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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
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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.
• Sirtuins are nicotinamide-adenine dinucleotide (NAD)-dependent deacylation enzymes. 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). It has been known for a long time that calorie restriction prolongs lifespan and suppresses various diseases called metabolic diseases, such as metabolic diseases, cancer, heart/nerve diseases, and inflammatory diseases. It is considered that sirtuin has a central role in the mechanism of calorie restriction, because the lifespan extension due to calorie restriction is not observed when sirtuin is deleted in model organisms such as insects (Non-Patent Document 2). ).
• NAD nicotinamide-adenine dinucleotide
• SIRT1-7 There are seven 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 is mainly localized in the heterochromatin region, and SIRT7 is mainly localized 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.
• 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). On the other hand, 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 compound of 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, and the like, Alternatively, a novel manufacturing method and 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 5 A C1-C6 alkyl group substituted with 1 or 2 groups selected from Group B, A hydroxy C1-C6 alkyl group substituted with 1 or 2 groups selected from Group B, C3-C6 cycloalkyl group substituted with 1 or 2 groups selected from Group B, or Groups shown below
• Group B A carboxy group, or C1-C6 alkoxycarbonyl group Z: Any group selected from the following
• R Z1 Halogen atom, A halo C1-C6 alkyl group, A halo C1-C6 alkoxy group, or C3-C6 cycloalkylcarbonyl group
• R Z2 Hydrogen atom or halogen atom 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, or Methoxycarbonyl group
• R 5 is A methyl group substituted with 1 or 2 groups selected from Group B1, An ethyl group substituted with 1 or 2 groups selected from Group B1, or A propyl group substituted with 1 or 2 groups selected from the B1 group, The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof.
• Group B1 Carboxy group, Methoxycarbonyl group, Ethoxycarbonyl group, Propoxycarbonyl group
• R 5 is A hydroxymethyl group substituted with 1 or 2 groups selected from B1 group, A hydroxyethyl group substituted with 1 or 2 groups selected from Group B1, or A hydroxypropyl group substituted with 1 or 2 groups selected from the B1 group, The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof.
• Group B1 Carboxy group, Methoxycarbonyl group, Ethoxycarbonyl group, Propoxycarbonyl group [Five]
• R 5 is A cyclobutyl group substituted with 1 or 2 groups selected from B1 group, A cyclopentyl group substituted with 1 or 2 groups selected from B1 group, or A cyclohexyl group substituted with 1 or 2 groups selected from Group B1, The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof.
• Group B1 Carboxy group, Methoxycarbonyl group, Ethoxycarbonyl group, Propoxycarbonyl group [6] The compound according to [1] or [2], wherein R 5 is any group selected from the following, or a pharmaceutically acceptable salt thereof.
• R Z1 is any group selected from the following, Fluorine atom, chlorine atom, Cyclopropylcarbonyl group, Difluoromethyl group,
• R Z2 is any group selected from the following, Hydrogen atom, fluorine atom
• [8] Z is a group shown below,
• R Z1 is any group selected from the following, Fluorine atom, chlorine atom, Cyclopropylcarbonyl group, Difluoromethyl group,
• R Z2 is any group selected from the following, Hydrogen atom, fluorine atom
• Z is any group selected from the following,
• R Z1 is any group selected from the following, Fluorine atom, chlorine atom, Cyclopropylcarbonyl group, Difluoromethyl group, Difluoromethoxy group
• [Ten] Z is any group selected from the following,
• Y is any group selected from the following,
• R Y1 is a hydrogen atom or a methyl group
• [12] The compound according to [1] selected from the following compounds, or a pharmaceutically acceptable salt thereof.
• [14] [1]-A pharmaceutical composition containing the compound according to any one of [12] or a pharmaceutically acceptable salt thereof as an active ingredient. [15] The pharmaceutical composition according to [14], which is an external preparation. [16] The pharmaceutical composition according to [14], for treating and/or preventing a peripheral inflammatory disease. [17] The compound according to any one of [1]-[12], or a pharmaceutically acceptable salt thereof, 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, sunlight and/or UV sunburn dermatitis, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgar
• 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, sinusitis
• 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.
• the pharmaceutical composition according to [16] which is selected from the group consisting of acne, pressure ulcer, wound, burn, intractable stomatitis, glossitis, and Behcet's disease. [twenty one] A method for treating and/or preventing a peripheral inflammatory disease, which comprises administering an effective amount of the pharmaceutical composition according to [14] or [15].
• Another aspect of the present invention relates to the following [1A]-[32A].
• [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 5 A C1-C6 alkyl group substituted with 1 or 2 groups selected from Group B, A hydroxy C1-C6 alkyl group substituted with 1 or 2 groups selected from Group B, C3-C6 cycloalkyl group substituted with 1 or 2 groups selected from Group B, or The groups shown below are shown.
• n 1, 2, or 3
• Group B A carboxy group, or C1-C6 alkoxycarbonyl group Z: One of the groups selected from the following is shown.
• R Z1 Halogen atom, A halo C1-C6 alkyl group, A halo C1-C6 alkoxy group, or C3-C6 cycloalkylcarbonyl group
• R Z2 Hydrogen atom or halogen atom Y: One of the groups selected from the following is shown.
• 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 represent any group selected from the following.
• R 12 methyl group, hydroxyethyl group, acetyl group, or methoxycarbonyl group [3A]R 5 A methyl group substituted with 1 or 2 groups selected from Group B1, An ethyl group substituted with 1 or 2 groups selected from Group B1, or A propyl group substituted with 1 or 2 groups selected from Group B1 is shown, The compound according to [1A] or [2A], or a pharmaceutically acceptable salt thereof.
• Group B1 Carboxy group, Methoxycarbonyl group, Ethoxycarbonyl group, Propoxycarbonyl group [4A]R 5 A hydroxymethyl group substituted with 1 or 2 groups selected from B1 group, A hydroxyethyl group substituted with 1 or 2 groups selected from Group B1, or A hydroxypropyl group substituted with 1 or 2 groups selected from Group B1 is shown, The compound according to [1A] or [2A], or a pharmaceutically acceptable salt thereof.
• Group B1 Carboxy group, Methoxycarbonyl group, Ethoxycarbonyl group, Propoxycarbonyl group [5A]R 5 A cyclobutyl group substituted with 1 or 2 groups selected from B1 group, A cyclopentyl group substituted with 1 or 2 groups selected from B1 group, or Represents a cyclohexyl group substituted with 1 or 2 groups selected from Group B1, The compound according to [1A] or [2A], or a pharmaceutically acceptable salt thereof.
• Group B1 Carboxy group, Methoxycarbonyl group, Ethoxycarbonyl group, Propoxycarbonyl group [6A] The compound according to [1A] or [2A], wherein R 5 represents any group selected from the following, or a pharmaceutically acceptable salt thereof.
• [7A]Z is the group shown below,
• R Z1 represents any group selected from the following, Fluorine atom, chlorine atom, Cyclopropylcarbonyl group, Difluoromethyl group
• R Z2 represents any group selected from the following, Hydrogen atom, fluorine atom
• [8A]Z is a group shown below,
• R Z1 represents any group selected from the following, Fluorine atom, chlorine atom, Cyclopropylcarbonyl group, Difluoromethyl group,
• R Z2 represents any group selected from the following, Hydrogen atom, fluorine atom
• [9A]Z represents any group selected from the following,
• R Z1 represents any group selected from the following, Fluorine atom, chlorine atom, Cyclopropylcarbonyl group, Difluoromethyl group, Difluoromethoxy group
• [10A]Z represents any group selected from the following,
• R Y1 represents a hydrogen atom or a methyl group
• [12A] The compound according to [1A] selected from the following compounds, or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition containing the compound according to any one of [1A]-[12A] 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
• 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 sores, wounds, burns, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, warts vulgaris, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic
• 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
• peripheral inflammatory disease rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, non-alcoholic steatohepatitis, contact dermatitis, sun and/or ultraviolet 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 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
• Peripheral inflammatory disease is rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, non-alcoholic steatohepatitis, contact dermatitis, sun and/or UV 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
• 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 eczem
• peripheral inflammatory disease rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, non-alcoholic steatohepatitis, contact dermatitis, sun and/or ultraviolet 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 sores, wounds, burns, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, warts vulgaris, diabetic ulcers, leg ulcers, keloids, hypertrophic scars, seborrheic ker
• 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.
• 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 , R 1 and R 2 are preferably a hydrogen atom or any group selected from the following, which is bonded to each other to form a substituent.
• R 12 methyl group, hydroxyethyl group, acetyl group, or Methoxycarbonyl group Particularly preferably, R 1 and R 2 are the following groups which are bonded to each other to form a substituent.
• groups represented by any of the following (1) to (4) are preferable.
• R 5 the group shown in the above (1) is particularly preferable.
• R Z1 is any group selected from the following, Fluorine atom, chlorine atom, Cyclopropylcarbonyl group, Difluoromethyl group, Difluoromethoxy group
• R Z2 is any group selected from the following: hydrogen atom, fluorine atom
• R Z1 is any group selected from the following, Fluorine atom, chlorine atom, Cyclopropylcarbonyl group, Difluoromethyl group, Difluoromethoxy group
• R Z2 is any group selected from the following: hydrogen atom, fluorine atom
• R Z1 is any group selected from the following fluorine atom, chlorine atom, Cyclopropylcarbonyl group, Difluoromethyl group, Difluoromethoxy group
• any group selected from the following is preferable.
• R Y1 is a hydrogen atom or a methyl group
• a further preferred embodiment of the present invention is the compound described in Examples 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, a 2,3-dimethyl-1-butyl group or the like, 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 an oxygen atom is bonded to a C1-C6 alkyl 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 a hydroxyl group is bonded to a C1-C6 alkyl group, preferably 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 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.
• 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 C3-C6 cycloalkyl group is bonded to a carbonyl group, preferably a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, Alternatively, it is a cyclohexylcarbonyl group.
• 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 halogen atom is substituted on a C1-C6 alkyl group, and is preferably 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 halogen atom is substituted on the C1-C6 alkoxy group, and is preferably a difluoromethoxy group, a trifluoromethoxy group, or a difluoroethoxy 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; or 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 arrangement is indicated by the * mark (R * and S * ) when the arrangement of the asymmetric center described first is R or S, or the prefix (symbol) rel- (before 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]
• (A1 step) 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 P a1 represents a commonly used protective 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 0 to 100°C, and the reaction time is usually 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)
• 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.
• compound (E-III) is obtained from compound (E-II) using a base and a carbamate-forming reagent. This step can be performed by the same method as in (B2 step).
• 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 the compound (F-IV) of the present invention.
• 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 5 has the same meaning 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 are the groups shown below.
• R 1′′′ and R 2′′′ are bonded to each other to form a substituent, and are 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 alkoxycarbonylmethyl 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.
• a 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 and R 5 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.
• Step H1 Step of Coupling with Heterocycle
• compound (HI) is reacted with ZY-Cl in the presence of a base to give 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.
• 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.
• 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 5 and Z represent the same meaning as in the case of the compound of the above formula (1), R k1 represents a phenoxy group which may have a substituent, or an imidazolyl group. Indicates. ]
• 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.
• (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.
• the solvent examples 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.
• 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.
• (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 5 and Z have the same meanings as in the case of the compound of the general formula (1), Ph represents a phenyl group, Imd represents an imidazolyl group, and R x1 Indicates OPh or Imd. ]
• Step X1 Step of performing coupling Step of obtaining compound (X-II) from compound (XI), in the presence of a base, in the presence of 1,1′-thiocarbonyldiimidazole or phenyl chlorothionoformate, the 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.
• Step N1 Step of Ureaization Step of obtaining compound (N-II) from compound (NI). This step can be performed by the same method as in (F2 step).
• Step N2 Step of Performing Ring Formation
• compound (N-II) is reacted with a dehydrating agent in the presence or absence of a base to give 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 5 , and Z 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 5 , and Z 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.
• 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 5 , Z, 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) In this step, 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 (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 (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).
• 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.
• (Formulation Example 1) 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.
• (Formulation Example 3) Tablets The compound of the present invention or a salt thereof 5 g, lactose 90 g, corn starch 34 g, crystalline cellulose 20 g and magnesium stearate 1 g are mixed in a blender and then tableted by a tableting machine to give tablets.
• Ointment A mixture of the compound of the present invention or a salt thereof (5 g) in a mixture of 50 g of propylene glycol, 50 g of polyethylene glycol and 50 g of glyceryl monooleate (Capmul GMO-50 EP, NF) at 60°C to 80°C. Dissolve by heating.
• White petrolatum (350 g) is added, and the mixture is stirred at 60°C to 80°C for 15 minutes, and then slowly cooled with stirring to obtain a 1.0% ointment.
• White vaseline (350 g) is added, and the mixture is stirred at 60°C to 80°C for 15 minutes, and then slowly cooled with stirring to give a 1.0% ointment.
• the pharmacological activity of the compound of the present invention or a pharmaceutically acceptable salt thereof was confirmed by the following tests.
• 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 concentration of compound showing relative enzyme activity 150%) of the test substance was calculated from the Sigmoidal dose-response (variable slope) of GraphPad Prism (GraphPad Software) using the relative enzyme activity (%) value at each concentration. Shown in 1.
• 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 (4.47 kg), acetonitrile (8 L) and 12 M hydrochloric acid (719 mL) were added, cooled to 10°C, and benzylamine (2.98 kg) was added at 10-30°C. It was added dropwise. 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 1b-1 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (150 g) of Example 1(1a) 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 at 50° C. for 20 hours under a hydrogen (50 psi) atmosphere. 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.
• Example 1b-2 Tetrahydrofuran (1.2 L) and sodium hydrogen carbonate (327 g) were added to the mixture obtained in Example 1b-1 and the mixture was stirred at room temperature for 1 hr, di-tert-butyl dicarbonate (339 g) was added, and the mixture was stirred at 30- The mixture was stirred at 40°C for 16 hours. After filtering the reaction mixture, the filtrate was extracted three times with ethyl acetate.
• Example 1(1b) Tert-Butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (300 g) of Example 1(1b) was dissolved in toluene (1.4 L), and pyrrolidine (146 mL). ) And tosyl acid monohydrate (30.0 g) were added at room temperature, and the mixture was stirred at 135° C. for 4 hours using a Dean-Stark apparatus. The solvent was distilled off from the reaction mixture under reduced pressure, the obtained residue was dissolved in methanol (1.5 L), sulfur (43.0 g) and cyanamide (68.0 g) were added, and the mixture was stirred at room temperature for 18 hr.
• 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, 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 hours, slowly cool to room temperature, collect the precipitated solid by filtration, and wash with ethyl acetate/petroleum ether (100 mL/100 mL) to give tert-butyl (4S,8S)-2.
• Example 6 3-(cyclopropanecarbonyl)-N'-hydroxybenzene-1-carboximidamide of Example 6 (6d) (150 mg) was dissolved in N,N-dimethylformamide (3 mL), Example 6 (6c ) Methyl N-[(10-cyano-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl)carbamoyl ] Glycinate (212 mg), zinc chloride (29 mg), and tosylic acid monohydrate (36 mg) were sequentially added at room temperature, and the mixture was stirred at 80°C for 12 hr.
• the title compound (25 mg, yield: 6.4%) was obtained as a white solid.
• Tetrahydrofuran (600 mL) and sodium hydrogencarbonate (234 g) were added to an aqueous solution (700 mL) of 3-oxa-9-azabicyclo[3.3.1]nonane-7-one hydrochloride synthesized in Example 1 (1b-1).
• a solution of the residue obtained above in tetrahydrofuran (450 mL) was added over 30 minutes, and the mixture was stirred at room temperature for 16 hours.
• the reaction mixture was extracted with ethyl acetate three times, and the combined organic layers were dried over anhydrous sodium sulfate.
• Example 7(7b) 2-(Trimethylsilyl)ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (90 g) of Example 7(7b) 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 7(7a) 3-(difluoromethyl)-N'-hydroxybenzene-1-carboximidamide (1.72 g) of Example 7(7a) was dissolved in N,N-dimethylformamide (17 mL), Example 7(7f) Tert-Butyl (10-cyano-4,7,8,9-tetrahydro-5H-4,8-epiminooxocino[5,4-d][1,3]thiazol-2-yl)carbamate (3.14 g), zinc chloride (252 mg), and tosyl acid monohydrate (352 mg) were sequentially added at room temperature, and the mixture was stirred at 80°C for 12 hours.
• 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.
• reaction mixture was added dropwise to a solution of 1,1-dibromoformamidoxime (3.66 g) in tetrahydrofuran (50 mL) at -10°C over 10 minutes,- The mixture was stirred at 10°C for 1 hour. Subsequently, 1-ethynyl-4-fluorobenzene (5.2 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted 3 times with ethyl acetate. The combined organic layers were washed successively with dilute hydrochloric acid, water, and saturated brine, and dried over anhydrous sodium sulfate.
• tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (CAS registry number: 185099-67-6) (103 g) was dissolved in methanol (300 mL) and 4 M hydrogen chloride was added. -1,4-Dioxane solution (320 mL) was added, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off from the reaction mixture under reduced pressure to obtain 81 g (yield: quantitative) of the title compound as a pale yellow solid.
• Example 9(9b) 2-(Trimethylsilyl)ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (123 g) of Example 9(9b) was dissolved in toluene (500 mL) and pyrrolidine (49.4 g) Tosyl acid monohydrate (14.0 g) was added at room temperature, and the mixture was stirred at 135°C for 3 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), sulfur (16.5 g) and cyanamide (17.5 g) were added, and the mixture was stirred at room temperature for 16 hours.
• the precipitated solid was collected by filtration and washed with ethyl acetate to obtain 3.5 g of the hydrochloride of the title compound as a yellow solid.
• the obtained hydrochloride was dissolved in water (50 mL), sodium hydrogen carbonate (2.47 g) was added, and the mixture was stirred at room temperature for 30 min.
• 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.
• 1,1'-Carbonyldiimidazole (1.06 g) was added to a solution of N'-hydroxybicyclo[2.2.2]octane-1-carboxymidamide (1.00 g) in Example 10 (10c) in tetrahydrofuran (25 mL). And stirred at 60° C. for 3.5 hours. The reaction mixture was concentrated under reduced pressure to about half amount, saturated saline was added, and the mixture was extracted 3 times with ethyl acetate.
• Example 11 4,4-Difluorocyclohexane-1-carbonitrile (0.70 g) of Example 11 (11d) was dissolved in tetrahydrofuran (10 mL), hydroxylamine hydrochloride (0.37 g) and triethylamine (1.24 g) were added, and 65 The mixture was stirred at °C for 12 hours. 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 washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (0.50 g, yield: 69%) as a white solid. It was
• Example 11 (11e) 4,4-difluoro-N'-hydroxycyclohexane-1-carboximidamide (108 mg) of Example 11 (11e) was dissolved in N,N-dimethylformamide (10 mL) to give Example 11 (11c).
• Methyl N-[(5-cyano-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbamoyl]glycinate (200 mg), zinc chloride (24 mg ) And tosylic acid monohydrate (28 mg) were sequentially added at room temperature, and the mixture was stirred at 80° C. for 12 hours.

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