WO2023145804A1 - 新規なｂ０ａｔ１阻害剤 - Google Patents

新規なｂ０ａｔ１阻害剤 Download PDF

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Publication number
WO2023145804A1
WO2023145804A1 PCT/JP2023/002387 JP2023002387W WO2023145804A1 WO 2023145804 A1 WO2023145804 A1 WO 2023145804A1 JP 2023002387 W JP2023002387 W JP 2023002387W WO 2023145804 A1 WO2023145804 A1 WO 2023145804A1
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group
optionally substituted
substituent
alkyl
substituted
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PCT/JP2023/002387
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English (en)
French (fr)
Japanese (ja)
Inventor
秀憲 轟木
崇史 齋藤
一成 下岡
孝博 山田
謙二 福永
廉太郎 菅野
拓也 今津
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Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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Priority to JP2023576967A priority Critical patent/JPWO2023145804A1/ja
Priority to EP23747014.1A priority patent/EP4470533A4/en
Priority to CN202380018988.1A priority patent/CN118678949A/zh
Priority to US18/833,439 priority patent/US20250170126A1/en
Publication of WO2023145804A1 publication Critical patent/WO2023145804A1/ja
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to novel cinnamic acid glycinamide compounds that have an inhibitory effect on the neutral amino acid transporter B0AT1 and are useful for the prevention and/or treatment of B0AT1-associated amino acid metabolism disorders.
  • the causative gene of Hartnup disease, SLC6A19 is located at 5p15.33 and consists of 12 exons. Its gene product, the neutral amino acid transporter B0AT1, consists of 634 amino acids and has 12 transmembrane sites (Non-Patent Documents 1 and 2). B0AT1 is a major transporter of neutral amino acids in the small intestine and kidney, and is responsible for the absorption of glycine, leucine, phenylalanine, etc. in the small intestine and their reabsorption in the kidney (Non-Patent Documents 3-5).
  • B0AT1 knockout mice are known to exhibit high urinary amino acid levels (Non-Patent Document 6), and clinically, B0AT1 dysfunction causes severe neutral amino aciduria known as Hartnup's disease described above (non-patent document 6). Patent Document 7). Therefore, the inhibition of B0AT1 has been considered to improve (alleviate) various diseases or pathological conditions associated with neutral amino acids, which are transport substrates.
  • phenylketonuria model mice can be improved by either congenitally deficient in B0AT1 or by administering a nucleic acid compound that binds to mRNA to suppress its expression acquiredly (non Patent document 4) and other publications have also reported specific examples of the therapeutic effect of disease by suppressing the function of B0AT1.
  • Amino acid metabolism disorders include, for example, phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia designated intractable diseases such as dysentery, methylmalonic acidemia, isovaleric acidemia, etc., and continuous diet therapy is mainly known as a treatment for these diseases.
  • continuous diet therapy is mainly known as a treatment for these diseases.
  • administration of drugs that increase coenzymes and enzymes, and enzyme injections are also known, but none of them are fundamental treatments (for example, Non-Patent Document 8, etc.).
  • compounds having B0AT1 inhibitory activity include, for example, nucleic acids having a sequence that partially or completely matches RNA of B0AT1 (Non-Patent Document 4), existing marketed products of nimesulide and its derivatives (Non-Patent References 9 and 10), Synlomide which is a known compound (Non-Patent Reference 11), basic compounds found in library screening (Non-Patent References 12 and 13), and the like are known.
  • Non-Patent Document 4 Non-Patent Document 4
  • Non-Patent References 9 and 10 existing marketed products of nimesulide and its derivatives
  • Synlomide which is a known compound
  • basic compounds found in library screening Non-Patent References 12 and 13
  • the like are known.
  • the cinnamic acid glycinamide compound according to the present invention exhibits B0AT1 inhibitory activity.
  • An object of the present invention is to provide a medicament capable of preventing and/or treating diseases, specifically amino acid metabolism disorders, which exhibit excellent B0AT1 inhibitory action and whose symptoms can be alleviated by this action.
  • R 1 is a halogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, substituted optionally substituted C 3-8 cycloalkyloxy group, optionally substituted C 1-6 alkylsulfanyl group, optionally substituted C 3-8 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted represents an optionally substituted C 6-14 aryl group or an optionally substituted 5- to 6-membered aromatic heterocyclic group; n Xs each independently represent a fluorine atom or a chlorine atom; n represents an integer of 0 to 2; and R 2 represents a C 1-6 alkyl group optionally substituted with a substituent selected from substituent group a, and R 3 represents a substituent group represents a C 1-6 alkyl group optionally substituted by a substituent selected from a or a C
  • Substituent group b halogen atom; hydroxy group; cyano group; carboxy group; oxo group; thioxo group; an amino group optionally substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkyl-carbonyl group and a C 1-6 alkoxy-carbonyl group; a C 1-6 alkyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group and a C 1-6 alkoxy group; a C 1-6 alkoxy group optionally substituted with a halogen atom; a C 1-6 alkylsulfonyl group optionally substituted with a halogen atom; a C 1-6 alkyl-carbonyl group optionally substituted with a halogen atom; C 1-6 alkoxy-carbonyl group; substituted with 1 to 2 C 1-6 alkyl groups optionally substitute
  • R 1 is a halogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, substituted optionally substituted C 3-8 cycloalkyloxy group, optionally substituted C 1-6 alkylsulfanyl group, optionally substituted C 3-8 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted represents an optionally substituted C 6-14 aryl group or an optionally substituted 5- to 6-membered aromatic heterocyclic group; n Xs each independently represent a fluorine atom or a chlorine atom; n represents an integer of 0 to 2; and R 2 represents a C 1-6 alkyl group optionally substituted with a substituent selected from substituent group a, and R 3 represents a substituent group represents a C 1-6 alkyl group optionally substituted by a substituent selected from a or a C
  • Substituent group b halogen atom; hydroxy group; cyano group; carboxy group; oxo group; thioxo group; an amino group optionally substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkyl-carbonyl group and a C 1-6 alkoxy-carbonyl group; a C 1-6 alkyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group and a C 1-6 alkoxy group; a C 1-6 alkoxy group optionally substituted with a halogen atom; a C 1-6 alkylsulfonyl group optionally substituted with a halogen atom; a C 1-6 alkyl-carbonyl group optionally substituted with a halogen atom; C 1-6 alkoxy-carbonyl group; substituted with 1 to 2 C 1-6 alkyl groups optionally substitute
  • a B0AT1 inhibitor comprising a compound represented by or a pharmaceutically acceptable salt thereof.
  • R 1 is a C 2-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkoxy group, halo C 2-6 alkoxy group, C 3-6 cycloalkyloxy group , C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted with a halogen atom a C 6-14 aryl group which may be substituted, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with a halogen atom or a C 1-6 alkyl group, and n is 0
  • R 2 is a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the substituent group a, and R 3 is 1 to 3 selected from the substituent group a
  • the B0AT1 inhibitor according to any one of [1] to [3] above, which is a C 1-4 alkyl group optionally substituted with one substituent.
  • R 2 and R 3 are bonded to each other and optionally substituted with 1 to 3 substituents selected from the above substituent group b together with the nitrogen atom to which they are bonded, the following formula:
  • Y and Z each independently represent a carbon atom or a nitrogen atom
  • ring A represents a 5- to 8-membered non-aromatic heterocyclic ring
  • ring B represents a 5- to 6-membered non-aromatic heterocyclic ring or aromatic heterocyclic ring, or represents a benzene ring
  • m represents an integer of 0 to 3
  • * represents a bonding site with a carbonyl group.
  • Amino acid metabolism disorders such as phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia disease, methylmalonic acidemia, or isovaleric acidemia, the pharmaceutical composition of the above [9].
  • R 1′ is a C 2-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkoxy group, a halo C 2-6 alkoxy group, a C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, halogen atom represents an optionally substituted C 6-14 aryl group, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with a halogen atom or a C 1-6 alkyl group; n'X' each independently represents a fluorine atom or a chlorine atom; n' represents an integer of 0 to 2; and R 2' represents
  • Substituent group b halogen atom; hydroxy group; cyano group; carboxy group; oxo group; thioxo group; an amino group optionally substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkyl-carbonyl group and a C 1-6 alkoxy-carbonyl group; a C 1-6 alkyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group and a C 1-6 alkoxy group; a C 1-6 alkoxy group optionally substituted with a halogen atom; a C 1-6 alkylsulfonyl group optionally substituted with a halogen atom; a C 1-6 alkyl-carbonyl group optionally substituted with a halogen atom; C 1-6 alkoxy-carbonyl group; substituted with 1 to 2 C 1-6 alkyl groups optionally substitute
  • R 1′′ is a halogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, substituted optionally substituted C 3-8 cycloalkyloxy group, optionally substituted C 1-6 alkylsulfanyl group, optionally substituted C 3-8 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted represents an optionally substituted C 6-14 aryl group, or an optionally substituted 5- to 6-membered aromatic heterocyclic group; n''X'' each independently represents a fluorine atom or a chlorine atom; n′′ represents an integer from 0 to 2; and R 2′′ is (i) a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group optionally substituted with a substituent selected from substituent group c, and (ii) a substituent selected from substituent group b substituted
  • Substituent group b halogen atom; hydroxy group; cyano group; carboxy group; oxo group; thioxo group; an amino group optionally substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkyl-carbonyl group and a C 1-6 alkoxy-carbonyl group; a C 1-6 alkyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group and a C 1-6 alkoxy group; a C 1-6 alkoxy group optionally substituted with a halogen atom; a C 1-6 alkylsulfonyl group optionally substituted with a halogen atom; a C 1-6 alkyl-carbonyl group optionally substituted with a halogen atom; C 1-6 alkoxy-carbonyl group; substituted with 1 to 2 C 1-6 alkyl groups optionally substitute
  • Y' and Z' each independently represent a carbon atom or a nitrogen atom
  • Ring A′ represents a 5- to 8-membered non-aromatic heterocyclic ring
  • Ring B′ represents a 5- to 6-membered non-aromatic heterocyclic ring or aromatic heterocyclic ring
  • m' represents an integer of 0 to 3
  • *' represents a bonding site with a carbonyl group.
  • Phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia The pharmaceutical composition according to [18] above, for use in treating and/or preventing a disease selected from the group consisting of dysentery and isovaleric acidemia.
  • [22] The pharmaceutical composition according to any one of [8] to [11] and [18] to [21] above, which is administered in combination with another drug.
  • the pharmaceutical composition according to any one of [26] The above-mentioned [ 22] to the pharmaceutical composition according to any one of [24].
  • [27] The pharmaceutical composition according to any one of [22] to [26] above, for use in treating and/or preventing amino acid metabolism disorders.
  • [29] A pharmaceutical composition containing the pharmaceutical composition according to any one of [8] to [11] and [18] to [21] above and another drug. [30] The pharmaceutical composition of [29] above for use in treating and/or preventing amino acid metabolism disorders. [31] Phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia The pharmaceutical composition according to [29] above for use in treating and/or preventing a disease selected from the group consisting of disease and isovaleric acidemia.
  • a method for preventing or treating amino acid metabolism disorders in a mammal which comprises administering an effective amount of the B0AT1 inhibitor according to any one of [1] to [7] above to the mammal.
  • method of prevention or treatment of [34] A method for preventing or treating amino acid metabolism disorders in a mammal, which comprises administering an effective amount of the compound or salt thereof according to any one of [12] to [17] above to the mammal.
  • Phenylketonuria hypertyrosinemia (1 -3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia and isovaleric acidemia
  • An effective amount of the pharmaceutical composition according to any one of [8] to [11] and [18] to [21] above and another agent are simultaneously or sequentially administered to a mammal.
  • Phenylketonuria hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia
  • B0AT1 inhibitor according to any one of the above [1] to [7] for manufacturing a therapeutic or preventive agent for a disease selected from the group consisting of disease and isovaleric acidemia.
  • Phenylketonuria hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia
  • a therapeutic or prophylactic agent for a disease selected from the group consisting of dysentery and isovaleric acidemia.
  • Phenylketonuria hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia
  • a pharmaceutical composition containing the compound relieves symptoms by B0AT1 inhibitory action. It is useful for the treatment and/or prevention of diseases that can Examples of such diseases include phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, Examples include amino acid metabolic disorders such as methylmalonic acidemia and isovaleric acidemia. These amino acid metabolism disorders are designated intractable diseases that require long-term treatment such as a very strict diet (amino acid-restricted diet) that lasts for life. Such salts may provide novel and effective prophylactic and/or therapeutic agents.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • alkyl (group) means a linear or branched monovalent group having 1 or more carbon atoms in which one hydrogen atom is removed from any carbon atom of an alkane, Unless otherwise specified, it is a C 1-20 alkyl group, preferably a C 1-6 alkyl group.
  • C 1-20 alkyl (group) means an alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl , undecyl, dodecyl, tridecyl, eicosyl and the like.
  • C 1-6 alkyl (group) means an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -butyl, pentyl, isopentyl, neopentyl, sec-pentyl (pentan-2-yl), 3-pentyl (pentan-3-yl), tert-pentyl (1,1-dimethylpropyl), hexyl, isohexyl, 1,1 -dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 1-4 alkyl (group) means an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -Butyl and the like.
  • haloalkyl (group) means that one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms in the alkyl group are halogen. means a substituted group. Specifically, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl , pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6 , 6-trifluorohexyl and the like. Among them, “haloC 1-6 alkyl” is preferred, and “haloC 1-4 alkyl” is more preferred.
  • cycloalkyl (group) means a cyclic alkyl group, preferably a C 3-8 cycloalkyl group, unless the carbon number range is particularly limited.
  • C 3-8 cycloalkyl (group) means a cyclic alkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. are mentioned. Among them, a C 3-6 cycloalkyl group is preferred.
  • C 3-8 cycloalkyloxy (group) means a group in which the above C 3-8 cycloalkyl group is bonded to an oxygen atom, specifically, for example, cyclopropyloxy , cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
  • C 3-8 cycloalkylsulfanyl (group) means a group in which the above C 3-8 cycloalkyl group is bonded to a sulfur atom, specifically, for example, cyclopropylsulfanyl , cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, cyclooctylsulfanyl and the like.
  • alkoxy (group) means a group in which a straight-chain or branched-chain alkyl group is bonded to an oxygen atom. group, preferably a C 1-6 alkoxy group.
  • C 1-6 alkoxy (group) means an alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Among them, a C 1-4 alkoxy group is preferred.
  • haloalkoxy (group) means a group in which one or more hydrogen atoms in the alkoxy group are substituted with halogen.
  • haloC 1-6 alkoxy is preferred, and “haloC 1-4 alkoxy” is more preferred.
  • alkylsulfanyl (group) means a group in which a straight or branched chain alkyl group is bonded to a sulfur atom, preferably a C 1-6 alkylsulfanyl group.
  • C 1-6 alkylsulfanyl (group) means an alkylsulfanyl group having 1 to 6 carbon atoms, such as methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, neopentylsulfanyl, hexylsulfanyl and the like.
  • haloalkylsulfanyl (group) means a group in which one or more hydrogen atoms in the alkylsulfanyl group are substituted with halogen.
  • fluoromethylsulfanyl difluoromethylsulfanyl, trifluoromethylsulfanyl, 2-chloroethylsulfanyl, 2-bromoethylsulfanyl, 2-iodoethylsulfanyl, 2-fluoroethylsulfanyl, 2,2-difluoroethyl Sulfanyl, 2,2,2-trifluoroethylsulfanyl, pentafluoroethylsulfanyl, 2,2,3,3-tetrafluoropropylsulfanyl, 3,3,3-trifluoropropylsulfanyl, 4,4,4-trifluoro butylsulfanyl, 5,5,5-
  • C 1-6 alkylsulfonyl (group) includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentyl sulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl and the like.
  • alkyl-carbonyl (group) means a group in which the above alkyl group is bonded to a carbonyl group, and the carbon number range is not particularly limited, but preferably a C 1-6 alkyl-carbonyl group is.
  • alkoxy-carbonyl (group) means a group in which the alkoxy group is bonded to a carbonyl group, and the carbon number range is not particularly limited, but preferably a C 1-6 alkoxy-carbonyl group is.
  • carbamoyl (group) optionally substituted with 1 to 2 C 1-6 alkyl groups means that 1 or 2 hydrogen atoms of the carbamoyl group (—CONH 2 ) are respectively It independently means a group optionally substituted on the C 1-6 alkyl group, preferably a mono- or di-C 1-6 alkyl-carbamoyl group.
  • aryl (group) means a monocyclic or polycyclic (condensed) hydrocarbon group exhibiting aromaticity, and specifically includes, for example, phenyl, 1-naphthyl, Examples thereof include C 6-14 aryl groups such as 2-naphthyl, biphenylyl, 2-anthryl, fluorenyl, etc. Among them, C 6-10 aryl groups are preferred.
  • C 6-10 aryl (group) includes, for example, phenyl, 1-naphthyl and 2-naphthyl, with phenyl being preferred.
  • aryl-carbonyl (group) means a group in which the above aryl group is bonded to a carbonyl group, and the carbon number range is not particularly limited, but preferably a C 6-14 aryl-carbonyl group is.
  • C 6-14 aryloxy (group) means a group in which the above C 6-14 aryl group is bonded to an oxygen atom, and specific examples include phenyloxy, 1- naphthyloxy, 2-naphthyloxy, biphenylyloxy, 2-anthryloxy and the like. Among them, a phenyloxy group is particularly preferred.
  • C 7-18 aralkyl (group) means a group in which the above C 6-14 aryl group is bonded to the above C 1-4 alkyl group, specifically, for example, benzyl , phenethyl, naphthylmethyl, biphenylylmethyl and the like. Among them, a C 7-10 aralkyl group is preferred, and a benzyl group is particularly preferred.
  • C 7-18 aralkyloxy (group) means a group in which the above C 7-18 aralkyl group is bonded to an oxygen atom, and specific examples include benzyloxy, phenethyloxy , naphthylmethyloxy, biphenylylmethyloxy and the like. Among them, a benzyloxy group is particularly preferred.
  • acyl (group) means a formyl group, a linear or branched alkyl-carbonyl group, or an aryl-carbonyl group, and the carbon number range is not particularly limited, but preferably , a formyl group, a C 1-6 alkyl-carbonyl group, or a C 6-14 aryl-carbonyl group.
  • acyl (group) include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl (pivaloyl), hexanoyl, heptanoyl, benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
  • acyloxy (group) means a group in which the above acyl group is bonded to an oxygen atom, preferably a C 1-6 alkyl-carbonyloxy group or a C 6-14 aryl-carbonyloxy is the base.
  • amino (group) optionally substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group It means an unsubstituted amino group, or a group in which 1 to 2 hydrogen atoms of an amino group are substituted with the above C 1-6 alkyl group and/or C 1-6 alkoxy-carbonyl group.
  • heterocyclic ring (group) includes, for example, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring-constituting atoms (i ) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, (iii) 6- to 10-membered bridged cyclic non-aromatic heterocyclic groups, and (iv) 6- to 12-membered spirocyclic non-aromatic groups. heterocyclic groups.
  • aromatic heterocyclic group includes, for example, a 5- to 14-membered heteroatom containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring-constituting atoms. and aromatic heterocyclic groups.
  • aromatic heterocyclic group examples include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, , 3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, 5- or 6-membered monocyclic aromatic heterocyclic groups such as triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyri
  • non-aromatic heterocyclic group includes, for example, 3 to 14 heteroatoms containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring-constituting atoms. membered non-aromatic heterocyclic groups.
  • non-aromatic heterocyclic group examples include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuryl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidyl, piperazinyl, tetrahydropyridyl, dihydropyridyl, dihydrothiopyranyl, tetrahydropyrimidinyl, t
  • non-aromatic heterocyclic group examples include pyrrolidinyl, piperidyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 1,2,3 ,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, 1,2,3,4-tetrahydro- 2,7-naphthyridinyl and the like.
  • preferred examples of the "6- to 10-membered bridged non-aromatic heterocyclic group" include 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2 .2.2]octyl, 7-azabicyclo[2.2.1]heptanyl, quinuclidinyl and the like.
  • preferred examples of the "6- to 12-membered spirocyclic non-aromatic heterocyclic group" include 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[3.5 ] nonyl, 2,6-diazaspiro[3.3]heptyl and the like.
  • nitrogen-containing aromatic heterocyclic group or “nitrogen-containing non-aromatic heterocyclic group” means that the aromatic heterocyclic group or non-aromatic heterocyclic group has at least one nitrogen atom as a ring-constituting atom.
  • trisubstituted silyl (group) means a silyl group substituted with three identical or different substituents (e.g., C 1-6 alkyl group, C 6-10 aryl group, etc.)
  • substituents e.g., C 1-6 alkyl group, C 6-10 aryl group, etc.
  • groups include, for example, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a trialkylsilyl group such as a tert-butyldimethylsilyl group (preferably a tri-C 1-6 alkylsilyl group), tert-butyl diphenylsilyl group, triphenylsilyl group, and the like.
  • trisubstituted silyloxy (group) means a group in which a trisubstituted silyl group is bonded to an oxygen atom, and examples of such groups include a trimethylsilyloxy group, a triethylsilyloxy group, and a triisopropylsilyl oxy group, trialkylsilyloxy group such as tert-butyldimethylsilyloxy group (preferably tri-C 1-6 alkylsilyloxy group), tert-butyldiphenylsilyloxy group, triphenylsilyloxy group and the like.
  • substituent means unsubstituted or substituted with a specific substituent at any substitutable position (any hydrogen atom is replaced with a substituent) means The "substituent” is not particularly limited, but the following (substituent group a), (substituent group a'), (substituent group a''), (substituent group b), (substituent group c ) and (substituent group d). If no particular substituent group is specified, it means that it may be substituted with one or more substituents selected from the following (substituent group d).
  • the number of substituents is not particularly limited as long as it can be substituted, but it is usually 1 to 5, preferably 1 to 3. When multiple substituents are present, each substituent may be the same or different.
  • Substituent group a' hydroxy group; carboxy group; a C 1-6 alkoxy group optionally substituted with a halogen atom (e.g., methoxy group, ethoxy group); substituted with 1 to 2 C 1-6 alkyl groups optionally substituted by a substituent selected from the group consisting of a hydroxy group, a di-C 1-6 alkylamino group and a C 1-6 alkoxy group carbamoyl group (e.g., methylcarbamoyl group, dimethylcarbamoyl group); a C 1-6 alkylsulfonyl group optionally substituted by a halogen atom (eg, a methylsulfonyl group); A 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group c (e.g., pyridazinyl group, pyrazolyl group, thiazolyl group,
  • Substituent group a'' hydroxy group; carboxy group; a C 1-6 alkoxy group optionally substituted with a halogen atom (e.g., methoxy group, ethoxy group); substituted with 1 to 2 C 1-6 alkyl groups optionally substituted by a substituent selected from the group consisting of a hydroxy group, a di-C 1-6 alkylamino group and a C 1-6 alkoxy group a carbamoyl group (eg, methylcarbamoyl group, dimethylcarbamoyl group) which may be substituted; and a C 1-6 alkylsulfonyl group optionally substituted with a halogen atom (eg, methylsulfonyl group).
  • Substituent group b halogen atom; hydroxy group; cyano group; carboxy group; oxo group; thioxo group; an amino group optionally substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkyl-carbonyl group and a C 1-6 alkoxy-carbonyl group; a C 1-6 alkyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group and a C 1-6 alkoxy group; a C 1-6 alkoxy group optionally substituted with a halogen atom; a C 1-6 alkylsulfonyl group optionally substituted with a halogen atom; a C 1-6 alkyl-carbonyl group optionally substituted with a halogen atom; C 1-6 alkoxy-carbonyl group; substituted with 1 to 2 C 1-6 alkyl groups optionally substitute
  • substituted halogen atom; hydroxy group; carboxy group; nitro group; cyano group; an amino group optionally substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group; a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from substituent group a; a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from substituent group a; C 1-6 alkoxy-carbonyl group; a C 1-6 alkylsulfonyl group optionally substituted with 1 to 3 substituents selected from substituent group a; a C 3-8 cycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group b; an acyl group optionally substituted with 1 to 3 substituents selected from substituent group a; an acyloxy group optionally substituted with 1 to 3 substituents selected from substituent group a; an
  • (substituent group d) represents an optional substituent of “optionally substituted C 1-6 alkyl group” or “optionally substituted C 1-6 alkoxy group”
  • “substituted Other than a C 1-6 alkyl group optionally substituted with a substituent selected from group a and a C 7-18 aralkyl group optionally substituted with a substituent selected from group b means a substituent of
  • a pharmaceutically acceptable salt thereof means a salt that can be used as a pharmaceutical.
  • the compound (I) of the present invention has an acidic group or basic group, it can be converted into a basic salt or an acidic salt by reacting with a base or an acid, so the salt is shown. Salts are preferably water-soluble.
  • Pharmaceutically acceptable "basic salts" of the compound (I) of the present invention include, for example, alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salts such as ammonium salts and tetramethylammonium salts; N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidine salts, pyridine salts, 4-pyrrolidinopyridine salts, Examples include organic base salts such as picoline salts, etc., preferably alkali metal salts.
  • alkali metal salts such as sodium salt, potassium salt and lithium salt
  • alkaline earth metal salts such as magnesium salt and calcium salt
  • ammonium salts such as ammonium salts and tetramethylammonium salts
  • N-methylmorpholine salts trie
  • composition salts of the compound (I) of the present invention include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide. , nitrates, perchlorates, sulfates, inorganic salts such as phosphates; methanesulfonates, trifluoromethanesulfonates, lower alkanesulfonates such as ethanesulfonates, benzenesulfonates, p- Arylsulfonates such as toluenesulfonate, organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. and preferably hydrohalides (especially hydrochlorides).
  • hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide.
  • salt thereof means all salts including the aforementioned “pharmaceutically acceptable salt thereof”.
  • prevention includes prevention of disease onset, delay of disease onset, and prevention of pathological conditions.
  • a “prophylactically effective amount” refers to a dose of active ingredient sufficient to achieve a prophylactic purpose.
  • treatment includes curing a disease, ameliorating the pathology of a disease (eg, one or more symptoms), and suppressing the progression of (the severity of) a disease.
  • a “therapeutically effective amount” refers to a dose of active ingredient sufficient to achieve its therapeutic purpose. Therefore, “improvement” is a concept encompassed by “treatment.”
  • the term "subject” refers to a subject to be administered a drug (pharmaceutical composition) containing an effective amount of an active ingredient necessary to prevent and/or treat (or improve) a disease or the pathology of a disease. means.
  • Such “subjects” include humans or non-human animals (particularly mammals (eg, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.)).
  • B0AT1 inhibitor means a drug comprising a compound that has the effect of inhibiting B0AT1, a transporter responsible for the reabsorption of neutral amino acids such as phenylalanine in the kidney.
  • compound (I) of the present invention or a pharmaceutically acceptable salt thereof, exhibits excellent inhibitory activity against B0AT1.
  • the inhibitory activity of B0AT1 can be measured, for example, by the method described in Non-Patent Document 11 (SLAS Discovery, 2019; 24(2): p.111-120) or the method described in the test examples described later.
  • the term "diseases whose symptoms can be alleviated by B0AT1 inhibitory action” refers to diseases caused by increased levels of neutral amino acids in the blood due to mutations in genes related to amino acid metabolic pathways. means. Specific examples of such diseases include phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, non-ketotic hyperglycinemia, Amino acid metabolic disorders such as propionic acidemia, methylmalonic acidemia, and isovaleric acidemia are included.
  • R 1 is a halogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, substituted optionally substituted C 3-8 cycloalkyloxy group, optionally substituted C 1-6 alkylsulfanyl group, optionally substituted C 3-8 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted represents an optionally substituted C 6-14 aryl group or an optionally substituted 5- to 6-membered aromatic heterocyclic group;
  • R 1 is preferably C 2-6 alkyl group, haloC 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkoxy group, haloC 2-6 alkoxy group, C 3-6 cyclo alkyloxy group, C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, halogen a C 6-14 aryl group optionally substituted with an atom, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with a halogen atom or a C 1-6 alkyl group, More preferably, it is a haloC 1-4 alkyl group.
  • Each of the n X's independently represents a fluorine atom or a chlorine atom.
  • X is preferably a chlorine atom.
  • n an integer from 0 to 2;
  • n is preferably 0 or 1, more preferably 0.
  • R 2 represents a C 1-6 alkyl group optionally substituted with a substituent selected from the substituent group a.
  • R 2 is preferably a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the above substituent group a, More preferably, it is a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the substituent group a′, More preferably, it is a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the substituent group a''.
  • R 3 is a C 1-6 alkyl group optionally substituted with a substituent selected from the above substituent group a or a C 3- optionally substituted with a substituent selected from the above substituent group b 6 represents a cycloalkyl group.
  • R 3 is preferably a C 1-4 alkyl group optionally substituted with 1 to 3 substituents selected from the substituent group a, more preferably a C 1-4 alkyl group optionally substituted with 1 to 3 substituents selected from the substituent group a′, More preferably, it is a C 1-4 alkyl group optionally substituted with 1 to 3 substituents selected from the substituent group a''.
  • R 2 and R 3 are bonded to each other to form a nitrogen-containing non-aromatic heterocyclic group optionally substituted with a substituent selected from the above substituent group b together with the nitrogen atom to which they are bonded. may be formed.
  • R 2 and R 3 are preferably bonded to each other and substituted with 1 to 3 substituents selected from the substituent group b, together with the nitrogen atom to which they are bonded.
  • R 2 and R 3 are bonded to each other and together with the nitrogen atom to which they are bonded, 1 to 1 selected from the substituent group b optionally substituted with 3 substituents, the following formula:
  • Y and Z each independently represent a carbon atom or a nitrogen atom
  • a condensed nitrogen-containing non-aromatic heterocyclic group represented by (e.g., optionally substituted with 1 to 3 substituents selected from the substituent group b, the following formula:
  • R 2 and R 3 are bonded to each other and optionally substituted with a substituent selected from the substituent group b together with the nitrogen atom to which they are bonded, the following formula :
  • Y and Z each independently represent a carbon atom or a nitrogen atom
  • a condensed nitrogen-containing non-aromatic heterocyclic group represented by (e.g., optionally substituted with 1 to 3 substituents selected from the substituent group b, the following formula:
  • R 1 is a C 2-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkoxy group, a halo C 2-6 alkoxy group, a C 3-6 cycloalkyloxy group , C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted with halogen atom a C 6-14 aryl group which may be substituted, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with a halogen atom or a C 1-6 alkyl group; n Xs are each independently a fluorine atom or a chlorine
  • R 1 is a C 2-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkoxy group, a halo C 2-6 alkoxy group, a C 3-6 cycloalkyloxy group , C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted with halogen atom a C 6-14 aryl group which may be substituted, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with a halogen atom or a C 1-6 alkyl group; n is 0; R 2 is a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the substitu
  • R 1 is a C 2-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkoxy group, halo C 2-6 alkoxy group, C 3-6 cycloalkyloxy group , C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted with a halogen atom a C 6-14 aryl group which may be substituted, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with a halogen atom or a C 1-6 alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n is an integer of 0 to 2 (
  • R 1 is a haloC 1-4 alkyl group; n is 0; and R 2 and R 3 are bonded to each other and substituted with 1 to 3 substituents selected from the above substituent group b together with the nitrogen atom to which they are bonded 3- to 10-membered (preferably 5- to 8-membered) monocyclic nitrogen-containing non-aromatic heterocyclic group, 6- to 10-membered bridged cyclic nitrogen-containing non-aromatic heterocyclic group, 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or 9- to 14-membered condensed nitrogen-containing non-aromatic heterocyclic group (e.g., pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 3 ,8-diazabicyclo[3.2.1]octyl group, diazepanyl group, 5,6,7,
  • R 1 is a C 2-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkoxy group, halo C 2-6 alkoxy group, C 3-6 cycloalkyloxy group , C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted with a halogen atom a C 6-14 aryl group which may be substituted, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with a halogen atom or a C 1-6 alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n is an integer of 0 to 2 (
  • R 1 is a haloC 1-4 alkyl group; n is 0; and R 2 and R 3 are bonded to each other and substituted with 1 to 3 substituents selected from the above substituent group b together with the nitrogen atom to which they are bonded. forming a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group, Compound (I) or a pharmaceutically acceptable salt thereof.
  • R 1 is a C 2-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkoxy group, a halo C 2-6 alkoxy group, a C 3-6 cycloalkyloxy group , C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted with halogen atom a C 6-14 aryl group which may be substituted, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with a halogen atom or a C 1-6 alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n
  • Y and Z each independently represent a carbon atom or a nitrogen atom
  • A represents a 5- to 8-membered non-aromatic heterocyclic ring
  • ring B represents a 5- to 6-membered non-aromatic heterocyclic ring or aromatic heterocyclic ring, or represents a benzene ring
  • m represents an integer of 0 to 3
  • * represents a bonding site with a carbonyl group.
  • R 1 is a C 2-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkoxy group, halo C 2-6 alkoxy group, C 3-6 cycloalkyloxy group , C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted with a halogen atom a C 6-14 aryl group which may be substituted, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with a halogen atom or a C 1-6 alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n is an integer of 0 to 2
  • Y and Z each independently represent a carbon atom or a nitrogen atom
  • A represents a single bond or a double bond
  • ring A represents a 5- to 8-membered non-aromatic heterocyclic ring
  • ring B represents a 5- to 6-membered non-aromatic heterocyclic ring or aromatic heterocyclic ring
  • m represents an integer of 0 to 3
  • * represents a bonding site with a carbonyl group.
  • R 1 is a haloC 1-4 alkyl group; n is 0; and R 2 and R 3 are bonded to each other and substituted with 1 to 3 substituents selected from the above substituent group b together with the nitrogen atom to which they are bonded.
  • R 1 is a haloC 1-4 alkyl group; n is 0; and R 2 and R 3 are bonded to each other and substituted with 1 to 3 substituents selected from the above substituent group b together with the nitrogen atom to which they are bonded.
  • Y and Z each independently represent a carbon atom or a nitrogen atom
  • a condensed nitrogen-containing non-aromatic heterocyclic group represented by (e.g., optionally substituted with 1 to 3 substituents selected from the substituent group b, the following formula:
  • R 1 is a haloC 1-4 alkyl group; n is 0; and R 2 and R 3 are bonded to each other and substituted with 1 to 3 substituents selected from the above substituent group b together with the nitrogen atom to which they are bonded.
  • R 1 is a haloC 1-4 alkyl group; n is 0; and R 2 and R 3 are bonded to each other and substituted with 1 to 3 substituents selected from the above substituent group b together with the nitrogen atom to which they are bonded.
  • Y and Z each independently represent a carbon atom or a nitrogen atom
  • a condensed nitrogen-containing non-aromatic heterocyclic group represented by (e.g., optionally substituted with 1 to 3 substituents selected from the substituent group b, the following formula:
  • R 1 is a C 2-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkoxy group, halo C 2-6 alkoxy group, C 3-6 cycloalkyloxy group , C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted with a halogen atom a C 6-14 aryl group which may be substituted, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with a halogen atom or a C 1-6 alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n is an integer of 0 to 2 (
  • R 1 is a haloC 1-4 alkyl group; n is 0; and R 2 and R 3 are bonded to each other and substituted with 1 to 3 substituents selected from the above substituent group b together with the nitrogen atom to which they are bonded pyrrolidinyl group, piperidyl group, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, 5,6,7,8-tetrahydro-[ 1,2,4]triazolo[1,5-a]pyrazinyl group, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, 1,2,3,4-tetrahydroisoquinolyl 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, 1,2,3,4-tetrahydro-2,6-naphthyridinyl group or 1,2,3,4
  • the compounds represented by the above formulas (I′) and (I′′) that is, compound (I′) and compound (I '')) or salts thereof are novel compounds.
  • R 1′ is a C 2-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkoxy group, a halo C 2-6 alkoxy group, a C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, halogen atom represents an optionally substituted C 6-14 aryl group, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with a halogen atom or a C 1-6 alkyl group;
  • R 1′ is preferably a haloC 1-4 alkyl group.
  • n' X's each independently represent a fluorine atom or a chlorine atom.
  • X' is preferably a chlorine atom.
  • n' represents an integer of 0 to 2;
  • n' is preferably 0 or 1, more preferably 0.
  • R 2′ represents a C 1-4 alkyl group substituted with a substituent selected from the substituent group a.
  • R 2' is preferably a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the above substituent group a'.
  • R 3′ is a C 1-4 alkyl group optionally substituted with a substituent selected from the above substituent group a or a C 3 optionally substituted with a substituent selected from the above substituent group b -6 represents a cycloalkyl group.
  • R 3' is preferably a C 1-4 alkyl group optionally substituted with 1 to 3 substituents selected from the above substituent group a', More preferably, it is a C 1-4 alkyl group optionally substituted with 1 to 3 substituents selected from the substituent group a''.
  • R 2' and R 3' are bonded to each other and substituted with a substituent selected from the substituent group b together with the nitrogen atom to which R 2' and R 3' are bonded. may form a nitrogen-containing non-aromatic heterocyclic group.
  • R 2' and R 3' are preferably bonded to each other and each substituted with 1 to 3 substituents selected from the substituent group b together with the nitrogen atom to which they are bonded.
  • R 1′ is a C 2-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkoxy group, halo C 2-6 alkoxy group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl-C 1-4 alkoxy group, C 2-6 alkylsulfanyl group, haloC 1-6 alkylsulfanyl group, C 3-6 cycloalkylsulfanyl group, pentafluorosulfanyl group, halogen atom an optionally substituted C 6-14 aryl group, or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with a halogen atom or a C 1-6 alkyl group; n'X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n'
  • R 1′ is a haloC 1-4 alkyl group
  • n'X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n' is an integer from 0 to 2 (preferably 0 or 1, more preferably 0);
  • R 2' is a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the substituent group a'; and
  • R 3' is selected from the substituent group a' is a C 1-4 alkyl group optionally substituted with 1 to 3 substituents, compound (I') or a salt thereof;
  • R 1′ is a haloC 1-4 alkyl group; n' is 0; R 2′ is a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the substituent group a′′; and R 3′ is selected from the substituent group a′′ a C 1-4 alkyl group optionally substituted with 1 to 3 selected substituents, compound (I') or a salt thereof;
  • R 1′ is a haloC 1-4 alkyl group
  • n'X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n' is an integer from 0 to 2 (preferably 0 or 1, more preferably 0);
  • R 2' and R 3' are bonded to each other and optionally substituted with 1 to 3 substituents selected from the substituent group b, together with the nitrogen atoms to which they are bonded, 3 to 10-membered monocyclic nitrogen-containing non-aromatic heterocyclic group, 6- to 10-membered bridged nitrogen-containing non-aromatic heterocyclic group, or 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group , or to form a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group, compound (I') or a salt thereof;
  • R 1′ is a haloC 1-4 alkyl group
  • n'X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n' is an integer from 0 to 2 (preferably 0 or 1, more preferably 0);
  • R 2' and R 3' are bonded to each other and optionally substituted with 1 to 3 substituents selected from the substituent group b, together with the nitrogen atoms to which they are bonded, 3 to 10-membered monocyclic nitrogen-containing non-aromatic heterocyclic group, 6- to 10-membered bridged nitrogen-containing non-aromatic heterocyclic group, or 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group , or a 9- to 14-membered condensed nitrogen-containing non-aromatic heterocyclic group (e.g., pyrrolidinyl group, piperidyl group, piperazinyl group, morpholiny
  • R 1′ is a haloC 1-4 alkyl group
  • n'X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n' is an integer from 0 to 2 (preferably 0 or 1, more preferably 0); Pyrrolidinyl, wherein R 2' and R 3' are bonded to each other and optionally substituted with 1 to 3 substituents selected from the substituent group b, together with the nitrogen atoms to which they are bonded.
  • R 1′′ is a halogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, substituted optionally substituted C 3-8 cycloalkyloxy group, optionally substituted C 1-6 alkylsulfanyl group, optionally substituted C 3-8 cycloalkylsulfanyl group, pentafluorosulfanyl group, substituted represents an optionally substituted C 6-14 aryl group, or an optionally substituted 5- to 6-membered aromatic heterocyclic group.
  • R 1′′ is preferably a halogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy optionally substituted C 3-8 cycloalkyloxy group, pentafluorosulfanyl group or optionally substituted C 6-14 aryl group, more preferably haloC 1-4 alkyl group be.
  • n'' X'' independently represents a fluorine atom or a chlorine atom.
  • X'' is preferably a chlorine atom.
  • n'' represents an integer from 0 to 2.
  • n′′ is preferably 0 or 1, more preferably 0.
  • R2 '' is (i) a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group optionally substituted with a substituent selected from the substituent group c; and (ii) selected from the substituent group b substituted with a group selected from the group consisting of optionally substituted 5- to 6-membered nitrogen-containing monocyclic nitrogen-containing non-aromatic heterocyclic groups, and further selected from the substituent group a represents a C 1-4 alkyl group which may be substituted with a group;
  • R 2′′ is preferably a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the substituent group c (e.g., pyridazinyl group, pyrazolyl group, thiazolyl group, pyridyl group, triazolyl group, pyrimidinyl group, oxadiazolyl group, imidazolyl group) and further with 1 to 3 substituents selected from the substituent group a'' It is an optionally substituted C 1-4 alkyl group.
  • substituent group c e.g., pyridazinyl group, pyrazolyl group, thiazolyl group, pyridyl group, triazolyl group, pyrimidinyl group, oxadiazolyl group, imidazolyl group
  • substituent group a'' It is an optionally substituted C 1-4 alkyl group.
  • R 3′′ represents a C 1-4 alkyl group substituted with a substituent selected from the substituent group a.
  • R 3′′ is preferably a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the above substituent group a′, More preferably, it is a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the substituent group a''.
  • R 2 '' and R 3 '' are bonded to each other and substituted with a substituent selected from the substituent group b together with the nitrogen atom to which they are bonded.
  • a condensed nitrogen-containing non-aromatic heterocyclic group (excluding a tetrahydroquinolyl group and a tetrahydroisoquinolyl group) may be formed.
  • R 2′′ and R 3′′ are preferably bonded to each other and together with the nitrogen atom to which they are bonded, 1 to 3 substituents selected from the above substituent group b. optionally substituted with a group of the following formula:
  • Y' and Z' each independently represent a carbon atom or a nitrogen atom
  • Ring A′ represents a 5- to 8-membered non-aromatic heterocyclic ring
  • Ring B′ represents a 5- to 6-membered non-aromatic heterocyclic ring or aromatic heterocyclic ring
  • m' represents an integer of 0 to 3 (preferably 0 to 2); and *' represents a bonding site with a carbonyl group. ) to form a condensed nitrogen-containing non-aromatic heterocyclic group represented by More preferably, each optionally substituted with 1 to 3 substituents selected from the substituent group b, the following formula:
  • R 1′′ is a halogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, substituted optionally substituted C 3-8 cycloalkyloxy group, pentafluorosulfanyl group, or optionally substituted C 6-14 aryl group;
  • n''X'' are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n'' is an integer from 0 to 2 (preferably 0 or 1);
  • R 2′′ is a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (e.g., pyridazinyl group, pyrazolyl group, thiazolyl group, pyridyl group, triazolyl group, pyrimidinyl group, oxadiazolyl group, imidazolyl group) and further substituted with 1 to 3 substituents
  • R 1′′ is a halogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, substituted optionally substituted C 3-8 cycloalkyloxy group, pentafluorosulfanyl group, or optionally substituted C 6-14 aryl group; n'' is 0; R 2′′ is a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (e.g., pyridazinyl group, pyrazolyl group, thiazolyl group, pyridyl group, triazolyl group, pyrimidinyl group, oxadiazolyl group, imidazolyl group) and further substituted with 1 to 3 substituents selected from the substituent group a'' and R 3′′ is a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the above substituent group a
  • R 1′′ is a haloC 1-4 alkyl group; n'' is 0; R 2′′ is a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (e.g., pyridazinyl group, pyrazolyl group, thiazolyl group, pyridyl group, triazolyl group, pyrimidinyl group, oxadiazolyl group, imidazolyl group) and further substituted with 1 to 3 substituents selected from the substituent group a'' and R 3′′ is a C 1-4 alkyl group substituted with 1 to 3 substituents selected from the above substituent group a′′. , compound (I'') or a salt thereof;
  • Y' and Z' each independently represent a carbon atom or a nitrogen atom
  • Ring A′ represents a 5- to 8-membered non-aromatic heterocyclic ring
  • Ring B′ represents a 5- to 6-membered non-aromatic heterocyclic ring or aromatic heterocyclic ring
  • m' represents an integer of 0 to 3 (preferably 0 to 2); and *' represents a bonding site with a carbonyl group.
  • R 1′′ is a halogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 cycloalkyl group, optionally substituted C 1-6 alkoxy group, substituted optionally substituted C 3-8 cycloalkyloxy group, pentafluorosulfanyl group, or optionally substituted C 6-14 aryl group;
  • n''X'' are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n′′ is an integer from 0 to 2 (preferably 0 or 1); and R 2′′ and R 3′′ are bonded together with the nitrogen atom to which they are bonded, optionally substituted with 1 to 3 substituents selected from group b, the following formula:
  • Y' and Z' each independently represent a carbon atom or a nitrogen atom
  • Ring A′ represents a 5- to 8-membered non-aromatic heterocyclic ring
  • Ring B′ represents a 5- to 6-membered non-aromatic heterocyclic ring or aromatic heterocyclic ring
  • m' represents an integer of 0 to 3 (preferably 0 to 2); and *' represents a bonding site with a carbonyl group.
  • R 1′′ is a haloC 1-4 alkyl group; n′′ is 0; and R 2′′ and R 3′′ are bonded to each other and together with the nitrogen atom to which they are bonded, 1 to 3 selected from the substituent group b optionally substituted with a substituent, the following formula:
  • suitable compound (I) are the compounds of Examples 1 to 283 (compound (I-1) to compound (I-283)) described below, or pharmaceutically acceptable salts thereof (or salts thereof) ).
  • the compound (I) of the present invention When the compound (I) of the present invention has an asymmetric carbon atom in the molecule, it may exist as multiple stereoisomers (i.e., diastereomers, optical isomers) based on the asymmetric carbon atom. , the present invention encompasses any one of these stereoisomers and mixtures of these stereoisomers in any ratio. Further, isomers due to conformation or tautomerism may be produced, and such isomers or mixtures thereof are also included in the compound (I) of the present invention.
  • Compound (I) of the present invention is a compound labeled or substituted with an isotope (e.g., 2 H, 3 H, 13 C, 14 C , 15 N, 18 F, 32 P, 35 S , 125 I , etc.).
  • the isotope-labeled or substituted compound can be used as a tracer (PET tracer) for use in, for example, positron emission tomography (PET), and is useful in fields such as medical diagnosis. is.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be a crystal, and may have a single crystal form or a mixture of multiple crystal forms.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may also include its inner salt, adduct, and solvate thereof.
  • These solvates are compound (I) or a salt thereof in which a solvent molecule is coordinated, and hydrates are also included. Examples thereof include compound (I) or a hydrate, ethanolate, dimethylsulfoxide solute, and the like of compound (I) or a salt thereof.
  • the compound (I) of the present invention may be a prodrug.
  • a prodrug of compound (I) of the present invention refers to a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like in vivo.
  • Prodrugs of Compound (I) are contemplated as monoesters or diesters of phosphate groups, the ester function preferably having a structure that is readily hydrolyzed or metabolized after administration to a patient.
  • Specific examples of the ester functional group of such prodrugs include C 1-6 alkyl esters optionally substituted with acyloxy groups, phenyl esters, benzyl esters and the like (Bioorganic Chemistry, 1984; 12: p. 118-129).
  • prodrugs other than monoesters or diesters of the phosphate group include, for example, Current opinion in investigational drugs, 2006; 7: p.109-117, J. Med. Chem.1994; 37: p.1857- 1864, and J. Med. Chem. 2000; 43: p.4570-4574.
  • Another aspect of the prodrug of compound (I) is, for example, when compound (I) has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (e.g., compound (I) The amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidylmethylated, pivaloyloxy methylated, acetoxymethylated, tert-butylated compounds, etc.); when compound (I) has a hydroxyl group, the hydroxyl group is acylated, alkylated, phosphorylated, or borated (e.g., compound (I ) are acetylated, palmitoylated, propanoylated, pivaloylated, succinyl
  • prodrugs of compound (I) may be either hydrates or non-hydrates.
  • prodrugs of compound (I) are represented by compound (I) under physiological conditions, as described in Hirokawa Shoten 1990, "Drug Development”, Vol. 7, “Molecular Design”, pages 163-198. It may be changed to a compound that
  • Each raw material compound may form a salt as long as it does not inhibit the reaction, and examples of such a salt include those similar to those of compound (I).
  • starting compounds can be readily obtained from commercial sources, or can be manufactured according to a method known per se or a method analogous thereto.
  • Intermediates produced in the following production methods may be isolated and purified by methods such as column chromatography, recrystallization, and distillation, or may be used in the next step without isolation.
  • This production method is a method for obtaining compound (Ia) by condensing compound (1-1) and compound (2-1).
  • compound (1-1) one synthesized by a method known per se (see, for example, US Pat. No. 10,836,736) can be preferably used.
  • Step A-1 This step is a step of producing compound (Ia) by condensing compound (1-1) and compound (2-1) in the presence of a condensing agent.
  • the amount of compound (2-1) to be used is 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (1-1).
  • Condensing agents include o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3-(3'- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (WSC hydrochloride), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBop), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzo triazolium 3-oxide hexafluorophosphate (HCTU), O-
  • condensation additives 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (HOCt), 1-hydroxy-7-azabenzotriazole (HOAt) as condensation additives You may react under the coexistence of such as.
  • the amount of condensation additive to be used is generally 0 to 1.5 mol per 1 mol of compound (1-1).
  • the base examples include organic bases such as triethylamine, pyridine, N,N-diisopropylethylamine, etc. Among them, triethylamine and N,N-diisopropylethylamine are preferred.
  • the amount of the base to be used is generally 1-5 mol, preferably 1.5 mol, per 1 mol of compound (1-1).
  • reaction solvent is not particularly limited, but for example, aromatic hydrocarbons such as toluene and xylene; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; diethyl ether, tetrahydrofuran, dioxane and the like. ethers; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile; and mixtures thereof.
  • the reaction temperature is usually -78°C to room temperature, preferably 0°C to room temperature, and the reaction time is usually 1 to 48 hours.
  • This production method is a method for obtaining compound (Ia) by condensing compound (3-1) and compound (4-1).
  • compound (3-1) a commercially available product or one synthesized by a method known per se can be preferably used.
  • Step B-1 This step is a step of producing compound (Ia) by condensing compound (3-1) and compound (4-1) in the presence of a condensing agent.
  • the amount of compound (4-1) to be used is 1-5 mol, preferably 1-3 mol, per 1 mol of compound (3-1).
  • Step B-1 is the same as step A above, except that compound (3-1) is used in place of compound (1-1) and compound (4-1) is used in place of compound (2-1).
  • the reaction can be carried out under conditions similar to -1.
  • Ring A′ is a nitrogen-containing non-aromatic heterocyclic group which may further have a heteroatom as a ring-constituting atom and may be further substituted with a substituent selected from the substituent group b. and other symbols have the same meanings as above.
  • Step C-1 This step is a step of producing compound (Ib) by condensing compound (1-1) and compound (2-2) in the presence of a condensing agent.
  • step C-1 the reaction can be carried out under the same conditions as in step A-1 above, except that compound (2-2) is used in place of compound (2-1).
  • the amount of compound (2-2) to be used is 1-5 mol, preferably 1-3 mol, per 1 mol of compound (1-1).
  • Step C-2 This step is a step of obtaining a compound (Ic) by deprotecting the amino-protecting group (P 1 ).
  • reaction conditions can be selected according to the type of protecting group (P 1 ).
  • Deprotection reaction conditions are determined by a method known per se, for example, Wiley-Interscience, 2007, “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts); Thieme, 2004, “Protecting Groups 3rd Ed.”Ed.” (written by P. J. Kocienski), etc., or according to the methods described in Examples described later.
  • Step C-3 the compound (Id) of the present invention is obtained by reacting compound (Ic) with R 4 —CHO in the presence of a reducing agent and an acid in a solvent that does not affect the reaction (reductive amination reaction). is the process of obtaining
  • the amount of R 4 —CHO to be used is 1-3 mol, preferably 1-2 mol, per 1 mol of compound (Ic).
  • reducing agents include sodium triacetoxyborohydride and sodium borohydride.
  • the amount of the reducing agent to be used is 1-10 mol, preferably 1-3 mol, per 1 mol of compound (Ic).
  • the acid examples include organic acids such as acetic acid; and Lewis acids such as titanium (IV) chloride and tetraisopropyl titanate.
  • the amount of the acid to be used is 1-10 mol, preferably 1-3 mol, per 1 mol of compound (Ic).
  • the reaction solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran; halogenated hydrocarbons such as chloroform and dichloromethane; Alternatively, mixtures thereof may be mentioned.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • alcohols such as methanol and ethanol
  • ethers such as tetrahydrofuran
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • the reaction temperature is usually -10°C to 100°C, preferably 10°C to 50°C, and the reaction time is usually 1 hour to 48 hours.
  • Ring A'' represents a nitrogen-containing non-aromatic heterocyclic group which may further have a heteroatom as a ring-constituting atom and may be further substituted with a substituent selected from the substituent group b; has the same meaning as above.
  • Step D-1 This step is a step of producing compound (Ie) by condensing compound (1-1) and compound (2-3) in the presence of a condensing agent.
  • step D-1 the reaction can be carried out under the same conditions as in step A-1 above, except that compound (2-3) is used in place of compound (2-1).
  • the amount of compound (2-3) to be used is 1-5 mol, preferably 1-3 mol, per 1 mol of compound (1-1).
  • Step D-2 This step is a step of obtaining compound (If) by deprotecting the protecting group (P 2 ) of compound (Ie).
  • reaction conditions can be selected according to the type of protecting group (P 2 ).
  • Deprotection reaction conditions are determined by a method known per se, for example, Wiley-Interscience, 2007, “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts); Thieme, 2004, “Protecting Groups 3rd Ed.”Ed.” (written by P. J. Kocienski), etc., or according to the methods described in Examples described later.
  • This production method is a method for obtaining the compound (Ih) of the present invention through a cross-coupling reaction between compound (Ig) and compound (5-1) in the presence of a metal catalyst and a base.
  • X 0 represents a halogen atom
  • Ar 1 represents an optionally substituted C 6-14 aryl group
  • R 5 and R 6 each independently represent a hydrogen atom or an alkyl group, or R 5 and R 6 may be joined together to form a cyclic boronic ester such as the pinacol ester of boronic acid with the boron atom, and the other symbols are as defined above.
  • Step E-1 In this step, compound (Ig) and arylboronic acid or arylboronic acid ester (e.g., pinacol ester of arylboronic acid, etc.) are prepared in the presence of a metal catalyst (e.g., palladium catalyst) and a base in a solvent that does not affect the reaction. ) (compound (5-1)) by a cross-coupling reaction (Suzuki coupling reaction).
  • Compound (Ig) can be produced by the production method (A) or (B), or a method analogous thereto.
  • Compound (5-1) is a commercially available product, or a method known per se [for example, "Advanced Organic Chemistry, 4th Ed.” (by Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (Richard C by Larock)] or a method based on these.
  • the amount of compound (5-1) to be used is generally 1-4 mol per 1 mol of compound (Ig).
  • Metal catalysts include palladium(II) acetate, palladium(II) chloride, dichlorobis(tricyclohexylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0).
  • 1,1′-bis(diphenylphosphino)ferrocene dppf
  • 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl SPhos
  • 2-dicyclohexylphosphino-2′, 4′,6′-triisopropylbiphenyl XPhos
  • 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos), 3,6-dimethoxy-2-dicyclohexylphosphino-2′,4′ ,6′-triisopropylbiphenyl (BrettPhos)
  • tri-t-butylphosphine tricyclohexylphosphine, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (AmPhos)
  • the amount of the metal catalyst to be used is generally 0.01 mol-1 mol, preferably 0.05 mol-0.1 mol, per 1 mol of compound (Ig).
  • the amount of the ligand to be used is generally 0.05 mol-1 mol, preferably 0.1 mol-0.4 mol, per 1 mol of compound (Ig).
  • bases include alkali metal amides such as lithium diisopropylamide, sodium amide and lithium bistrimethylsilylamide; alkali metal carbonate salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; sodium phosphate, phosphoric acid Phosphate alkali metal salts such as potassium; and amines such as triethylamine, N,N-diisopropylethylamine, pyridine and N-methylmorpholine.
  • the amount of the base to be used is generally 1 mol-5 mol, preferably 2 mol-4.5 mol, per 1 mol of compound (Ig).
  • This step can be carried out in the presence or absence of additives.
  • additives include alkali metal halides such as potassium fluoride.
  • the amount of the additive to be used is generally 1 mol-5 mol, preferably 1.5 mol-2.5 mol, per 1 mol of compound (Ig).
  • reaction solvent examples include, but are not limited to, amides such as N,N-dimethylformamide and N-methylpyrrolidone; ethers such as tetrahydrofuran and 1,4-dioxane; and halogenated hydrocarbons such as chloroform and dichloromethane.
  • aromatic hydrocarbons such as toluene and xylene; nitriles such as acetonitrile; water; or mixtures thereof.
  • the reaction temperature is usually -78°C to 200°C, preferably -78°C to 120°C.
  • the reaction time is usually 0.5 to 12 hours.
  • Compound (I) or a pharmaceutically acceptable salt thereof obtained by the production method described above can be isolated and purified by ordinary separation means such as recrystallization, distillation, and chromatography.
  • optical resolution means e.g., fractional crystallization, resolution using a chiral column
  • Optical isomers can also be synthesized using optically pure starting materials.
  • Optical isomers can also be synthesized by stereoselectively performing each reaction using an asymmetric auxiliary group or an asymmetric catalyst.
  • the medicament of the present invention comprises compound (I), or a pharmaceutically acceptable salt thereof, or a B0AT1 inhibitor consisting of compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient, A drug for preventing and/or treating diseases whose symptoms can be alleviated by B0AT1 inhibitory action.
  • compound (I′) and compound (I′′) which are novel compounds, are also included in compound (I), a drug containing compound (I′) or compound (I′′) as an active ingredient , Compound (I), or a medicament containing a pharmaceutically acceptable salt thereof as an active ingredient.
  • the medicament of the present invention is a medicament consisting only of compound (I) or a pharmaceutically acceptable salt thereof (or a B0AT1 inhibitor consisting of compound (I) or a pharmaceutically acceptable salt thereof), or Any pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or the like may be used.
  • the medicament of the present invention can be administered to subjects (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.) in prophylactically or therapeutically effective amounts.
  • Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.).
  • excipients e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.
  • binders e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.
  • lubricants e.g., magnesium stearate, talc, etc.
  • disintegrants e.g., carboxymethylcellulose, talc, etc.
  • solvents e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.
  • solubilizers e.g., polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, citric acid sodium, sodium salicylate, sodium acetate, etc.
  • suspending agents e.g., stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, surfactants such as glyce
  • water-insoluble lake pigments e.g., the water-soluble edible tar pigments aluminum salts
  • natural pigments e.g, ⁇ -carotene, chlorophyll, red iron oxide
  • sweeteners eg, sodium saccharin, dipotassium glycyrrhizinate, stevia, etc.
  • the medicament (pharmaceutical composition) of the present invention can be prepared according to a known means, for example, tablets, fine granules, granules, capsules, dry syrup, etc. for oral administration, or injection agents (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, etc.), external preparations (e.g., transdermal preparations, ointments, lotions, patches), suppositories preparations for parenteral administration such as preparations (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, liposome preparations, etc. be able to.
  • formulations for oral administration such as tablets are particularly preferable.
  • the content of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in the medicament (pharmaceutical composition) of the present invention varies depending on the form of the preparation, but it is usually about 0.00 for the whole preparation. 01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight.
  • the dosage of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof depends on the administration subject (subject's age, body weight, general health condition, sex, degree of disease, etc.), administration route, type of disease. , can be appropriately selected according to the type of concomitant drug, etc.
  • the daily dose of compound (I) or a pharmaceutically acceptable salt thereof is, for example, in the case of humans, when orally administered to an adult patient (body weight of about 60 kg), the active ingredient compound (I) equivalent to 0.001 mg to 1000 mg, preferably 0.01 mg to 100 mg, can be administered once or several times a day, regardless of before, after or between meals.
  • the administration period is not particularly limited.
  • Compound (I) of the present invention can alleviate symptoms by B0AT1 inhibitory action, especially phenylketonuria, hypertyrosinemia (type 1-3),
  • phenylketonuria especially phenylketonuria, hypertyrosinemia (type 1-3)
  • amino acid metabolism disorders such as hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia Especially effective.
  • the compound (I) of the present invention can be administered (concomitantly) in combination with other drugs (concomitant drugs) as long as their efficacy is not impaired.
  • the concomitant drug is not particularly limited, and for example, one or more known drugs conventionally used for the treatment of the above-exemplified "diseases whose symptoms can be alleviated by B0AT1 inhibitory action" can be suitably used. .
  • the compound (I) of the present invention is treated with phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease,
  • Concomitant drugs used for the treatment and/or prevention of amino acid metabolism disorders such as homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia include:
  • vitamin preparations e.g., folic acid (vitamin B9), nicotinamide (vitamin B3), thiamine (vitamin B1), pyridoxine (vitamin B6), etc.
  • drugs for alleviating various symptoms of amino acid metabolism disorders e.g., L-dopa, LNAAs such as 5-hydroxytryptophan, sapropterin hydrochloride, Pegvaliase, nicotinic acid, nitisinone, S-adenosylme
  • the timing of administration is not limited, and these may be administered to the subject at the same time or at different times.
  • the medicament of the present invention may be administered first and the concomitant drug may be administered later, or the concomitant drug may be administered first and the medicament of the present invention may be administered later.
  • Each administration method may be the same or different.
  • a single preparation containing compound (I) of the present invention or a pharmaceutically acceptable salt thereof and a concomitant drug in combination can be administered.
  • the dosage of the concomitant drug can be appropriately selected based on the clinically used dosage.
  • the compounding ratio of the compound of the present invention or a pharmaceutically acceptable salt thereof and the concomitant drug depends on the administration subject (subject's age, body weight, general health condition, sex, degree of medical condition, etc.), administration route, disease can be appropriately selected according to the type of drug, the type of concomitant drug, etc.
  • the mass ratio of compound (I) or a pharmaceutically acceptable salt thereof and the concomitant drug is not particularly limited.
  • concomitant drugs that complement and/or enhance the therapeutic effect of compound (I) or a pharmaceutically acceptable salt thereof have not been found to date based on the above-described mechanism, and will be used in the future. Anything found is also included.
  • compound (I) in order to complement and/or enhance the therapeutic effect of compound (I) or a pharmaceutically acceptable salt thereof, it is also effective to use it in combination with a diet that avoids intake of specific amino acids or enzyme replacement therapy. .
  • the medicament or pharmaceutical composition of the present invention may be provided in the form of a kit together with instructions such as an administration method.
  • the drug contained in the kit can effectively sustain the activity of the constituent components of the pharmaceutical or pharmaceutical composition for a long period of time, and the container is manufactured from a material that does not adsorb to the inside of the container or degrade the constituent components.
  • a sealed glass ampoule may contain a buffer or the like sealed in the presence of a neutral, non-reactive gas such as nitrogen gas.
  • the kit may also be accompanied by instructions for use.
  • the instructions for use of this kit may be printed on paper or the like, or may be stored in an electromagnetically readable medium such as a CD-ROM or DVD-ROM and supplied to the user.
  • % indicates mol/mol % for yields, otherwise indicates weight % unless otherwise specified. Further, room temperature indicates a temperature of 15°C to 30°C unless otherwise specified. * in the following structural formulas indicates racemic carbon. Other abbreviations used in the text have the following meanings.
  • THF tetrahydrofuran
  • DMF N,N-dimethylformamide
  • HATU o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • WSC 1-ethyl- 3-(3′-dimethylaminopropyl)carbodiimide
  • DABSO bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct
  • HOBt 1-hydroxybenzotriazole
  • methyl N-(triethylammoniumsulfonyl)carbamate (1.89 g) was added, and the mixture was stirred at 70°C for 50 minutes. After allowing to cool, the solvent was distilled off under reduced pressure, ethyl acetate and saturated brine were added to the residue, and the organic layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Reference Example 16 By treating the corresponding starting compounds in the same manner as in Reference Example 15, crude products of the compounds shown in Table 1-2 below were obtained.
  • N-bromosuccinimide (65 mg) was added to a solution of tert-butyl 6-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (182 mg) in dichloromethane (1.8 ml). ) was added and stirred at room temperature for 3 hours. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Triethylamine (1.4 ml) was added to a solution of 2-(3-bromophenyl)ethanamine (1 g), 2-methoxyacetic acid (540 mg), and HATU (2.4 g) in dichloromethane (17 ml), and the mixture was stirred at room temperature for 3 hours. Stirred for an hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid and 1N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude N-[2-(3-bromophenyl)ethyl]-2-methoxyacetamide. The product (1.36 g) was obtained as a yellow oil.
  • Piperazin-2-one was added to a solution of 2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetic acid (2.00 g) in DMF (25 ml) at room temperature. (770 mg), N,N-diisopropylethylamine (1.5 ml) and HATU (3.36 g) were added and the reaction mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was stirred at room temperature for a while, and then the aqueous layer was extracted with ethyl acetate.
  • Examples 2-102 By treating the corresponding starting compounds in the same manner as in Example 1, the compounds shown in Tables 2-1 to 2-21 below were obtained.
  • Examples 104-118 By treating the corresponding starting compounds in the same manner as in Example 103, the compounds shown in Tables 3-1 to 3-3 below were obtained.
  • Examples 120-122 By treating the corresponding compounds of Examples 153 to 155 (Compound (I-153) to Compound (I-155)) in the same manner as in Example 119, the compounds shown in Table 4 below were obtained.
  • Examples 124-125 Compounds (compound (I-157) to compound (I-158)) of Examples 157 to 158 described below were treated in the same manner as in Example 123 to obtain the compounds shown in Table 5 below.
  • Examples 127-128 By treating the corresponding starting compounds in the same manner as in Example 126, the compounds shown in Table 6 below were obtained.
  • Example 130 4-Methoxy-3-[2-methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]-N-methylbutane Production of amide (compound (I-130))
  • Example 135 2-[2-methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]acetic acid (compound (I-135)) Manufacturing of
  • Example 140 7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,8-dihydro-5H-imidazo[1,2-a] Production of pyrazine-2-carboxylic acid (compound (I-140))
  • Examples 172-260 By treating the corresponding starting compounds in the same manner as in Example 1, the compounds shown in Tables 9-1 to 9-18 below were obtained.
  • Examples 262-275 By treating the corresponding starting compound in the same manner as in Example 261, the compounds shown in Tables 10-1 to 10-3 below were obtained.
  • Example 276 2-[2-[[(E)-3-[4-(pentafluoro- ⁇ 6-sulfanyl)phenyl]prop-2-enoyl]amino]acetyl]-3,4-dihydro-1H-isoquinoline-6-carvone Production of acid (compound (I-276))
  • Example 277 By treating the corresponding starting compounds in the same manner as in Example 276, the compounds shown in Table 11-1 below were obtained.
  • Examples 279-281 By treating the corresponding starting compounds in the same manner as in Example 278, the compounds shown in Table 12-1 below were obtained.
  • Trifluoroacetic acid (0.1 ml) was added, and the mixture was stirred at an external temperature of 50°C for 2 hours. Further, trifluoroacetic acid (0.1 ml) was added, and the mixture was stirred at an external temperature of 50°C for 2 hours. Further, trifluoroacetic acid (0.1 ml) was added again, and the mixture was stirred at an external temperature of 50°C for 2 hours.
  • the reaction mixture was distilled off under reduced pressure, toluene was added, and diethyl ether was added to the crude product obtained by distillation under reduced pressure to crystallize it. %) was obtained as a colorless amorphous.
  • Test Example 1 hB0AT1 inhibition test
  • DMSO dimethylsulfoxide
  • buffer (96 mM sodium chloride, 2 mM potassium chloride, 1.8 mM calcium chloride, 1 mM magnesium chloride, 0.01% bovine serum albumin, 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid 90 ⁇ l of human B0AT1 stably expressing CHO cells suspended in a buffer solution containing the cells (pH 7.0) was added so that 75000 cells/well. After standing at room temperature for 30 minutes or more, the phenylalanine uptake experiment was performed.
  • the efficacy of the B0AT1 inhibitor found in the present invention in vivo can be measured, for example, as follows.
  • Test example 2 Mouse urinary phenylalanine excretion evaluation test
  • L-Phenylalanine (Sigma-Aldrich) was dissolved in physiological saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory) by sonication and adjusted to 25 mg/ml. A dosing solution was prepared on the day of phenylalanine administration.
  • phenylalanine was intraperitoneally administered at 500 mg/20 ml/kg.
  • Urine was collected 4 hours, 6 hours, or 24 hours after administration of the test compound, and the urine weight was measured.
  • the mouse was restrained and the urine in the bladder was urinated. Contaminants and urine were separated by centrifugation, and the supernatant was collected.
  • Glucose, occult blood, and leukocyte measurements were performed using urinalysis strip Lifesticks (Siemens Healthcare Diagnostics). The collected urine was stored at ⁇ 20° C. or lower and used for phenylalanine concentration measurement.
  • compound (I) or salts thereof of the present invention were confirmed to have excellent inhibitory activity against B0AT1.
  • the compound (I) or a salt thereof of the present invention is effective for phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, non-ketosis type It was suggested that it exerts preventive and/or therapeutic effects on amino acid metabolic disorders such as hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.
  • a pharmaceutical composition containing it alleviates symptoms by its B0AT1 inhibitory action.
  • diseases specifically, for example, phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propion It can be used for the treatment and/or prevention of amino acid metabolic disorders such as acidemia, methylmalonic acidemia, and isovaleric acidemia.
  • amino acid metabolism disorders are designated intractable diseases that require long-term treatment such as a very strict diet (amino acid-restricted diet) that lasts for life.
  • Such salts can provide novel and effective prophylactic and/or therapeutic agents.

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KR20250173526A (ko) 2023-04-06 2025-12-10 미쓰비시 타나베 파마 코퍼레이션 신규한 b0at1 저해제

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