 6.77-6.86 (m, 1H), 6.96-7.09 (m, 2H), 7.30-7.46 (m, 5H)
    • 1-(5-Benzyloxy-2-fluorophenyl)-4-methyl-piperazine
  • Figure US20110269960A1-20111103-C00786
  • (2) Under an argon atmosphere at room temperature, the compound (7.5 g) obtained in Reference Example 6-(1) and thereafter a solution of 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-1 phosphino-bicyclo[3,3,3]-undecane (1.1 g) in toluene (320 ml) were added to tris dibenzylidenedipalladium (1.45 g) and t-butoxysodium (4.26 g). Then, a solution of N-methylpiperazine (1.02 g) in toluene (20 ml) was added at room temperature, and the mixture was stirred at 100° C. for 60 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica-gel column chromatography (NH SiO2, AcOEt/hexane=0-30%) to give the titled compound (2.27 g) as a yellow oily substance.
  • 1H NMR (600 MHz, CDCl3) δ ppm: 2.35 (s, 3H), 2.55-2.63 (m, 4H), 3.06-3.15 (m, 4H), 5.00 (s, 2H), 6.46-6.51 (m, 1H), 6.56-6.59 (m, 1H), 6.89-6.95 (m, 1H), 7.29-7.45 (m, 5H)
    • 4-Fluoro-3-(4-methylpiperazin-1-yl)-phenol
  • Figure US20110269960A1-20111103-C00787
  • (3) A suspension of the compound (2.48 g) obtained in Reference Example 6-(2) and palladium hydroxide (10%, 250 mg) in methanol (30 ml) was stirred under a hydrogen atmosphere at 65° C. for two hours and a half and thereafter at room temperature for overnight. The reaction solution was filtered through celite, and the filtrate was concentrated. The resulting residue was purified by silica-gel column chromatography (NH SiO2, AcOEt/hexane=0-99%, methanol/chloroform=0-10%). Thereafter, the resulting compound was purified again by silica-gel column chromatography (OH SiO2, methanol/chloroform=0-10%) to give the titled compound (877 mg) as an ocher solid.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm: 2.21 (s, 3H), 2.39-2.48 (m, 4H), 2.89-2.99 (m, 4H), 6.26-6.31 (m, 1H), 6.35-6.39 (m, 1H), 6.84-6.91 (m, 1H), 9.20 (s, 1H)
  • The following describes an exemplary method of producing an intermediate represented by Formula (II) of the present application.
  • Starting from the corresponding starting materials, the same procedures as shown in Examples 1-(1) to 1-(7), Examples 2-(1) and 2-(2), Examples 7-(1) and 7-(2), Examples 17-(1) and 17-(2), Example 18-(1), Example 21-(1), Example 22-(1), Example 23-(1), and Examples 26-(1) to 26-(8) were repeated, followed by salt formation as needed to obtain compounds or salts of the compounds which are intermediates useful in producing the compound of Formula (I) of the present application. The resulting intermediates are shown in Table 2 together with the intermediates obtained in the Examples above.
  • TABLE 2
    Compound
    number Chemical structure 1H NMR
    Intermediate 1
    Figure US20110269960A1-20111103-C00788
         		(200 MHz, CDCl3) δ ppm: 1.25 (t, J = 7.3 Hz, 3H), 3.12 (dd, J = 13.3, 8.6 Hz, 1H), 3.38 (dd, J = 13.3, 6.1 Hz, 1H), 3.60-4.30 (m, 3H), 7.10-7.46 (m, 10H)
    Intermediate 2
    Figure US20110269960A1-20111103-C00789
         		(600 MHz, DMSO-d6) δ ppm: 1.29 (t, J = 7.3 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 2.30 (s, 3H), 3.96- 4.09 (m, 3H), 7.15-7.30 (m, 4H)
    Intermediate 3
    Figure US20110269960A1-20111103-C00790
         		(600 MHz, DMSO-d6) δ ppm: 1.33 (t, J = 7.1 Hz, 3H), 1.42 (d, J = 6.4 Hz, 3H), 2.23 (s, 3H), 4.00- 4.12 (m, 3H), 7.10-7.40 (m, 4H)
    Intermediate 4
    Figure US20110269960A1-20111103-C00791
         		(600 MHz, DMSO-d6) δ ppm: 1.22-1.30 (m, 3H), 1.41-1.48 (m, 3H), 2.33 (s, 3H), 3.83-4.10 (m, 3H), 7.04-7.14 (m, 3H), 7.26-7.37 (m, 1H)
    Intermediate 5
    Figure US20110269960A1-20111103-C00792
         		(600 MHz, CDCl3) δ ppm: 1.46 (t, J = 7.1 Hz, 3H), 1.57 (d, J = 6.9 Hz, 3H), 4.05-4.25 (m, 3H), 6.81- 7.32 (m, 4H)
    Intermediate 6
    Figure US20110269960A1-20111103-C00793
         		(200 MHz, CDCl3) δ ppm: 1.41 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.6 Hz, 3H), 3.87-4.26 (m, 3H), 7.14- 7.26 (m, 1H), 7.30-7.45 (m, 4H)
    Intermediate 7
    Figure US20110269960A1-20111103-C00794
         		(600 MHz, CDCl3) δ ppm: 1.35-1.45 (m, 3H), 1.53- 1.62 (m, 3H), 3.95-4.20 (m, 3H), 7.27-7.40 (m, 4H)
    Intermediate 8
    Figure US20110269960A1-20111103-C00795
         		(600 MHz, CDCl3) δ ppm: 1.41 (t, J = 7.1 Hz, 3H), 1.60(d, J = 6.9 Hz, 3H). 3.90-4.25 (m, 3H), 7.15-7.50 (m, 4H)
    Intermediate 9
    Figure US20110269960A1-20111103-C00796
         		(600 MHz, DMSO-d6) δ ppm: 1.14 (t, J = 7.3 Hz, 3H), 2.30 (s, 3H), 3.00 (dd, J = 13.3, 7.3 Hz, 1H), 3.19 (dd, J = 13.3, 6.9 Hz, 1H), 3.77-3.98 (m, 2H), 4.11 (t, J = 7.1 Hz, 1H), 7.13-7.139 (m, 9H)
    Intermediate 10
    Figure US20110269960A1-20111103-C00797
         		(600 MHz, CDCl3) δ ppm: 1.41 (t, J = 7.4 Hz, 3H). 1.57 (d, J = 6.8 Hz, 3H), 3.80 (s, 3H), 3.95-4.20 (m, 3H), 6.82-6.97 (m, 2H), 7.21-7.34 (m, 2H)
    Intermediate 11
    Figure US20110269960A1-20111103-C00798
         		(600 MHz, CDCl3) δ ppm: 1.41 (t, J = 7.3 Hz, 3H), 1.58 (d, J = 6.4 Hz, 3H), 3.95-4.23 (m, 3H), 6.90-7.15 (m, 2H), 7.30-7.44 (m, 2H)
    Intermediate 12
    Figure US20110269960A1-20111103-C00799
         		(600 MHz, CDCl3) δ ppm: 1.41 (t, J = 7.4 Hz, 3H), 1.60 (d, J = 6.8 Hz, 3H), 3.98-4.21 (m, 3H), 7.26-7.65 (m, 3H)
    Intermediate 13
    Figure US20110269960A1-20111103-C00800
         		(600 MHz, CDCl3) δ ppm: 1.40 (t, J = 7.1 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H), 2.24 (s, 3H), 2.25 (s, 3H), 3.95- 4.23 (m, 3H), 7.00-7.19 (m, 3H)
    Intermediate 14
    Figure US20110269960A1-20111103-C00801
         		(200 MHz, CDCl3) δ ppm: 1.05-2.03 (m, 16 H), 2.32- 2.65 (m, 1 H), 3.87-4.29 (m, 3 H), 700-7.46 (m, 4 H)
    Intermediate 15
    Figure US20110269960A1-20111103-C00802
         		(200 MHz, CDCl3) δ ppm: 1.43 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 7.0 Hz, 3 H), 3.87 (s, 6 H), 3.96-4.27 (m, 3 H), 6.82-6.88 (m, 2 H), 6.97 (d, J = 2.6 Hz, 1 H)
    Intermediate 16
    Figure US20110269960A1-20111103-C00803
         		(600 MHz, CDCl3) δ ppm: 1.42 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 6.4 Hz, 3 H), 3.80 (s, 3 H), 3.82 (s, 6 H), 3.99-4.12 (m, 2 H), 4.13-4.19 (m, 1 H), 6.63 (s, 2 H)
    Intermediate 17
    Figure US20110269960A1-20111103-C00804
         		(600 MHz, CDCl3) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.12 (s, 3 H), 2.26 (s, 6 H), 3.96-4.07 (m, 2 H), 4.14 (q, J = 6.6 Hz, 1 H), 6.97 (s, 2 H)
    Intermediate 18
    Figure US20110269960A1-20111103-C00805
         		(600 MHz, CDCl3) δ ppm: 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.30 (s, 6 H), 3.94-4.08 (m, 2 H) 4.15 (q, J = 6.9 Hz, 1 H), 6.81 (s, 1 H), 6.95 (s, 2 H)
    Intermediate 19
    Figure US20110269960A1-20111103-C00806
         		(600 MHz, CDCl3) δ ppm: 1.43 (t, J = 7 .3 Hz, 3 H), 1.63 (d, J = 6.9 Hz, 3 H), 3.81 (s, 6 H), 4.00-4.12 (m, 2 H), 4.20 (q, J = 6.7 Hz, 1 H), 6.33 (s, 1 H), 6.59 (s, 2 H)
    Intermediate 20
    Figure US20110269960A1-20111103-C00807
         		(600 MHz, CDCl3) δ ppm: 0.96-0.98 (m, 3 H), 1.40 (t, J = 7.3 Hz, 3 H), 1.43-1.52 (m, 2 H), 1.56 (d, J = 6.9 Hz, 3 H), 1.71-1.78 (m, 2H), 3.93 (t, J = 6.4 Hz, 2 H), 3.97-4.08 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 6.85- 6.89 (m, 2 H) 7.23-7.28 (m, 2 H)
    Intermediate 21
    Figure US20110269960A1-20111103-C00808
         		(600 MHz, CDCl3) δ ppm: 1.42 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 3.99-4.13 (m, 2H), 4.17 (q, J = 6.9 Hz, 1H), 6.98-7.05 (m, 4H), 7.07-7.13 (m, 1H), 7.29-7.39 (m, 4H)
    Intermediate 22
    Figure US20110269960A1-20111103-C00809
         		(600 MHz, CDCl3) δ ppm: 1.41 (t, J = 7 .1 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H), 3.99-4.10 (m, 2H), 4.16 (q, J =6.9 Hz, 1H), 5.05 (s, 2H). 6.94-7.00 (m, 2H). 7.25- 7.31 (m, 2H), 7.31-7.35 (m, 1H), 7.36-7.41 (m, 2H), 7.41-7.44 (m, 2H)
    Intermediate 23
    Figure US20110269960A1-20111103-C00810
         		(600 MHz, CDCl3), δ ppm: 1.23 (t, J = 7.6 Hz, 3 H), 1.40 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6.4 Hz, 3 H), 2.64 (q, J = 7.5 Hz, 2 H), 3.98-4.11 (m, 2H), 4.16 (q, J = 6.9 Hz, 1 H), 7.16-7.31 (m, 4 H)
    Intermediate 24
    Figure US20110269960A1-20111103-C00811
         		(600 MHz, CDCl3), δ ppm: 0.94 (t, J =7.3 Hz, 3 H), 1.40 (t, J = 7.3 Hz, 3 H), 1.54-1.67 (m, 5 H), 2.53- 2.61 (m, 2 H), 3.94-4.10 (m, 2 H), 4.17 (q, J = 6.4 Hz, 1 H), 7.12-7.31 (m, 4 H)
    Intermediate 25
    Figure US20110269960A1-20111103-C00812
         		(600 MHz, , CDCl3) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.35 (s, 3 H), 3.96-4.09 (m, 2 H), 4.14 (q, J = 6.6 Hz, 1 H), 7.14 (dd, J = 8.7, 3.7 Hz, 1 H), 7.27 (d, J = 3.2 Hz, 1 H), 7.31 (d, J = 8.7 Hz, 1 H)
    Intermediate 26
    Figure US20110269960A1-20111103-C00813
         		(600 MHz, , CDCl3) δ ppm: 1.40 (t, J = 7.3 Hz, 3 H), 1.56 (d, J = 6.9 Hz, 3 H), 3.99-4.10 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.30-6.33 (m, 2 H), 6.99-7.03 (m, 2 H), 7.34-7.38 (m, 2 H), 7.41-7.44 (m, 2 H)
    Intermediate 27
    Figure US20110269960A1-20111103-C00814
         		(600 MHz, , CDCl3) δ ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.94 (s, 6 H), 3.95-4.07 (m, 2 H), 4.14 (q, J = 6.9 Hz, 1 H), 6.52 (dd, J = 8.7, 2.8 Hz, 1 H), 6.60 (dd, J = 8.7, 2.3 Hz, 1 H), 6.72 (t, J = 2.3 Hz, 1 H), 7.18 (t, J = 8.3 Hz, 1 H)
    Intermediate 28
    Figure US20110269960A1-20111103-C00815
         		(600 MHz, CDCl3) δ ppm 1..43 (t, J = 7.1 Hz, 3H), 1.60 (d, J = 6.9 Hz, 3H), 4.02-4.13 (m, 2H), 4.19 (q, J = 6.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.40-7.48 (m, 4H), 7.55-7.62 (m, 4H)
    Intermediate 29
    Figure US20110269960A1-20111103-C00816
         		(600 MHz, CDCl3) δ ppm: 1.40 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 4.00-4.12 (m, 2H), 4.17-4.23 (m, 1H), 7.19-7.23 (m, 1H), 7.37-7.42 (m, 2H)
    Intermediate 30
    Figure US20110269960A1-20111103-C00817
         		(600 MHz, CDCl3) δ ppm: 1.42 (t, J = 7.1 Hz, 3H), 1.60 (d, J = 6.4 Hz, 3H), 4.01-4.13 (m, 2H), 4.17(q, J = 6.4 Hz, 1H), 7.13-7.18 (m, 1H), 7.30-7.34 (m, 1H), 7.51-7.54 (m, 1H)
    Intermediate 31
    Figure US20110269960A1-20111103-C00818
         		(600 MHz, CDCl3), δ ppm: 0.92 (t, J = 7.6 Hz, 3 H), 1.30-1.44 (m, 5 H), 1.54-1.63 (m, 5 H), 2.55-2.64 (m, 2 H), 3.97-4.10 (m, 2 H), 4.17 (q, J = 6.6 Hz, 1 H), 7.15-7.29 (m, 4 H)
    Intermediate 32
    Figure US20110269960A1-20111103-C00819
         		(600 MHz, CDCl3), δ ppm: 1.42 (t, J = 7.3 Hz, 3 H), 1.60 (d, J = 6.9 Hz, 3 H), 4.00-4.15 (m, 2 H), 4.18 (q, J = 6.9 Hz, 1 H), 7.19-7.28 (m, 2 H), 7.39-7.47 (m, 2 H)
    Intermediate 33
    Figure US20110269960A1-20111103-C00820
         		(600 MHz, , CDCl3) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6 .4 Hz, 3 H), 3.12-3.19 (m, 4 H), 3.79- 3.86 (m, 4 H), 3.95-4.09 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.71 (dd, J = 8.0, 2.1 Hz, 1 H), 6.79 (dd, J = 8.3, 2.3 Hz, 1 H) 7.00-7.03 (m, 1 H), 7.21-7.25 (m, 1 H)
    Intermediate 34
    Figure US20110269960A1-20111103-C00821
         		(600 MHz, CDCl3) δ ppm: 1.39 (t, J = 7.1 Hz, 3 H), 1.56 (d, J = 6.9 Hz, 3 H), 2.33 (s, 6 H), 2.67-2.76 (m, 2 H), 3.95-4.08 (m, 4 H), 4.14 (q, J = 6.6 Hz, 1 H), 6.84- 6.93 (m, 2 H), 7.19-7.31 (m, 2 H)
    Intermediate 35
    Figure US20110269960A1-20111103-C00822
         		(600 MHz, CDCl3) δ ppm: 1.40 (t, J = 7.1 Hz, 3 H), 1.56 (d, J = 6.9 Hz, 3 H), 2.54-2.59 (m, 4 H), 2.78 (t, J = 5.7 Hz, 2 H), 3.71-3.75 (m, 4 H), 3.98-4.06 (m, 2 H), 4.08 (t, J = 5.7 Hz, 2 H), 4.14 (q, J = 6.6 Hz, 1 H), 6.86-6.90 (m, 2 H), 7.24-7.28 (m, 2 H)
    Intermediate 36
    Figure US20110269960A1-20111103-C00823
         		(600 MHz, CDCl3), δ ppm: 1.41 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.27 (d, J = 1.8 Hz, 3 H), 3.98-4.11 (m, 2 H), 4.17 (q, J = 6.9 Hz, 1 H), 6.95- 7.03 (m, 1 H), 7.11-7.16 (m, 1 H), 7.21-7.24 (m, 1 H)
    Intermediate 37
    Figure US20110269960A1-20111103-C00824
         		(200 MHz, CDCl3) δ ppm: 1.00-1.20 (m, 4H), 1.58 (d, J = 6.6 Hz, 3H), 2.90-3.06 (m, 1H), 3.80 (s, 3H), 4.05- 4.32 (m, 1H), 6.38-6.95 (m, 2H), 7.20-7.30 (m, 2H)
    Intermediate 38
    Figure US20110269960A1-20111103-C00825
         		(600 MHz, , CDCl3) δ ppm: 1.23 (d, J = 7.3 Hz, 6 H), 1.39 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.86- 2.93 (m, 1 H), 3.97-4.09 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 7.19-7.23 (m, 2 H) 7.24-7.27 (m, 2 H)
    Intermediate 39
    Figure US20110269960A1-20111103-C00826
         		(600 MHz, CDCl3), δ ppm: 1.25 (d, J = 6.9 Hz, 6 H), 1.41 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 6.4 Hz, 3 H), 2.85-2.97 (m, 1 H), 3.99-4.10 (m, 2 H), 4.16 (q, J = 6.7 Hz, 1 H), 7.06-7.10 (m, 1 H), 7.13-7.18 (m, H), 7.20-7.24 (m, 1 H), 7.26-7.32 (m, 1 H)
    Intermediate 40
    Figure US20110269960A1-20111103-C00827
         		(600 MHz, CDCl3) δ ppm: 1.48 (t, J = 7.3 Hz, 3 H), 1.61 (d, J = 6.9 Hz, 3 H), 4.09-4.24 (m, 3 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.51-7.56 (m, 2 H), 7.61 (d, J = 6.9 Hz, 1 H), 7.68 (d, J = 8.3 Hz, 1 H), 7.85-7.90 (m, 1 H), 8.11- 8.16 (m,1 H)
    Intermediate 41
    Figure US20110269960A1-20111103-C00828
         		(600 MHz, CDCl3) δ ppm: 1.43 (t, J = 7.3 Hz, 3 H), 1.60 (d, J = 6.4 Hz, 3 H), 4.02-4.13 (m, 2 H), 4.18 (q, J = 6.6 Hz, 1 H), 7.41-7.51 (m, 3 H), 7.76-7.92 (m, 4 H)
    Intermediate 42
    Figure US20110269960A1-20111103-C00829
         		(600 MHz, CDCl3), δ ppm: 1.41 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.93 (s, 6 H), 3.96-4.09 (m, 2 H), 4.15 (q, J = 6.9 Hz, 1 H), 6.66-6.76 (m, 2 H), 7.17-7.25 (m, 2 H)
    Intermediate 43
    Figure US20110269960A1-20111103-C00830
         		(600 MHz, CDCl3) δ ppm 1.38-1.61 (m, 6 H), 4.00-4.19 (m, 3 H), 6.69-7.37 (m, 3 H)
    Intermediate 44
    Figure US20110269960A1-20111103-C00831
         		(600 MHz, CDCl3) δ ppm: 1.40 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 2.35 (s, 3H), 2.52-2.61 (m, 4H), 3.22-3.27 (m, 4H), 3.97-4.08 (m, 2H), 4.15 (q, J = 6.9 Hz, 1H), 6.71-6.80 (m, 2H), 6.99- 7.03 (m, 1H) , 7.20-7.25 (m, 1H)
    Intermediate 45
    Figure US20110269960A1-20111103-C00832
         		(600 MHz, CDCl3) δ ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.82 (s, 3 H), 4.02-4.14 (m, 2 H), 4.18 (q, J = 6.7 Hz, 1 H), 7.42 (dd, J = 8.7, 2.8 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.85 (d, J = 2.3 Hz, 1 H)
    Intermediate 46
    Figure US20110269960A1-20111103-C00833
         		(200 MHz, CDCl3), δ ppm: 1.33-1.47 (m, 3 H), 1.57 (d, J = 7.0 Hz, 3 H), 3.03-3.19 (m, 4 H), 3.78-3.92 (m, 4 H), 3.95-4.25 (m, 3 H), 6.81-7.00 (m, 2 H), 7.18-7.33 (m, 2 H)
    Intermediate 47
    Figure US20110269960A1-20111103-C00834
         		(200 MHz, CDCl3), δ ppm: 1.34-1.46 (m, 3 H), 1.48-1.82 (m, 9 H), 3.02-3.18 (m, 4 H), 3.89-4.27 (m, 3 H), 6.88-7.00 (m, 2 H), 7.16-7.29 (m, 2 H)
    Intermediate 48
    Figure US20110269960A1-20111103-C00835
         		(600 MHz, CDCl3), δ ppm: 1.41 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.4 Hz, 3 H), 1.96-2.03 (m, 4 H), 3.23- 3.30 (m, 4 H), 3.96-4.09 (m, 2 H), 4.16 (q, J = 6.6 Hz, 1 H), 6.47-6.56 (m, 2 H), 7.15-7.22 (m, 2 H)
    Intermediate 49
    Figure US20110269960A1-20111103-C00836
         		(600 MHz, CDCl3), δ ppm: 1.41 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.4 Hz, 3 H), 1.96-2.03 (m, 4 H), 3.23- 3.30 (m, 4 H), 3.96-4.09 (m, 2 H), 4.16 (q, J = 6.6 Hz, 1 H), 6.47-6.56 (m, 2 H), 7.15-7.22 (m, 2 H)
    Intermediate 50
    Figure US20110269960A1-20111103-C00837
         		(600 MHz, CDCl3) δ ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.56 (s, 3 H), 4.03-4.14 (m, 2 H), 4.17 (q, J = 6.6 Hz, 1 H), 7.19 (d, J = 8.7 Hz, 1 H), 7.81 (dd, J = 8.7, 2.8 Hz, 1 H), 8.52 (d, J = 3.2 Hz, 1 H)
    Intermediate 51
    Figure US20110269960A1-20111103-C00838
         		(600 MHz, CDCl3) δ ppm: 1.40(t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 2.35 (s, 3H), 2.52-2.61 (m, 4H), 3.22-3.27 (m, 4H), 3.97-4.08 (m, 2H), 4.15 (q, J = 6.9 Hz, 1H), 6.71-6.80 (m, 2H), 6.09-7.03 (m, 1H), 7.20- 7.25 (m, 1H)
    Intermediate 52
    Figure US20110269960A1-20111103-C00839
         		(600 MHz, CDCl3) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.63 (d, J = 6.9 Hz, 3 H), 3.96-4.09 (m, 2 H), 4.20 (q, J = 6.9 Hz, 1 H), 7.13-7.17 (m, 1 H), 7.30-7.34 (m, 1 H), 7.77-7.81 (m, 1 H), 8.22-8.25 (m, 1 H)
    Intermediate 53
    Figure US20110269960A1-20111103-C00840
         		(600 MHz, CDCl3) δ ppm 1.46 (t, J = 7.3 Hz, 3 H), 1.62 (d, J = 6.4 Hz, 3 H), 4.06-4.17 (m, 2 H), 4.20 (q, J = 6.6 Hz, 1 H), 7.64-7.68 (m, 1 H), 7.70-7.73 (m, 1 H), 7.85-7.90 (m, 1 H), 8.10-8.13 (m, 1 H), 8.52-8.54 (m, 1 H), 9.19-9.25 (m, 1 H)
    Intermediate 54
    Figure US20110269960A1-20111103-C00841
         		(600 MHz, CDCl3) δ ppm.: 1.57 (d, J = 6.9 Hz, 3H), 2.34 (s, 3H), 3.59 (s, 3H), 4.16-4.22(m, 1H), 7.15- 7.18 (m, 2H), 7.21-7.25 (m, 2H)
    Intermediate 55
    Figure US20110269960A1-20111103-C00842
         		(600 MHz, CDCl3) δ ppm: 0.99 (t, J = 7.3 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H). 1.77-1.85 (m, 2H), 2.34 (s, 3H), 3.85-3.99 (m, 2H), 4.12 (q, J = 6.9 Hz, 1H), 7.15-7.18 (m, 2H), 7.21-7.24 (m, 2H)
    Intermediate 56
    Figure US20110269960A1-20111103-C00843
         		(600 MHz, CDCl3) δ ppm: 1.53-1.58 (m, 9H), 2.34 (s, 3H), 4.20 (q, J = 6.9 Hz, 1H), 4.66-4.72 (m, 1H), 7.15- 7.19 (m, 2H), 7.21-7.24 (m, 2H)
    Intermediate 57
    Figure US20110269960A1-20111103-C00844
         		(200 MHz, CDCl3) δ ppm: 1.31 (t, J = 7.3Hz, 3H), 1.60 (d, J = 6.6 Hz, 3H), 2.28 (s, 3H), 3.60-4.30 (m, 3H), 6.96-7.02 (m, 4H)
    Intermediate 58
    Figure US20110269960A1-20111103-C00845
         		(600 MHz, CDC13) δ ppm: 1.40 (t, J = 7.3 Hz, 3H), 1.58 (d, J = 6.4 Hz, 3H), 2.34 (s, 3H), 3.99-4.09 (m, 2H). 4.16 (q, J = 6.4 Hz, 1H), 7.15-7.19 (m, 2H), 7.22-7.25 (m, 2H)
    Intermediate 59
    Figure US20110269960A1-20111103-C00846
         		(600 MHz, CDCl3), δ ppm: 1.44 (t, J = 7.1 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 4.02-4.13 (m, 2 H), 4.17 (q, J = 6.6 Hz, 1 H), 6.44-6.47 (m, 1 H), 7.04-7.08 (m, 1 H), 7.15-7.25 (m, 2 H), 7.50-7.57 (m, 1 H), 8.72 (s, 1 H)
    Intermediate 60
    Figure US20110269960A1-20111103-C00847
         		(600 MHz, CDCl3), δ ppm: 1.42 (t, J = 7.1 Hz, 3 H), 1.58 (d, J = 6.4 Hz, 3 H), 3.98-4.10 (m, 2 H), 4.15 (q, J = 6.7 Hz, 1 H), 6.30-6.39 (m, 1 H), 6.87-7.00 (m, 2 H), 7.39-7.52 (m, 2 H), 9.55 (s, 1 H)
    Intermediate 61
    Figure US20110269960A1-20111103-C00848
         		(600 MHz, CDCl3), δ ppm: 1.43 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.34 (s, 3 H), 3.99-4.12 (m, 2 H), 4.16 (q, J = 6.9 Hz, 1 H), 6.03-6.13 (m, 1 H), 6.86-7.07 (m, 2 H), 7.28-7.37 (m, 1 H), 8.76 (s, 1 H)
    Intermediate 62
    Figure US20110269960A1-20111103-C00849
         		(600 MHz, CDCl3) δ ppm: 1.38 (t, J = 7.1 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 2.40 (s, 3H), 3.96-4.07 (m, 2H), 4.23 (q, J = 6.9 Hz, 1H), 6.95-6.97 (m, 1H), 7.13-7.1.5 (m, 1H), 8.07-8.09 (m, 1H)
    Intermediate 63
    Figure US20110269960A1-20111103-C00850
         		(600 MHz, CDCl3) δ ppm: 1.36-1.45 (m, 3H), 1.60- 1.70 (m, 3H), 2.32 (s, 3H), 3.96-4.10 (m, 2H), 4.16- 4.27 (m, 1H), 7.22-7.27 (m, 1H), 7.56-7.66 (m, 1H). 8.02-8.10 (m, 1H)
    Intermediate 64
    Figure US20110269960A1-20111103-C00851
         		(600 MHz, CDCl3) δ ppm: 1.43 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.4 Hz, 3H), 2.59-2.63 (m, 2H). 2.92-2.99 (m, 2H), 4.00-4.11 (m, 2H), 4.18 (q, J = 6.4 Hz, 1H), 6.80-6.84 (m, 1H), 7.11-7.16 (m, 1H), 7.21-7.25 (m, 1H), 8.28-8.72 (m, 1H)
    Intermediate 65
    Figure US20110269960A1-20111103-C00852
         		(600 MHz, CDCl3) δ ppm: 1.35 (t, J = 7.3 Hz, 3 H), 1.54 (d, J = 6.9 Hz, 3 H), 3.76 (s, 3 H), 3.93-4.05 (m, 2 H), 4.11 (q, J = 6.4 Hz, 1 H), 6.69 (dd, J = 8.3, 2.3 Hz, 1 H), 6.87 (dd, J = 8.3, 2.3 Hz, 1 H), 6.92 (t, J = 2.3 Hz, 1 H), 7.18-7.24 (m, 1 H)
    Intermediate 66
    Figure US20110269960A1-20111103-C00853
         		(600 MHz, , CDCl3) δ ppm: 1.14 (t, J = 7.1 Hz, 6 H), 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 3.32 (q, J = 6.9 Hz, 4 H), 3.95-4.07 (m, 2 H), 4.11-4.17 (m, 1 H), 6.46 (dd, J = 8.7, 2.3 Hz, 1 H), 6.50 (dd, J = 8.0, 2.5 Hz, 1 H), 6.67 (t, J = 2.5 Hz, 1 H), 7.14 (t, J = 8.3 Hz, 1 H)
    Intermediate 67
    Figure US20110269960A1-20111103-C00854
         		(600 MHz, CDCl3) δ ppm: 1.39 (t, J = 7.3 Hz, 3H), 1.62 (d, J = 6.4 Hz, 3H), 2.45 (s, 3H), 3.97-4.09 (m, 2H), 4.19 (q, J = 6.4 Hz, 1H), 6.98-7.01 (m, 1H), 7.13-7.16 (m, 1H), 7.64-7.67 (m, 1H)
    Intermediate 68
    Figure US20110269960A1-20111103-C00855
         		(600 MHz, CDCl3) δ ppm: 1.45 (t, J = 7.3 Hz, 3H), 1.62 (d, J = 6.9 Hz, 3H), 4.05-4.15 (m, 2H), 4.20 (q, J = 6.9 Hz, 1H), 7.37-7.41 (m, 1H), 7.65-7.68 (m, 1H), 7.84-7.88 (m, 1H), 7.94-7.96 (m, 1H), 8.14-8.19 (m, 1H), 8.90-8.93 (m, 1H)
    Intermediate 69
    Figure US20110269960A1-20111103-C00856
         		(600 MHz, CDCl3) δ ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.53-1.60 (m, 5 H), 1.64-1.71 (m, 4 H), 3.95-4.07 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.69-6.74 (m, 2 H), 6.95 (t, J = 2.5 Hz, 1 H), 7.19 (t, J = 8.3 Hz, 1 H)
    Intermediate 70
    Figure US20110269960A1-20111103-C00857
         		(600 MHz, CDCl3) δ ppm: 1.41 (t, J = 7.1 Hz, 3H). 1.58 (d, J = 6.9 Hz, 3H), 2.57-2.61 (m, 2H), 2.89-2.93 (m, 2H), 3.99-4.11 (m, 2H), 4.17 (q, J= 6.9 Hz, 1H), 6.90-6.97 (m, 2H), 7.11-7.15 (m, 1H), 8.66 (s, 1H)
    Intermediate 71
    Figure US20110269960A1-20111103-C00858
         		(600 MHz, CDCl3) δ ppm: 1.38 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 2.30-2.39 (m, 2 H), 3.85- 3.89 (m, 4 H), 3.94-4.06 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 6.22-6.25 (m, 1 H), 6.43 (t, J = 2.3 Hz, 1 H), 6.59- 6.63 (m, 1 H), 7.15 (t, J = 8.0 Hz, 1 H)
    Intermediate 72
    Figure US20110269960A1-20111103-C00859
         		(600 MHz, CDCl3) δ ppm: 1.24 (d, J = 6.4 Hz, 6 H), 1.39 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 2.39- 2.46 (m, 2 H), 3.42-3.46 (m, 2 H), 3.73-3.81 (m, 2 H), 3.97-4.09 (m, 2 H), 4.15 (q, J = 6.9 Hz, 1 H), 6.71 (dd, J = 8.0, 2.1 Hz, 1 H), 6.76 (dd, J = 8.5, 2.1 Hz, 1 H), 6.98 (t, J = 2.3 Hz, 1 H), 7.22 (t, J = 8.3 Hz, 1 H)
    Intermediate 73
    Figure US20110269960A1-20111103-C00860
         		(600 MHz, CDCl3) δ ppm: 1.42 (d, J = 7.3 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 3.92 (s, 3H), 4.02-4.13 (m, 2H), 4.16 (q, J = 6.9 Hz, 1H); 6.90 (s, 1H)
    Intermediate 74
    Figure US20110269960A1-20111103-C00861
         		(600 MHz, CDCl3) δ ppm: 1.45 (t, J = 7.3 Hz, 3 H), 1.63 (d, J= 6.4 Hz, 3 H), 4.06-4.17 (m, 2 H), 4.18- 4.23 (m, 1 H), 7.39-7.44 (m, 1 H), 7.65-7.71 (m, 1 H), 8.02-8.05 (m, 1 H), 8.11-8.16 (m, 2 H), 8.88- 8.91 (m, 1 H)
    Intermediate 75
    Figure US20110269960A1-20111103-C00862
         		(600 MHz, CDCl3) δ ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.67 (d, J = 6.4 Hz, 3 H), 1.94-2.02 (m, 4 H), 3.22- 3.29 (m, 4 H), 3.95-4.07 (m, 2 H), 4.10-4.19 (m, 1 H), 6.36 (dd, J = 8.2, 2.3 Hz, 1 H), 6.50-6.56 (m, 2 H), 7.16 (t, J = 8.3 Hz, 1 H)
    Intermediate 76
    Figure US20110269960A1-20111103-C00863
         		(600 MHz, CDCl3) δ ppm: 1.38 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 2.53 (s, 6H), 3.98-4.11 (m, 2H), 4.18 (q, J = 6.9 Hz, 1H), 7.05 (s, 2H)
    Intermediate 77
    Figure US20110269960A1-20111103-C00864
         		(600 MHz, CDCl3) δ ppm: 1.46 (t, J = 7.1 Hz, 3H), 1.63 (d, J = 6.9 Hz, 3H), 4.07-4.24 (m, 3H), 7.63-7.65 (m, 1H), 8.00-8.03(m, 1H), 8.11-8.13 (m, 1H)
    Intermediate 78
    Figure US20110269960A1-20111103-C00865
         		(600 MHz, CDCl3) δ ppm: 1.37 (t, J = 7.1 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 3.96-4.05 (m, 2 H), 4.15 (q, J = 6.7 Hz, 1 H), 6.45-6.50 (m, 1 H), 6.62-6.67 (m, 1 H), 6.71-6.75 (m, 1 H), 7.11 (t, J = 8.0 Hz, 1 H)
    Intermediate 79
    Figure US20110269960A1-20111103-C00866
         		(600 MHz, CDCl3) δ ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 2.27 (s, 6 H), 2.45-2.56 (m, 4 H), 2.58-2.63 (m, 4 H), 3.20-3.24 (m, 4 H), 3.95- 4.07 (m, 2 H), 4.11-4.17 (m, 1 H), 6.68-6.78 (m, 2 H), 6.95-6.98 (m, 1 H), 7.21 (t, J = 8.3 Hz, 1 H)
    Intermediate 80
    Figure US20110269960A1-20111103-C00867
         		(600 MHz, CDCl3) δ ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.60 (d, J = 6.9 Hz, 3 H), 4.02-4.15 (m, 2 H), 4.15- 4.22 (m, 1 H), 7.18-7.20 (m, 1 H), 7.22-7.25 (m, 1 H), 7.28-7.30 (m, 1 H), 7.38-7.41 (m, 1 H), 7.46- 7.51 (m, 1 H), 7.54-7.57 (m, 1 H), 7.85-7.89 (m, 1 H)
    Intermediate 81
    Figure US20110269960A1-20111103-C00868
         		(600 MHz, CDCl3) δ ppm: 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 1.77-1.83 (m, 4 H), 3.27- 3.36 (m, 4 H), 3.95-4.06 (m, 6 H), 4.14 (q, J = 6.9 Hz, 1 H), 6.70-6.75 (m, 2 H), 6.97 (t, J = 2.3 Hz, 1 H), 7.20 (t, J = 8.3 Hz, 1 H)
    Intermediate 82
    Figure US20110269960A1-20111103-C00869
         		(600 MHz, CDCl3) δ ppm: 1.42-1.47 (m, 3 H) 1.62 (dd, J = 6.65, 2.06 Hz, 3 H) 4.05-4.17 (m, 2 H) 4.17-4.22 (m, 1 H) 7.24-7.28 (m, 1 H) 7.48-7.61 (m, 2 H) 7.66 (s, 1 H) 8.52 (s, 2 H)
    Intermediate 83
    Figure US20110269960A1-20111103-C00870
         		(600 MHz, CDCl3) δ ppm: 1.07 (d, J = 6.9 Hz, 6 H), 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.4 Hz, 3 H), 2.62- 2.67 (m, 4 H), 2.67-2.74 (m, 1 H), 3.19-3.24 (m, 4 H), 3.96-4.08 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.71 (dd, J = 8.3, 2.3 Hz, 1 H), 6.75 (dd, J =8.3, 2.3 Hz, 1 H), 6.97 (t, J = 2.3 Hz, 1 H), 7.21 (t, J = 8.3 Hz, 1 H)
    Intermediate 84
    Figure US20110269960A1-20111103-C00871
         		(600 MHz, CDCl3) δ ppm: 1.38 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 2.33 (s, 3H) , 2.40 (s, 3H), 3.97- 4.09 (m, 2H), 4.18 (q, J = 6.9 Hz. 1H), 6.82-6.83 (m, 1H), 6.97-6.98 (m, 1H)
    Intermediate 85
    Figure US20110269960A1-20111103-C00872
         		(600 MHz, CDCl3) δ ppm: 1.30-1.76 (m, 6H), 2.56 (s, 3H), 2.68 (s, 3H), 4.08-4.19 (m, 3H), 6.59 (s, 1H), 6.73 (s, 1H)
    Intermediate 86
    Figure US20110269960A1-20111103-C00873
         		(600 MHz, CDCl3) δ ppm: 1.26 (d, J = 6.9 Hz, 6H), 1.40 (t, J = 7.3 Hz, 3H), 1.57 (d, J = 6.9 Hz, 3H), 2.87-2.94 (m, 1H), 3.72 (s, 3H), 3.99-4.11 (m, 2H), 4.14 (q, J = 6.9 Hz, 1H), 6.25 (s, 1H)
    Intermediate 87
    Figure US20110269960A1-20111103-C00874
         		(600 MHz, CDCl3) δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 3.34 (s, 6 H), 3.50-3.57 (m, 8 H), 3.96-4.07 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 6.51 (dd, J = 8.5, 2.5 Hz, 1 H), 6.56 (dd, J = 7.8, 2.3 Hz, 1 H), 6.69 (t, J = 2.3 Hz, 1 H), 7.15 (t, J = 8.3 Hz, 1 H)
    Intermediate 88
    Figure US20110269960A1-20111103-C00875
         		(600 MHz, CDCl3) δ ppm: 1.36-1.41 (m, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.28 (s, 6 H), 2.45-2.50 (m, 2 H), 2.94 (s, 3 H), 3.39-3.48 (m, 2 H), 3.94-4.08 (m, 2 H), 4.14 (q, J = 6.9 Hz, 1 H), 6.50 (dd, J = 8.3, 2.3 Hz, 1 H), 6.58 (dd, J = 8.3, 2.3 Hz, 1 H), 6.67 (t, J = 2.5 Hz, 1 H), 7.16 (t, J = 8.3 Hz, 1 H)
    Intermediate 89
    Figure US20110269960A1-20111103-C00876
         		(600 MHz, CDCl3) δ ppm: 1.39 (t, J = 7.1 Hz; 3H), 1.59 (d, J = 6.4 Hz, 3H), 2.34 (s, 6H), 2.73 (t, J = 5.7 Hz, 2H), 3.98-4.09 (m, 1H), 4.16 (q, J = 6.4 Hz, 1H), 6.75- 6.77 (m, 1H), 6.91-6.93 (m, 1H) , 6.98-7.00 (m, 1H), 7.24-7.27 (m, 1H)
    Intermediate 90
    Figure US20110269960A1-20111103-C00877
         		(600 MHz, CDCl3) δ ppm: 1.25 (d, J = 6.9Hz, 12H), 1.40 (t, J = 7.1 Hz, 3H), 1.58 (d, J= 6.9 Hz, 3H), 3.76- 3.85 (m, 2H), 3.96-1.08 (m, 2H), 4.15 (q, J = 6.9 Hz, 1H), 6.57-6.70 (m, 2H), 6.88-6.93 (m, 1H), 7.10-7.17 (m, 1H)
    (Intermediate 91
    Figure US20110269960A1-20111103-C00878
         		(600 MHz, CDCl3) δ ppm: 1.06 (d, J = 6.42 Hz, 6 H) 1.39 (t, J = 7.3 Hz, 3 H), 1.58 (d, J = 6.9 Hz, 3 H), 1.68- 1.89 (m, 4 H), 2.17-2.25 (m, 2 H), 2.44-2.53 (m, 1 H), 2.70-2.77 (m, 1 H), 2.94-3.03 (m, 2 H) 3.96-4.08 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 7.03-7.07 (m, 1 H), 7.15-7.22 (m, 2 H), 7.28 (t, J = 8.0 Hz, 1 H)
    Intermediate 92
    Figure US20110269960A1-20111103-C00879
         		(600 MHz, CDCl3), δ ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.58-1.62 (m, 12 H), 4.01-4.13 (m, 2 H), 4.18 (q, J = 6.6 Hz, 1 H), 7.42-7.46 (m, 1 H), 7.61-7.65 (m, 1 H), 7.82-7.85 (m, 1 H), 7.87-7.91 (m, 1 H)
    Intermediate 93
    Figure US20110269960A1-20111103-C00880
         		(600 MHz, DMSO-d6) δ ppm: 1.23 (t, J = 7.3 Hz, 3 H), 1.54 (d, J = 6.9 Hz, 3 H), 3.82-4.09 (m, 2 H), 4.60 (q, J = 6.0 Hz, 1 H), 6.61-6.69 (m, 2 H), 6.70- 6.77 (m, 1 H), 7.14-7.21 (m, 1 H), 8.28-9.11 (m, 2 H), 9.43-10.55 (m, 1 H)
    Intermediate 94
    Figure US20110269960A1-20111103-C00881
         		(600 MHz, CDCl3), δ ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.60 (d, J = 6.4 Hz, 3 H), 3.96-4.09 (m, 2 H), 4.17 (q, J = 6.9 Hz, 1 H), 5.06 (s, 2 H), 6.79-6.84 (m, 1 H), 6.91-6.96 (m, 1 H), 7.04-7.08 (m, 1 H), 7.22- 7.46 (m, 6 H)
    Intermediate 95
    Figure US20110269960A1-20111103-C00882
         		(200 MHz, CDCl3) δ ppm: 1.34 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.8 Hz. 3H). 3.80-4.23 (m, 3H), 5.96 (br s, 1H), 6.88-7.05 (m, 2H), 7.08-7.25 (m, 2H)
    Intermediate 96
    Figure US20110269960A1-20111103-C00883
         		(600 MHz, CDCl3) δ ppm: 1.42-1.66 (m, 9H), 4.06- 4.20 (m, 5H), 7.01-7.05 (m, 1H), 7.24-7.26 (m, 1H), 7.62-7.69 (m, 2H)
    Intermediate 97
    Figure US20110269960A1-20111103-C00884
         		(600 MHz, CDCl3) δ ppm: 1.02-1.16 (m, 4 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.35 (s, 3 H), 2.52-2.61 (m, 4 H), 2.92-3.01 (m, 1 H), 3.21-3.25 (m, 4 H), 4.24 (q, J = 6.6 Hz, 1 H), 6.68-6.75 (m, 2 H), 6.94-6.98 (m, 1 H), 7.19-7.25 (m, 1 H)
    Intermediate 98
    Figure US20110269960A1-20111103-C00885
         		(600 MHz, CDCL3) δ ppm: 1.03-1.18 (m, 4 H), 1.59 (d, J = 6.9 Hz, 2 H), 2.98-3.04 (m, 1 H), 4.25 (q, J = 6.6 Hz, 1 H), 7.04-7.10 (m, 2 H), 7.30-7.35 (m, 2 H)
    Intermediate 99
    Figure US20110269960A1-20111103-C00886
         		(600 MHz, CDCl3) δ ppm: 0.98-1.20 (m, 4 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.93-3.05 (m, 1 H), 4.22- 4.31 (m, 1 H), 6.33-6.44 (m, 1 H), 6.90-7.05 (m, 2 H), 7.31-7.43 (m, 1 H), 7.46-7.55 (m, 1 H), 9.08- 9.32 (m, 1 H)
    Intermediate 100
    Figure US20110269960A1-20111103-C00887
         		(CDCl3, 200 MHz) δ 1.02 (t, J = 7.5 Hz, 3H), 1.39 (t, J = 7.3 Hz, 3H), 1.68 (bs, 2H), 1.91-2.14 (m, 2H), 2.34 (s, 3H), 3.90 (t, J = 6.4 Hz, 1H), 4.03(q, J = 7.3 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H)
    Intermediate 101
    Figure US20110269960A1-20111103-C00888
         		(CDCl3, 200 MHz) δ 0.96 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 7.8 Hz, 3H), 1.71 (bs, 2H), 2.06-2.24 (m, 1H), 2.34 (s, 3H), 3.69 (d, J = 7.5 Hz, 1H), 4.01 (q, J = 7.3 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H)
    Intermediate 102
    Figure US20110269960A1-20111103-C00889
         		(200 MHz, CDCl3) δ ppm: 1.01 (t, J = 7.3 Hz, 3H), 1.39 (t, J = 7.3 Hz, 3H), 1.70-2.11 (m, 2H), 2.35 (s, 3H), 2.56 (t, J = 5.0 Hz, 4H), 3.24 (t, J = 5.0 Hz, 4H), 3.89 (t, J = 7.3 Hz, 1H), 4.02 (q, J = 7.3 Hz, 2H), 6.74 (dt, J = 2.4, 8.4 Hz, 2H), 7.02 (t, J = 2.4 Hz, 1H), 7.22 (t, J = 8.4 Hz, 1H)
    Intermediate 103
    Figure US20110269960A1-20111103-C00890
         		(600 MHz, CDCl3) δ ppm: 1.41 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.4 Hz, 3H), 2.36 (s, 3H), 2.55-2.65 (m, 4H), 3.11-3.19 (m, 4H), 3.98-4.19 (m, 3H), 6.87- 6.92 (m, 1H), 6.96-7.04 (m, 2H)
    Intermediate 104
    Figure US20110269960A1-20111103-C00891
         		(600 MHz, CDCl3) δ ppm: 1.42 (t, J = 6.9 Hz, 3H), 1.62 (s, 6H), 4.31 (q, J = 6.9 Hz, 2H), 7.04-7.09 (m, 2H), 7.34-7.40 (m, 2H)
    Intermediate 105
    Figure US20110269960A1-20111103-C00892
         		(600 MHz, CDCl3) δ ppm: 1.40 (t, J = 7.1 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 2.98-3.04 (m, 4H), 3.14- 3.19 (m, 4H), 3.97-4.09 (m, 2H), 4.13-4.18 (m, 1H), 6.70-6.80 (m, 2H), 6.97-7.03 (m, 1H), 7.21- 7.26 (m, 1H)
    Intermediate 106
    Figure US20110269960A1-20111103-C00893
         		(600 MHz, CDCl3) δ ppm: 1.35 (t, J = 7.3 Hz, 3H), 1.72 (d, J = 6.4 Hz, 3H), 2.12 (s, 3H), 3.14-3.23 (m, 4H), 3.57-3.64 (m, 2H), 3.71-3.77 (m, 2H), 3.87- 4.10 (m, 2H), 4.57-4.66 (m, 1H), 6.70-6.81 (m, 2H), 6.95-6.99 (m, 1H), 7.21-7.26 (m, 1H)
    Intermediate 107
    Figure US20110269960A1-20111103-C00894
         		(200 MHz, CDCl3) δ ppm: 0.94-1.08 (m, 2H), 1.22- 1.31 (m, 2H), 1.47 (t, J = 7.1 Hz, 3H), 4.18 (q, J = 7.1 Hz, 2H), 6.98-7.15 (m, 2H), 7.29- 7.42 (m, 2H)
    Intermediate 108
    Figure US20110269960A1-20111103-C00895
         		(600 MHz, CDCl3) δ ppm: 1.43 (t, J = 7.3 Hz, 3H), 3.97-4.11 (m, 2H), 4.47-4.54 (m, 1H), 7.06- 7.12 (m, 2H), 7.35-7.40 (m, 2H)
    Intermediate 109
    Figure US20110269960A1-20111103-C00896
         		(200 MHz, CDCl3) δ ppm: 1.41 (t, J = 7.5 Hz, 3H), 3.62 (dd, J = 4.8, 11.8 Hz, 1H), 3.88 (dd, J = 4.8, 11.8 Hz, 1H), 4.05 (q, J = 7.5 Hz, 2H), 4.51-4.60 (m, 1H), 7.04-7.13 (m, 2H), 7.23-7.31 (m, 3H), 7.53 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.8, 2.2 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H)
    • INDUSTRIAL APPLICABILITY
  • Since the compounds of the present invention are excellent Edg-1 (S1P1) ligands, they are useful as agents for treating or preventing autoimmune diseases, such as Crohn disease, hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis, and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, organ transplant rejection, cancer, retinopathy, psoriasis, osteoarthritis, and age-related macular degeneration.

Claims (15)

1. A compound represented by Formula (I)
Figure US20110269960A1-20111103-C00897
or a pharmaceutically acceptable salt thereof, wherein
A represents:
an oxygen atom,
R1 represents:
a hydrogen atom,
an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
a hydroxyl group,
a halogen atom,
an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group, and
a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms,
a cycloalkyl group having from 3 to 8 carbon atoms,
an alkenyl group having from 2 to 8 carbon atoms,
an alkynyl group having from 2 to 8 carbon atoms, or
a phenyl group;
R1A represents:
a hydrogen atom or
an alkyl group having from 1 to 6 carbon atoms;
R1 and R1A optionally form, together with a carbon atom to which said R1 and
R1A are attached, a cycloalkyl group having from 3 to 6 carbon atoms;
R2 represents:
a hydrogen atom,
an alkyl group having from 1 to 6 carbon atoms,
an alkenyl group having from 2 to 8 carbon atoms,
an alkynyl group having from 2 to 8 carbon atoms, or
a cycloalkyl group having from 3 to 6 carbon atoms;
R3 represents:
a 2-naphthyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms,
a 3-pyrazolyl group, optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom, or
a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a 7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a 7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms,
an unsubstituted phenyl group, or
a substituted phenyl group (A) or (B) below:
(A) a phenyl group substituted at 4 position with a substituent selected from the group consisting of:
an alkyl group having from 1 to 6 carbon atoms,
a cycloalkyl group having from 3 to 8 carbon atoms,
an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,
a halogen atom,
a trifluoromethoxy group,
a phenoxy group,
a phenyl group,
a 1-pyrrolyl group, and
—NRARB, wherein each of RA and R3 is an alkyl group having from 1 to 6 carbon atoms, or RA and RB optionally form, together with the nitrogen atom to which said RA and RB are attached, a 3- to 5-membered saturated hydrocarbon ring,
wherein said phenyl group substituted at 4 position is further optionally substituted at 3 position with a substituent selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having from 1 to 6 carbon atoms; and
(B) a phenyl group substituted at 3 position with a substituent selected from the group consisting of:
a hydroxyl group,
an alkyl group having from 1 to 6 carbon atoms, and
an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a substituent(s) selected from the group consisting of an amino group substituted with two alkyl groups each having from 1 to 4 carbon atoms, a morpholino group, and a phenyl group,
wherein said phenyl group substituted at 3 position is further optionally substituted with one or two alkyl groups each having from 1 to 6 carbon atoms, or is further optionally substituted at 4 position with a halogen atom;
R4 represents:
a hydrogen atom or
an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a carboxyl group;
R5 represents:
(i) an alkyl group having from 1 to 10 carbon atoms,
(ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
a cycloalkyl group having from 3 to 8 carbon atoms,
a pyridyl group, and
a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms,
(iii) a cycloalkyl group having from 3 to 8 carbon atoms,
(iv) an alkenyl group having from 2 to 8 carbon atoms,
(v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,
(vi) an alkynyl group having from 2 to 8 carbon atoms,
(vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or
(viii) an optionally substituted aryl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, in Formula (I):
R1 represents:
a hydrogen atom,
an alkyl group having from 1 to 6 carbon atoms,
an alkyl group having from 1 to 6 carbon atoms and substituted with a phenyl group,
a cycloalkyl group having from 3 to 8 carbon atoms,
an alkenyl group having from 2 to 8 carbon atoms,
an alkynyl group having from 2 to 8 carbon atoms, or
a phenyl group;
R1A represents a hydrogen atom;
R2 represents:
an alkyl group having from 1 to 6 carbon atoms,
an alkenyl group having from 2 to 8 carbon atoms,
an alkynyl group having from 2 to 8 carbon atoms, or
a cycloalkyl group having from 3 to 6 carbon atoms;
R4 represents:
a hydrogen atom, or
an alkyl group having from 1 to 6 carbon atoms;
R5 represents:
(i) an alkyl group having from 1 to 10 carbon atoms,
(ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
a cycloalkyl group having from 3 to 8 carbon atoms,
a phenyl group,
a naphthyl group,
a pyridyl group, and
a phenyl group substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms,
(iii) a cycloalkyl group having from 3 to 8 carbon atoms,
(iv) an alkenyl group having from 2 to 8 carbon atoms,
(v) an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,
(vi) an alkynyl group having from 2 to 8 carbon atoms,
(vii) an alkynyl group having from 2 to 8 carbon atoms and substituted with a phenyl group, or
(viii) an optionally substituted aryl group.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R1 represents an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a substituent(s) selected from the group consisting of:
a hydroxyl group,
a halogen atom,
an alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted with a phenyl group; and
a phenyl group, optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms;
R1A represents:
a hydrogen atom; or
an alkyl group having from 1 to 6 carbon atoms; and
R1 and R1A optionally form, together with a carbon atom to which said R1 and R1A are attached, a cycloalkyl group having from 3 to 6 carbon atoms.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R1 is:
an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a halogen atom(s), or
a benzyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom and an alkyl group having from 1 to 6 carbon atoms; and
R1A is a hydrogen atom.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is a methyl group or an ethyl group, and R1A is a hydrogen atom.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is a hydrogen atom.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is an alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is an ethyl group or a cyclopropyl group.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is:
(i) an alkyl group having from 1 to 10 carbon atoms,
(ii) an alkyl group having from 1 to 10 carbon atoms and substituted with 1 to 2 substituents selected from the group consisting of:
a cycloalkyl group having from 3 to 8 carbon atoms,
a pyridyl group, and
a phenyl group, a phenoxy group, and a naphthyl group, each optionally substituted with 1 to 2 substituents selected from the group consisting of a halogen atom and an alkoxy group having from 1 to 6 carbon atoms;
(iii) an alkenyl group having from 2 to 8 carbon atoms and optionally substituted with a phenyl group, or
(iv) a phenyl group, a naphthyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group, a pyridyl group, a furanyl group, a benzothienyl group, an isoquinolinyl, an isoxazolyl group, a thiazolyl group, a benzothiadiazolyl group, a benzoxadiazolyl group, a dihydrobenzodioxepinyl group, a dihydrobenzodioxynyl group, a benzodioxolyl group, a dihydrobenzofuranyl group, an indanyl group, an uracil group, a coumaryl group, a chromanyl group, a dihydroindolyl group, a tetrahydronaphthyl group, or a tetrahydroisoquinolinyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of:
an alkyl group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),
an alkenyl group having from 2 to 8 carbon atoms,
a halogen atom,
an alkoxy group having from 1 to 6 carbon atoms and optionally substituted with a fluorine atom(s),
a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiadiazolyl group,
and a pyrimidinyl group, each optionally substituted with a substituent(s) selected from Group X consisting of a methyl group, a trifluoromethyl group, a halogen atom, and a methylsulfanyl group,
an alkylthio group having from 1 to 6 carbon atoms,
an alkylsulfonyl group having from 1 to 6 carbon atoms,
a benzenesulfonyl group,
a morpholinosulfonyl group,
a morpholinocarbonylamino group,
an aminosulfonyl group,
an alkoxycarbonyl group having from 2 to 10 carbon atoms,
a morpholino group optionally substituted with an alkyl group(s) having from 1 to 6 carbon atoms
a phenyl group optionally substituted with an alkoxy group(s) having from 1 to 6 carbon atoms,
a phenoxy group,
a pyridinecarbonyl group,
a pyridineoxy group,
a cyano group,
an alkanoyl group having from 2 to 7 carbon atoms and optionally substituted with a fluorine atom(s), and
an alkanoylamino group having from 2 to 7 carbon atoms.
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is:
an alkyl group having from 1 to 10 carbon atoms and substituted with a cycloalkyl group having from 3 to 8 carbon atoms,
an alkyl group having from 1 to 10 carbon atoms and substituted with a naphthyl group,
an alkenyl group having from 2 to 8 carbon atoms and substituted with a phenyl group,
a phenyl group or a naphthyl group, each optionally substituted with 1 to 5 substituents selected from the group consisting of:
an alkyl group having from 1 to 6 carbon atoms;
a halogen atom,
an alkoxy group having from 1 to 6 carbon atoms;
a trifluoromethoxy group,
a difluoromethoxy group,
a trifluoromethyl group,
an alkenyl group having from 1 to 6 carbon atoms,
an alkylsulfonyl group having from 1 to 6 carbon atoms,
an alkanoyl group having from 2 to 7 carbon atoms,
an alkoxycarbonyl group having from 2 to 7 carbon atoms, and
a cyano group,
a pyrrolyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a methoxycarbonyl group;
a furanyl group optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;
a thienyl group optionally substituted with a substituent (s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a trifluoromethyl group, a thiadiazolyl group, an oxazolyl group, and a halogen atom; or
a benzothienyl group, a dihydrobenzodioxepinyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group, a benzoxadiazolyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom.
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is:
an alkyl group having from 1 to 6 carbon atoms and substituted with a naphthyl group,
an alkenyl group having from 2 to 6 carbon atoms and substituted with a phenyl group;
an unsubstituted phenyl group,
a phenyl group substituted with 1 to 5 substituents selected from the group consisting of a methyl group, a methoxy group, and a halogen atom,
a phenyl group substituted with 1 to 3 substituents selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms,
a halogen atom,
a methoxy group,
a trifluoromethoxy group,
a difluoromethoxy group,
a trifluoromethyl group,
an alkenyl group having from 1 to 6 carbon atoms,
a methylsulfonyl group,
an acetyl group,
a methoxycarbonyl group, and
a cyano group,
said phenyl group substituted at either 3 or 4 position or both;
a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of:
a halogen atom,
an alkyl group having from 1 to 6 carbon atoms,
a cyano group, and
an alkylsulfonyl group having from 1 to 6 carbon atoms, or
a benzothienyl group, a benzoxadiazolyl group, a benzodioxolyl group, a dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, an indanyl group, or a benzothiadiazolyl group, each optionally substituted with a substituent(s) selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and a halogen atom.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is:
a phenyl group substituted at 3 and 4 positions each with a halogen atom, or
a naphthyl group optionally substituted with a substituent(s) selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms, and a cyano group.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is a phenyl group substituted at 4 position with a fluorine atom or a chlorine atom.
14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is a 6-indolyl group.
15. A pharmaceutical preparation, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.
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