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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed 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 (metabolic diseases, cancer, heart/nerve diseases, inflammatory diseases, etc.). It is considered that sirtuin has a central role in the mechanism of calorie restriction, since 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 thereafter rapidly show premature aging-like symptoms such as subcutaneous fat loss, bone density loss, 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, NF- ⁇ B-induced expression of inflammatory cytokines 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 present invention provides a compound having a chemical structure having an activity of activating SIRT6, useful as an active ingredient for the prevention and treatment of inflammatory diseases, a pharmaceutically acceptable salt thereof, etc., or a novel production method thereof. And an intermediate.
• 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 is any group selected from the following substituents. Halogen atom, C1-C6 alkyl group, Hydroxy C1-C6 alkyl group, A C1-C6 alkyl group substituted by 1 or 2 halo C1-C6 alkoxy, A halo C1-C6 alkyl group substituted with 1 or 2 phenyl groups substituted with 1 or 2 halogen atoms, A phenyl group which may be substituted with 1 or 2 groups selected from the substituent group a, C3-C6 cycloalkyl group optionally substituted with 1 or 2 groups selected from the substituent group b, 4-7 membered saturated heterocyclic group optionally substituted by 1 or 2 groups selected from the substituent group c, A pyridyl group substituted with 1 or 2 C1-C6 alkyl groups, A bicyclo[1.1.1]pentanyl group substituted with 1 or 2 halo C1-C6 alkyl groups,
• Hydrogen atom, C1-C6 alkyl group R 2′ is any group selected from the following substituents.
• Hydrogen atom, C1-C6 alkyl group R 3 is any group selected from the following substituents, C1-C6 alkyl group optionally substituted with 1 or 2 groups selected from the substituent group d, C3-C6 cycloalkyl group optionally substituted by 1 or 2 groups selected from the substituent group e, A halo C1-C6 alkyl group, 4-7 membered saturated heterocyclic group
• Substituent group d Hydroxyl group, amino group, carbamoyl group, C1-C6 alkoxycarbonyl group, C1-C6 alkylsulfonyl group, C3-C6 cycloalkyl group
• Substituent group e Carbamoyl group, C1-C6 alkoxycarbonyl group, hydroxy C1-C6 alkyl group
• R 4 is a hydrogen
• Ring A is any ring selected from the following.
• R 1 is any group selected from the following substituents.
• Hydrogen atom, methyl group, ethyl group, propyl group [Four] The compound according to any one of [1] to [3], wherein R 2′ is any group selected from the following substituents, or a pharmaceutically acceptable salt thereof. Hydrogen atom, methyl group, ethyl group, propyl group
• R 1a is any group selected from the following substituents.
• Methyl group A fluorophenyl group, Difluoromethylphenyl group, Difluoromethoxyphenyl group, Methoxycarbonylphenyl group, Propoxycarbonylphenyl group, Difluorocyclohexyl group, Methoxycarbonyltetrahydrofuryl group, A difluorotetrahydropyranyl group, Bicyclo[2.2.2]octanyl group, Ethoxycarbonylbicyclo[2.2.2]octanyl group, Oxoisochroman group R 2a is any group selected from the following substituents.
• Hydrogen atom, methyl group, ethyl group, propyl group R 2a′ is any group selected from the following substituents.
• Hydrogen atom, methyl group, ethyl group, propyl group R 3a is any group selected from the following substituents.
• the hydrogen atom n is 1.
• Ring A is any ring selected from the following.
• [12] [1]-A pharmaceutical composition containing the compound according to any one of [10] or a pharmaceutically acceptable salt thereof as an active ingredient. [13] The pharmaceutical composition according to [12], for treating and/or preventing a peripheral inflammatory disease. [14] The compound according to any one of [1]-[10], 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, sun and/or UV sunburn, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, arth
• 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.
• 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 [13] which is selected from the group consisting of acne, pressure ulcer, wound, burn, intractable stomatitis, glossitis, and Behcet's disease.
• a method for treating and/or preventing a peripheral inflammatory disease which comprises administering an effective amount of the pharmaceutical composition according to [12].
• [1A] A compound of formula (1) or a pharmaceutically acceptable salt thereof.
• R 1 is any group selected from the following substituents. Halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, Hydroxy C1-C6 alkyl group, C3-C6 cycloalkylcarbonyl group, An oxoisochromanyl group, A phenyl group which may be substituted with 1 or 2 groups selected from the substituent group a, A pyridyl group optionally substituted by 1 or 2 groups selected from the substituent group a, C3-C6 cycloalkyl group optionally substituted with 1 or 2 groups selected from the substituent group b, 4-7 membered saturated heterocyclic group optionally substituted by 1 or 2 groups selected from the substituent group c, A norbornane group optionally substituted with 1 or 2 groups selected from the substituent group c, A bicyclo[2.2.2]octanyl group optionally substituted with 1 or 2 groups selected from the substituent group c,
• Hydrogen atom, C1-C6 alkyl group R 2′ is any group selected from the following substituents.
• Hydrogen atom, C1-C6 alkyl group R 3 is any group selected from the following substituents.
• C1-C6 alkyl group optionally substituted with 1 or 2 groups selected from the substituent group d C3-C6 cycloalkyl group optionally substituted by 1 or 2 groups selected from the substituent group e, A halo C1-C6 alkyl group, 4-7 membered saturated heterocyclic group
• Substituent group d Hydroxyl group, amino group, carbamoyl group, C1-C6 alkoxycarbonyl group, C1-C6 alkylsulfonyl group, C3-C6 cycloalkyl group
• Substituent group e Carbamoyl group, C1-C6 alkoxycarbonyl group, hydroxy C1-C6 alkyl group
• R 4 is a
• Ring A is any ring selected from the following.
• R 1 is any group selected from the following substituents.
• Hydrogen atom, methyl group, ethyl group, propyl group [4A] The compound according to any one of [1A]-[3A], wherein R 2′ is any group selected from the following substituents, or a pharmaceutically acceptable salt thereof.
• Hydrogen atom, methyl group, ethyl group, propyl group [5A] The compound according to any one of [1A]-[4A], wherein R 3 is any group selected from the following substituents, or a pharmaceutically acceptable salt thereof.
• R 1a is any group selected from the following substituents.
• R 2a is any group selected from the following substituents.
• Hydrogen atom, methyl group R 2a′ is any group selected from the following substituents.
• Hydrogen atom, methyl group R 3a is any group selected from the following substituents.
• R 4a is a hydrogen atom.
• R 3 and R 4 are bonded to each other to form a substituent, which is a group shown below.
• Ring A is any ring selected from the following.
• [10A] The compound according to [1A] selected from the following compounds, or a pharmaceutically acceptable salt thereof.
• [10A-12] N-(2-hydroxy-2-methylpropyl)-N'- ⁇ 4-methyl-5-[4-(oxan-2-yl)pyrimidin-2-yl]-4,5,6,7-tetrahydropyra Zolo[1,5-a]pyrazin-2-yl ⁇ urea or a pharmaceutically acceptable salt thereof.
• [10A-13] N-[(2R)-2-Hydroxypropyl]-N'- ⁇ 5-[4-(oxan-2-yl)pyrimidin-2-yl]-4,5,6,7-tetrahydropyrazolo[1, 5-a]pyrazin-2-yl ⁇ urea or a pharmaceutically acceptable salt thereof.
• [10A-32] Propyl 3-(5- ⁇ 4-methyl-2-[(methylcarbamoyl)amino]-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl ⁇ -1,3,4 -Oxadiazol-2-yl)benzoate or a pharmaceutically acceptable salt thereof.
• [10A-33] N- ⁇ 5-[3-(bicyclo[2.2.2]octane-1-yl)-1,2,4-oxadiazol-5-yl]-4-methyl-4,5,6,7-tetrahydro Pyrazolo[1,5-a]pyrazin-2-yl ⁇ -N'-methylurea, or a pharmaceutically acceptable salt thereof.
• [10A-34] N-(5- ⁇ 5-[3-(cyclopropanecarbonyl)phenyl]-1,3,4-oxadiazol-2-yl ⁇ -4-methyl-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazin-2-yl)-N'-methylurea or a pharmaceutically acceptable salt thereof.
• [10A-35] N- ⁇ 5-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a] Pyrazin-2-yl ⁇ -N'-methylurea, or a pharmaceutically acceptable salt thereof.
• [12A] A pharmaceutical composition comprising the compound according to any one of [1A] to [10A] or a pharmaceutically acceptable salt thereof as an active ingredient.
• [13A] The pharmaceutical composition according to [12A], which is an oral preparation.
• [14A] The pharmaceutical composition according to [12A], which is an external preparation.
• [15A] The pharmaceutical composition according to any one of [12A] to [14A], for treating and/or preventing a peripheral inflammatory disease.
• 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 dermatitis, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis
• 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, erythroderma psoriasis , Pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns, sinus
• Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, nonalcoholic steatohepatitis, contact dermatitis, sun and/or UV sunburn, radiation dermatitis, atopic dermatitis, seborrheic Dermatitis, psoriasis vulgaris, psoriatic arthritis, erythroderma psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigoid group, erythroderma, acne vulgaris Acne, pressure ulcer, wound, burn, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, vulgaris vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis, androgenetic
• 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 dermatiti
• 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, erythroderma psoriasis , Pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns, sinus
• Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, nonalcoholic steatohepatitis, contact dermatitis, sun and/or UV sunburn, radiation dermatitis, atopic dermatitis, seborrheic Dermatitis, psoriasis vulgaris, psoriatic arthritis, erythroderma psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigoid group, erythroderma, acne vulgaris Acne, pressure ulcer, wound, burn, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, vulgaris vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis, androgenetic
• 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,
• 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, erythroderma psoriasis , Pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns, sinus
• Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, nonalcoholic steatohepatitis, contact dermatitis, sun and/or UV sunburn, radiation dermatitis, atopic dermatitis, seborrheic Dermatitis, psoriasis vulgaris, psoriatic arthritis, erythroderma psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigoid group, erythroderma, acne vulgaris Acne, pressure ulcer, wound, burn, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, vulgaris vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis, androgenetic
• 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, chronic rhosis, chronic rhosis, chronic rhosis, chronic rhosis, chronic fibrospondylitis, acute eczema, Subacute eczema, chronic
• 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, erythroderma psoriasis , Pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, pressure ulcers, wounds, burns, sinus
• Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, alcoholic hepatitis, nonalcoholic steatohepatitis, contact dermatitis, sun and/or UV sunburn, radiation dermatitis, atopic dermatitis, seborrheic Dermatitis, psoriasis vulgaris, psoriatic arthritis, erythroderma psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigoid group, erythroderma, acne vulgaris Acne, pressure ulcer, wound, burn, intractable stomatitis, glossitis, Behcet's disease, vitiligo vulgaris, vulgaris vulgaris, diabetic ulcer, leg ulcer, keloid, hypertrophic scar, seborrheic keratosis, androgenetic
• 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.
• a preferred embodiment of the present invention is the compound of formula (1') or a pharmaceutically acceptable salt thereof.
• a further preferred embodiment of the present invention is the compound described in Examples or a pharmaceutically acceptable salt thereof.
• halogen atom in the present specification includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. It is preferably a fluorine atom or a chlorine atom.
• 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
• 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, an isopropyl group or the like can be mentioned. .
• 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 examples include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxyisopropyl group, a hydroxyisobutyl group, and the like.
• C3-C6 cycloalkyl group in the present specification is a cyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.
• 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, oxepane, etc. are mentioned, and the following rings are preferable.
• 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.
• the specific group include a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, and the like.
• 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, a difluoroethoxy group, and the like.
• 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.
• 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 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.
• C1-C3 alkylene group in the present specification is an alkylene group having 1 to 3 carbon atoms, and preferably a methylene group, an ethylene group or a propylene group.
• halo C1-C3 alkylene group in the present specification is a group in which a C1-C3 alkylene group is substituted with an arbitrary number of halogen atoms.
• the specific group include a difluoromethylene group, a trifluoromethylene group, a difluoroethylene group, and the like.
• 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.
• the "pharmaceutically acceptable salt” refers to a salt that can be used as a medicine. In the compound, when it has an acidic group, it is reacted with a base to form a basic salt, and when it has a basic group, it is reacted with an acid to form an acidic salt. Shows the salt of.
• 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 chlorate, sulfate and phosphate; 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 salt
• 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 stereoscopic configuration of the compound may be described by distinguishing the sign (+, -) of optical rotation. Right-handedness is indicated by (+) and left-handedness is indicated by (-).
• 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 prodrug (1) When the compound has an amino group, Compounds whose amino groups are acylated, alkylated, phosphorylated (for example, their amino groups are eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4- A) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compound, etc.) and the like, (2) If 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
• the compound used in the process of production and the compound finally obtained may be appropriately protected or deprotected by a suitable protecting group in the production process depending on the kind of the functional group of the compound. May be required.
• a suitable protecting group include a hydroxyl group, a carboxy group, an amino group, and the like, and protection and deprotection may be appropriately performed under commonly known reaction conditions.
• hydroxyl-protecting group examples include trityl, C7-C11 aralkyl (eg, benzyl etc.), formyl, C1-C6 alkylcarbonyl (eg, acetyl, propionyl etc.), benzoyl, C7-C11 aralkylcarbonyl (eg, benzylcarbonyl).
• 2-tetrahydropyranyl 2-tetrahydrofuranyl
• silyl eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.
• C2-C6 alkenyl eg, 1- Allyl etc.
• groups include 1-3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C1-C6 alkyl (eg, methyl, ethyl, n-propyl, etc.), C1-C6 alkoxy (eg, methoxy).
• the protecting group for the carboxy group examples include C1-C6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C7-C11 aralkyl (eg, benzyl, etc.), phenyl, trityl, silyl ( For example, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C2-C6 alkenyl (eg, 1-allyl etc.) and the like are used.
• C1-C6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.
• C7-C11 aralkyl eg, benzyl, etc.
• These groups may be substituted with 1-3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C1-C6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.), nitro, etc.
• halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
• C1-C6 alkoxy eg, methoxy, ethoxy, propoxy, etc.
• nitro etc.
• amino-protecting group include formyl, C1-C6 alkylcarbonyl (eg, acetyl, propionyl, etc.), C1-C6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), benzoyl, C7.
• -C11 aralkylcarbonyl eg, benzylcarbonyl etc.
• C7-C14 aralkyloxycarbonyl eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl etc.
• trityl phthaloyl, N,N-dimethylaminomethylene, silyl (eg , Trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C2-C6 alkenyl (eg, 1-allyl etc.) and the like are used.
• These groups may be substituted with 1-3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C1-C6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.), nitro, etc.
• halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
• C1-C6 alkoxy eg, methoxy, ethoxy, propoxy, etc.
• nitro etc.
• the compound of the present invention can be mainly divided into three partial structures of a right chain portion, a central skeleton portion, and a left chain portion as shown below.
• the partial structures are appropriately linked and proceeded, but the order of the linkage can be appropriately selected depending on the kind of functional group contained in the compound and the like.
• the central skeleton portion may be manufactured first, then the right chain portion, and finally the left chain portion, to complete the preparation of the compound.
• the central skeleton portion is first produced, then the left chain portion is produced, and finally the right chain portion is produced, whereby the production of the compound is completed.
• Method A is a method for producing the central skeleton portion and is a method for producing the compound (AV).
• R 2 has the same meaning as in the case of the compound of the above formula (1), R O1 and R 2′ independently represent the same or different C1-C6 alkyl group, and P N represents A protecting group for an amino group is shown, and LG is a leaving group. ]
• Step A1 Step of performing alkylation
• compound (AI) is reacted with a corresponding alkylating reagent in the presence of a base to obtain compound (A-II).
• the alkylating reagent include alkyl halides such as alkyl iodide and alkyl bromide, and sulfonic acid esters such as alkyl tosylate and alkyl mesylate.
• the base include triethylamine, diisopropylethylamine, potassium carbonate and the like.
• the solvent include tetrahydrofuran, acetone, 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.
• Step A2 Hydrolysis step is a step in which the compound (A-II) is reacted with a base to obtain the compound (A-III).
• the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
• the solvent include a solvent containing water (methanol, ethanol, tetrahydrofuran, etc.), water, 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.
• Step A3 Step of performing amidation Step of obtaining compound (A-IV) from compound (A-III) in the presence of a base, using a condensing agent and N,O-dimethylhydroxylamine hydrochloride Is.
• 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,
• 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.
• Step A4 Step of carrying out ketone synthesis
• compound (AV) is obtained by reacting compound (A-IV) with an organometallic reagent such as a Grignard reagent or an organolithium agent.
• organometallic reagent include methyl magnesium bromide and methyl lithium.
• the solvent include tetrahydrofuran, diethyl ether 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 0.5 to 24 hours.
• Method B is a method for producing a central skeleton portion, and is a method for producing compound (B-III).
• R 2 has the same meaning as in the case of the compound of the above formula (1), and R O 1 and P N have the same meaning as above. ]
• Step B1 Step of Reducing Ester This is a step of carrying out a reaction from compound (BI) using a reducing agent to obtain compound (B-II).
• the reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride and the like.
• the solvent include tetrahydrofuran, diethyl ether, dichloromethane and the like, or a mixture thereof.
• the reaction temperature is usually about -78°C to 60°C, and the reaction time is usually about 0.5 to 24 hours.
• Step B2 Step of Performing Oxidation of Alcohol This is a step of reacting the compound (B-II) with an oxidizing agent to obtain the compound (B-III).
• the oxidizing agent include Dess-Martin Periodinane, manganese dioxide, pyridine-sulfur trioxide complex and the like.
• the solvent include dichloromethane, acetonitrile and the like.
• the reaction temperature is usually about -20°C to 40°C, and the reaction temperature is usually about 0.5 to 72 hours.
• Method C is a method for producing the central skeleton portion, and is a method for producing the compound (C-III).
• R 2 has the same meaning as in the case of the compound of the above formula (1), P N has the same meaning as described above, and LG represents a leaving group. ]
• Step C1 Step of converting hydroxy group into leaving group (when using halogenating reagent)
• compound (C-II) is obtained by reacting compound (CI) with a halogenating reagent and triphenylphosphine in the presence or absence of a base.
• the halogenating reagent include N-bromosuccinimide, carbon tetrabromide, bromine, iodine, N-iodosuccinimide and the like.
• the base include imidazole and the like.
• the solvent include dichloromethane, tetrahydrofuran 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.
• the compound (C-II) is obtained by reacting the compound (CI) with a sulfonylating reagent in the presence of a base.
• a sulfonylating reagent include p-toluenesulfonyl chloride, methanesulfonyl chloride and the like.
• the base include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like.
• the solvent include dichloromethane, tetrahydrofuran 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.
• (C2 step) Deprotection step (In the case of t-butoxycarbonyl (Boc) group)
• a compound (C-III) containing an amino group protected by a t-butoxycarbonyl group is reacted with an acid to obtain a compound (C-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.
• a compound (C-II) containing an amino group protected by a 2-(trimethylsilyl)ethoxycarbonyl group is reacted with a desilylation reagent or an acid to obtain a compound (C-III).
• the 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.
• 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.
• amines 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.
• a compound (C-II) containing an amino group protected with a benzyloxycarbonyl (Cbz) group is reacted in a hydrogen atmosphere in the presence or absence of an acid with a transition metal catalyst to give a compound (C-II).
• 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.
• Method D is a method for producing the central skeleton portion, and is a method for producing the compound (D-II).
• R 2 has the same meaning as in the case of the compound of the above formula (1), and R O1 and P N have the same meaning as above. ]
• Step D1 Deprotection step This is a step of obtaining compound (D-II) from compound (DI). This step can be performed by the same method as in (C2 step).
• Method E is a method for producing the central skeleton portion, and is a method for producing compound (E-IV).
• R 2 has the same meaning as in the case of the compound of the above formula (1), and R O 1 , LG and P N have the same meaning as described above. ]
• Step E1 Step of Cyanation This is a step of obtaining a compound (E-II) from the compound (EI) by using a cyanation reagent.
• the cyanating reagent include sodium cyanide, potassium cyanide and the like.
• the solvent include dimethyl sulfoxide, N,N-dimethylformamide, water and the like.
• the reaction temperature is usually room temperature to about 100° C., and the reaction time is usually about 1 to 24 hours.
• Step E2 Step of Converting Cyano Group into Ester Group This is a step of obtaining a compound (E-III) by reacting the compound (E-II) with an acid in an alcohol solvent.
• the acid include hydrochloric acid, hydrogen chloride-1,4-dioxane, sulfuric acid and the like.
• the alcohol solvent include methanol and ethanol.
• the reaction temperature is usually about 0 to 100° C., and the reaction time is usually about 0.5 to 24 hours.
• Step E3 Step of Deprotecting This is a step of obtaining compound (E-IV) from compound (E-III). This step can be performed by the same method as in (C2 step).
• Method F is a method relating to the production of the right chain portion, and is a method of producing the compound (F-III).
• R 3 has the same meaning as in the case of the compound of the above formula (1).
• Step F1 Step of reducing nitro group to amino group (When using metal)
• a compound (F-II) is obtained by reacting the compound (FI) with a metal and an acid.
• the metal include iron, zinc, tin chloride and the like.
• the acid include acetic acid, ammonium chloride, hydrochloric acid and the like.
• the solvent include methanol, ethanol, dioxane, water 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.
• compound (F-II) is obtained by reacting compound (FI) with a metal catalyst in the presence or absence of an acid in a hydrogen atmosphere.
• the metal catalyst include palladium/carbon and palladium hydroxide/carbon.
• the acid include acetic acid and hydrochloric acid.
• the solvent include methanol, ethanol, ethyl acetate and the like.
• the reaction temperature is usually room temperature to about 100° C.
• the hydrogen pressure is usually about 1 to 5 atm
• the reaction time is usually about 0.5 to 24 hours.
• compound (F-II) is obtained by reacting compound (FI) with a reducing agent.
• the reducing agent include lithium aluminum hydride and sodium borohydride.
• Nickel chloride or the like can be added as an additive.
• the reaction may be allowed to proceed smoothly depending on the additive.
• the solvent include tetrahydrofuran and methanol.
• the reaction temperature is usually about -78°C to 80°C, and the reaction time is usually about 0.5 to 24 hours.
• (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.
• Method G is a method relating to the production of the right chain portion and is a method for producing the compound (G-II).
• P N represents a protecting group for an amino group.
• (G1 step) Protection step (For carbamate group)
• compound (G-II) is obtained by reacting compound (GI) 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.
• compound (G-II) is obtained by reacting compound (GI) with a base and an acylating reagent.
• the 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.
• Method H is a method for producing a central skeleton portion, and is a method for producing compound (H-III).
• R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), P N has the same meaning as described above, and m represents 0 or 1. ]
• Step H1 Step of forming a ring
• the compound (HI) is reacted with an acid to obtain the compound (H-II).
• the acid include trifluoroacetic acid, hydrogen chloride-1,4-dioxane, p-toluenesulfonic acid and the like.
• the solvent include dichloromethane, methanol, tetrahydrofuran 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.
• compound (H2 step) Step of reducing imine (In case of catalytic reduction)
• compound (H-III) is obtained by reacting compound (H-II) with a metal catalyst in the presence or absence of an acid in a hydrogen atmosphere.
• the metal catalyst include palladium/carbon and palladium hydroxide/carbon.
• the acid include acetic acid and hydrochloric acid.
• the solvent include methanol, ethanol, ethyl acetate and the like.
• the reaction temperature is usually room temperature to about 100° C.
• the hydrogen pressure is usually about 1 to 5 atm
• the reaction time is usually about 0.5 to 24 hours.
• a compound (H-III) is obtained by reacting the compound (H-II) with a metal hydride reagent in the presence or absence of an acid.
• the metal hydride reagent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
• 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.
• Method I is a method for producing the central skeleton portion, and is a method for producing the compound (I-II).
• R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), and m and LG have the same meanings as described above. ]
• Step I1 Step of Forming Ring This is a step of reacting compound (II) with a base to give compound (I-II).
• the base include sodium hydride, diisopropylethylamine, potassium carbonate and the like.
• the solvent include N,N-dimethylformamide, acetonitrile 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 J is a method for producing a central skeleton portion, and is a method for producing compound (J-III).
• R 2 has the same meaning as in the case of the compound of the above formula (1), and m and R O1 have the same meaning as described above. ]
• Step J1 Step of forming a ring
• the compound (JI) is reacted in the presence of a base to obtain the compound (J-II).
• the base include triethylamine and diisopropylethylamine.
• the solvent include n-butanol, toluene and the like.
• the reaction temperature is usually room temperature to 140° C., and the reaction time is usually 1 to 24 hours.
• Step J2 Step of reducing lactam to amine
• compound (J-II) is reacted with a reducing agent to obtain compound (J-III).
• the reducing agent include borane-tetrahydrofuran complex and lithium aluminum hydride.
• the solvent include tetrahydrofuran, diethyl ether and the like.
• the reaction temperature is usually about 0 to 80° C., and the reaction time is usually about 0.5 to 48 hours.
• Method K is a method for producing a central skeleton portion by protecting and deprotecting an amino-protecting group, and is a method for producing compound (KV).
• R 2 and R 2′ represent the same meaning as in the case of the compound of the above formula (1), m represents the same meaning as described above, and P N , P N1 and P N2 are amino. A protecting group for the group is shown. ]
• Step K1 Step of protecting This is a step of obtaining the compound (K-II) from the compound (KI). This step can be performed by the same method as in (G1 step).
• Step K2 Deprotection step is a step of obtaining compound (K-III) from compound (K-II). This step can be performed by the same method as in (C2 step).
• Step K3 Step of performing protection This is a step of obtaining compound (K-IV) from compound (K-III). This step can be performed by the same method as in (G1 step).
• Step K4 Step of Deprotecting Step of obtaining compound (KV) from compound (K-IV). This step can be performed by the same method as in (C2 step).
• Method L is a method relating to the production of the left chain portion and is a method of producing the compound (L-II).
• Step L1 Step of Coupling with Heterocycle This is a step of reacting compound (LI) with R 1 -A-Cl in the presence of a base to give compound (L-II).
• a 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 M is a method relating to the production of the left chain portion and is a method for producing the compound (M-II).
• R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), and m has the same meaning as above. ]
• Step M1 Step of Coupling with Heterocycle This is a step of reacting compound (MI) with a condensing agent in the presence of a base to give compound (M-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 N is a method relating to the production of the left chain portion and is a method for producing the compound (N-III).
• R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), and m has the same meaning as above. ]
• Step N1 Step of Cyanamide Formation
• the compound (NI) is reacted with cyanogen halide in the presence or absence of a base to obtain the compound (N-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 N2 Step of forming a ring
• the compound (N-II) is reacted with a metal halide, an acid and a corresponding amidoxime to obtain a compound (N-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 O is a method relating to the production of the left chain portion and is a method of producing compound (OV).
• R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), and m has the same meaning as above. ]
• Step O1 Step of Performing Carbonylation This is a step of obtaining a compound (O-II) by reacting the compound (OI) with a carbonylating agent in the presence of a base.
• compound (O-II) was shown when 4-nitrophenyl chloroformate was used as the carbonylating agent.
• 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.
• a 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.
• (O3 step) Step of amidating acylhydrazine (When using the corresponding carboxylic acid and condensing agent)
• compound (O-IV) is obtained by reacting compound (O-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 (O-IV) is obtained by reacting a compound (O-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 (O-IV) is obtained by reacting compound (O-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.
• a compound (OV) is obtained by reacting the compound (O-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 P is a method relating to the production of the left chain portion and is a method of producing the compound (PV).
• R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), and m has the same meaning as above. ]
• Step P1 Step of performing thiourea
• a reaction is performed. is there.
• 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 P2 Step of performing amidation with hydrazine From compound (P-II), in the presence or absence of a base, using hydrazine hydrate, a reaction to obtain a compound (P-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 P3 Step of amidating carbothiohydrazide This is a step of obtaining compound (P-IV) from compound (P-III). This step can be performed by the same method as in (O3 step).
• Step P4 Step of forming a ring (When using a condensing agent)
• compound (P-IV) is obtained by reacting compound (P-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.
• the compound (PV) is obtained by reacting the compound (P-IV) with a dehydrating agent.
• a 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 Q is a method relating to the production of the left chain portion and is a method of producing the compound (Q-II).
• R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), and m has the same meaning as above. ]
• Step Q1 Step of performing ring formation
• 1,1-dibromoformaldoxime and a corresponding alkyne are used to carry out a reaction to obtain a compound (Q-II) from the step of forming a ring.
• 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 R is a method for producing the left chain portion and is a method for producing compound (R-VI).
• R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), m has the same meaning as above, Ph represents a phenyl group and Imd Represents an imidazolyl group, and R x1 represents OPh or Imd. ]
• (R1 step) Step of performing coupling From compound (RI), in the presence of a base, in the presence of 1,1'-thiocarbonyldiimidazole or phenyl chlorothionoformate, the reaction is carried out to obtain compound (R-II) Is.
• the 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.
• (R2 step) Step of performing coupling Step of obtaining a compound (R-IV) from the compound (R-II), in the presence or absence of a base, using the compound (R-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 R3 Step of Performing Methylation
• the compound (R-IV) is reacted with a methylating reagent in the presence of a base to obtain the compound (RV).
• the 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 R4 Step of Performing Ring Formation
• the compound (RV) is reacted in the presence or absence of a base in the presence of hydroxylamine or its hydrochloride to obtain the compound (R-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 S is a method relating to the production of the left chain portion and is a method for producing the compound (S-III).
• R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), and m has the same meaning as above. ]
• 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-II) is reacted with a dehydrating agent in the presence or absence of a base to obtain compound (S-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 T is a method relating to the production of the left chain portion and is a method of producing the compound (T-II).
• R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), and m has the same meaning as above. ]
• Step T1 Step of performing benzoxazole ring formation From the compound (TI), in the presence of an acid or a base, in the presence of tetramethoxymethane or dichlorodiphenoxymethane, a reaction is performed to obtain a compound (T-II).
• 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 U is a method relating to the production of the left chain portion, and is a method of producing the compound (U-II).
• R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), and m and LG have the same meanings as described above. ]
• Step U1 Step of performing coupling reaction using transition metal catalyst From compound (UI), using copper or palladium catalyst, in the presence or absence of a base and a ligand, the reaction is carried out, compound (U -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 V is a method for producing the right chain portion, and is a method for producing compound (V-II).
• Step V1 Step of forming a hydantoin ring From the compound (VI), a urea-forming reagent, a corresponding amine or a hydrochloride thereof is reacted in the presence or absence of a base to give a compound (V-II).
• 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 W is a method relating to the production of the right chain portion and is a method for producing the compound (W-III) of the present invention.
• rings A, R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), m has the same meaning as described above, and R x1 is C 1 A -C6 alkyl group is shown. ]
• Step W1 Step of Urea Formation This is a step of obtaining compound (W-II) from compound (WI). This step can be performed by the same method as in (F2 step).
• Step W2 Step of Performing Ring Formation
• compound (W-III) is obtained from compound (W-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 X is a method relating to the production of the right chain portion and is a method for producing the compound (X-IV).
• rings A, R 1 , R 2 and R 2′ have the same meanings as in the case of the compound of the above formula (1), m has the same meaning as described above, and P N is amino. A protecting group for the group is shown. ]
• Step X1 Step of performing amidation
• compound (X-II) is obtained by reacting compound (XI) with a condensing agent and the corresponding amino acid 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.
• HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-t
• 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.
• (X2 step) Deprotection step (In the case of t-butoxycarbonyl (Boc) group) In this step, a compound (X-III) containing an amino group protected by a t-butoxycarbonyl group is reacted with an acid to give a compound (X-III). This step can be performed by the same method as in (C2 step).
• Step X3 Step of Performing Ring Formation
• compound (X-IV) is obtained by reacting compound (X-III) in the presence or absence of a base with a urea-forming reagent.
• a 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 Y is a method relating to the production of the left chain portion by performing transesterification, and is a method of producing the compound (Y-III).
• rings A, R 2 , R 2′ , R 3 and R 4 have the same meanings as in the case of the compound of the above formula (1), m has the same meaning as described above, and R Y1 And R Y2 represent different C1-C6 alkyl groups. ]
• Step Y1 Step of Hydrolyzing This is a step of obtaining a compound (Y-II) by reacting the compound (YI) with a base.
• the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
• the solvent include a solvent containing water (methanol, ethanol, tetrahydrofuran, etc.), water, 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.
• compound (Y-III) is obtained by reacting compound (Y-II) with a corresponding alkylating reagent in the presence of a base.
• the alkylating reagent include alkyl halides such as alkyl iodide and alkyl bromide, and sulfonic acid esters 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.
• a compound (Y-III) is obtained by reacting the compound (Y-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.
• 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 daily dose of about 0.0001-10 mg/kg of body weight is appropriate, 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.
• 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, Add 10 ⁇ L of a mixture of AL138, final concentration: 10 ⁇ g/mL) and AlphaScreen Streptavidin Donor beads (PerkinElmer, 6760002, final concentration: 5 ⁇ g/mL), react at room temperature for 60 minutes, then stop the reaction and acetylate. 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.
• Boc tert-butoxycarbonyl group
• Cbz benzyloxycarbonyl group
• Alloc allyloxycarbonyl group
• Methyl 3-nitro-1H-pyrazole-5-carboxylate (CAS registry number: 181585-93-3) (20 g) was dissolved in acetone (600 mL), and potassium carbonate (34 g) and tert were added under nitrogen atmosphere.
• -Butyl (2-bromoethyl)carbamate (32 g) was sequentially added at 0°C, and the mixture was stirred at 0°C for 30 minutes and then at 60°C for 12 hours. After filtration of the reaction mixture, the solvent was distilled off from the filtrate under reduced pressure, the resulting residue was triturated with ethyl acetate and collected by filtration to obtain 19 g of the title compound (yield: 49%). Obtained as a white solid.
• N,O-Dimethylhydroxylamine hydrochloride (6.50 g) and triethylamine (10 mL) were suspended in N,N-dimethylformamide (250 mL), and the mixture was stirred at room temperature for 30 minutes.
• the reaction mixture was charged with 1- ⁇ 2-[(tert-butoxycarbonyl)amino]ethyl ⁇ -3-nitro-1H-pyrazole-5-carboxylic acid (18.0 g) of Example 1(1b), 1-hydroxybenzotriazole.
• Monohydrate (11.0 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.8 g) were sequentially added, and the mixture was stirred at room temperature for 12 hours.
• the solvent was distilled off from the reaction mixture under reduced pressure, water was poured into the obtained residue, and the reaction mixture was extracted three 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 and the obtained residue was triturated with ethyl acetate and collected by filtration to give the title compound (19.0 g, yield: 90%) as a white solid.
• Example 1(1c) The tert-butyl (2- ⁇ 5-[methoxy(methyl)carbamoyl]-3-nitro-1H-pyrazol-1-yl ⁇ ethyl)carbamate (19.0 g) of Example 1(1c) was added to methanol (200 mL). It melt
• N-methyl-N'-(4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)urea of Example 1 (1 g) urea (9.87 g) was added to methanol (100 mL). , Sodium borohydride (3.49 g) was added at 0° C., and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was slowly added to the reaction mixture, 1 M hydrochloric acid (100 mL) was added, the mixture was concentrated under reduced pressure, and methanol was evaporated. The aqueous layer containing the title compound was used in the next step without further purification.
• Example 1 N-(5-cyano-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-N'-methylurea of Example 1 (1k) (1.50 g ), Example 1 (1n) methyl 4-(N'-hydroxycarbamimidoyl)bicyclo[2.2.2]octane-1-carboxylate (1.59 g) and zinc chloride (1.15 g) N,N-dimethyl The formamide (40 mL) suspension was stirred under a nitrogen atmosphere at 60°C for 2 hours. Subsequently, concentrated sulfuric acid (1 mL) was added to the reaction mixture, and the mixture was stirred at 80° C. for 5.5 hours.
• 5-Bromo-2-chloropyrimidine (CAS Registry Number: 32779-36-5) (3.87 g) was dissolved in a mixed solvent of acetone (30 mL)/water (30 mL), and tetrahydrofuran-2-carboxylic acid (11.6 g) and potassium peroxodisulfate (16.2 g) were added, and the mixture was stirred at 120° C. for 4 hours. Water was added to the reaction mixture, which was extracted 3 times with dichloromethane and dried over anhydrous sodium sulfate.
• Example 2(2a) 5-(5-Bromo-2-chloropyrimidin-4-yl)oxolane-2-carboxylic acid (0.53 g) of Example 2(2a) was dissolved in methanol (10 mL), and trimethylsilyldiazomethane (0.60) was added at room temperature. Mn-hexane solution, 4.0 mL) was added dropwise, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, which was extracted 3 times with dichloromethane and dried over anhydrous sodium sulfate.
• Example 2(2b) Methyl 5-(5-bromo-2-chloropyrimidin-4-yl)oxolane-2-carboxylate (0.350 g) of Example 2(2b) was dissolved in 1-methyl-2-pyrrolidone (1.5 mL), N-Methyl-N'-(4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)urea monohydrochloride of Example 1(1j) (0.320 g ) And N,N-diisopropylethylamine (1.90 mL) were added, and the mixture was stirred at 120°C for 2 hr.
• 1-methyl-2-pyrrolidone 1.5 mL
• N-Methyl-N'-(4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)urea monohydrochloride of Example 1(1j) (0.
• 5-Bromo-2-chloropyrimidine (CAS Registry Number: 32779-36-5) (20.0 g) was dissolved in a mixed solvent of acetone (200 mL)/water (100 mL) to give oxan-4-one (52.3 g ) And potassium peroxodisulfate (34.0 g) were added, and the mixture was stirred at 100° C. for 10 hr. The solvent was distilled off from the reaction mixture under reduced pressure, aqueous sodium carbonate solution 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 3(3a) 2-(5-Bromo-2-chloropyrimidin-4-yl)oxan-4-one (5.5 g) of Example 3(3a) was dissolved in dichloromethane (100 mL), and at 0° C. (diethylamino)sulfur. Trifluoride (8.5 g) was slowly added dropwise, and the mixture was stirred at 0°C to room temperature for 2 hr. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution, and the reaction mixture was extracted with dichloromethane three times. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate.
• Example 3 Sodium hydrogen carbonate (10 g) and benzyl chloroformate (10 mL) were dissolved in a mixed solvent of tetrahydrofuran (80 mL)/water (50 mL), and tert-butyl 2-amino-6 of Example 3 (3 g) was used.
• a tetrahydrofuran solution (20 mL) of 7,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (10 g) was added at 0°C, and the mixture was stirred at 0°C to room temperature for 10 hours. ..
• Example 3 (3i) benzyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylcarbamate hydrochloride (7.0 g) was dissolved in dimethyl sulfoxide (100 mL) 5-Bromo-2-chloro-4-(4,4-difluorooxan-2-yl)pyrimidine of Example 3(3b) (5.5 g) and N,N-diisopropylethylamine (15 mL) were added, and the temperature was changed to 80°C. The mixture was stirred for 12 hours. The reaction mixture was poured into water, stirred at room temperature for 30 minutes, and the precipitated solid was collected by filtration. Subsequently, the solid collected by filtration was triturated with petroleum ether/ethyl acetate and collected by filtration to obtain 6.3 g (yield: 86%) of the title compound as a yellow solid.
• Example 4(4a) 4,4-Difluorocyclohexane-1-carbonitrile (0.70 g) of Example 4(4a) 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 4 prop-2-en-1-yl (4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)carbamate (14.5 g) was added to methanol (15 (mL)/dichloromethane (150 mL) mixed solvent, sodium borohydride (3.0 g) was added at 15°C, and the mixture was stirred at 15°C for 30 min. The solvent was distilled off from the reaction mixture under reduced pressure, acetonitrile was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure to give the title compound (14 g, yield: 96%) as a white solid.
• reaction mixture was poured into water, the reaction mixture was extracted three times with ethyl acetate, the combined organic layers were washed successively 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 (6.4 g, yield: 67%) as a yellow solid.
• Example 4(4i) 5-[3-(4,4-Difluorocyclohexyl)-1,2,4-oxadiazol-5-yl]-4-methyl-4,5,6,7-tetrahydropyra of Example 4(4i)
• zolo[1,5-a]pyrazin-2-amine 5.2 g
• 1-amino-2-methyl-2-propanol 4.2 g
• 3,4-Dihydro-2H-pyran-5-boronic acid pinacol ester (CAS Registry number: 1046811-99-7) (10 g), 2,4-dichloropyrimidine (6.2 g), and potassium carbonate (12.3 g) was suspended in a mixed solution of 1,4-dioxane (100 mL)/water (20 mL), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (CAS Registry number: 95464 -05-4) (1.6 g) was added under a nitrogen atmosphere, and the mixture was stirred at 70°C for 12 hr.
• 5-Methoxybenzoxazole (CAS Registry number: 132227-03-3) (2.4 g) is suspended in tetrahydrofuran (50 mL), and lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 16 mL) is slowly added dropwise at -78°C. did. After stirring at -78°C for 20 minutes, hexachloroethane (5.7 g) was added, and the mixture was stirred at -78°C for 10 minutes and at room temperature for 1 hour. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
• Example 10 (10c) tert-butyl [2-(5-acetyl-3- ⁇ [(benzyloxy)carbonyl]amino ⁇ -1H-pyrazol-1-yl)ethyl]carbamate (150g) By a method similar to that in Example 1 (1 g), 102 g (yield: 96%) of the title compound was obtained as a pale yellow solid.
• Example 10 Using benzyl (4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-2-yl)carbamate (102g) of Example 10 (10d), the same as Example 1 (1h) By the method, 97 g of the title compound (yield: 96%) was obtained as a white solid.
• Example 10(10e) Benzyl (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)carbamate of Example 10(10e) (1.8 g) in dimethyl sulfoxide (20 mL) After dissolution, 2-chloro-5-methoxy-1,3-benzoxazole (1.3 g) and N,N-diisopropylethylamine (5.5 mL) of Example 10 (10a) were added, and the mixture was allowed to stand at room temperature overnight. Water was added to the reaction mixture, the precipitated solid was collected by filtration, and the obtained solid was washed with ethyl acetate to obtain the title compound (2.15 g, yield: 79%) as a pale yellow solid.
• Example 10 (10 g) of 5-(5-(5-methoxy-1,3-benzoxazol-2-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a ] Pyrazin-2-amine (0.5 g) was dissolved in dichloromethane (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and 4-nitrophenyl chloroformate (0.4 g) were added, and the mixture was left at room temperature overnight. The precipitated solid was collected by filtration and washed successively with water and ethyl acetate to give the title compound (0.7 g, yield: 90%) as a yellow solid.
• Example 10(10e) Benzyl (4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)carbamate (168 g) of Example 10(10e) was dissolved in dichloromethane (2 L). Then, triethylamine (245 mL) and di-tert-butyl dicarbonate (141 g) were sequentially added at room temperature, and the mixture was stirred at room temperature for 16 hours. Di-tert-butyl dicarbonate (76.8 g) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water, and the organic layer was dried over anhydrous sodium sulfate.
• Example 12(12b) Tert-Butyl 2-amino-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (3.5 g) of Example 12(12b) was added to dichloromethane (10 mL). ), a 4 M hydrogen chloride-1,4-dioxane solution (20 mL) was added, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure to obtain 2.5 g of the title compound (yield: 96%) as a white solid.
• Example 12(12c) 4-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine dihydrochloride of Example 12(12c) (1.08 g), 5 of Example 6(6a) -Bromo-2-chloro-4-(oxan-2-yl)pyrimidine (1.35 g) and dimethylsulfoxide (10 mL) were added with N,N-diisopropylethylamine (2.7 mL) and the mixture was heated at 100°C for 12 hours. It was stirred. The reaction mixture was added to water, extracted 5 times with ethyl acetate, the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate.
• Example 17 (17a) Methyl 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate (400 mg) of Example 17 (17a) was dissolved in methanol (10 mL) and water (2 mL), and lithium hydroxide ( 220 mg) was added, and the mixture was stirred at room temperature for 10 hours. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH 1 with 1 M hydrochloric acid and 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 give the title compound (320 mg, yield: 92%) as a pale yellow oil.
• Example 17(17b) 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid of Example 17(17b) was synthesized in the same manner as in Example 1(1l), 1(1m), 1(1n) 3-( Difluoromethyl)-N'-hydroxybicyclo[1.1.1]pentane-1-carboximidamide (1.52g), and prop-2-en-1-yl (5-cyano-4- of Example 4 (4g)) Using methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl ⁇ carbamate (1.3g), the title compound 1.0 was obtained in the same manner as in Example 4(4h). g (yield: 43%) was obtained as a yellow solid.
• Example 10 (10 g) of 5-(5-methoxy-1,3-benzoxazol-2-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine- 2-Amine (0.20 g) was dissolved in N,N-dimethylformamide (4 mL), 1,1′-carbonyldiimidazole (0.22 g) was added, and the mixture was left at room temperature overnight. (R)-3-Aminotetrahydrofuran (0.17 g) was added and the mixture was stirred at room temperature for 3 hours.
• Example 20-37 The compounds of Examples 20-37 were synthesized according to the above general production method and Example 1-19. The names of the synthesized compounds are shown below. The structures of the synthesized compounds are shown in Tables 3-1 to 3-3.
• Example 20 N-[(1r,3r)-3-Hydroxycyclobutyl]-N'-(5- ⁇ 4-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl ⁇ -4,5,6,7 -Tetrahydropyrazolo[1,5-a]pyrazin-2-yl)urea
• Example 21 1-[5-(5-chloro-1,3-benzoxazol-2-yl)-4-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl]-3 -Methyl-urea
• Example 22 N-(5- ⁇ 5-[3-(difluoromethyl)phenyl]-1,2-oxazol-3-yl ⁇ -4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a ]Pyrazin-2-yl)-N'-[(3R)-oxo

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