WO2020153431A1 - Composé ester - Google Patents

Composé ester Download PDF

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Publication number
WO2020153431A1
WO2020153431A1 PCT/JP2020/002349 JP2020002349W WO2020153431A1 WO 2020153431 A1 WO2020153431 A1 WO 2020153431A1 JP 2020002349 W JP2020002349 W JP 2020002349W WO 2020153431 A1 WO2020153431 A1 WO 2020153431A1
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group
vulgaris
amino
tetrahydro
chronic
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PCT/JP2020/002349
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Japanese (ja)
Inventor
準也 川井
勝義 中島
理 岩本
鶴岡　弘幸
啓志 齋藤
伸也 栗川
夏海 西濱
田中　伸治
桃子 扇谷
真 平沢
航 齊藤
宗義 真壁
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第一三共株式会社
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Publication of WO2020153431A1 publication Critical patent/WO2020153431A1/fr

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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/18—Bridged systems

Definitions

  • the present invention provides a compound having a specific chemical structure having an activity of activating SIRT6, or a pharmaceutically acceptable salt thereof.
  • Sirtuin is a nicotinamide-adenine dinucleotide (NAD)-dependent deacylation enzyme. It is highly conserved from prokaryotes to eukaryotes and plays an important role in various life phenomena such as DNA repair, control of energy metabolism, aging and life span (Non-Patent Document 1).
  • NAD nicotinamide-adenine dinucleotide
  • Non-Patent Document 2 Non-Patent Document 2
  • SIRT1-7 There are 7 kinds of sirtuins up to SIRT1-7 in mammals including humans.
  • SIRT1, SIRT6, and SIRT7 are mainly localized in the nucleus.
  • SIRT1 is mainly localized in the nucleoplasm, SIRT6 in the heterochromatin region, and SIRT7 mainly in the nucleolus.
  • SIRT2 is localized in the cytoplasm and SIRT3-5 is localized in mitochondria (Non-patent document 3).
  • SIRT6 has deacylation activity and mono-ADP ribosylation activity.
  • the deacetylation activity of histone H3K9 by SIRT6 has higher substrate specificity than SIRT1, which is also localized in the nucleus, and H3K9 acetylation is enhanced in cells that knock out SIRT6. It is considered to act as an enzyme (Non-Patent Documents 4 and 5).
  • SIRT6 knockout mice develop normally up to about 2-3 weeks after birth, but then rapidly exhibit premature aging-like symptoms such as subcutaneous fat loss, low bone density, spinal curvature, and lymphocyte phenomenon ( Non-Patent Document 6).
  • SIRT6 regulates the transcription factor NF- ⁇ B involved in inflammation and immune response through deacetylation of H3K9, and in mice lacking SIRT6, the expression of inflammatory cytokines by NF- ⁇ B is constitutively active. And a chronic inflammatory condition has formed.
  • Premature aging-like symptoms in SIRT6 knockout mice are improved by suppressing NF- ⁇ B (Non-patent Document 7).
  • the SIRT6 transgenic mouse that highly expresses SIRT6 becomes resistant to a high fat diet load (HFD) as in the case of calorie restriction and the lifespan is extended (Non-Patent Document 8).
  • HFD high fat diet load
  • SIRT6 has a telomere stabilizing action, DNA repairing action, anti-aging action, anti-fatty liver action, anti-obesity action, anti-diabetic action, anti-atherosclerotic action, and anti-atherogenic action. It has been suggested to have various functions such as idiopathic pulmonary fibrosis (IPF) action, cardioprotective action, and anti-inflammatory/anti-rheumatic action (Non-patent documents 6-14). From these facts, it is expected that a compound that increases the expression level of SIRT6 or enhances the activity of SIRT6 will be a drug showing a therapeutic effect on the diseases including the above.
  • IPF idiopathic pulmonary fibrosis
  • SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 2008 452(7186):492-496. Michishita E, McCord RA, Boxer LD, et al. Cell-cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle. 2009 8(16):2664-2666. Mostoslavsky R, Chua KF, Lombard DB, et al. Genomic instability and aging-like phenotype in the absence mammalian SIRT6. Cell. 2006 124(2):315-329 KawaharaTL, Michishita E, Adler AS, et al.
  • SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organism life span.
  • SIRT6 stabilizes DNA-dependent proteinkinase at chromatin for DNA double-strand break repair.
  • the present invention has a chemical structure as a specific antedrug having an activity of activating SIRT6, a compound useful as an active ingredient for the prevention and treatment of inflammatory diseases, a pharmaceutically acceptable salt thereof, or the like, or The novel manufacturing method and an intermediate thereof are provided.
  • the compound of the present invention, or a pharmaceutically acceptable salt thereof, is considered to be useful as a novel drug, since it has properties different from existing anti-inflammatory agents in various aspects.
  • the present inventors have conducted diligent research on compounds useful as active ingredients for the prevention and treatment of inflammatory diseases, pharmaceutically acceptable salts thereof, etc., and as a result, the compounds of the present invention, their pharmaceutically acceptable salts, and the like. I found salt and the like. That is, the present invention is as described below.
  • a compound of formula (1) or a pharmaceutically acceptable salt thereof is a compound of formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 Each independently, the same or different, a hydrogen atom, or a C1-C6 alkyl group, Alternatively, R 1 and R 2 are bonded to each other to form a substituent and represent any group selected from the following.
  • R 12 C1-C6 alkyl group, hydroxy C1-C6 alkyl group, C1-C6 alkylcarbonyl group, or C1-C6 alkoxycarbonyl group
  • R 3 Hydrogen atom, C1-C6 alkyl group optionally substituted with 1 or 2 groups selected from Group A, A C3-C6 cycloalkyl group optionally substituted with 1 or 2 groups selected from Group A, 4-7 membered saturated heterocyclic group optionally substituted with 1 or 2 groups selected from Group A, or Halo C1-C6 alkyl group
  • R 4 hydrogen atom or R 3 and R 4 are bonded to each other to form a substituent, and represent any group selected from the following.
  • R 34-1 , R 34-2 Independently, the same or different, a hydrogen atom, a C1-C6 alkyl group, A hydroxy C1-C6 alkyl group, or C1-C6 alkoxy C1-C6 alkyl group
  • Group A Hydroxyl group, An oxo group, Amino group, C1-C6 alkyl group, C1-C6 alkylsulfonyl group, C3-C6 cycloalkyl group, Hydroxy C1-C6 alkyl group, C1-C6 alkoxy group, Mono(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonyl group, 4-7 membered saturated heterocyclic group,
  • R X1 C1-C6 alkoxycarbonyl group, C1-C6 alkylcarbonyloxy group, A C3-C6 cycloalkoxycarbonyl group, or Halo C1-C6 alkoxycarbonyl group
  • R X2 Hydrogen atom, halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, Halo C1-C6 alkyl group, halo C1-C6 alkoxy group, Mono(C1-C6 alkyl)amino group, or A di(C1-C6 alkyl)amino group, or R X1 and R X2 are bonded to each other to form a substituent, and any group selected from the following:
  • the group can take either left or right orientation.
  • n 0, 1, or 2
  • R X3 C1-C6 alkylcarbonyloxy group, C1-C6 alkoxycarbonyl C1-C6 alkoxy group, C3-C6 cycloalkylcarbonyloxy group
  • Y Any group selected from the following
  • R Y1 hydrogen atom or C1-C6 alkyl group
  • R 1 and R 2 are hydrogen atoms, or The compound according to [1], or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are bonded to each other to form a substituent and are any groups selected from the following.
  • R 12 methyl group, hydroxyethyl group, acetyl group, ethylcarbonyl group, or Methoxycarbonyl group [3]
  • R 3 is any group selected from the following, or a pharmaceutically acceptable salt thereof.
  • R 3 is any group selected from the following, or a pharmaceutically acceptable salt thereof.
  • Difluoroethyl group, Trifluoroethyl group [7] R 3 and R 4 are bonded to each other to form a substituent, which is any group selected from the following, [1] or [2], or a pharmaceutically acceptable salt thereof ..
  • X is any group selected from the following,
  • R X1 is any group selected from the following, Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, Isopropoxycarbonyl group, 1-methylpropoxycarbonyl group, Acetoxy group, ethylcarbonyloxy group, propylcarbonyloxy group, Cyclobutyloxycarbonyl group, Trifluoroethoxycarbonyl group, Difluoroethoxycarbonyl group
  • R X2 is any group selected from the following, Hydrogen atom, fluorine atom, chlorine atom, methyl group, methoxy group, Difluoromethoxy group, methylamino group
  • [9] X is any group selected from the following,
  • R X1 and R X2 are bonded to each other to form a substituent, which is any group selected from the following:
  • the group can take either left or right direction,
  • [Ten] X is any group selected from the following,
  • R X1 is any group selected from the following, Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, Isopropoxycarbonyl group, 1-methylpropoxycarbonyl group, Acetoxy group, ethylcarbonyloxy group, propylcarbonyloxy group, Cyclobutyloxycarbonyl group, Trifluoroethoxycarbonyl group, Difluoroethoxycarbonyl group.
  • [11] X is any group selected from the following,
  • X is an ethyl group substituted with any group selected from R X3 , R X3 is any group selected from the following, Cyclopentylcarbonyloxy group, Cyclohexylcarbonyloxy group, Acetoxy group, Isopropylcarbonyloxy group, Ethoxycarbonylmethoxy group
  • R Y1 in Y is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof.
  • [16] [1]-A pharmaceutical composition containing the compound according to any one of [14] or a pharmaceutically acceptable salt thereof as an active ingredient. [17] The pharmaceutical composition according to [16], which is an external preparation. [18] The pharmaceutical composition according to [16], for treating and/or preventing a peripheral inflammatory disease. [19] The compound or a pharmaceutically acceptable salt thereof according to any one of [1]-[14], for use in the treatment and/or prevention of peripheral inflammatory diseases.
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, acute hepatitis, Chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, peripheral neuritis, ankylosing spondylitis, acute eczema, Subacute eczema, chronic eczema, contact dermatitis, sun and/or UV sunburn, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, arth
  • Pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns, conjunctivitis, keratitis, scleritis, Acute/chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute/chronic salivary gland inflammation, cheilitis, cheilitis, Behcet's disease, multiple sclerosis
  • the pharmaceutical composition according to [18] which is selected from the group consisting of, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, and chronic heart failure.
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic fat Hepatitis, ankylosing spondylitis, contact dermatitis, sun and/or UV sunburn, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, arthritic psoriasis, psoriatic erythema , Pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns,
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, nonalcoholic steatohepatitis, contact dermatitis, sun and/or UV sunburn, radiation dermatitis, atopic dermatitis, seborrhea.
  • Dermatitis, psoriasis vulgaris, psoriasis arthritis, erythroderma psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, vulgaris
  • the pharmaceutical composition according to [18] which is selected from the group consisting of acne, pressure ulcer, wound, burn, intractable stomatitis, glossitis, and Behcet's disease. [twenty three] A method for treating and/or preventing a peripheral inflammatory disease, which comprises administering an effective amount of the pharmaceutical composition according to [16] or [17].
  • Another aspect of the present invention relates to the following [1A]-[34A].
  • [1A] The compound of formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 Each independently, the same or different, a hydrogen atom, or a C1-C6 alkyl group, Alternatively, R 1 and R 2 are bonded to each other to form a substituent and represent any group selected from the following.
  • R 12 C1-C6 alkyl group, hydroxy C1-C6 alkyl group, C1-C6 alkylcarbonyl group, Or C1-C6 alkoxycarbonyl group
  • R 3 Hydrogen atom, C1-C6 alkyl group optionally substituted with 1 or 2 groups selected from Group A, A C3-C6 cycloalkyl group optionally substituted with 1 or 2 groups selected from Group A, 4-7 membered saturated heterocyclic group optionally substituted with 1 or 2 groups selected from Group A, or Halo C1-C6 alkyl group
  • R 4 hydrogen atom or R 3 and R 4 are bonded to each other to form a substituent, and represent any group selected from the following.
  • R 34-1 , R 34-2 Independently, the same or different, a hydrogen atom, a C1-C6 alkyl group, A hydroxy C1-C6 alkyl group, or C1-C6 alkoxy C1-C6 alkyl group
  • Group A Hydroxyl group, An oxo group, Amino group, C1-C6 alkyl group, C1-C6 alkylsulfonyl group, C3-C6 cycloalkyl group, Hydroxy C1-C6 alkyl group, C1-C6 alkoxy group, Mono(C1-C6 alkyl)amino group, C1-C6 alkoxycarbonyl group, 4-7 membered saturated heterocyclic group,
  • R X1 C1-C6 alkoxycarbonyl group, C1-C6 alkylcarbonyloxy group, A C3-C6 cycloalkoxycarbonyl group, or Halo C1-C6 alkoxycarbonyl group
  • R X2 Hydrogen atom, halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, Halo C1-C6 alkyl group, halo C1-C6 alkoxy group, Mono(C1-C6 alkyl)amino group, or A di(C1-C6 alkyl)amino group, or R X1 and R X2 are bonded to each other to form a substituent, and any group selected from the following:
  • the group can take either left or right orientation.
  • n 0, 1, or 2
  • R X3 C1-C6 alkylcarbonyloxy group, C1-C6 alkoxycarbonyl C1-C6 alkoxy group, C3-C6 cycloalkylcarbonyloxy group
  • Y Any group selected from the following
  • R Y1 hydrogen atom or C1-C6 alkyl group [2A]
  • R 1 and R 2 are hydrogen atoms, or The compound according to [1A] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are bonded to each other to form a substituent and are any groups selected from the following.
  • R 12 methyl group, hydroxyethyl group, acetyl group, ethylcarbonyl group, or Methoxycarbonyl group [3A]
  • R 3 is any group selected from the following, or a pharmaceutically acceptable salt thereof.
  • R 3 is any group selected from the following, or a pharmaceutically acceptable salt thereof.
  • R 3 is any group selected from the following, or a pharmaceutically acceptable salt thereof.
  • Difluoroethyl group, Trifluoroethyl group [7A] R 3 and R 4 are bonded to each other to form a substituent and are any groups selected from the following, [1A] or [2A], or a pharmaceutically acceptable compound thereof. Salt.
  • [8A]X is any group selected from the following,
  • R X1 is any group selected from the following, Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, Isopropoxycarbonyl group, 1-methylpropoxycarbonyl group, Acetoxy group, ethylcarbonyloxy group, propylcarbonyloxy group, Cyclobutyloxycarbonyl group, Trifluoroethoxycarbonyl group, Difluoroethoxycarbonyl group
  • R X2 is any group selected from the following, Hydrogen atom, fluorine atom, chlorine atom, methyl group, methoxy group, Difluoromethoxy group, methylamino group
  • [9A]X is any group selected from the following,
  • R X1 and R X2 combine to form a substituent, which is any group selected from the following:
  • the group can take either left or right direction,
  • [10A]X is any group selected from the following,
  • R X1 is any group selected from the following, Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, Isopropoxycarbonyl group, 1-methylpropoxycarbonyl group, Acetoxy group, ethylcarbonyloxy group, propylcarbonyloxy group, Cyclobutyloxycarbonyl group, Trifluoroethoxycarbonyl group, Difluoroethoxycarbonyl group.
  • [11A]X is any group selected from the following,
  • X is an ethyl group substituted with any group selected from R X3 , R X3 is any group selected from the following, Cyclopentylcarbonyloxy group, Cyclohexylcarbonyloxy group, Acetoxy group, Isopropylcarbonyloxy group, Ethoxycarbonylmethoxy group
  • R Y1 is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof.
  • a SIRT6 activator containing the compound according to any one of [1A] to [14A] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition comprising the compound according to any one of [1A] to [14A] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, Acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, peripheral neuritis, ankylosing spondylitis, Acute eczema, subacute eczema, chronic eczema, contact dermatitis, sunlight and/or UV sunburn, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris
  • Dermatosis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns, conjunctivitis, keratitis, sclera Inflammation, acute/chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute/chronic salivary gland inflammation, cheilitis, cheilitis, Behcet's disease, multiple Sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, chronic heart failure, vitiligo vulgaris, warts vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis , Androgenetic alopecia, female a
  • peripheral inflammatory disease rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, non-alcoholic steatohepatitis, contact dermatitis, sunlight and/or UV-induced sun dermatitis, radiation dermatitis, atopic dermatitis, Seborrheic dermatitis, psoriasis vulgaris, arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, hives, alopecia areata, pemphigus group, erythroderma, Acne vulgaris, pressure ulcer, wound, burn, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, vulgaris vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis, Male
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, Acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, liver cirrhosis, peripheral neuritis, ankylosing spondylitis, Acute eczema, subacute eczema, chronic eczema, contact
  • Dermatosis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns, conjunctivitis, keratitis, sclera Inflammation, acute/chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute/chronic salivary gland inflammation, cheilitis, cheilitis, Behcet's disease, multiple Sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, chronic heart failure, vitiligo vulgaris, warts vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis , Androgenetic alopecia, female a
  • peripheral inflammatory disease rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, nonalcoholic steatohepatitis, contact dermatitis, sunlight and/or UV-induced dermatitis, radiation dermatitis, atopic dermatitis, Seborrheic dermatitis, psoriasis vulgaris, arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, hives, alopecia areata, pemphigus group, erythroderma, Acne vulgaris, pressure ulcer, wound, burn, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, vulgaris vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis, Male pattern
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, Acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, peripheral neuritis, ankylosing spondylitis, Acute eczema, subacute eczema, chronic eczema, contact derma
  • Dermatosis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns, conjunctivitis, keratitis, sclera Inflammation, acute/chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute/chronic salivary gland inflammation, cheilitis, cheilitis, Behcet's disease, multiple Sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, chronic heart failure, vitiligo vulgaris, warts vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis , Androgenetic alopecia, female a
  • peripheral inflammatory disease rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, nonalcoholic steatohepatitis, contact dermatitis, sunlight and/or UV-induced sunburn, radiation dermatitis, atopic dermatitis, Seborrheic dermatitis, psoriasis vulgaris, arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, hives, alopecia areata, pemphigus group, erythroderma, Acne vulgaris, pressure ulcer, wound, burn, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, vulgaris vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis, Male pattern baldness
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, Acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, peripheral neuritis, ankylosing spondylitis, Acute eczema, subacute eczema,
  • Dermatosis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns, conjunctivitis, keratitis, sclera Inflammation, acute/chronic otitis media, perennial allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute/chronic salivary gland inflammation, cheilitis, cheilitis, Behcet's disease, multiple Sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, chronic heart failure, vitiligo vulgaris, warts vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis , Androgenetic alopecia, female a
  • peripheral inflammatory disease rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, non-alcoholic steatohepatitis, contact dermatitis, sunlight and/or UV-induced sun dermatitis, radiation dermatitis, atopic dermatitis, Seborrheic dermatitis, psoriasis vulgaris, arthritic psoriasis, psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, hives, alopecia areata, pemphigus group, erythroderma, Acne vulgaris, pressure ulcer, wound, burn, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, vulgaris vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis, Male
  • the compound having a specific chemical structure having an anti-inflammatory effect of the present invention or a pharmaceutically acceptable salt thereof has different properties from existing anti-inflammatory agents from various aspects, and thus is a novel drug. Considered to be useful as
  • the compounds of the present invention and pharmaceutically acceptable salts thereof have anti-inflammatory activity, bioavailability, solubility, cell membrane permeability, oral absorbability, blood concentration, metabolic stability, tissue translocation, in Excellent properties in terms of in vitro activity, in vivo activity, ex vivo activity, rapid onset of drug effect, sustained drug effect, physical stability, drug interaction, safety (eg, cardiotoxicity or hepatotoxicity) Therefore, it is considered to be useful as a medicine.
  • One aspect of the present invention is a compound of formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are hydrogen atoms, or R 1 and R 2 are bonded to each other to form a substituent, and any group selected from the following is preferable.
  • R 12 methyl group, hydroxyethyl group, acetyl group, ethylcarbonyl group, or Methoxycarbonyl group
  • R 1 and R 2 are hydrogen atoms or the following groups in which R 1 and R 2 are bonded to each other to form a substituent.
  • R 3 is any group selected from the following, and R 4 is a hydrogen atom methyl group, ethyl group, propyl group, isopropyl group, Hydroxyethyl group, hydroxypropyl group, Aminoethyl group, Methylaminoethyl group, 2-hydroxy-1-methylethyl group, Methoxyethyl group, 2-(methanesulfonyl)ethyl group, 2-cyclobutyl-2-hydroxy-ethyl group 2-hydroxy-2-methylpropyl group 1-hydroxycyclobutylmethyl group
  • R 3 is any group selected from the following, R 4 is a hydrogen atom cyclobutyl group, Hydroxycyclopentyl group, Methylaminocyclobutyl group, Aminocyclopentyl group, Hydroxycyclobutyl group, Hydroxycyclohexyl group, 1-hydroxymethylcyclobutyl group
  • R 3 is any group selected from the following, R 4 is a hydrogen atom tetrahydrofuranyl group, Hydroxytetrahydropyranyl group, An oxopiperidinyl group, Azepanyl group, An isopropyl piperidinyl group, 2-oxotetrahydrofuran-3-yl group, 1,4-dioxanyl group, An oxetanyl group, A methyloxetanyl group, Hydroxy oxetanyl group, Hydroxymethyloxetanyl group
  • R 3 is any group selected from the following, and R 4 is a hydrogen atom 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group
  • R 3 is a methyl group, an isopropyl group, a 2,2,2-trifluoroethyl group, a 2,2-difluoroethyl group, or a 2-(methanesulfonyl)ethyl group, and R 4 is hydrogen. Is an atom.
  • any of the following (1) to (5) is preferable.
  • (1) X is any group selected from the following
  • R X1 is any group selected from the following: methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, Isopropoxycarbonyl group, 1-methylpropoxycarbonyl group, Acetoxy group, ethylcarbonyloxy group, propylcarbonyloxy group, Cyclobutyloxycarbonyl group, Trifluoroethoxycarbonyl group, Difluoroethoxycarbonyl group
  • R X2 is any group selected from the following: hydrogen atom, fluorine atom, chlorine atom, methyl group, methoxy group, Difluoromethoxy group, methylamino group
  • X is a group selected from the following
  • R X1 and R X2 are bonded to each other to form a substituent, and any group selected from the following:
  • the base can take either left or right orientation.
  • X is any group selected from the following
  • R X1 is any group selected from the following: methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, Isopropoxycarbonyl group, 1-methylpropoxycarbonyl group, Acetoxy group, ethylcarbonyloxy group, propylcarbonyloxy group, Cyclobutyloxycarbonyl group, Trifluoroethoxycarbonyl group, Difluoroethoxycarbonyl group
  • X is any group selected from the following
  • X is an ethyl group substituted with any group selected from R X3
  • R X3 is any group selected from the following cyclopentylcarbonyloxy group, Cyclohexylcarbonyloxy group, Acetoxy group, Isopropylcarbonyloxy group, Ethoxycarbonylmethoxy group
  • X is any group selected from the above (1) or (2).
  • any group selected from the following is preferable.
  • the group can take either left or right orientation.
  • Y is any group selected from the following.
  • Another aspect of the present invention is a compound described below, or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of the present invention is the compound described below or a pharmaceutically acceptable salt thereof.
  • C1-C6 alkyl group in the present specification is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, 1-propyl group, isopropyl group, 1- Butyl group, 2-butyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-1-pentyl group, 3-methyl-1-pentyl group, 2-ethyl-1-butyl group It is a 2,2-dimethyl-1-butyl group or a 2,3-dimethyl-1-butyl group, preferably a methyl group, an ethyl group, a 1-propyl group or an isopropyl group.
  • C1-C6 alkoxy group in the present specification is a group in which a C1-C6 alkyl group is bonded to an oxy group, and examples thereof include a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group and a 1-butoxy group.
  • hydroxy C1-C6 alkyl group in the present specification is a group in which an arbitrary number of hydroxyl groups are bonded to the C1-C6 alkyl group. It is preferably a group having 1 to 3 hydroxyl groups bonded, and more preferably a group having 1 hydroxyl group bonded. Specific groups are, for example, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxyisopropyl group, or a hydroxyisobutyl group.
  • C1-C6 alkylcarbonyl group in the present specification is a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and is preferably an acetyl group, an ethylcarbonyl group or a propylcarbonyl group.
  • C1-C6 alkylcarbonyloxy group in the present specification is a group in which a C1-C6 alkylcarbonyl is bonded to an oxy group, preferably an acetoxy group, an ethylcarbonyloxy group, or a propylcarbonyloxy group. is there.
  • C1-C6 alkylsulfonyl group in the present specification is a group in which a C1-C6 alkyl group is bonded to a sulfonyl group, and is preferably a methanesulfonyl group, an ethanesulfonyl group or a propanesulfonyl group.
  • C1-C6 alkoxycarbonyl group in the present specification is a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, preferably a methoxycarbonyl group, an ethoxycarbonyl group, or a t-butoxycarbonyl group. is there.
  • C1-C6 alkoxycarbonyl C1-C6 alkoxy group in the present specification is a group in which C1-C6 alkoxycarbonyl is bonded to a C1-C6 alkoxy group, preferably a methoxycarbonylmethoxy group, an ethoxycarbonylmethoxy group. Or an ethoxycarbonylethoxy group.
  • C3-C6 cycloalkyl group in the present specification is a cyclic alkyl group having 3 to 6 carbon atoms, preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • C3-C6 cycloalkylcarbonyl group in the present specification is a group in which a cyclic alkyl group having 3 to 6 carbon atoms is bonded to a carbonyl group, preferably a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, It is a cyclopentylcarbonyl group or a cyclohexylcarbonyl group.
  • C3-C6 cycloalkylcarbonyloxy group in the present specification is a group in which a C3-C6 cycloalkylcarbonyl is bonded to an oxy group, preferably a cyclopropylcarbonyloxy group, a cyclobutylcarbonyloxy group, cyclopentyl. It is a carbonyloxy group or a cyclohexylcarbonyloxy group.
  • the "4-7 membered saturated heterocyclic group" in the present specification a nitrogen atom, an oxygen atom, and a monocyclic 4-containing monocyclic 4- to 1-3 atoms selected from the group consisting of sulfur atoms.
  • a 7-membered saturated heterocyclic group for example, azetidine, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, thiazolidine, piperidine, azepan, piperazine, hexahydropyrimidine, morpholine, thiomorpholine, oxetane, tetrahydrofuran, tetrahydropyran, dioxane, Thioxane and oxepane, preferably, the following rings are mentioned.
  • halogen atom in the present specification is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.
  • halo C1-C6 alkyl group in the present specification is a group in which a C1-C6 alkyl group is substituted with an arbitrary number of halogen atoms.
  • Specific groups are, for example, a difluoromethyl group, a trifluoromethyl group, or a difluoroethyl group.
  • halo C1-C6 alkoxy group in the present specification is a group in which a C1-C6 alkoxy group is substituted with an arbitrary number of halogen atoms.
  • Specific groups include, for example, a difluoromethoxy group, a trifluoromethoxy group, or a difluoroethoxy group.
  • halo C1-C6 alkoxycarbonyl group in the present specification is a group in which a halo C1-C6 alkoxy group is bonded to a carbonyl group, and is preferably a difluoromethoxycarbonyl group, a trifluoromethoxycarbonyl group, or difluoro. It is an ethoxycarbonyl group.
  • C1-C6 alkoxy C1-C6 alkyl group in the present specification is a group in which one C1-C6 alkoxy group is bonded to a C1-C6 alkyl group, preferably a methoxymethyl group, an ethoxymethyl group. Or an ethoxyethyl group.
  • the "mono(C1-C6 alkyl)amino group” in the present specification is a group in which one C1-C6 alkyl group is bonded to an amino group, preferably a methylamino group, an ethylamino group, or, It is a propylamino group.
  • the "di (C1-C6 alkyl) amino group” in the present specification is a group in which two C1-C6 alkyl groups which are the same or different independently from each other are bonded to an amino group, and preferably a dimethylamino group, It is a diethylamino group or a dipropylamino group.
  • the pharmaceutically acceptable salt refers to a salt that can be used as a medicine. When the compound has an acidic group or a basic group, it can be converted to a basic salt or an acidic salt by reacting with a base or an acid, and therefore the salt is shown.
  • the pharmaceutically acceptable "basic salt" of the compound is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt; N- Organic base salts such as methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt, lysine salt, An amino acid salt such as an arginine salt, an ornithine salt, a glutamate salt, and an aspartate salt, and preferably an alkali metal salt.
  • an alkali metal salt such as sodium salt, potassium salt or lithium salt
  • an alkaline earth metal salt such as magnesium salt or calcium salt
  • N- Organic base salts such as methylmorpholine salt, triethylamine salt, tributylamine salt, diis
  • the pharmaceutically acceptable “acid salt” of the compound is preferably hydrofluoride, hydrochloride, hydrobromide, hydrohalide such as hydroiodide, nitrate, persulfate.
  • Inorganic acid salts such as chlorates, sulfates and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, benzene sulfonate, p-toluene sulfonate
  • Aryl sulfonates such as salts, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates and other organic acid salts; and glycine Amino acid salts such as salts, lysine salts, arginine salts, ornithine salts, glutamate salts and aspartate
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may be left in the air or recrystallized to absorb water, adsorbed water, or become a hydrate.
  • the present invention also includes such various hydrates, solvates and polymorphic compounds.
  • the compound of the present invention may be a geometric isomer such as cis isomer or trans isomer, a tautomer, a rotational isomer or a d isomer depending on the kind and combination of substituents.
  • Various isomers such as optical isomers (including enantiomers and diastereomers) such as 1-form.
  • the compounds of the present invention include all isomers, stereoisomers and mixtures of these isomers and stereoisomers in any ratios, unless otherwise specified. A mixture of these isomers can be separated by a known separation means.
  • the compound of the present invention also includes a label, that is, a compound in which one or more atoms of the compound are substituted with an isotope (eg, 2H, 3H, 13C, 14C, 35S, etc.).
  • the compounds of the present invention are usually named according to the nomenclature of International Union of Pure and Applied Chemistry (IUPAC).
  • IUPAC International Union of Pure and Applied Chemistry
  • R and S absolute configuration
  • Relative configuration is indicated by adding an asterisk (R * and S * ) to the configuration display when the configuration of the asymmetric center described first is R or S, or prefix (symbol) rel- (in front of the name. It may be shown by putting relative).
  • Racemic mixtures usually indicate, in particular, their absolute configuration without R and S, but with the symbols RS and SR in place of R * and S * , or with the prefix (symbol) rac- (in front of the name. (Meaning of racemic).
  • the present invention also includes so-called prodrugs.
  • the prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group or the like of the compound by hydrolysis or under physiological conditions, and as a group forming such a prodrug, Med., Vol. 5, pp. 2157-2161, 1985 etc.
  • the compound has an amino group
  • a compound whose amino group is acylated, alkylated, phosphorylated for example, its amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4- A) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compound, etc.
  • the compound has a hydroxyl group
  • Compounds whose hydroxyl groups are acylated, alkylated, phosphorylated, borated (for example, their hydroxyl groups are acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated) Compounds, etc.) and the like
  • Method A is a method for producing compound (AV).
  • Bn represents a benzyl group
  • R 1 and R 2 are bonded to each other to form a substituent, and represent any group selected from the following.
  • R 12 C1-C6 alkyl group, hydroxy C1-C6 alkyl group, C1-C6 alkylcarbonyl group, or C1-C6 alkoxycarbonyl group]
  • Step A1 Step of oxidative cleavage (when ozone is used)
  • compound (A-II) is obtained by reacting compound (AI) with ozone and a reducing agent.
  • the reducing agent include triphenylphosphine and dimethyl sulfide.
  • the solvent include methanol, dichloromethane and the like, or a mixture thereof.
  • the reaction temperature is usually about -78°C to room temperature, and the reaction time is usually about 0.25 to 24 hours.
  • compound (A-II) is obtained by reacting compound (AI) with an oxidizing agent.
  • the oxidizing agent include potassium permanganate, osmium tetroxide, sodium periodate, and the like, or a mixture thereof.
  • the solvent include tetrahydrofuran, acetonitrile, water, dichloromethane and the like, or a mixture thereof.
  • the reaction temperature is usually 0° C. to room temperature, and the reaction time is usually 0.5 to 24 hr.
  • Step A2 Step of Epoxidation This is a step of obtaining a compound (A-III) by reacting the compound (AI) with an oxidizing agent in the presence or absence of a base.
  • the base include sodium hydrogen carbonate, pyridine and the like.
  • the oxidizing agent include 3-chloroperbenzoic acid (mCPBA), hydrogen peroxide and the like.
  • the solvent include dichloromethane, acetonitrile, methanol, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0°C to 60°C, and the reaction time is usually about 0.25 to 24 hours.
  • Step A3 Step of ring opening of epoxy Step of obtaining compound (A-IV) from compound (A-III) in the presence or absence of acid or base using an aqueous solvent Is.
  • the acid include sulfuric acid and the like.
  • the base include sodium hydroxide and the like.
  • the solvent include tetrahydrofuran, methanol, water and the like, or a mixture thereof.
  • the reaction temperature is usually room temperature to about 100° C., and the reaction time is usually about 0.25 to 24 hours.
  • Step A4 Step of Performing Oxidative Cleavage This is a step of reacting the compound (A-IV) with an oxidizing agent to obtain the compound (A-II).
  • the oxidizing agent include sodium periodate and the like.
  • the solvent include tetrahydrofuran, acetonitrile, methanol, water and the like, or a mixture thereof.
  • the reaction temperature is usually 0° C. to room temperature, and the reaction time is usually 0.5 to 24 hr.
  • Step A5 Step of forming a ring
  • the compound (A-II) is reacted with benzylamine and 1,3-acetonedicarboxylic acid in the presence of an acid to obtain the compound (AV).
  • the acid include hydrochloric acid and the like.
  • the solvent include tetrahydrofuran, acetonitrile, methanol, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0°C to 60°C, and the reaction time is usually about 0.5 to 24 hours.
  • Method B is a method for producing compound (B-III).
  • Bn represents a benzyl group
  • R 1 and R 2 are bonded to each other to form a substituent, and represent any group selected from the following.
  • R 12 C1-C6 alkyl group, hydroxy C1-C6 alkyl group, C1-C6 alkylcarbonyl group, or
  • the C1-C6 alkoxycarbonyl group Pa1 represents a commonly used protecting group for an amino group.
  • Step B1 Step of Deprotection This is a step of obtaining the compound (B-II) from the compound (BI) in a hydrogen atmosphere in the presence or absence of an acid using a transition metal catalyst.
  • the acid include hydrochloric acid, hydrogen chloride-1,4-dioxane, hydrogen chloride-ethyl acetate and the like.
  • the transition metal catalyst include palladium-carbon, palladium hydroxide-carbon, Raney nickel and the like.
  • the solvent include methanol, ethanol, ethyl acetate, chloroform and the like, or a mixture thereof.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • a compound (B-III) is obtained by reacting the compound (B-II) with a carbamate-forming reagent in the presence of a base.
  • the carbamate group is generally a t-butoxycarbonyl (Boc) group, 2-(trimethylsilyl)ethoxycarbonyl (Teoc) group, allyloxycarbonyl (Alloc) group, benzyloxycarbonyl (Cbz) group or the like.
  • a carbamate group used in the synthesis as a protecting group for an amino group is shown.
  • Examples of the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, 4-dimethylaminopyridine and the like.
  • Examples of the carbamate-forming reagent include chloroformic acid ester, dicarbonic acid diester, succinimidyl carbonate and the like.
  • Examples of the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0 to 80° C., and the reaction time is usually about 0.5 to 24 hours.
  • Method C is a method for producing compound (C-II).
  • R 1 and R 2 have the same meanings as in the case of the compound of the above formula (1), and P a1 has the same meaning as above. ]
  • (C1 step) Deprotection step (In the case of t-butoxycarbonyl (Boc) group)
  • a compound (C-II) containing an amino group protected by a t-butoxycarbonyl group is reacted with an acid to give a compound (C-II).
  • the acid include hydrochloric acid, hydrogen chloride-1,4-dioxane, hydrogen chloride-ethyl acetate, trifluoroacetic acid, p-toluenesulfonic acid and the like.
  • the solvent include methanol, ethanol, tetrahydrofuran, dichloromethane, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • a compound (C-II) is obtained by performing a reaction from a compound (CI) containing an amino group protected by a benzyl group in a hydrogen atmosphere, in the presence or absence of an acid, using a transition metal catalyst. ..
  • This step can be performed by the same method as in (B1 step).
  • Method D is a method for producing compound (D-III).
  • R 1 and R 2 have the same meanings as in the case of the compound of the above formula (1), and P a1 has the same meaning as above. ]
  • Step D1 Step of forming thiazole ring (When using sulfur)
  • a compound (D-II) is obtained by reacting the compound (DI) with a base, sulfur, cyanamide, and an acid.
  • the base include pyrrolidine, piperidine, diethylamine, pyridine and the like.
  • the acid include hydrogen chloride-1,4-dioxane, p-toluenesulfonic acid and the like.
  • the solvent include methanol, ethanol, isopropanol, toluene and the like.
  • the reaction temperature is usually about 0 to 130° C., and the reaction time is usually about 0.5 to 24 hours.
  • compound (D-II) is obtained by reacting compound (DI) with a halogenating reagent and thiourea in the presence or absence of a base.
  • a halogenating reagent include N-bromosuccinimide, bromine, bromine-1,4-dioxane complex, pyridinium bromide perbromide, iodine, N-iodosuccinimide and the like.
  • the base include sodium hydrogen carbonate and the like.
  • the solvent include chloroform, ethanol and the like, or a mixture thereof.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • (D2 step) Deprotection step (In the case of t-butoxycarbonyl (Boc) group)
  • a compound (D-III) containing an amino group protected by a t-butoxycarbonyl group is reacted with an acid to obtain a compound (D-III).
  • the acid include hydrochloric acid, hydrogen chloride-1,4-dioxane, hydrogen chloride-ethyl acetate, trifluoroacetic acid, p-toluenesulfonic acid and the like.
  • the solvent include methanol, ethanol, tetrahydrofuran, dichloromethane, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • Method E is a method for producing compound (E-IV).
  • R 1 and R 2 have the same meanings as in the case of the compound of the above formula (1), P a1 has the same meaning as described above, and P a2 independently of P a1.
  • the commonly used amino-protecting groups selected are shown below.
  • Step E1 Step of forming thiazole ring This is a step of obtaining compound (E-II) from compound (EI). This step can be performed by the same method as in (D1 step).
  • (E2 step) Protection step (For carbamate group)
  • a compound (E-III) is obtained by reacting the compound (E-II) with a base and a carbamate-forming reagent.
  • This step can be performed by the same method as in (B2 step).
  • the carbamate group is generally a t-butoxycarbonyl (Boc) group, 2-(trimethylsilyl)ethoxycarbonyl (Teoc) group, allyloxycarbonyl (Alloc) group, benzyloxycarbonyl (Cbz) group or the like.
  • a carbamate group used in the synthesis as a protecting group for an amino group is shown.
  • acyl group refers to an acyl group which is generally used as a protective group for an amino group in synthesis such as acetyl group, trifluoroacetyl group, benzoyl group and the like.
  • the base include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like.
  • the acylating reagent include acyl chloride and acid anhydride.
  • the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide and the like.
  • the reaction temperature is usually about 0 to 80° C., and the reaction time is usually about 0.5 to 24 hours.
  • the compound (E-III) containing an amino group protected by a 2-(trimethylsilyl)ethoxycarbonyl group is reacted with a desilylation reagent or an acid to obtain a compound (E-IV).
  • a desilylation reagent include tetrabutylammonium fluoride (TBAF), hydrogen fluoride, hydrogen fluoride pyridine and the like.
  • Examples of the acid include hydrochloric acid, sulfuric acid, hydrochloric acid-methanol, hydrochloric acid-1,4-dioxane, hydrochloric acid-ethyl acetate, acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc.
  • the solvent include methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0 to 60° C., and the reaction time is usually about 0.5 to 24 hours.
  • Method F is a method for producing compound (F-IV).
  • R 1 , R 2 , R 3 and R 4 have the same meanings as in the case of the compound of the above formula (1), and P a1 has the same meaning as above. ]
  • Step F1 Step of forming thiazole ring This is a step of obtaining compound (F-II) from compound (FI). This step can be performed by the same method as in (D1 step).
  • (F2 step) Step of performing urea formation From the compound (F-II), a urea formation reagent, a corresponding amine or a hydrochloride thereof is reacted in the presence or absence of a base to give a compound (F-III).
  • a urea-forming reagent include carbonyldiimidazole, triphosgene, phenyl chloroformate, 4-nitrophenyl chloroformate and the like.
  • the base include triethylamine, diisopropylethylamine and the like.
  • the solvent include N,N-dimethylformamide, dichloromethane, tetrahydrofuran and the like.
  • the reaction temperature is usually about 0 to 60° C., and the reaction time is usually about 1 to 48 hours.
  • Step F3 Deprotection step This is a step of obtaining compound (F-IV) from compound (F-III). This step can be performed by the same method as in (E3 step).
  • Method G is a method for producing compound (G-VI).
  • R 3 and R 4 have the same meanings as in the case of the compound of the above formula (1), and P a1 has the same meaning as above.
  • R 1′ and R 2′ are bonded to each other to form a substituent and represent the groups shown below.
  • P a3 represents a commonly used protecting group for an amino group, which is selected independently of P a1 and P a2 .
  • R 1′′ and R 2′′ are bonded to each other to form a substituent and represent the following groups.
  • R 1 ′′' and R 2 ′′' are bonded to each other to form a substituent and represent the groups shown below.
  • R 12 is a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C1-C6 alkylcarbonyl group, Alternatively, it represents a C1-C6 alkoxycarbonyl group.
  • Step G1 Step of forming thiazole ring This is a step of obtaining compound (G-II) from compound (GI). This step can be performed by the same method as in (D1 step).
  • Step G2 Step of Ureaization This is a step of obtaining compound (G-III) from compound (G-II). This step can be performed by the same method as in (F2 step).
  • Step G3 Deprotection step is a step of obtaining compound (G-IV) from compound (G-III). This step can be performed by the same method as in (E3 step).
  • Step G4 Step of modifying amino group (In case of carbamate)
  • a compound (GV) is obtained by reacting the compound (G-IV) with a base and a carbamate-forming reagent.
  • the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, 4-dimethylaminopyridine and the like.
  • the carbamate forming reagent include chloroformic acid ester, dicarbonic acid diester and the like.
  • the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide and the like.
  • the reaction temperature is usually about 0 to 80° C., and the reaction time is usually about 0.5 to 24 hours.
  • a compound (GV) is obtained by reacting the compound (G-IV) with a base and an acylating reagent.
  • the base include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like.
  • the acylating reagent include acyl chloride and acid anhydride.
  • the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide and the like.
  • the reaction temperature is usually about 0 to 80° C., and the reaction time is usually about 0.5 to 24 hours.
  • compound (GV) is reacted with a corresponding alkylating reagent in the presence of a base to give compound (GV).
  • alkylating reagent include alkyl halides such as alkyl iodide and alkyl bromide, and sulfonates such as alkyl tosylate and alkyl mesylate.
  • base include triethylamine, diisopropylethylamine, potassium carbonate and the like.
  • the solvent include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and the like.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • compound (GV) is obtained by reacting compound (G-IV) with a reducing agent and a corresponding aldehyde in the presence or absence of an acid.
  • the reducing agent include sodium triacetoxyborohydride and sodium cyanoborohydride.
  • the acid include acetic acid, tetraisopropyl orthotitanate, zinc chloride and the like.
  • the solvent include methanol, acetonitrile, tetrahydrofuran, dichloromethane and the like, or a mixture thereof.
  • the reaction temperature is usually about 0 to 80° C., and the reaction time is usually about 0.5 to 24 hours.
  • Step G5 Deprotection step is a step of obtaining compound (G-VI) from compound (GV). This step can be performed by the same method as in (E3 step).
  • R 1 , R 2 , R 3 and R 4 have the same meanings as in the case of the compound of the above formula (1).
  • a necessary compound such as the following compound is appropriately used as a starting material.
  • Manufacture can also be performed to provide the desired compound of the invention.
  • R 1 and R 2 have the same meaning as in the case of the compound of the above formula (1), and P a2 has the same meaning as above. ]
  • Method H is a method for producing the compound (H-II) of the present invention.
  • R 1 , R 2 , R 3 , R 4 , X and Y have the same meanings as in the case of the compound of the above formula (1).
  • Step H1 Step of Coupling with Heterocycle
  • compound (HI) is reacted with XY-Cl in the presence of a base to obtain compound (H-II).
  • the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, potassium carbonate and the like.
  • the solvent include N,N-dimethylformamide, dimethylsulfoxide and the like.
  • the reaction temperature is usually about 0 to 140° C., and the reaction time is usually about 0.5 to 48 hours.
  • Method I is a method for producing the compound (I-II) of the present invention.
  • R 1 , R 2 , R 3 , R 4 and X have the same meanings as in the case of the compound of the above formula (1).
  • Step I1 Step of Coupling with Heterocycle This is a step of reacting compound (II) with a condensing agent in the presence of a base to give compound (I-II).
  • the base include triethylamine, diisopropylethylamine and the like.
  • the condensing agent include phosphorus nitride chloride (trimer).
  • the solvent include N,N-dimethylformamide, dimethylsulfoxide and the like.
  • the reaction temperature is usually about 0 to 140° C., and the reaction time is usually about 0.5 to 48 hours.
  • Method J is a method for producing the compound (J-III) of the present invention.
  • R 1 , R 2 , R 3 , R 4 and X have the same meanings as in the case of the compound of the above formula (1).
  • Step J1 Step of Cyanamide Formation
  • the compound (JI) is reacted with cyanogen halide in the presence or absence of a base to obtain the compound (J-II).
  • the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, potassium carbonate and the like.
  • the solvent include acetonitrile, acetone, dichloromethane, tetrahydrofuran and the like.
  • the reaction temperature is usually about 0° C. to room temperature, and the reaction time is usually about 0.5 to 48 hours.
  • Step J2 Step of Performing Ring Formation
  • the compound (J-II) is reacted with a metal halide, an acid and a corresponding amide oxime to obtain the compound (J-III).
  • the metal halide include zinc chloride and zinc bromide.
  • the acid include p-toluenesulfonic acid, sulfuric acid, hydrochloric acid and the like.
  • the solvent include diethyl ether, tetrahydrofuran, ethyl acetate, ethanol, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 48 hours.
  • Method K is a method for producing the compound (KV) of the present invention.
  • R 1 , R 2 , R 3 , R 4 and X have the same meanings as in the case of the compound of the above formula (1), R k1 is a phenoxy group which may have a substituent, Alternatively, it represents an imidazolyl group. ]
  • Step K1 Step of Carboxylation This is a step of obtaining a compound (K-II) from a compound (KI) by reacting it with a carbonylating agent in the presence of a base.
  • the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate and the like.
  • the carbonylating agent include carbonyldiimidazole, phenyl chloroformate, 4-nitrophenyl chloroformate and the like.
  • the solvent include tetrahydrofuran, dichloromethane, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0° C. to room temperature, and the reaction time is usually about 0.5 to 24 hours.
  • Step K2 Step of performing amidation using hydrazine From compound (K-II), in the presence or absence of a base, using a hydrazine hydrate, a reaction to obtain a compound (K-III) Is.
  • the base include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like.
  • the solvent include ethanol, tetrahydrofuran, acetonitrile and the like, or a mixture thereof.
  • the reaction temperature is usually room temperature to about 100° C., and the reaction time is usually about 1 to 24 hours.
  • Step K3 Step of amidating acylhydrazine (When using the corresponding carboxylic acid and condensing agent)
  • compound (K-IV) is obtained by reacting compound (K-III) with a condensing agent and a corresponding carboxylic acid in the presence of a base.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylronium hexafluorophosphate
  • DMT-MM 4-(4,6-dimethoxy- 1,3,5-triazin-2-yl)-4-methylmorpholine
  • WSC or EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • BOP reagent 1H-benzotriazole- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like.
  • N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) or the like can be added.
  • the reaction may be allowed to proceed smoothly depending on the additive.
  • Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, dichloromethane and the like, or a mixed solvent thereof.
  • the reaction temperature is usually about 0° C. to room temperature, and the reaction time is usually about 0.5 to 24 hours.
  • a compound (K-IV) is obtained by reacting a compound (K-III) with a carboxylic acid chloride prepared from a corresponding carboxylic acid using a dehydration chlorinating agent in the presence of a base.
  • a dehydrating chlorinating agent include oxalyl chloride, thionyl chloride, sulfuryl chloride, phosphorus pentachloride and the like.
  • the base include triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine and the like.
  • the solvent examples include tetrahydrofuran, dichloromethane, N,N-dimethylformamide and the like, or a mixed solvent thereof.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • compound (K-IV) is obtained by reacting compound (K-III) with a corresponding carboxylic acid chloride in the presence of a base.
  • a base include triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine and the like.
  • the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide and the like, or a mixed solvent thereof.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • Step K4 Step of forming a ring
  • the compound (K-IV) is reacted with a dehydrating agent to obtain the compound (KV).
  • the dehydrating agent include (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt and tosyl chloride.
  • the solvent include toluene, acetonitrile, dichloromethane and the like.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • Method L is a method for producing the compound (LV) of the present invention.
  • R 1 , R 2 , R 3 , R 4 and X have the same meanings as in the case of the compound of the above formula (1).
  • (L1 step) Step of performing thiourea
  • a reaction is carried out.
  • the base include triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, sodium carbonate and the like.
  • the solvent include tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetonitrile, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0°C to 80°C, and the reaction time is usually about 0.5 to 24 hours.
  • Step L2 Step of performing amidation with hydrazine From compound (L-II), in the presence or absence of a base, using hydrazine hydrate, a reaction to obtain a compound (L-III) Is.
  • the base include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like.
  • the solvent include ethanol, tetrahydrofuran, acetonitrile and the like, or a mixture thereof.
  • the reaction temperature is usually room temperature to about 100° C., and the reaction time is usually about 1 to 24 hours.
  • Step L3 Step of amidating carbothiohydrazide This is a step of obtaining compound (L-IV) from compound (L-III). This step can be performed by the same method as in (K3 step).
  • compound (LV) is obtained by reacting compound (L-IV) with or without a base using a condensing agent.
  • a condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI), 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) Etc.
  • the base include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like.
  • Examples of the solvent include dimethyl sulfoxide, tetrahydrofuran, N,N-dimethylformamide and the like, or a mixed solvent thereof.
  • the reaction temperature is usually room temperature to about 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • a compound (LV) is obtained by reacting the compound (L-IV) with a dehydrating agent.
  • the dehydrating agent include (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt and tosyl chloride.
  • Examples of the solvent include toluene, acetonitrile, dichloromethane and the like.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • Method M is a method for producing the compound (M-II) of the present invention.
  • R 1 , R 2 , R 3 , R 4 and X have the same meanings as in the case of the compound of the above formula (1).
  • (M1 step) Step of performing ring formation
  • 1,1-dibromoformaldoxime and a corresponding alkyne are used to carry out a reaction to obtain a compound (M-II) from the compound (MI).
  • the base include triethylamine, diisopropylethylamine and the like.
  • the solvent include tetrahydrofuran, N,N-dimethylformamide and the like, or a mixture thereof.
  • the reaction temperature is usually about 0° C. to room temperature, and the reaction time is usually about 0.5 to 48 hours.
  • Method X is a method for producing the compound (X-VI) of the present invention.
  • R 1 , R 2 , R 3 , R 4 and X have the same meanings as in the case of the compound of the general formula (1), Ph represents a phenyl group, and Imd represents an imidazolyl group. , R x1 represents OPh or Imd. ]
  • Step X1 Step of performing coupling Step of obtaining compound (X-II) from compound (XI), in the presence of a base, using 1,1′-thiocarbonyldiimidazole or phenyl chlorothionoformate to carry out a reaction Is.
  • a base include sodium tert-butoxide, lithium bis(trimethylsilyl)amide and the like.
  • the solvent include tetrahydrofuran, N,N-dimethylformamide and the like, or a mixture thereof.
  • the reaction temperature is usually about 0°C to 60°C, and the reaction time is usually about 0.5 to 24 hours.
  • Step X2 Step of performing coupling Step of obtaining a compound (X-IV) from the compound (X-II), in the presence or absence of a base, using the compound (X-III), a coupling reaction Is.
  • the base include triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, sodium carbonate and the like.
  • the solvent include tetrahydrofuran, N,N-dimethylformamide, ethanol and the like, or a mixture thereof.
  • the reaction temperature is usually about 0°C to 100°C, and the reaction time is usually about 0.5 to 24 hours.
  • Step X3 Step of Performing Methylation
  • compound (X-IV) is reacted in the presence of a base using a methylating reagent to obtain compound (XV).
  • a methylating reagent include iodomethane and dimethylsulfate.
  • the base include triethylamine, diisopropylethylamine, potassium carbonate and the like.
  • the solvent include tetrahydrofuran, acetonitrile, N,N-dimethylformamide, or a mixture thereof.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • Step X4 Step of Performing Cyclization
  • the compound (XV) is reacted with hydroxylamine or its hydrochloride in the presence or absence of a base to obtain the compound (X-VI).
  • the base include triethylamine, sodium acetate, sodium hydrogen carbonate and the like.
  • the solvent include methanol, ethanol, water and the like, or a mixed solvent thereof.
  • the reaction temperature is usually room temperature to about 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • Method N is a method for producing the compound (N-III) of the present invention.
  • R 1 , R 2 , R 3 , R 4 and X have the same meanings as in the case of the compound of the above formula (1).
  • Step N1 Step of Ureaization Step of obtaining compound (N-II) from compound (NI). This step can be performed by the same method as (F2 step).
  • Step N2 Step of forming a ring
  • the compound (N-II) is reacted with a dehydrating agent in the presence or absence of a base to obtain the compound (N-III).
  • the dehydrating agent include trifluoroacetic anhydride, phosphorus oxychloride and the like.
  • the base include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like.
  • the solvent include dichloromethane, tetrahydrofuran and the like, or no solvent.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • Method Y is a method for producing the compound (Y-II) of the present invention.
  • R 1 , R 2 , R 3 , R 4 , and X have the same meanings as in the case of the compound of the general formula (1), and Ph represents a phenyl group.
  • Step Y1 a step of forming a benzoxazole ring
  • the reaction is performed.
  • the acid include acetic acid and the like.
  • the base include triethylamine and the like.
  • the solvent include chloroform, toluene and the like.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 48 hours.
  • Method Z is a method for producing the compound (Z-II) of the present invention.
  • R 1 , R 2 , R 3 , R 4 , and X have the same meanings as in the case of the compound of the general formula (1), and LG represents a leaving group.
  • Step Z1 Step of carrying out coupling reaction using transition metal catalyst From compound (ZI), using copper or palladium catalyst, in the presence or absence of a base and a ligand, the reaction is carried out to give compound (Z -II) is obtained.
  • the copper catalyst include copper iodide, copper chloride, copper acetate, copper sulfate and the like.
  • the palladium catalyst include tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, bis(triphenylphosphine)palladium dichloride and the like.
  • Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, cesium carbonate and the like.
  • Examples of the solvent include tetrahydrofuran, 1,4-dioxane, water, N,N-dimethylformamide, dimethylsulfoxide, toluene, and the like, or a mixture thereof.
  • the reaction temperature is usually room temperature to about 150° C., and the reaction time is usually about 0.5 to 48 hours.
  • Method O is a method for producing the compound (O-III) of the present invention.
  • R 1 , R 2 , R 3 , R 4 , X and Y have the same meanings as in the case of the compound of the above formula (1).
  • Step O1 Step of forming thiazole ring This is a step of obtaining compound (O-II) from compound (OI). This step can be performed by the same method as in (D1 step).
  • (O2 step) Step of performing urea formation This is a step of obtaining compound (O-III) from compound (O-II). This step can be performed by the same method as in (F2 step).
  • Method Q is a method for producing the compound (Q-III) of the present invention.
  • R 1 , R 2 , R 3 , R 4 , X and Y have the same meanings as in the case of the compound of the above formula (1), and P a2 has the same meaning as above. ]
  • (Q1 step) Deprotection step (In the case of t-butoxycarbonyl (Boc) group)
  • the compound (QI) containing an amino group protected by a t-butoxycarbonyl group is reacted with an acid to give the compound (Q-II).
  • This step can be performed by the same method as in the case of the t-butoxycarbonyl (Boc) group in (C1 step).
  • a compound (Q-II) is obtained by reacting a compound (QI) containing an amino group protected with a 2-(trimethylsilyl)ethoxycarbonyl group with a desilylation reagent or an acid.
  • This step can be performed by the same method as in the case of the 2-(trimethylsilyl)ethoxycarbonyl (Teoc) group in (E3 step).
  • the palladium catalyst examples include tetrakis(triphenylphosphine)palladium, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, acetylacetone palladium, bis(triphenylphosphine). ) Palladium dichloride and the like can be mentioned.
  • Phosphine ligands used with palladium catalysts include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2 2,2'-bis(diphenylphosphino)-1,1-binaphthyl (BINAP), bis(diphenylphosphino)methane (DPPM), triphenylphosphine or 1,2-bis(diphenylphosphino)ethane (DPPE) Can be mentioned.
  • the base include diethylamine and morpholine.
  • the solvent include acetonitrile, tetrahydrofuran, dichloromethane, water and the like, or a mixture thereof.
  • the reaction temperature is usually room temperature to 60° C., and the reaction time is usually 0.5 to 48 hours.
  • Step Q2 Step of Ureaization This is a step of obtaining compound (Q-III) from compound (Q-II). This step can be performed by the same method as in (F2 step).
  • Method R is a method for producing the compound (R-II) of the present invention.
  • Step R1 Step of forming a hydantoin ring Forming a compound (RI) from a compound (RI) using a urea reagent, a corresponding amine or a hydrochloride thereof in the presence or absence of a base.
  • a urea-forming reagent include carbonyldiimidazole, triphosgene, phenyl chloroformate, 4-nitrophenyl chloroformate and the like.
  • the base include triethylamine, diisopropylethylamine and the like.
  • the solvent include N,N-dimethylformamide, dichloromethane, tetrahydrofuran and the like.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 1 to 48 hours.
  • Method S is a method for producing the compound (S-III) of the present invention.
  • R 1 , R 2 , R 34-1 , R 34-2 , X and Y have the same meanings as in the case of the compound of the above formula (1), and R s1 is a C1-C6 alkyl group. Indicates. ]
  • Step S1 Step of Urea Formation This is a step of obtaining compound (S-II) from compound (SI). This step can be performed by the same method as in (F2 step).
  • Step S2 Step of Performing Ring Formation
  • compound (S-III) is obtained from compound (S-II) in the presence or absence of a base using a condensing agent.
  • a condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI), 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) Etc.
  • the base include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like.
  • the solvent include N,N-dimethylformamide, tetrahydrofuran and the like, or a mixed solvent thereof.
  • the reaction temperature is usually room temperature to about 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • Method T is a method for producing the compound (T-IV) of the present invention.
  • R 1 , R 2 , R 34-1 , R 34-2 , X and Y have the same meanings as in the case of the compound of the above formula (1), and P a4 is a commonly used amino group. A protecting group for the group is shown. ]
  • Step T1 Step of performing amidation
  • compound (TI) is reacted with a condensing agent and the corresponding amino acid in the presence of a base to obtain compound (T-II).
  • a condensing agent O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylronium hexafluorophosphate (HATU), 4-(4,6-dimethoxy- 1,3,5-triazin-2-yl)-4-methylmorpholine (DMT-MM), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI), 1H-benzotriazole- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) and the like can be mentioned.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetra
  • Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like.
  • N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) or the like can be added.
  • the reaction may be allowed to proceed smoothly depending on the additive.
  • Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, dichloromethane and the like, or a mixed solvent thereof.
  • the reaction temperature is usually about 0° C. to room temperature, and the reaction time is usually about 0.5 to 24 hours.
  • T2 step Deprotection step (In the case of t-butoxycarbonyl (Boc) group)
  • a compound (T-III) containing an amino group protected with a t-butoxycarbonyl group is reacted with an acid to obtain a compound (T-III).
  • This step can be performed by the same method as in (C1 step).
  • Step T3 Step of Performing Ring Formation
  • compound (T-IV) is reacted with a urea-forming reagent in the presence or absence of a base to obtain compound (T-IV).
  • the urea forming reagent include carbonyldiimidazole and triphosgene.
  • the base include triethylamine, diisopropylethylamine and the like.
  • the solvent include N,N-dimethylformamide, dichloromethane, tetrahydrofuran and the like.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 1 to 48 hours.
  • Method U is a method for producing the compound (U-III) of the present invention by transesterification.
  • R 1 , R 2 , R 3 and Y have the same meanings as in the case of the compound of the above formula (1), and R u1 and R u2 are each independently and different from C1-C6.
  • An alkyl group, a C3-C6 cycloalkyl group, or a halo C1-C6 alkyl group is shown.
  • Step U1 Step of Hydrolyzing This is a step of obtaining a compound (U-II) by reacting the compound (UI) with a base.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the solvent include various solvents containing water (methanol, ethanol, tetrahydrofuran), water and the like, or a mixed solvent thereof.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 1 to 48 hours.
  • (U2 process) Process for esterification (When using an alkyl halide)
  • compound (U-II) is reacted with a corresponding alkylating reagent in the presence of a base to give compound (U-III).
  • the alkylating reagent include alkyl halides such as alkyl iodide and alkyl bromide, and sulfonates such as alkyl tosylate and alkyl mesylate.
  • the base include triethylamine, diisopropylethylamine, potassium carbonate and the like.
  • the solvent include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and the like.
  • the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
  • compound (U-III) is obtained by reacting compound (U-II) with a condensing agent and a corresponding alcohol in the presence of a base.
  • a condensing agent O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylronium hexafluorophosphate (HATU), 4-(4,6-dimethoxy- 1,3,5-triazin-2-yl)-4-methylmorpholine (DMT-MM), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC or EDCI), 1H-benzotriazole- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) and the like can be mentioned.
  • Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine and the like.
  • N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) can be added.
  • the reaction may be allowed to proceed smoothly depending on the additive.
  • Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, dichloromethane and the like, or a mixed solvent thereof.
  • the reaction temperature is usually about 0° C. to room temperature, and the reaction time is usually about 0.5 to 24 hours.
  • Method V is a method for producing the compound (V-III) of the present invention.
  • R 1 , R 2 , R 3 and Y have the same meanings as in the case of the compound of the above formula (1), and R v1 , R v2 are each independently the same or different.
  • a hydrogen atom or a C1-C6 alkyl group R v3 represents a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl C1-C6 alkyl group, or a C3-C6 cycloalkylcarbonyl group
  • P o1 represents a commonly used hydroxyl-protecting group.
  • the desilylation reagent include acid or tetrabutylammonium fluoride (TBAF), hydrogen fluoride, hydrogen fluoride pyridine and the like.
  • Examples of the acid include hydrochloric acid, sulfuric acid, hydrochloric acid-methanol, hydrochloric acid-1,4-dioxane, hydrochloric acid-ethyl acetate, acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc., and react in a catalytic amount.
  • Examples of the solvent include methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, water and the like, or a mixture thereof.
  • the reaction temperature is usually about 0 to 60° C., and the reaction time is usually about 0.5 to 24 hours.
  • Step V2 Step of Acylation Step of obtaining compound (V-III) from compound (V-II). This step can be performed by the same method as in (K3 step).
  • the compound produced by the above method can be isolated and purified by a known method, for example, extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like. Further, when the compound or the intermediate for production has an asymmetric carbon, an optical isomer is present. Each of these optical isomers can be isolated and purified by a conventional method such as fractional recrystallization (salt resolution) in which an appropriate salt is recrystallized or column chromatography. References for methods of resolving optical isomers from racemates include "Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.” by J. Jacques et al.
  • Dose form It is administered orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections for intra-articular, intravenous, intramuscular, etc., suppositories, eye drops, eye ointments, transdermal solutions. , Ointment, transdermal patch, transmucosal solution, transmucosal patch, parenteral administration such as inhalant.
  • a solid composition for oral administration Tablets, powders, granules and the like are used.
  • Such a solid composition comprises one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. , And/or magnesium aluminometasilicate and the like.
  • the solid composition contains an inert additive, for example, a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent. May be.
  • the tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • liquid composition for oral administration Pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like are used.
  • the liquid composition may contain solubilizers, auxiliary agents such as humectants, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
  • Aseptic aqueous or non-aqueous solutions, suspensions or emulsions are used.
  • the aqueous solvent include distilled water for injection and physiological saline.
  • the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.
  • Such an injectable composition may further contain a tonicity agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent.
  • injectable compositions can be sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. Further, these injectable compositions can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • Ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like are used.
  • These external preparations include commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions and the like.
  • ointment or lotion base polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. used.
  • a solid, liquid or semi-solid transmucosal agent such as an inhalant or a nasal agent is used, and can be manufactured according to a conventionally known method.
  • known excipients and, in addition, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • an appropriate device for inhalation or insufflation can be used as the administration method.
  • the compounds are administered alone or as powders of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known tevices or nebulizers such as metered dose inhalers. be able to.
  • the dry powder inhaler or the like may be for single or multiple administration, and dry powder or powder-containing capsule can be used.
  • a suitable ejection agent can be used.
  • it may be in the form of a pressurized aerosol spray using a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • the daily dose is about 0.001-100 mg/kg of body weight, preferably O.1-30 mg/kg, more preferably 0.1-10 mg/kg. Or, administer in two or more divided doses.
  • a suitable daily dose is about 0.0001-10 mg/kg of body weight, and the daily dose may be administered once or in several divided doses.
  • a transmucosal agent about 0.001-100 mg/kg of body weight is administered once a day or in divided doses. The dose is appropriately determined according to each case in consideration of symptoms, age, sex and the like.
  • the present invention in the present invention, it can be used in combination with various therapeutic or prophylactic agents for diseases considered to exhibit their effectiveness.
  • the combination may be administered simultaneously, or separately and continuously or at desired time intervals.
  • the preparation for co-administration may be a combination drug or separately formulated.
  • Powder A powder is obtained by mixing 5 g of the compound of the present invention or a salt thereof, 895 g of lactose and 100 g of corn starch with a blender.
  • (Formulation Example 2) Granules After mixing 5 g of the compound of the present invention or a salt thereof, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain a granule.
  • test substance final concentration example: 0.046, 0.14, 0.41, 1.2, 3.7, 11, 33, 100 ⁇ M
  • DMSO 0.1 ⁇ L was dispensed to the plate and assay buffer (10 mM Tris-HCl pH 5 ⁇ L of SIRT6 enzyme diluted with 8.0, 0.1% BSA, 0.01% Tween 20, 1 mM DTT, 12.5% Glycerol (prepared by Daiichi Sankyo RD Novare Co., Ltd., final concentration: 25 ng/mL) was added. ..
  • the enzymatic reaction was [Lys(Ac)9]-Histone H3 (1-21)-NH2, H3K9 (Ac), biotin-labeled, amide (AnaSpec, AS-64190, final concentration: 2 nM) and ⁇ -Nicotinamide adenine.
  • the reaction was started by adding 5 ⁇ L of a mixed solution of dinucleotide (Sigma-Aldrich, N8285-15VL, final concentration: 10 ⁇ M), and reacted at room temperature for 30 minutes.
  • Nicotinamide (Sigma-Aldrich, 72340-100G, final concentration: 100 mM) prepared with AlphaLISA Epigenetics Buffer (PerkinElmer, AL008C), AlphaLISA Anti-unmodified Histone H3 Lysine 9/Lysine 27 (H3K9/K27) Acceptor Beads (PerkinElmer, 10 ⁇ L of a mixture of AL138, final concentration: 10 ⁇ g/mL) and AlphaScreen Streptavidin Donor beads (PerkinElmer, 6760002, final concentration: 5 ⁇ g/mL) was added, reacted at room temperature for 60 minutes, and then stopped and acetylated. Was detected. The emission intensity was measured by EnVision (PerkinElmer).
  • the relative enzyme activity (%) of the test substance was calculated from the following mathematical formula.
  • Relative enzyme activity (%) [(test substance added well luminescence intensity-DMSO(-) well luminescence intensity)/(DMSO(+) well luminescence intensity-DMSO(-) well luminescence intensity)] x 100
  • EC 150 compound concentration showing 150% relative enzyme activity
  • Sigmoidal dose-response variable slope
  • GraphPad Prism GraphPad Software
  • N-Methyl-N'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea (WO 2010/024258) (17 g) , Sodium hydrogen carbonate (13 g) were dissolved in dichloromethane (500 mL) and water (100 mL), and a dichloromethane solution (100 mL) of bromocyan (10 g) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 hours and at room temperature for 13 hours. The reaction mixture was poured into water and the reaction mixture was extracted with dichloromethane three times. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title compound (13.0 g, yield: 68%) as a yellow solid.
  • N-Methyl-N'-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)urea (International Publication No. 2010/024258) (5.0 g) was suspended in tetrahydrofuran (50 mL), 1,1′-thiocarbonyldiimidazole (4.6 g) was added, and the mixture was left at room temperature for 2 days. The precipitated solid was collected by filtration and washed with tetrahydrofuran to give the title compound (7.5 g, yield: 99%) as a white solid.
  • tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (CAS registry number: 185099-67-6) (110 g) was dissolved in toluene (500 mL) and pyrrolidine (49 mL) was added. ) And tosyl acid monohydrate (8.4 g) were added at room temperature, and the mixture was stirred at 130° C. for 18 hours using a Dean Stark apparatus. The solvent was distilled off from the reaction mixture under reduced pressure, and the obtained residue was dissolved in methanol (500 mL) and cooled to 0°C.
  • Example 3(3c) N-methyl-N'-(5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d][1,3]thiazol-2-yl)urea of Example 3(3c)
  • the monohydrochloride (300 mg) and N,N-diisopropylethylamine (0.71 mL) were dissolved in N,N-dimethylformamide (3 mL), and the mixture was cooled to -10°C.
  • a tetrahydrofuran solution (3 mL) of 1,1-dibromoformaldoxime (0.27 mL) was added, and the mixture was stirred at -10°C for 30 minutes.
  • methyl 3-ethynylbenzoate (Journal of Medicinal Chemistry, 56(8), 3281-3295; 2013) (520 mg) was added, and the mixture was stirred at room temperature for 12 hours.
  • the reaction mixture was poured into water and neutralized with 1 M hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate.
  • Acetonitrile (12 L) was added to the reaction mixture, the mixture was stirred at room temperature for 30 minutes, the precipitated solid was filtered off, the filtrate was concentrated under reduced pressure, and most of the acetonitrile was distilled off. Subsequently, 1,3-acetonedicarboxylic acid (CAS registry number: 542-05-2) (4.47 kg), acetonitrile (8 L), and 12 M hydrochloric acid (719 mL) were added, and the mixture was cooled to 10°C and benzylamine was added. (2.98 kg) was added dropwise at 10-30°C. After stirring at 10 to 20°C for 1 hour, the mixture was stirred at 50°C for 16 hours. The precipitated solid was collected by filtration and washed with ethanol (300 mL) to give the title compound (2.70 kg, yield: 33%) as a pale yellow solid.
  • Example 4b-1 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (150 g) of Example 4(4a) was dissolved in 1 M hydrochloric acid (1 L) and ethanol (700 mL), 10% Palladium on carbon (20 g) was added, and the mixture was stirred under hydrogen (50 psi) atmosphere at 50° C. for 20 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to remove most of the ethanol and obtain a mixture containing 3-oxa-9-azabicyclo[3.3.1]nonan-7-one hydrochloride. It was
  • Example 4b-2 Tetrahydrofuran (1.2 L) and sodium hydrogen carbonate (327 g) were added to the mixture obtained in Example 4b-1, and the mixture was stirred at room temperature for 1 hr, di-tert-butyl dicarbonate (339 g) was added, Stirred at ⁇ 40°C for 16 hours. After filtering the reaction mixture, the filtrate was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the residue obtained by evaporating the solvent under reduced pressure was triturated with ethyl acetate/petroleum ether and collected by filtration to give the title compound 190 g (yield: 61%) was obtained as a yellow solid.
  • tert-butyl (4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazole-10 -For the absolute configuration of carboxylate, the compound synthesized using this compound ((4S,8S)-10-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl] -4,7,8,9-Tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-amine) determined by X-ray crystallography.
  • the obtained solid was added to 1 M aqueous sodium hydroxide solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (1 L) at 60°C, and petroleum ether (1 L) was added. After stirring at 60°C for 0.5 hour, the mixture was slowly cooled to room temperature, the precipitated solid was collected by filtration, and washed with ethyl acetate/petroleum ether (100 mL/100 mL) to give 285 g of the title compound (yield: 29% ) Was obtained as a white solid.
  • N-Methyl-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1 of Example 4(4f) ,3]Thiazol-2-yl]urea monohydrochloride (14.5 g) was suspended in tetrahydrofuran (150 mL), 1,1′-thiocarbonyldiimidazole (9.78 g) and triethylamine (20.9 mL) were added, and the mixture was allowed to come to room temperature. Left for 3 days. The reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate three times.
  • Example 5(5a) 2-(Trimethylsilyl)ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (90 g) of Example 5(5a) was dissolved in toluene (450 mL), and pyrrolidine was used. (31 g) and tosylic acid monohydrate (10 g) were added at room temperature, and the mixture was stirred at 135° C. for 6 hours using a Dean-Stark apparatus. The residue obtained by evaporating the solvent from the reaction mixture under reduced pressure was dissolved in methanol (450 mL), sulfur (10.3 g) and cyanamide (17.5 g) were added, and the mixture was stirred at room temperature for 20 hr.
  • Example 5(5d) Tert-Butyl 4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-ylcarbamate of Example 5(5d) (5.0 g) was dissolved in a saturated sodium hydrogen carbonate aqueous solution (80 mL), dichloromethane (80 mL) and 4-nitrophenyl chloroformate (4.0 g) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and the reaction mixture was extracted with dichloromethane three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • a saturated sodium hydrogen carbonate aqueous solution 80 mL
  • dichloromethane 80 mL
  • 4-nitrophenyl chloroformate 4.0 g
  • Example 5 (5 g) of methyl 3-(2- ⁇ 2-[(tert-butoxycarbonyl)amino]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4 Dissolve -d][1,3]thiazole-10-carbonyl ⁇ hydrazinecarbonyl)benzoate (7.2 g) in dichloromethane (300 mL), add tosyl chloride (4.0 g) and triethylamine (9.7 mL) at room temperature and Stir for hours. The reaction mixture was poured into dilute hydrochloric acid, and the reaction mixture was extracted with dichloromethane three times.
  • the obtained residue was dissolved in dichloromethane/methanol (500 mL/50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was triturated with ethyl acetate and collected by filtration to give the title compound (5.0 g, yield: 96%) as a pale yellow solid.
  • Methyl 3-formylbenzoate (100 g) was dissolved in methanol (2 L), p-toluenesulfonylmethyl isocyanide (119 g) and potassium carbonate (126 g) were added, and the mixture was stirred at 70° C. for 1 hr. Water was added to the residue obtained by distilling off the solvent from the reaction mixture under reduced pressure, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (106 g, yield: 86%) as a pale yellow solid.
  • Example 6(6a) Under a nitrogen atmosphere, methyl 3-(1,3-oxazol-5-yl)benzoate (75 g) of Example 6(6a) was suspended in tetrahydrofuran (750 mL), and lithium bis(trimethylsilyl) was added at -78°C. Amide (1 M tetrahydrofuran solution, 443 mL) was slowly added. After stirring at -78°C for 30 minutes, hexachloroethane (105 g) was added, and the mixture was stirred at -78°C for 30 minutes and at room temperature for 12 hours.
  • Example 6(6c) Dissolve dihydrochloride (5.0g) in dimethylsulfoxide (50mL) and prepare methyl 3-(2-chloro-1,3-oxazol-5-yl)benzoate (4.4g) in Example 6(6b), N ,N-Diisopropylethylamine (16 mL) was added, and the mixture was stirred at 100°C for 10 hours, and then left overnight at room temperature. Furthermore, the mixture was stirred at 100° C. for 10 hours and then left overnight at room temperature.
  • the title compound (4.9 g, yield: 95%) was obtained as a yellow solid.
  • Example 8 3-(1,3-oxazol-5-yl)benzoic acid (20.0 g) of Example 8 (8a) was dissolved in N,N-dimethylformamide (200 mL), potassium carbonate (44.0 g), 1- Iodopropane (26.1 g) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 15.2 g (yield: 62%) of the title compound as a yellow solid.
  • Example 8(8e) Epiminooxocino[5,4-d][1,3]thiazol-2-yl]urea (0.70 g) was dissolved in dimethyl sulfoxide (7 mL), and propyl 3-(2) of Example 8(8c) was dissolved. -Chlorooxazol-5-yl)benzoate (0.62g) and N,N-diisopropylethylamine (2.0mL) were added, and the mixture was stirred at 90°C for 10 hours and left at room temperature overnight.
  • 3-Bromo-2-fluorobenzaldehyde (CAS registry number: 149947-15-9) (2.0 g) is dissolved in methanol (20 mL) and p-toluenesulfonylmethyl isocyanide (2.3 g) and potassium carbonate (2.7 g) are added. In addition, the mixture was stirred at 70°C for 3 hours. The reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 9 5-(3-bromo-2-fluorophenyl)-1,3-oxazole (2.49 g) of Example 9 (9a) was dissolved in toluene (30 mL), palladium (II) acetate (0.115 g), 4 Add 5,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.595 g) and N,N-diisopropylethylamine (3.58 mL), heat to 80°C, and formic acid 2,4,6-triethyl Chlorophenyl (3.48 g) was added in 3 batches every 30 minutes, and the mixture was stirred at 80°C for 1 hour.
  • Example 12 (12b) Methyl 3-bromo-2-(2-methoxy-2-oxoethyl)benzoate (6.3 g) of Example 12 (12b) was dissolved in methanol (100 mL), palladium acetate (500 mg), 1,3-bis (Diphenylphosphino)propane (920 mg) and triethylamine (31 mL) were added, and the mixture was stirred at 80°C for 66 hr under a carbon monoxide (50 psi) atmosphere.
  • lithium aluminum hydride (4.0 g) was suspended in tetrahydrofuran (100 mL), and dimethyl 2-(2-methoxy-2-oxoethyl)benzene-1, of Example 12(12c).
  • a tetrahydrofuran solution 50 mL of 3-dicarboxylate (5.6 g) was added, and the mixture was stirred at 0°C to 15°C for 16 hr.
  • Water (3 mL) was slowly added to the reaction mixture, then 15% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred at room temperature for 5 min, filtered through Celite, and the solvent was evaporated under reduced pressure.
  • Example 12 2-[2,6-bis(hydroxymethyl)phenyl]ethane-1-ol (2.2 g) of Example 12 (12d) was dissolved in dichloromethane (100 mL), and manganese dioxide (20 g) was added to 10°C. The mixture was added and stirred at 40° C. for 12 hours. The reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure to give the title compound (1.2 g, yield: 56%) as a white solid.
  • Example 12(12f) 5-(1,3-oxazol-5-yl)-3,4-dihydro-1H-2-benzopyran-1-one 932 mg
  • tetrahydrofuran 30 mL
  • lithium bis(trimethylsilyl)amide 1.12 M tetrahydrofuran solution, 4.64 mL
  • Hexachloroethane (1.53 g) was added to the reaction mixture, and the mixture was stirred at ⁇ 78° C. for 30 min and then at room temperature for 3 hr.
  • Example 12 (12 g) of 5-(2-chloro-1,3-oxazol-5-yl)-3,4-dihydro-1H-2-benzopyran-1-one (1.50 g),
  • Example 4 (4f ) N-methyl-N'-[(4S,8S)-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazole- 2-yl]urea monohydrochloride (2.56 g) was dissolved in dimethyl sulfoxide (12 mL), N,N-diisopropylethylamine (6.17 mL) was added, and the mixture was stirred at 100°C for 7 hr.
  • Example 13(13a) 1-Bromo-2- ⁇ 2-[(2-methoxyethoxy)methoxy]ethyl ⁇ benzene (8.0 g) of Example 13(13a) was dissolved in dichloromethane (100 mL), cooled to -30°C, and filtered. A dichloromethane solution (15 mL) of titanium chloride (6.6 g) was added dropwise. The mixture was stirred at -30°C for 2 hours and further at room temperature for 12 hours. Water was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes, then the separated organic layer was washed with water and dried over anhydrous sodium sulfate.
  • Example 13(13b) 5-Bromo-3,4-dihydro-1H-2-benzopyran (1.0 g) of Example 13(13b) was dissolved in N,N-dimethylformamide (12 mL), and tetrakis(triphenylphosphine)palladium(0 ) (1.1 g) and zinc cyanide (1.1 g) were added, and the mixture was stirred at 120° C. for 1.5 hours. The reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate three times.
  • Example 13 3,4-Dihydro-1H-2-benzopyran-5-carbonitrile (0.30 g) of Example 13 (13c) was dissolved in ethanol (10 mL), and hydroxylamine hydrochloride (0.26 g) and triethylamine (0.38 g) were dissolved. ) was added and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate three times.
  • Example 13 N-hydroxy-3,4-dihydro-1H-2-benzopyran-5-carboxymidamide (60 mg) of Example 13 (13d) was dissolved in tetrahydrofuran (3 mL), and 1,1′-carbonyldiimidazole was added. (71 mg) was added, and the mixture was stirred at room temperature for 2 hours. Subsequently, 1,8-diazabicyclo[5.4.0]-7-undecene (0.047 mL) was added to the reaction mixture, and the mixture was stirred at 5°C to 15°C for 16 hr.
  • the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the reaction mixture was washed with ethyl acetate three times.
  • the pH of the aqueous layer was adjusted to 3 to 4 with 1 M hydrochloric acid, and the precipitated solid was collected by filtration to give the title compound (50 mg, yield: 74%) as a white solid.
  • Example 13 (13g) tert-butyl (10-[3-(1-oxo-3,4-dihydro-1H-2-benzopyran-5-yl)-1,2,4-oxadiazole-5- Ill]-4,7,8,9-tetrahydro-5H-4,8-epiminooxocinno[5,4-d][1,3]thiazol-2-yl ⁇ carbamate (0.17 g) in 4 M chloride Hydrogen-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 15°C for 4 hr.
  • Example 14 2-hydroxy-3-(1,3-oxazol-5-yl)benzoic acid (2.4 g) of Example 14 (14a) was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (6.5 g) was added. ) And iodomethane (2.2 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 14(14b) Under a nitrogen atmosphere, methyl 2-methoxy-3-(1,3-oxazol-5-yl)benzoate (2.3 g) of Example 14(14b) was suspended in tetrahydrofuran (50 mL), and lithium was added at -78°C. Bis(trimethylsilyl)amide (1.1 M tetrahydrofuran solution, 11 mL) was slowly added dropwise. After stirring at -78°C for 20 minutes, hexachloroethane (3.5 g) was added, and the mixture was stirred at -78°C for 10 minutes and then at room temperature for 1 hour. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate three times.
  • Example 15(15b) 4,8-Epiminooxocinno[5,4-d][1,3]thiazol-2-yl]urea (0.50 g) was dissolved in dimethylsulfoxide (5 mL) and the methyl of Example 6(6b) was prepared.
  • tert-Butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (CAS registry number: 73286-70-1) (10 g) was dissolved in dichloromethane (50 mL) and 4 M hydrogen chloride-ethyl acetate solution was added. (40 mL) was added at 15° C., and the mixture was stirred for 3 hours. The solvent was distilled off from the reaction mixture under reduced pressure to obtain 6.8 g of the title compound (yield: 98%) as a gray solid.
  • Example 16b 1-(2,5-dihydro-1H-pyrrol-1-yl)ethan-1-one (7.0g) of Example 16 (16b) was dissolved in dichloromethane/methanol (100mL/10mL) and hydrogen carbonate was added. Sodium (4.8g) was added. Ozone gas was bubbled through the reaction mixture for 15 minutes while stirring at -78°C. Next, nitrogen gas was blown in at ⁇ 78° C. for 15 minutes. Subsequently, triphenylphosphine (7.4g) was added, the temperature was slowly raised, and the mixture was stirred at room temperature for 12 hours.
  • the reaction mixture was filtered, and about half of the solvent was distilled off under reduced pressure.
  • the residue obtained was 1,3-acetonedicarboxylic acid (5.6g), 12M hydrochloric acid (1.6mL), benzylamine (4.2mL). ) was added, and the mixture was stirred at 15°C for 1 hour and at 50°C for 12 hours.
  • Example 16 3-Acetyl-9-benzyl-3,9-diazabicyclo[3.3.1]nonan-7-one (1.4 g) of Example 16 (16c) was dissolved in ethanol (8 mL), and 1 M hydrochloric acid (7.1 mL) was added. ) And 10% palladium carbon (200 mg) were added, and the mixture was stirred under hydrogen (30 psi) atmosphere at 20° C. for 16 hours. The reaction mixture was filtered, sodium hydrogen carbonate (333 mg) and di-tert-butyl dicarbonate (317 mg) were added to the obtained filtrate, and the mixture was stirred at 15°C for 16 hr.
  • Example 16 (16 g) of N-(6-acetyl-4,5,6,7,8,9-hexahydro-4,8-epimino[1,3]thiazolo[5,4-d]azocine-2- Yl)-N'-methylurea monohydrochloride (120 mg) was dissolved in dimethylsulfoxide (2 mL), and methyl 3-(2-chloro-1,3-oxazol-5-yl) of Example 6(6b) was used. Benzoate (85 mg) and N,N-diisopropylethylamine (0.200 mL) were added, and the mixture was stirred at 100°C for 16 hr.
  • Methyl 4-cyanobicyclo[2.2.2]octane-1-carboxylate (6.3 g) of Example 18 (18b) was dissolved in dimethyl sulfoxide (100 mL), and hydroxylamine hydrochloride (4.5 g) and triethylamine (23 g) were added. (mL) was added at room temperature, and the mixture was stirred at 95°C for 12 hours. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the reaction mixture was extracted with ethyl acetate three times.
  • Example 18(18c) Methyl 4-(N'-hydroxycarbamimidoyl)bicyclo[2.2.2]octane-1-carboxylate (1.0 g) of Example 18(18c) was dissolved in N,N-dimethylformamide (15 mL), N-(5-cyano-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea of Example 1(1a) (860 mg ), zinc chloride (155 mg) and tosylic acid monohydrate (220 mg) were sequentially added at room temperature, and the mixture was stirred at 80° C. for 12 hours.
  • the reaction mixture was poured into water, the reaction mixture was extracted with ethyl acetate three times, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, the obtained residue was triturated with petroleum ether/ethyl acetate/methanol, the precipitated solid was filtered off, and the solvent was distilled off from the filtrate under reduced pressure.
  • D-(+)-methyl lactate (3.1 g) was dissolved in N,N-dimethylformamide (50 mL), imidazole (2.3 g) and tert-butyldimethylchlorosilane (4.92 g) were added, and the mixture was stirred at room temperature for 2 hours. It was stirred. The reaction mixture was poured into water, the reaction mixture was extracted with dichloromethane three times, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate.
  • Example 19 Dissolve [1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea (50 mg) in dichloromethane (2 mL), cyclopentanecarboxylic acid (32 mg), dimethylaminopyridine (5 mg) and N,N'-diisopropylcarbodiimide (41 mg) were added, and the mixture was stirred at room temperature for 1 hr.
  • Example 1(1a) N-(5-cyano-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-N'-methylurea of Example 1(1a) (150 mg ), N-hydroxycyclohexanecarboxamidine (CAS registry number: 633313-98-1) (135 mg) and zinc chloride (129 mg) are suspended in a mixed solution of tetrahydrofuran (30 mL) and ethyl acetate (30 mL). It became cloudy and stirred at 60° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the insoluble matter was collected by filtration and washed with ethyl acetate.
  • Example 22(22a) Il]-N′-methylurea (120 mg), N′-hydroxybicyclo[2.2.2]octane-1-carboxymidamide (80 mg) of Example 21(21c) and zinc chloride (76 mg) N, The N-dimethylformamide (4 mL) suspension was stirred under a nitrogen atmosphere at 60° C. for 3 hours. Concentrated sulfuric acid (0.1 mL) was added to the reaction mixture, and the mixture was stirred at 80°C for 3 hr.
  • Example 17 (17c) Methyl (1s,4s)-4-(N'-hydroxycarbamimidoyl)cyclohexane-1-carboxylate (300 mg) of Example 17 (17c) was dissolved in N,N-dimethylformamide (3 mL), N-[(4S,8S)-10-cyano-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1, of Example 23(23a)] 3]Thiazol-2-yl]-N'-methylurea (342 mg), zinc chloride (60 mg), and tosylic acid monohydrate (72 mg) were sequentially added at room temperature and stirred at 80°C for 12 hours. ..
  • Example 8(8a) To a mixture of 3-(1,3-oxazol-5-yl)benzoic acid (27g), 2-iodopropane (49g), and N,N-dimethylformamide (250mL) of Example 8(8a). Potassium carbonate (40g) was added, and the mixture was stirred at 15°C for 12 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, and the solvent was evaporated under reduced pressure to give 27.5 g (yield: 83%) of the title compound as a yellow solid.
  • Example 25(25c) propan-2-yl 3- ⁇ 2-[(4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5 ,4-d][1,3]Thiazol-10-yl]-1,3-oxazol-5-yl ⁇ benzoate (7 g) was dissolved in N,N-dimethylformamide (70 mL) to give 1,1 '-Carbonyldiimidazole (5.6g) was added and the mixture was stirred at 80°C for 2 hours.
  • N,N-Diisopropylethylamine (17 mL) and 2-aminoethylmethylsulfone hydrochloride (5.60 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
  • Lithium hydroxide monohydrate was prepared by dissolving methyl 4-cyanobicyclo[2.2.2]octane-1-carboxylate (85g) in Example 18 (18b) in methanol (400mL) and water (80mL). (40g) was added and stirred at room temperature for 10 hours. The solvent was evaporated from the reaction mixture under reduced pressure, water was added to the obtained residue, the pH was adjusted to 1 with 1M hydrochloric acid, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 75 g of the title compound (yield: 95%) as a white solid.
  • Example 26 Ethyl 4-cyanobicyclo[2.2.2]octane-1-carboxylate (70g) of Example 26 (26b) was dissolved in ethanol (200mL) and 50% hydroxylamine aqueous solution (80g) was added, The mixture was stirred at 70°C for 12 hours. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate.
  • Example 26 Ethyl 4-(N'-hydroxycarbamimidoyl)bicyclo[2.2.2]octane-1-carboxylate (0.2 g) of Example 26 (26c) was dissolved in N,N-dimethylformamide (2 mL), N-[(4S,8S)-10-cyano-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1, of Example 23(23a)] 3]Thiazol-2-yl]-N'-methylurea (0.22g), zinc chloride (0.021g), tosylic acid monohydrate (0.03g) were added sequentially at room temperature and stirred at 80°C for 12 hours. ..
  • Example 27(27b) A mixture of 4-(hydroxymethyl)-2-benzofuran-1(3H)-one (16.3g), manganese dioxide (86.2g), and dichloromethane (300mL) of Example 27(27b) at room temperature for 12 hours. It was stirred. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (14.2 g, yield: 88%) as a white solid.
  • Example 27(27d) 4-(1,3-oxazol-5-yl)-2-benzofuran-1(3H)-one (7.45 g) of Example 27(27d) was suspended in tetrahydrofuran (150 mL). Lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 34.3mL) was slowly added at °C. After stirring at -78°C for 20 minutes, hexachloroethane (12.4g) was added, and the mixture was stirred at -78°C for 20 minutes and at room temperature for 2 hours.
  • Example 27(27e) and (4S of Example 27(27f) ,8S)-4,7,8,9-Tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-amine (0.84 g) was added to dimethyl sulfoxide (8 mL), N,N-diisopropylethylamine (3.5 mL) was added, and the mixture was stirred at 100°C for 7 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
  • Example 27 (27g) of 4- ⁇ 2-[(4S,8S)-2-amino-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d] Dissolve [1,3]thiazol-10-yl]-1,3-oxazol-5-yl ⁇ -2-benzofuran-1(3H)-one (1.5 g) in N,N-dimethylformamide (30mL) Then, 1,1'-carbonyldiimidazole (922 mg) was added, and the mixture was left at room temperature for 3 days. Isopropylamine (0.972 mL) was added, and the mixture was stirred at room temperature for 4 hours.
  • the obtained residue was dissolved in ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, the obtained residue was triturated with ethyl acetate/hexane, and the solid obtained by filtration was dried at 60°C to give 1.33 g of the title compound ( Yield: 73%) was obtained as a pale yellow solid.
  • Example 28(28c) tert-butyl [(4S,8S)-10-(hydrazinecarbonyl)-4,7,8,9-tetrahydro-5H-4,8-epiminooxo of Example 28(28c) was used.
  • a solution of shino[5,4-d][1,3]thiazol-2-yl]carbamate (47g) in tetrahydrofuran (100mL) was added, and the mixture was stirred at 15°C for 12 hours.
  • Example 31(31e) ethyl 4-[5-(2-amino-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl)-1,2, 4-Oxadiazol-3-yl]bicyclo[2.2.2]octane-1-carboxylate (80 mg) was dissolved in N,N-dimethylformamide (1 mL) to dissolve 1,1'-carbonyldiimidazole (64.4). mg) was added and the mixture was stirred at room temperature for 12 hours. Tetrahydropyran-4-amine (40 mg) was added, and the mixture was stirred at room temperature for 2 hours.
  • Ethyl 4-methylenecyclohexanecarboxylate (CAS Registry number: 145576-28-9) (8.82 g) was dissolved in tetrahydrofuran (250mL) and lithium diisopropylamide (1 M n-hexane) was added at -78°C under nitrogen atmosphere. /Tetrahydrofuran solution, 53 mL) was added dropwise. After stirring at -78°C for 30 minutes, formaldehyde (2.26g) was added, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate.
  • Example 32 Ethyl 1-(hydroxymethyl)-4-methylidenecyclohexane-1-carboxylate (7.08g) of Example 32 (32a) was dissolved in acetonitrile (450mL), iodine (13.7g) was added, and the mixture was heated to 0°C. And stirred for 2.5 hours. Ethyl acetate and 10% sodium thiosulfate aqueous solution were added to the reaction mixture, and after stirring for a while, the separated organic layer was separated, washed successively with 0.1N sodium hydroxide aqueous solution and saturated brine, and dried over anhydrous sodium sulfate. ..
  • Example 32b The ethyl 1-(iodomethyl)-2-oxabicyclo[2.2.2]octane-4-carboxylate (1.10 g) of Example 32 (32b) was dissolved in N,N-dimethylformamide (15 mL) and the azide was added. Sodium (328 mg) was added and the mixture was stirred at 120°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate-hexane, washed three times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 830 mg (yield: quantitative) of the title compound as a yellow oily substance.
  • Example 32 (32 g) of ethyl 1-(5- ⁇ 2-[(methylcarbamoyl)amino]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl ⁇ -1,2,4-Oxadiazol-3-yl)-2-oxabicyclo[2.2.2]octane-4-carboxylate (500 mg) dissolved in ethanol (10 mL), water (2 mL) Then, lithium hydroxide monohydrate (181 mg) was added, and the mixture was stirred at 15°C for 3 hours and at 35°C for 12 hours.
  • the solvent was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the reaction mixture was washed with ethyl acetate.
  • the pH of the aqueous layer was adjusted to 3 with 1M hydrochloric acid, the reaction mixture was extracted 5 times with ethyl acetate, the combined organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 420 mg (yield: 89%) of the title compound as a white solid.
  • Example 33 1-(5- ⁇ 2-[(methylcarbamoyl)amino]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl ⁇ of Example 33(33a) -1,2,4-Oxadiazol-3-yl)-2-oxabicyclo[2.2.2]octane-4-carboxylic acid (0.37 g), propan-1-ol (102 mg), 4-dimethylamino N,N′-Diisopropylcarbodiimide (207 mg) was added to a mixture of pyridine (20.8 mg) and dichloromethane (5 mL) at 15° C., and the reaction mixture was stirred at 35° C. for 16 hours.

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Abstract

La présente invention aborde le problème de la fourniture d'un composé qui est utile en tant que principe actif pour la prévention et le traitement de maladies inflammatoires et qui a une structure chimique destinée à fonctionner comme un anti-médicament spécifique présentant un effet d'activation de SIRT6. La présente invention concerne un composé représenté par la formule (1), ou un sel pharmaceutiquement acceptable de ce dernier (chaque symbole dans la formule (1) étant identique à celui défini dans la description).
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CN115703787A (zh) * 2021-08-04 2023-02-17 成都先导药物开发股份有限公司 1，4-二取代2-氧杂二环[2,2,2]辛烷衍生物的制备方法

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