WO2024210198A1 - 新規なｂ０ａｔ１阻害剤 - Google Patents

新規なｂ０ａｔ１阻害剤 Download PDF

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Publication number
WO2024210198A1
WO2024210198A1 PCT/JP2024/014051 JP2024014051W WO2024210198A1 WO 2024210198 A1 WO2024210198 A1 WO 2024210198A1 JP 2024014051 W JP2024014051 W JP 2024014051W WO 2024210198 A1 WO2024210198 A1 WO 2024210198A1
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Prior art keywords
group
amino
prop
enoyl
acetyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/JP2024/014051
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English (en)
French (fr)
Japanese (ja)
Inventor
拓也 今津
和樹 中山
一成 下岡
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Tanabe Pharma Corp
Original Assignee
Mitsubishi Tanabe Pharma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mitsubishi Tanabe Pharma Corp filed Critical Mitsubishi Tanabe Pharma Corp
Priority to CN202480024192.1A priority Critical patent/CN121100112A/zh
Priority to AU2024252857A priority patent/AU2024252857A1/en
Priority to JP2025513193A priority patent/JPWO2024210198A1/ja
Priority to KR1020257036950A priority patent/KR20250173526A/ko
Priority to EP24784980.5A priority patent/EP4692057A1/en
Publication of WO2024210198A1 publication Critical patent/WO2024210198A1/ja
Priority to US19/322,058 priority patent/US20260001849A1/en
Priority to MX2025011682A priority patent/MX2025011682A/es
Priority to IL323760A priority patent/IL323760A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/403—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
    • A61K31/4035—Isoindoles, e.g. phthalimide
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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
    • A61K31/404—Indoles, e.g. pindolol
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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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    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Definitions

  • the present invention relates to a novel compound that has an inhibitory effect on the neutral amino acid transporter B0AT1.
  • the causative gene for Hartnup disease, SLC6A19 is localized on 5p15.33 and consists of 12 exons.
  • the 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 the main 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 to 5).
  • B0AT1 knockout mice are known to show high levels of amino acids in urine (Non-Patent Document 6), and in clinical practice, B0AT1 dysfunction results in severe neutral aminoaciduria, known as the aforementioned Hartnup disease (Non-Patent Document 7). Therefore, it was thought that various diseases or pathological conditions involving neutral amino acids, which are transport substrates, could be improved (alleviated) by inhibiting B0AT1.
  • Non-Patent Document 4 Specific examples of the therapeutic effects of inhibiting the function of B0AT1 have been reported, such as improving the pathology of phenylketonuria model mice by congenitally deleting B0AT1 or administering a nucleic acid compound that binds to mRNA to subsequently suppress its expression.
  • Amino acid metabolism disorders include, for example, designated intractable diseases such as phenylketonuria, urea cycle disorders, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.
  • Continuous dietary therapy is the main known treatment for these disorders.
  • administration of drugs that increase coenzymes or enzymes, and injection of enzymes are also known, but none of these are fundamental treatments (for example, Non-Patent Document 8, etc.).
  • Non-Patent Document 4 nucleic acids having a sequence that partially or completely matches the RNA of B0AT1
  • Non-Patent Documents 9 and 10 the existing marketed product nimesulide and its derivatives
  • Non-Patent Document 11 the known compound cinromide
  • Non-Patent Documents 12 and 13 basic compounds discovered by library screening
  • Cinnamic acid glycine amide compounds are also known (Patent Document 1).
  • the present invention provides a novel compound with excellent B0AT1 inhibitory activity, and a medicine containing the compound as an active ingredient.
  • R represents an optionally substituted C 6-10 aryl-ethenyl group
  • R 1 represents a carboxy group or a group biologically equivalent to a carboxy group
  • L represents a divalent organic group containing a group selected from the group consisting of a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to 14-membered divalent non-aromatic heterocyclic group, each of which may be further substituted
  • A represents a divalent nitrogen-containing heterocyclic group which may be further substituted.
  • the present invention has been accomplished based on the discovery that a compound represented by the formula (I) (hereinafter sometimes abbreviated as "compound (I)”), or a pharma- ceutically acceptable salt thereof, has an excellent inhibitory effect on the neutral amino acid transporter B0AT1.
  • R represents an optionally substituted C 6-10 aryl-ethenyl group
  • R 1 represents a carboxy group or a group biologically equivalent to a carboxy group
  • L represents a divalent organic group containing a group selected from the group consisting of a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to 14-membered divalent non-aromatic heterocyclic group, each of which may be further substituted
  • A represents a divalent nitrogen-containing heterocyclic group which may be further substituted. or a pharma- ceutically acceptable salt thereof.
  • R is a 2-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-8 cycloalkyloxy group, an optionally substituted C 1-6 alkylsulfanyl group, an optionally substituted C 3-8 cycloalkylsulfanyl group, and a pentafluorosulfanyl group;
  • R 1 is a carboxy group or a group bioisosteric to a carboxy group;
  • L is a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to 14-membered divalent non-
  • ring A1 represents a 3- to 10-membered monocyclic ring, an 8- to 14-membered fused ring, a 6- to 16-membered spiro ring or a 6- to 14-membered bridged ring, and may contain, as ring-constituting atoms, a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a nitrogen atom and a carbon atom.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the formula:
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group;
  • R 1 is a carboxy group or a group bioisosteric to a carboxy group;
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • R is a 2-(E)-phenyl-ethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group;
  • R 1 is a carboxy group or a group bioisosteric to a carboxy group;
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • L a C1-6 alkylene group which may have one or more divalent groups selected from the group consisting of -NR2- (wherein R2 represents a hydrogen atom or a C1-6 alkyl group), -O-, -S-, a C3-10 cycloalkylene group, and a 3- to 8-membered divalent non- aromatic heterocyclic group at its internal or terminal position and which may be further substituted with 1 to 3 substituents selected from the substituent group a;
  • the compound according to the above-mentioned [3] or [3'] which is a C 3-10 cycloalkylene group optionally further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a, or a 3- to 8-membered divalent non-ar
  • L is a C 1-6 alkylene group optionally further substituted with 1 to 3 substituents selected from the substituent group a.
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a:
  • the optionally further substituted substituent is selected from the group consisting of a C 6-14 hydrocarbon ring group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b' among the substituents of substituent group a; a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and a 3- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b'.
  • R is a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula: [8]
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-menti
  • a B0AT1 inhibitor comprising the compound according to any one of the above [1] to [14], [3'] and [9'] or a pharma- ceutically acceptable salt thereof.
  • the B0AT1 inhibitor according to the above-mentioned [15] which is a preventive and/or therapeutic agent for amino acid metabolic disorders.
  • [15''] The B0AT1 inhibitor according to the above-mentioned [15'], wherein the amino acid metabolism disorder is phenylketonuria, urea cycle disorder, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, or isovaleric acidemia.
  • a pharmaceutical composition comprising the compound according to any one of the above [1] to [14], [3'] and [9'] or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.
  • a method for preventing or treating an amino acid metabolic disorder in a mammal comprising administering to the mammal an effective amount of the compound according to any one of the above-mentioned [1] to [14], [3'] and [9'] or a pharma- ceutically acceptable salt thereof.
  • a disease selected from the group consisting of phenylketonuria, urea cycle disorder, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia and isovaleric acidemia
  • a method for preventing or treating amino acid metabolic disorders in a mammal comprising administering to the mammal effective amounts of the pharmaceutical composition according to any one of [16] to [20] above and another drug simultaneously or sequentially.
  • a method for preventing or treating a disease selected from the group consisting of phenylketonuria, urea cycle disorder, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia and isovaleric acidemia, comprising administering to a mammal an effective amount of the pharmaceutical composition according to any one of [16] to [20] above and another drug simultaneously or sequentially.
  • [34] A method for producing the compound according to any one of the above [1] to [14], [3'] and [9'] or a pharma- ceutically acceptable salt thereof.
  • [35] A prodrug of the compound according to any one of the above [1] to [14], [3'] and [9'] or a pharma- ceutically acceptable salt thereof.
  • Compound (I) of the present invention or a pharma- ceutical acceptable salt thereof has excellent inhibitory activity against B0AT1. Therefore, a pharmaceutical composition containing the compound is useful for treating and/or preventing diseases whose symptoms can be alleviated by the B0AT1 inhibitory action.
  • halogen atom means a fluorine atom, chlorine atom, bromine atom, or iodine atom.
  • alkyl (group) means a straight-chain or branched, monovalent group having one or more carbon atoms formed by removing one hydrogen atom from any carbon atom of an alkane, and when there is no particular limitation on the carbon number range, it is a C1-20 alkyl group, and of these, a C1-6 alkyl group is preferable.
  • C 1-20 alkyl (group) means an alkyl group having 1 to 20 carbon atoms, and examples thereof include 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, and examples thereof include 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, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • C 1-6 alkyl (group) optionally substituted with a halogen atom refers to the unsubstituted C 1-6 alkyl group or the C 1-6 alkyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms in the C 1-6 alkyl group are substituted with a halogen.
  • Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, 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.
  • the "C 1-4 alkyl (group) optionally substituted with a halogen atom" is more preferable.
  • C 1-6 alkyl (group) which may be substituted by a substituent selected from the group means the unsubstituted C 1-6 alkyl group or the C 1-6 alkyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted by the same or different substituents selected from the substituent group.
  • the "C 1-4 alkyl (group) which may be substituted by the same or different substituents selected from the group” is more preferable.
  • cycloalkyl (group) means a cyclic alkyl group, and, unless there is any particular limitation on the range of the carbon number, is preferably a C 3-14 cycloalkyl group, more preferably a C 3-8 cycloalkyl group.
  • C 3-14 cycloalkyl (group) refers to a cyclic alkyl group having 3 to 14 carbon atoms, and may be any of a monocyclic, fused ring, spirocyclic, and bridged ring.
  • C 3-14 cycloalkyl (group) include monocyclic C 3-14 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; fused ring C 5-14 cycloalkyl such as 1-decalinyl and 2-decalinyl; spirocyclic C 6-14 cycloalkyl such as spiro[3.4]octyl, spiro[4.5]decyl, and spiro[3.6]decyl; and bridged C 5-14 cycloalkyl such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Of these, a C 3-8 cycloalkyl group is preferred.
  • C 3-8 cycloalkyl (group) means a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Of these, a C 3-6 cycloalkyl group is preferred.
  • C 3-8 cycloalkyl (group) optionally substituted with a substituent selected from the group means the unsubstituted C 3-8 cycloalkyl group, or the C 3-8 cycloalkyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with the same or different substituents selected from the substituent group.
  • C3-8 cycloalkyloxy (group) means a group in which the C3-8 cycloalkyl group is bonded to an oxygen atom, and specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
  • C 3-8 cycloalkyloxy (group) optionally substituted by a substituent selected from the group means the unsubstituted C 3-8 cycloalkyloxy group, or the C 3-8 cycloalkyloxy group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with the same or different substituents selected from the substituent group.
  • C 3-8 cycloalkylsulfanyl (group) means a group in which the C 3-8 cycloalkyl group is bonded to a sulfur atom, and specific examples include 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, and, unless there is any particular limitation on the range of the carbon number, is a C1-20 alkoxy group, and preferably a C1-6 alkoxy group.
  • C 1-6 alkoxy (group) means an alkoxy group having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Of these, a C 1-4 alkoxy group is preferable.
  • C 1-6 alkoxy (group) optionally substituted with a halogen atom means the unsubstituted C 1-6 alkoxy group or the C 1-6 alkoxy group in which one or more hydrogen atoms have been substituted with a halogen.
  • the "C 1-6 alkoxy (group) which may be substituted by a substituent selected from the group” means the unsubstituted C 1-6 alkoxy group, or the C 1-6 alkoxy group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted by the same or different substituents selected from the substituent group.
  • a "C 1-4 alkoxy (group) which may be substituted by the same or different substituents selected from the group” is more preferable.
  • alkylsulfanyl (group) means a group in which a straight-chain or branched-chain alkyl group is bonded to a sulfur atom, and is preferably a C 1-6 alkylsulfanyl group.
  • C 1-6 alkylsulfanyl (group) means an alkylsulfanyl group having 1 to 6 carbon atoms, and examples thereof include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, neopentylsulfanyl, hexylsulfanyl and the like.
  • C 1-6 alkylsulfanyl (group) optionally substituted by substituents selected from the group means the unsubstituted C 1-6 alkylsulfanyl group, or the C 1-6 alkylsulfanyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with the same or different substituents selected from the substituent group.
  • C 1-6 alkylsulfonyl (group) examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl and the like.
  • C1-6 alkylsulfonyl (group) optionally substituted with a halogen atom means the unsubstituted C1-6 alkylsulfonyl group or the C1-6 alkylsulfonyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with halogen atoms.
  • Specific examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-chloroethylsulfonyl, 2-bromoethylsulfonyl, 2-iodoethylsulfonyl, 2-fluoroethylsulfonyl, 2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, pentafluoroethylsulfonyl, 2,2,3,3-tetrafluoropropylsulfonyl, 3,3,3-trifluoropropylsulfonyl
  • C 1-6 alkyl-carbonyl (group) means a group in which the above-mentioned C 1-6 alkyl group is bonded to a carbonyl group. Specific examples include acetyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hexylcarbonyl and the like.
  • C 1-6 alkyl-carbonyl (group) optionally substituted with a halogen atom means the unsubstituted C 1-6 alkyl-carbonyl group or the C 1-6 alkyl-carbonyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with halogen atoms.
  • Specific examples include acetyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hexylcarbonyl, fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, 2-chloroethylcarbonyl, 2-bromoethylcarbonyl, 2-iodoethylcarbonyl, 2-fluoroethylcarbonyl, 2,2-difluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, pentafluoroethylcarbonyl, 2,2,3,3-tetrafluoropropylcarbonyl, 3,3,3-trifluoropropylcarbonyl, 4,4,4-trifluorobutylcarbonyl, 5,5,5-trifluoropentylcarbonyl, and 6,6,6-trifluorohexylcarbonyl.
  • C 1-6 alkoxy-carbonyl (group) means a group in which the above-mentioned C 1-6 alkoxy group is bonded to a carbonyl group. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • optionally substituted carbamoyl refers to a carbamoyl group (-CONH 2 ) in which one or two hydrogen atoms may be independently substituted with other substituents (mono- or di-substituted carbamoyl group).
  • Di-substituted carbamoyl groups also include 1-pyrrolidinylcarbonyl groups and 1-piperidylcarbonyl groups.
  • carbamoyl (group) optionally substituted by 1 to 2 C 1-6 alkyl groups optionally substituted by substituents selected from the group consisting of a halogen atom, a hydroxy group, a di-C 1-6 alkylamino group and a C 1-6 alkoxy group means a group in which one or two hydrogen atoms of the carbamoyl group (-CONH 2 ) may be independently substituted by 1 to 2 C 1-6 alkyl groups optionally substituted by substituents selected from the group consisting of a halogen atom, a hydroxy group, a di-C 1-6 alkylamino group and a C 1-6 alkoxy group, and is preferably a mono- or di-C 1-6 alkyl-carbamoyl group.
  • C2-6 alkenyl group means a straight or branched monovalent group having 2 to 6 carbon atoms obtained by removing one hydrogen atom from any carbon atom of a C2-6 alkene, and specific examples include vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl and the like.
  • C2-6 alkynyl group means a straight or branched monovalent group having 2 to 6 carbon atoms obtained by removing one hydrogen atom from any carbon atom of a C2-6 alkyne, and specific examples include ethynyl, propargyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl and the like.
  • aryl (group) refers to a monocyclic or polycyclic (fused) hydrocarbon group exhibiting aromaticity. Among them, a C 6-14 aryl group is preferred, and a C 6-10 aryl group is more preferred.
  • C 6-14 aryl (group) examples include phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, phenanthryl, 2-anthryl, fluorenyl and the like.
  • examples of the "C 6-10 aryl (group)" include phenyl, 1-naphthyl and 2-naphthyl, and of these, phenyl is preferable.
  • aryl-carbonyl (group) means a group in which the above-mentioned aryl group is bonded to a carbonyl group, and although there are no particular limitations on the range of the number of carbon atoms, it is preferably a C 6-14 aryl-carbonyl group.
  • C 6-14 aryloxy (group) means a group in which the C 6-14 aryl group is bonded to an oxygen atom, and specific examples include phenyloxy, 1-naphthyloxy, 2-naphthyloxy, biphenylyloxy, phenanthryloxy, 2-anthryloxy etc. Of these, a C 6-10 aryloxy group is preferable, and a phenyloxy group is particularly preferable.
  • C6-14 hydrocarbon ring (group) means a monovalent, saturated or partially unsaturated aliphatic hydrocarbon ring (group) having 6 to 14 carbon atoms, or a monovalent aromatic hydrocarbon ring (group) having 6 to 14 carbon atoms.
  • C 7-18 aralkyl (group) means a group in which the C 6-14 aryl group is bonded to the C 1-4 alkyl group, and specific examples include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl, etc. Of these, a C 7-10 aralkyl group is preferable, and a benzyl group is particularly preferable.
  • C 7-18 aralkyloxy (group) means a group in which the above-mentioned C 7-18 aralkyl group is bonded to an oxygen atom, and specific examples include benzyloxy, phenethyloxy, naphthylmethyloxy, biphenylylmethyloxy and the like. Of these, a benzyloxy group is particularly preferable.
  • acyl (group) means a formyl group, a linear or branched alkyl-carbonyl group, or an aryl-carbonyl group, and is not particularly limited in terms of the range of carbon numbers, but is preferably a formyl group, a C 1-6 alkyl-carbonyl group, or a C 6-14 aryl-carbonyl group.
  • acyl (group) examples 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, and is preferably a C 1-6 alkyl-carbonyloxy group, or a C 6-14 aryl-carbonyloxy group.
  • di-C 1-6 alkylamino (group) means a group in which two hydrogen atoms of an amino group are substituted by the same or different C 1-6 alkyl groups as defined above.
  • C1-6 alkylene (group) refers to a divalent group obtained by removing one hydrogen atom from the above-mentioned C1-6 alkyl group.
  • Specific examples of the C1-6 alkylene (group) include methylene, dimethylene, methylmethylene, dimethylmethylene, trimethylene, propane-1,2-diyl, tetramethylene, pentamethylene, isopentane-2,4-diyl, hexamethylene, etc.
  • C6-10 arylene (group) refers to a divalent group obtained by removing one hydrogen atom from the " C6-10 aryl group".
  • Specific examples of the C6-10 arylene (group) include 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene group, 2,6-naphthylene, and the like.
  • C 2-6 alkynylene (group) refers to a divalent group obtained by removing one hydrogen atom from the above-mentioned "C 2-6 alkynyl group”. Of these, C 2-3 alkynylene is preferred. Specific examples of C 2-3 alkynylene (group) include ethynylene (-C ⁇ C-) and propynylene (-C ⁇ C-CH 2 -).
  • C 3-14 cycloalkylene (group) refers to a divalent group obtained by removing one hydrogen atom from the "C 3-14 cycloalkyl group”.
  • C 3-8 cycloalkylene is preferable.
  • Specific examples of the C 3-8 cycloalkylene (group) include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,3-diyl, bicyclo[2.1.1]hexane-1,2-diyl, bicyclo[1.1.1]pentane-1,3-diyl, and the like.
  • the term "3- to 14-membered divalent non-aromatic heterocyclic ring (group)” refers to a divalent group obtained by removing one hydrogen atom from the "3- to 14-membered non-aromatic heterocyclic ring (group)” described below. Among these, a 3- to 8-membered divalent non-aromatic heterocyclic ring is preferred.
  • 3- to 8-membered divalent non-aromatic heterocyclic ring include aziridine-1,2-diyl, oxetane-2,4-diyl, azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,2-diyl, piperidine-1,3-diyl, piperidine-1,4-diyl, etc.
  • a divalent organic group containing a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group means a divalent group having the above-mentioned "C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group", and "C” in "an organic group having a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14-membered divalent
  • moieties other than the " 1-6 alkylene group, C 6-10 arylene group, C 3-14 cycloalkylene group, C 2-6 alkenylene group, C 2-6 alkynylene group, or 3- to 14-membered divalent non-aromatic heterocyclic group" can be set arbitrarily.
  • Preferred examples of the "divalent organic group containing a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group” include, for example, -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group), -O-, -S-, -C( ⁇ O)-, a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to 14-membered divalent non-aromatic heterocyclic group, each of which may have one or more divalent groups at the interior or terminal thereof and each of which may be further substituted with 1 to 3 substituents
  • the two bonds of the divalent (organic) group may originate from the same carbon atom or different carbon atoms in the (organic) group, or may originate from a heteroatom constituting the (organic) group.
  • the terms "C 3-10 cycloalkylene group”, “C 2-4 alkenylene group” and “C 2-4 alkynylene group” have the same meaning as the above-mentioned “C 3-14 cycloalkylene group”, “C 2-6 alkenylene group” and “C 2-6 alkynylene group”, respectively, except that the range of the number of carbon atoms is different.
  • heterocyclic ring (group) examples include (i) aromatic heterocyclic groups and (ii) non-aromatic heterocyclic groups each containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring-constituting atoms.
  • Aromatic heterocyclic groups include 5- or 6-membered monocyclic aromatic heterocyclic groups and 8- to 14-membered fused aromatic heterocyclic groups
  • Non-aromatic heterocyclic groups include 3- to 10-membered monocyclic non-aromatic heterocyclic groups, 9- to 14-membered fused non-aromatic heterocyclic groups, 6- to 14-membered bridged cyclic non-aromatic heterocyclic groups, and 6- to 16-membered spirocyclic non-aromatic heterocyclic groups.
  • aromatic heterocyclic groups include 5- to 14-membered aromatic heterocyclic groups containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring-constituting atoms.
  • aromatic heterocyclic group examples include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.; benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyr
  • non-aromatic heterocyclic groups include 3- to 14-membered non-aromatic heterocyclic groups containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring-constituting atoms.
  • 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, and tetrahydroisoxazolyl.
  • non-aromatic heterocyclic group examples include pyrrolidinyl, piperidyl, tetrahydrotriazolopyrazinyl (e.g., 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), tetrahydropyrazolopyrazinyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl), tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydroisoquinolyl), tetrahydronaphthyridinyl (e.g., 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2), tetrahydr
  • non-aromatic heterocyclic group examples include 6- to 14-membered bridged ring non-aromatic heterocyclic groups such as 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.2]octyl, 7-azabicyclo[2.2.1]heptanyl, quinuclidinyl, etc.; and 6- to 16-membered spiro ring non-aromatic heterocyclic groups such as 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.3]heptyl, etc.
  • nitrogen-containing heterocyclic group includes nitrogen-containing aromatic heterocyclic groups and nitrogen-containing non-aromatic heterocyclic groups.
  • nitrogen-containing aromatic heterocyclic group or “nitrogen-containing non-aromatic heterocyclic group” refers to the above-mentioned aromatic heterocyclic group or non-aromatic heterocyclic group that has at least one nitrogen atom as a ring-constituting atom.
  • divalent nitrogen-containing aromatic heterocyclic group refers to a divalent group obtained by removing one hydrogen atom from the aforementioned "nitrogen-containing aromatic heterocyclic group.”
  • divalent nitrogen-containing non-aromatic heterocyclic group refers to a divalent group obtained by removing one hydrogen atom from the aforementioned "nitrogen-containing non-aromatic heterocyclic group.”
  • tri-substituted silyl (group) means a silyl group substituted by three identical or different substituents (e.g., a C 1-6 alkyl group, a C 6-10 aryl group, etc.), and examples of the group include trialkylsilyl groups such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, and a tert-butyldimethylsilyl group (preferably a tri-C 1-6 alkylsilyl group), a tert-butyldiphenylsilyl group, a triphenylsilyl group, and the like.
  • trialkylsilyl groups such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, and a tert-butyldimethylsilyl group (preferably a tri-C 1-6 alkylsilyl group),
  • tri-substituted silyloxy (group) means a group in which a tri-substituted silyl group is bonded to an oxygen atom, and examples of the group include trialkylsilyloxy groups such as a trimethylsilyloxy group, a triethylsilyloxy group, a triisopropylsilyloxy group, and a tert-butyldimethylsilyloxy group (preferably a tri - C alkylsilyloxy group), a tert-butyldiphenylsilyloxy group, and a triphenylsilyloxy group.
  • trialkylsilyloxy groups such as a trimethylsilyloxy group, a triethylsilyloxy group, a triisopropylsilyloxy group, and a tert-butyldimethylsilyloxy group (preferably a tri - C alkylsilyloxy group), a tert-buty
  • bioisomes refers to "functional groups that exhibit broadly similar biological effects and have chemical and physical similarities” proposed by Thornber in 1979 in the field of medicinal chemistry.
  • groups bioisosteric to a carboxy group include an optionally substituted C 1-6 alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, a group represented by the following formula:
  • substituent is not particularly limited, but examples thereof include substituents selected from the following (substituent group a), (substituent group a'), (substituent group b) or (substituent group b').
  • substituent group a substituted with substituents selected from the following (substituent group a), (substituent group a'), (substituent group b) or (substituent group b').
  • substituent group When no particular substituent group is specified, it means that the group may be substituted with one or more substituents selected from the following (substituent group c) or (substituent group c').
  • the number of substituents is not particularly limited as long as it is a substitutable number, but is usually 1 to 5, and preferably 1 to 3. When multiple substituents are present, the respective substituents may be the same or different.
  • Substituent group c Halogen atoms; Hydroxy group; Carboxy group; Nitro group; Cyano group; an amino group optionally substituted by 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 by 1 to 3 substituents selected from substituent group a or substituent group a'; a C 1-6 alkoxy group optionally substituted by 1 to 3 substituents selected from substituent group a or substituent group a'; C 1-6 alkoxy-carbonyl group; a C 1-6 alkylsulfonyl group optionally substituted by 1 to 3 substituents selected from substituent group a or substituent group a'; a C 3-8 cycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group a or substituent group a'; an acyl group optionally substituted by 1 to 3 substituents selected
  • Substituent group c' Halogen atoms; Hydroxy group; Carboxy group; Nitro group; Cyano group; an amino group optionally substituted by 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 by 1 to 3 substituents selected from substituent group a or substituent group a'; a C 1-6 alkoxy group optionally substituted by 1 to 3 substituents selected from substituent group a or substituent group a'; C 1-6 alkoxy-carbonyl group; a C 1-6 alkylsulfonyl group optionally substituted by 1 to 3 substituents selected from substituent group a or substituent group a'; a C 3-8 cycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group a or substituent group a'; an acyl group optionally substituted by 1 to 3 substituents
  • a pharma- ceutically acceptable salt thereof refers to a salt that can be used as a medicine.
  • the compound (I) of the present invention has an acidic or basic group, it can be converted into a basic salt or an acidic salt by reacting it with a base or an acid, and so the term refers to such a salt.
  • the salt is preferably water-soluble.
  • the pharma- ceutically acceptable "basic salts" of compound (I) of the present invention include, for example, alkali metal salts such as sodium salt, potassium salt, lithium salt, etc.; alkaline earth metal salts such as magnesium salt, calcium salt, etc.; ammonium salts such as ammonium salt, tetramethylammonium salt, etc.; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt, etc.; basic amino acid salts such as lysine salt, arginine salt, etc., and preferably alkali metal salts (particularly sodium salt or potassium salt) and basic amino acid salts.
  • alkali metal salts such as sodium salt, potassium salt, lithium salt, etc.
  • alkaline earth metal salts such as magnesium
  • Examples of pharma- ceutically acceptable "acid salts" of compound (I) of the present invention include hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate, etc.; lower alkanesulfonate salts such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.; arylsulfonate salts such as benzenesulfonate, p-toluenesulfonate, etc.; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; and the like, with hydrohalide salts (particularly hydrochloride) being preferred.
  • hydrohalide salts such as hydrofluoride, hydrochlor
  • salts thereof refers to all salts including the above-mentioned “pharmaceutical acceptable salts thereof”.
  • prevention includes preventing the onset of disease, delaying the onset of disease, and preventing the onset of pathology.
  • a “prophylactically effective amount” refers to the dose of an active ingredient sufficient to achieve the preventive purpose.
  • treatment includes curing a disease, improving the pathology of a disease (e.g., one or more symptoms), and inhibiting the progression of a disease (or its severity).
  • a “therapeutically effective amount” refers to the dose of an active ingredient sufficient to achieve the therapeutic objective. Therefore, “improvement” is a concept that is included in “treatment.”
  • the term "subject” refers to a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of an active ingredient required for preventing and/or treating (or ameliorating) a disease or the pathology of a disease is administered.
  • the "subject” in question may be a human or a non-human animal, particularly a mammal (e.g., a human, a mouse, a rat, a guinea pig, a hamster, a rabbit, a cat, a dog, a cow, a sheep, a monkey, etc.).
  • B0AT1 inhibitor refers to a drug consisting of 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 pharma- ceutically acceptable salt thereof, exhibits excellent inhibitory activity against B0AT1.
  • the inhibitory activity against 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 example described below.
  • diseases whose symptoms can be alleviated by B0AT1 inhibition refers to diseases caused by increased levels of neutral amino acids in the blood due to mutations in genes related to the amino acid metabolic pathway.
  • diseases include amino acid metabolic disorders such as phenylketonuria, urea cycle disorders, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.
  • R1 represents a carboxy group or a group biologically equivalent to a carboxy group.
  • R 1 is preferably a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or a group represented by the following formula:
  • L represents a divalent organic group containing a group selected from the group consisting of a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a divalent 3- to 14-membered non-aromatic heterocyclic group, each of which may be further substituted.
  • L is preferably a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group, each of which may have one or more divalent groups selected from the group consisting of -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group ), -O-, -S-, -C( ⁇ O)-, a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to 14 -membered divalent non-aromatic heterocyclic group at its internal or terminal end, and each of which may be further substituted with 1 to 3 substituents selected from the substituent
  • A represents a divalent nitrogen-containing heterocyclic group which may be further substituted.
  • A is preferably a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a':
  • ring A1 represents a 3- to 10-membered monocyclic ring, an 8- to 14-membered fused ring, a 6- to 16-membered spiro ring or a 6- to 14-membered bridged ring, and may contain, as ring-constituting atoms, a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a nitrogen atom and a carbon atom.
  • the aryl group is represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′:
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • aryl group may be a aryl group represented by the following formula:
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • the optionally further substituted substituent is selected from the group consisting of a C 6-14 hydrocarbon ring group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b' among the substituents of substituent group a or substituent group a'; a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and a 3- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b'.
  • the compound represented by the following formula (I) may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group
  • R represents an optionally substituted C 6-10 aryl-ethenyl group.
  • R is preferably a 2-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-8 cycloalkyloxy group, an optionally substituted C 1-6 alkylsulfanyl group, an optionally substituted C 3-8 cycloalkylsulfanyl group, and a pentafluorosulfanyl group; More preferably, it is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or a group represented by the following formula:
  • L is a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14 -membered divalent non-aromatic heterocyclic group, each of which may have one or more divalent groups selected from the group consisting of -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group ), -O-, -S-, -C( ⁇ O)-, a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to 14-membere
  • R is a 2-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-8 cycloalkyloxy group, an
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group
  • L is a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14 -membered divalent non-aromatic heterocyclic group, each of which may have one or more divalent groups selected from the group consisting of -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group ), -O-, -S-, -C( ⁇ O)-, a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to
  • R is a 2-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-8 cycloalkyloxy group, an
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or a group represented by the following formula:
  • R is a 2-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-8 cycloalkyloxy group, an
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or a group represented by the following formula:
  • C 1-6 alkylene group which may have one or more divalent groups selected from the group consisting of 3-10 cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3- to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl,
  • R is a 2-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-8 cycloalkyloxy group, an
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or a group represented by the following formula:
  • L is a C 1-6 alkylene group optionally further substituted by 1 to 3 substituents selected from the substituent group a or the substituent group a';
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • R is a 2-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-8 cycloalkyloxy group, an
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or a group represented by the following formula:
  • L is a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14 -membered divalent non-aromatic heterocyclic group, each of which may have one or more divalent groups selected from the group consisting of -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group ), -O-, -S-, -C( ⁇ O)-, a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to 14-membere
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R is a 2-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-8 cycloalkyloxy group, an optionally substituted C 1-6 alkylsulfanyl group, an optionally substituted C 3-8 cycloalkylsulfanyl group, and a pentafluorosulfanyl group.
  • Compound (I) or a pharma- ceutically acceptable salt thereof thereof.
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or a group represented by the following formula:
  • L is a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14 -membered divalent non-aromatic heterocyclic group, each of which may have one or more divalent groups selected from the group consisting of -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group ), -O-, -S-, -C( ⁇ O)-, a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to 14-membere
  • ring A1 represents a 3- to 10-membered monocyclic ring, an 8- to 14-membered fused ring, a 6- to 16-membered spiro ring or a 6- to 14-membered bridged ring, and may contain, as ring-constituting atoms, a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a nitrogen atom and a carbon atom.
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group; L, -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group), -O-, -S-, C A C 1-6 alkylene group which may have one or more divalent groups selected from the group consisting of 3-10 cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3- to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-di
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group
  • L is a C 1-6 alkylene group optionally further substituted by 1 to 3 substituents selected from the substituent group a or the substituent group a'
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • n represents an integer of 0 to 2
  • m represents an integer of 0 to 2
  • n 1 and n 2 each independently represent an integer of 0 to 2
  • m 1 and m 2 each independently represent an integer of 0 to 2
  • ** represents a bonding site with the carbonyl group
  • *** represents a bonding site with the group L.
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group; L, -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group), -O-, -S-, C A C 1-6 alkylene group which may have one or more divalent groups selected from the group consisting of 3-10 cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3- to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl),
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group
  • L is a C 1-6 alkylene group optionally further substituted by 1 to 3 substituents selected from the substituent group a or the substituent group a'
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group;
  • L is a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, or a 3- to 14 -membered divalent non-aromatic heterocyclic group, each of which may have one or more divalent groups selected from the group consisting of -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group ), -O-, -S-, -C( ⁇ O)-, a C 1-6 alkylene group, a C 6-10 arylene group, a C 3-14 cycloalkylene group, a C 2-6 alkenylene group, a C 2-6 alkynylene group, and a 3- to 14-member
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • the optionally further substituted substituent is selected from the group consisting of a C 6-14 hydrocarbon ring group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b' among the substituents of substituent group a or substituent group a'; a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and a 3- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b'.
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluor
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group; L, -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group), -O-, -S-, C A C 1-6 alkylene group which may have one or more divalent groups selected from the group consisting of 3-10 cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3- to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl
  • a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, which may be further substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group a or Substituent Group a′):
  • the optionally further substituted substituent is selected from the group consisting of a C 6-14 hydrocarbon ring group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b' among the substituents of substituent group a or substituent group a'; a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and a 3- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b or substituent group b'.
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluor
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group; L, -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group), -O-, -S-, C A C 1-6 alkylene group which may have one or more divalent groups selected from the group consisting of 3-10 cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3- to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group
  • L is a C 1-6 alkylene group optionally further substituted by 1 to 3 substituents selected from the substituent group a or the substituent group a'
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group; L, -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group), -O-, -S-, C A C 1-6 alkylene group which may have one or more divalent groups selected from the group consisting of 3-10 cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3- to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group
  • L is a C 1-6 alkylene group optionally further substituted by 1 to 3 substituents selected from the substituent group a or the substituent group a'
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group; L, -NR 2 - (wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group), -O-, -S-, C A C 1-6 alkylene group which may have one or more divalent groups selected from the group consisting of 3-10 cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3- to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • R 1 is a carboxy group, an optionally substituted C 1-6 alkoxy-carbonyl group, or an optionally substituted carbamoyl group
  • L is a C 1-6 alkylene group optionally further substituted by 1 to 3 substituents selected from the substituent group a or the substituent group a'
  • A is a group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a or the above-mentioned substituent group a′:
  • R is a 2-(E)-phenylethenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group optionally substituted by a halogen atom, and a pentafluorosulfanyl group.
  • Preferred specific examples of compound (I) include the compounds of Examples 1 to 403 (compounds (I-1) to (I-403)) described below, or pharma- ceutically acceptable 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 can exist as multiple stereoisomers (i.e., diastereoisomers, optical isomers) based on the asymmetric carbon atom, and the present invention includes any one of these stereoisomers, as well as mixtures containing these multiple stereoisomers in any ratio.
  • isomers may be generated due to conformation or tautomerism, and such isomers or mixtures thereof are also included in the compound (I) of the present invention.
  • Compound (I) of the present invention may be a compound labeled or substituted with an isotope (e.g., 2H , 3H , 13C , 14C , 15N , 18F , 32P , 35S , 123I , 125I , 131I , etc.), and the compound labeled or substituted with an isotope can be used as a tracer (PET tracer) used in, for example, Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET), and is useful in the field of medical diagnosis, etc.
  • an isotope e.g., 2H , 3H , 13C , 14C , 15N , 18F , 32P , 35S , 123I , 125I , 131I , etc.
  • PET tracer used in, for example, Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET),
  • the compound (I) of the present invention or a pharma- ceutically acceptable salt thereof may be crystalline, and may have a single crystalline form or a mixture of multiple crystalline forms.
  • the compound (I) of the present invention or a pharma- ceutically acceptable salt thereof may include its intramolecular salt, adduct, and solvate thereof.
  • These solvates are compounds in which the molecules of a solvent are coordinated to the compound (I) or its salt, and also include hydrates.
  • hydrates, ethanol solvates, and dimethylsulfoxide solvates of the compound (I) or its salt may be mentioned.
  • Compound (I) of the present invention may be a prodrug.
  • the prodrug of compound (I) of the present invention refers to a compound that is converted to compound (I) in vivo by a reaction with an enzyme, gastric acid, or the like.
  • the prodrug of compound (I) may be a monoester or diester of a phosphate group, and the ester functional group preferably has a structure that is easily hydrolyzed or metabolized after administration to a patient.
  • Specific examples of the ester functional group of such a prodrug include C 1-6 alkyl esters, phenyl esters, benzyl esters, etc., which may be substituted with an acyloxy group (see Bioorganic Chemistry, 1984; 12: p. 118-129).
  • examples of prodrugs other than the monoesters or diesters of the phosphate group include compounds having groups derived from the phosphate group, such as those described in 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.
  • prodrug of compound (I) include, for example, when compound (I) has an amino group, a compound in which the amino group has been acylated, alkylated or phosphorylated (for example, a compound in which the amino group of compound (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated or tert-butylated); when compound (I) has a hydroxyl group, a compound in which the hydroxyl group has been acylated, alkylated, phosphorylated or borated (for example, a compound in which the hydroxyl group of compound (I) has been acetylated, palmitoylated, propanoy
  • the prodrug of compound (I) may be either a hydrate or a non-hydrate.
  • the prodrug of compound (I) may be one that is converted into a compound represented by compound (I) under physiological conditions, as described in "Drug Development,” Vol. 7, “Molecular Design,” pp. 163-198, published by Hirokawa Shoten in 1990.
  • Each of the raw material compounds may form a salt as long as it does not inhibit the reaction.
  • Examples of such salts include the same salts as those of compound (I).
  • the raw material compounds can be easily obtained from commercial sources and used, or can be manufactured according to a method known per se or a method similar thereto.
  • intermediates produced in the following manufacturing methods may be isolated and purified by a method such as column chromatography, recrystallization, distillation, etc., or may be used in the next step without isolation.
  • R 1a -P 1 represents a protected R 1 , and the other symbols are as defined above.
  • Step A-1 This step is a step of producing compound (3-1) by condensing compound (1-1) and compound (2-1) in the presence of a condensing agent.
  • the amount of compound (2-1) used is 0.8 mol to 5 mol, preferably 0.8 mol to 3 mol, per mol of compound (1-1).
  • Condensation 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-benzotriazolium 3-oxide hexafluorophosphate (HCTU), and O
  • the reaction may be carried out in the presence of an additive such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (HOCt), or 1-hydroxy-7-azabenzotriazole (HOAt).
  • an additive such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (HOCt), or 1-hydroxy-7-azabenzotriazole (HOAt).
  • the amount of the additive used is usually 0 to 1.5 mol per 1 mol of the compound (1-1).
  • the base includes organic bases such as triethylamine, pyridine, and N,N-diisopropylethylamine, and among these, triethylamine or N,N-diisopropylethylamine is preferable.
  • the amount of the base used is usually 1 to 5 moles, preferably 1.5 moles, per mole of compound (1-1).
  • reaction solvents are not particularly limited, but examples include aromatic hydrocarbons such as toluene and xylene; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile, and mixtures thereof.
  • aromatic hydrocarbons such as toluene and xylene
  • amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide
  • ethers such as diethyl ether, tetrahydrofuran and dioxane
  • 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 hour to 48 hours.
  • Step A-2 This step is a step of obtaining compound (Ia) by deprotecting the amino-protecting group (P 1 ).
  • the reaction conditions for the deprotection step in step A-2 can be selected depending on the type of protecting group (P 1 ).
  • the deprotection reaction is carried out in accordance with a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or the method described in the Examples below.
  • the protecting group P3 in the compound (6-1) may be a tri-substituted silyl group such as a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a triisopropylsilyl group, etc.
  • the protecting group P3 is removed during the reaction in step B-2.
  • Step B-1 This step is a step of producing compound (5-1) by condensing compound (1-1) and compound (4-1) in the presence of a condensing agent.
  • the amount of compound (4-1) used is 0.8 mol to 5 mol, preferably 0.8 mol to 3 mol, per mol of compound (1-1).
  • step B-1 the reaction can be carried out under the same conditions as in step A-1, except that compound (4-1) is used instead of compound (2-1).
  • Step B-2 This step can be carried out by a cross-coupling reaction (Heck reaction) between compound (5-1) and compound (6-1) in a solvent that does not influence the reaction, in the presence of a metal catalyst (e.g., a palladium catalyst) and, where necessary, a base.
  • a cross-coupling reaction Heck reaction
  • a metal catalyst e.g., a palladium catalyst
  • the amount of compound (6-1) used is 0.8 mol to 5 mol, preferably 0.8 mol to 3 mol, per mol of compound (5-1).
  • Metal catalysts include palladium(II) acetate, palladium(II) chloride, dichlorobis(tricyclohexylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0) (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium(0), bis(tri-tert-butylphosphine)palladium(0), palladium(II) chloride ⁇ diphenylphosphinoferrocene (PdCl 2 (dppf)), PdCl 2 palladium catalysts such as (dppf) dichloromethane complex, palladium carbon (0), bis(triphenylphosphine)palladium dichloride (II), dichlorobis(tri-o-tolylphosphine)palladium (II), bis(tris(2-to
  • Palladium catalysts are preferred, and among them, dichlorobis(tricyclohexylphosphine)palladium (II), dichlorobis(tri-o-tolylphosphine)palladium (II), or bis(tri-tert-butylphosphine)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' Phosphine ligands such as 4',6'-triisopropylbiphenyl (BrettPhos), tri-t-butylphosphine, tricyclohexylphosphine, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (AmPhos), (S)-1-[
  • the amount of the metal catalyst used is usually 0.01 mol to 1 mol, and preferably 0.05 mol to 0.3 mol, per 1 mol of compound (5-1).
  • the amount of the ligand used is usually 0.05 mol to 1 mol, preferably 0.1 mol to 0.4 mol, per 1 mol of compound (5-1).
  • the reaction may be carried out in the presence of an additive such as zinc fluoride (ZnF 2 ), copper fluoride (CuF 2 ), or lithium fluoride (LiF).
  • an additive such as zinc fluoride (ZnF 2 ), copper fluoride (CuF 2 ), or lithium fluoride (LiF).
  • the amount of the additive used is usually 0 to 1.5 mol per 1 mol of compound (5-1).
  • the base examples include alkali metal amides such as lithium diisopropylamide, sodium amide, and lithium bistrimethylsilylamide; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; alkali metal phosphates such as sodium phosphate and potassium phosphate; and amines such as triethylamine, N,N-diisopropylethylamine, pyridine, and N-methylmorpholine.
  • the amount of the base used is usually 1 mol to 5 mol, preferably 1 mol to 2.5 mol, per 1 mol of compound (5-1).
  • the reaction solvent is not particularly limited, but examples include amides such as N,N-dimethylformamide and N-methylpyrrolidone; ethers such as tetrahydrofuran and 1,4-dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene and xylene; nitriles such as acetonitrile; and mixtures of these.
  • the reaction temperature is usually from -78°C to 200°C, preferably from -78°C to 120°C.
  • the reaction time is usually 0.5 to 12 hours.
  • Step B-3 This step is a step of obtaining compound (Ib) by deprotecting the protecting group (P 2 ).
  • the reaction conditions for the deprotection step of step B-3 can be selected depending on the type of protecting group (P 2 ).
  • the deprotection reaction is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or the method described in the Examples below.
  • R 1b -P 5 represent a protected R 1
  • X 1 represents a leaving group
  • P 4 and P 5 each independently represent a protecting group, and the other symbols are as defined above.
  • Step C-1 This step is a step of producing compound (9-1) by condensing compound (1-1) and compound (8-1) in the presence of a condensing agent.
  • the amount of compound (8-1) used is 0.8 mol to 5 mol, preferably 0.8 mol to 3 mol, per mol of compound (1-1).
  • step C-1 the reaction can be carried out under the same conditions as in step A-1, except that compound (8-1) is used instead of compound (2-1).
  • Step C-2 This step is a step of obtaining compound (10-1) by removing the amino-protecting group (P 4 ).
  • the reaction conditions for the deprotection step of step C-2 can be selected depending on the type of protecting group (P 4 ).
  • the deprotection reaction is carried out according to a method known per se, for example, a method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or a method described in the Examples below.
  • Step C-3 This step is a step of producing compound (12-1) by reacting compound (10-1) with compound (11-1) in the presence of a base.
  • the amount of compound (11-1) used is 1 mol to 5 mol, preferably 1 mol to 3 mol, per mol of compound (10-1).
  • the base examples include organic bases such as triethylamine, pyridine, and N,N-diisopropylethylamine; and inorganic bases such as sodium carbonate, potassium carbonate, and cesium carbonate, and among these, preferred is triethylamine or N,N-diisopropylethylamine.
  • organic bases such as triethylamine, pyridine, and N,N-diisopropylethylamine
  • inorganic bases such as sodium carbonate, potassium carbonate, and cesium carbonate, and among these, preferred is triethylamine or N,N-diisopropylethylamine.
  • the amount of the base used is usually 1 to 5 moles, preferably 1.5 moles, per mole of compound (10-1).
  • the reaction may be carried out in the presence of an additive such as tetrabutylammonium iodide (TBAI), sodium iodide, or silver trifluoromethanesulfonate.
  • an additive such as tetrabutylammonium iodide (TBAI), sodium iodide, or silver trifluoromethanesulfonate.
  • TBAI tetrabutylammonium iodide
  • sodium iodide sodium iodide
  • silver trifluoromethanesulfonate silver trifluoromethanesulfonate.
  • the amount of the additive used is usually 0 to 1.5 mol per 1 mol of compound (10-1).
  • reaction solvent is not particularly limited, but examples include aromatic hydrocarbons such as toluene and xylene; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile, and mixtures thereof.
  • aromatic hydrocarbons such as toluene and xylene
  • amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide
  • ethers such as diethyl ether, tetrahydrofuran and dioxane
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • nitriles such as acetonitrile, and mixtures thereof.
  • the reaction temperature is usually 0°C to 100°C, preferably 0°C to 50°C, and the reaction time is usually 1 hour to 48 hours.
  • the halo group can be converted to an alkyl or cycloalkyl group by a subsequent coupling reaction.
  • Step C-4 This step is a step of obtaining compound (Ic) by removing the amino-protecting group (P 5 ).
  • the reaction conditions for the deprotection step of step C-4 can be selected depending on the type of protecting group (P 5 ).
  • the deprotection reaction is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or the method described in the Examples below.
  • the halo group can be converted to an alkyl or cycloalkyl group by a subsequent coupling reaction.
  • R 1c -P 6 represents a protected R 1
  • P 6 represents a protecting group
  • L a represents a divalent organic group
  • Step D-1 This step is a step of reacting compound (10-1) with a reducing agent and compound (13-1) in a solvent that does not influence the reaction (reductive alkylation reaction) to obtain compound (14-1).
  • the amount of compound (13-1) used is 1 mol to 3 mol, preferably 1 mol to 2 mol, per mol of compound (10-1).
  • the reducing agent is not particularly limited, but examples thereof include sodium triacetoxyborohydride, sodium borohydride, and the like.
  • the amount of the reducing agent used is 1 to 10 moles, preferably 1 to 3 moles, per mole of compound (10-1).
  • the reaction may be carried out in the presence of an additive such as an organic acid (eg, acetic acid) or a Lewis acid (eg, titanium(IV) tetrachloride or tetraisopropyl titanate).
  • an additive such as an organic acid (eg, acetic acid) or a Lewis acid (eg, titanium(IV) tetrachloride or tetraisopropyl titanate).
  • the amount of the additive used is 1 to 10 moles, preferably 1 to 3 moles, per mole of compound (10-1).
  • Reaction solvents are not particularly limited, but examples include 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; and mixtures thereof.
  • 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.
  • This step is a step of obtaining compound (Id) by removing the amino-protecting group (P 6 ).
  • the reaction conditions for the deprotection step of step D-2 can be selected depending on the type of protecting group (P 6 ).
  • the deprotection reaction is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or the method described in the Examples below.
  • Step E-1 This step is a step of producing compound (15-1) by reacting compound (8-1) with compound (11-1) in the presence of a base.
  • the amount of the compound (11-1) used is 1 to 5 moles, preferably 1 to 3 moles, per mole of the compound (8-1).
  • step E-1 the reaction can be carried out under the same conditions as in step C-3, except that compound (8-1) is used instead of compound (10-1).
  • Step E-2 This step is a step of obtaining compound (16-1) by removing the amino-protecting group (P 4 ).
  • the reaction conditions for the deprotection step of step E-2 can be selected depending on the type of protecting group (P 4 ).
  • the deprotection reaction is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or the method described in the Examples below.
  • Step E-3 This step is a step of producing compound (12-1) by condensing compound (16-1) with compound (1-1) in the presence of a condensing agent.
  • the amount of compound (16-1) used is 0.8 mol to 5 mol, preferably 0.8 mol to 3 mol, per mol of compound (1-1).
  • step E-3 the reaction can be carried out under the same conditions as in step A-1, except that compound (16-1) is used instead of compound (2-1).
  • the halo group can be converted to an alkyl or cycloalkyl group by a subsequent coupling reaction.
  • Step E-4 This step is a step of obtaining compound (Ic) by removing the amino-protecting group (P 5 ).
  • the reaction conditions for the deprotection step of Step E-4 can be selected depending on the type of protecting group (P 5 ).
  • the deprotection reaction is carried out according to a method known per se, for example, a method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or a method described in the Examples below.
  • the halo group can be converted to an alkyl or cycloalkyl group by a subsequent coupling reaction.
  • Step F-1 This step is a step of reacting compound (8-1) with a reducing agent and compound (13-1) in a solvent that does not influence the reaction (reductive alkylation reaction) to obtain compound (17-1).
  • the amount of compound (13-1) used is 1 mol to 3 mol, preferably 1 mol to 2 mol, per mol of compound (8-1).
  • step F-1 the reaction can be carried out under the same conditions as in step D-1, except that compound (8-1) is used instead of compound (10-1).
  • Step F-2 This step is a step of obtaining compound (18-1) by removing the amino-protecting group (P 4 ).
  • the reaction conditions for the deprotection step of step F-2 can be selected depending on the type of protecting group (P 4 ).
  • the deprotection reaction is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or the method described in the Examples below.
  • Step F-3 This step is a step of producing compound (14-1) by condensing compound (18-1) with compound (1-1) in the presence of a condensing agent.
  • the amount of compound (18-1) used is 0.8 mol to 5 mol, preferably 0.8 mol to 3 mol, per mol of compound (1-1).
  • step F-3 the reaction can be carried out under the same conditions as in step A-1, except that compound (18-1) is used instead of compound (2-1).
  • the halo group can be converted to an alkyl or cycloalkyl group by a subsequent coupling reaction.
  • Step F-4 This step is a step of obtaining compound (Id) by removing the amino-protecting group (P 6 ).
  • the reaction conditions for the deprotection step of step F-4 can be selected depending on the type of protecting group (P 6 ).
  • the deprotection reaction is carried out according to a method known per se, for example, a method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or a method described in the Examples below.
  • the halo group can be converted to an alkyl or cycloalkyl group by a subsequent coupling reaction.
  • Step G-1 In this step, compound (19-1) is reacted with a halogenating agent in a solvent that does not influence the reaction to generate an acid halide, and then the acid halide is reacted with compound (8-1) to obtain compound (20-1).
  • the amount of compound (19-1) used is 1 mol to 3 mol, preferably 1 mol to 2 mol, per mol of compound (8-1).
  • the halogenating agent is not particularly limited, but examples thereof include thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, and the like.
  • the amount of the halogenating agent used is 1 mol to 10 mol, preferably 1 mol to 3 mol, per 1 mol of compound (19-1).
  • the reaction may be carried out in the presence of an additive such as DMF.
  • the amount of the additive used is 0.05 mol to 1 mol, preferably 10.05 mol to 0.1 mol, relative to 1 mol of the compound (19-1).
  • Reaction solvents are not particularly limited, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran; halogenated hydrocarbons such as chloroform and dichloromethane; and mixtures thereof.
  • 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.
  • Step G-2 This step is a step of obtaining compound (21-1) by removing the amino-protecting group (P 4 ).
  • the reaction conditions for the deprotection step in step G-2 can be selected depending on the type of protecting group (P 4 ).
  • the deprotection reaction is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or the method described in the Examples below.
  • Step G-3 This step is a step of producing compound (22-1) by reacting compound (21-1) with compound (11-1) in the presence of a base.
  • the amount of the compound (11-1) used is 1 to 5 moles, preferably 1 to 3 moles, per mole of the compound (21-1).
  • step G-3 the reaction can be carried out under the same conditions as in step C-3, except that compound (21-1) is used instead of compound (10-1).
  • Step G-4 This step is a step of obtaining compound (23-1) by removing the amino-protecting group (P 7 ).
  • the reaction conditions for the deprotection step in step G-4 can be selected depending on the type of protecting group (P 7 ).
  • the deprotection reaction is carried out according to a method known per se, for example, a method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or a method described in the Examples below.
  • Step G-5 This step is a step of producing compound (12-1) by condensing compound (23-1) and compound (24-1) in the presence of a condensing agent.
  • the amount of compound (23-1) used is 0.8 mol to 5 mol, preferably 0.8 mol to 3 mol, per mol of compound (24-1).
  • step G-5 the reaction can be carried out under the same conditions as in step A-1, except that compound (23-1) is used instead of compound (2-1).
  • Step G-6 This step is a step of obtaining compound (Ic) by removing the amino-protecting group (P 5 ).
  • the reaction conditions for the deprotection step of step G-6 can be selected depending on the type of protecting group (P 5 ).
  • the deprotection reaction is carried out according to a method known per se, for example, a method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski), published by Thieme in 2004, or a method described in the Examples below.
  • Compound (I) or a pharma- ceutically acceptable salt thereof obtained by the above-mentioned manufacturing method can be isolated and purified by conventional separation means such as recrystallization, distillation, chromatography, etc.
  • the compound (I) of the present invention or a pharma- ceutically acceptable salt thereof exists as an optical isomer based on an asymmetric carbon
  • it can be separated into individual optical isomers by conventional 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 carrying out each reaction using an asymmetric auxiliary group or an asymmetric catalyst.
  • the pharmaceutical of the present invention is a pharmaceutical for preventing and/or treating a disease whose symptoms can be alleviated by B0AT1 inhibitory action, which contains compound (I) or a pharma- ceutical acceptable salt thereof as an active ingredient.
  • the pharmaceutical of the present invention is at least one of a pharmaceutical for preventing the onset of a disease whose symptoms can be alleviated by B0AT1 inhibitory action, and a pharmaceutical for ameliorating the symptoms of the disease, which contains the active ingredient.
  • the pharmaceutical of the present invention may be either a pharmaceutical consisting of only compound (I) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition containing compound (I) or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable carrier, etc.
  • the pharmaceutical of the present invention may be administered to a subject (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.) in a prophylactically or therapeutically effective amount.
  • Examples of pharma- ceutically 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.), 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, etc.), and the like.
  • excipients e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.
  • binders e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.
  • solubilizing agents e.g., polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.
  • suspending agents e.g., surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; polyvinyl alcohol, hydrophilic polymers such as cellulose acetate, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like), isotonicity agents (e.g., sodium chloride, sodium stearyl tri
  • water-insoluble lake dyes e.g., aluminum salts of the above-mentioned water-soluble edible tar dyes
  • natural dyes e.g., ⁇ -carotene, chlorophyll, red iron oxide
  • sweeteners e.g., sodium saccharin, dipotassium glycyrrhizinate, stevia, etc.
  • the medicament (pharmaceutical composition) of the present invention can be prepared by mixing the above-mentioned components and then treating the mixture in a manner known per se to prepare preparations for oral administration such as tablets, fine granules, granules, capsules, dry syrups, etc., or preparations for parenteral administration such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, etc.), topical preparations (e.g., transdermal preparations, ointments, lotions, patches), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, liposome preparations, etc.
  • preparations for oral administration such as tablets are particularly preferred.
  • the content of the compound (I) of the present invention or a pharma- ceutical acceptable salt thereof in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, based on the total weight of the preparation.
  • the dosage of the compound (I) of the present invention, or a pharma- ceutically acceptable salt thereof can be appropriately selected depending on the subject (the subject's age, body weight, general health condition, sex, severity of the condition, etc.), the administration route, the type of disease, the type of concomitant medication, etc.
  • the daily dosage of the compound (I) or a pharma-ceutically acceptable salt thereof, when orally administered to an adult human patient (body weight approximately 60 kg), is usually 0.001 mg to 1000 mg, preferably 0.01 mg to 100 mg, calculated as the active ingredient compound (I), which can be administered once or several times a day, regardless of whether it is before, after, or between meals.
  • the administration period is not particularly limited.
  • Compound (I) of the present invention is useful for preventing the onset of diseases whose symptoms can be alleviated by the B0AT1 inhibitory action, or for treating said diseases.
  • it is particularly effective for preventing or treating amino acid metabolism disorders such as phenylketonuria, urea cycle disorders, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.
  • Compound (I) of the present invention can be administered (concomitantly used) in combination with other drugs (concomitant drugs) so long as the efficacy of the compound (I) is not impaired.
  • the concomitant drugs are not particularly limited, and for example, one or more known drugs conventionally used in the treatment of the above-mentioned "diseases whose symptoms can be alleviated by B0AT1 inhibitory action" can be suitably used.
  • compound (I) of the present invention or a pharma- ceutically acceptable salt thereof is used for the treatment and/or prevention of amino acid metabolism disorders such as phenylketonuria, urea cycle disorders, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia
  • concomitant drugs include vitamin preparations (e.g., folic acid (vitamin B9), nicotinamide (vitamin B3), thiamine (vitamin B1), pyridoxine (vitamin B6), etc.) and drugs for alleviating various symptoms of amino acid metabolism disorders (for example, L-dopa, LNAAs such as 5-hydroxytryptophan, sapropterin hydrochloride, pegvaliase, nicotinic acid, nitisinone, S-adeno
  • the administration time is not limited, and they may be administered to the subject at the same time or at a time lag.
  • 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.
  • the administration method for each may be the same or different.
  • the compound (I) of the present invention or a pharma- ceutical acceptable salt thereof may be administered in combination with the concomitant drug as a single preparation.
  • the dosage of the concomitant drug can be appropriately selected based on the dose used in clinical practice.
  • the mixing ratio of the compound of the present invention or a pharma- ceutically acceptable salt thereof to the concomitant drug can be appropriately selected depending on the subject (the subject's age, body weight, general health condition, sex, degree of illness, etc.), administration route, type of disease, type of concomitant drug, etc.
  • the mass ratio of compound (I) or a pharma- ceutically acceptable salt thereof to the concomitant drug is not particularly limited.
  • concomitant drugs that complement and/or enhance the therapeutic effect of compound (I) or a pharma- ceutically acceptable salt thereof include those that have not been discovered so far and will be discovered in the future, based on the above-mentioned mechanism.
  • compound (I) in order to complement and/or enhance the therapeutic effect of compound (I) or a pharma- ceutically acceptable salt thereof, it is also effective to use it in combination with a dietary therapy that avoids the intake of certain 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 on the administration method, etc.
  • the drug contained in the kit is supplied in a container made of a material that effectively maintains the activity of the components of the medicament or pharmaceutical composition for a long period of time, does not adsorb to the inside of the container, and does not deteriorate the 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 include an instruction manual.
  • the instruction manual for use of the kit may be printed on paper or stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM and provided to the user.
  • % indicates mol/mol%, and for others, % by weight unless otherwise specified.
  • room temperature indicates a temperature of 15°C to 30°C unless otherwise specified.
  • * indicates racemic carbon.
  • Other abbreviations used in the text have the following meanings.
  • THF Tetrahydrofuran
  • DMSO Dimethylsulfoxide
  • DMF N,N-Dimethylformamide
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • WSC 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
  • HOBt 1-hydroxybenzotriazole
  • Reference Example 36 The corresponding starting compounds were treated in the same manner as in Reference Example 35 to give crude products of the compounds shown in Table 2 below.
  • Trifluoroacetic acid (0.1 ml) was added to a mixture of tert-butyl 2-(2-methoxy-2-oxoethyl)-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate (34 mg) obtained in (3) above and dichloromethane (0.5 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product of the title compound (36 mg) as a colorless amorphous substance.
  • Trifluoroacetic acid (0.1 ml) was added to a mixture of tert-butyl 8-cyano-6-(2-methoxy-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (22 mg) obtained in (4) above and dichloromethane (1 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the crude product of the title compound (23 mg) as a colorless amorphous substance.
  • the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and methanol (20 ml) and an aqueous sodium hydroxide solution (1 mol/l, 20 ml) were added, and the reaction mixture was stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, and extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
  • Reference Example 48 The corresponding starting compounds were treated in the same manner as in Reference Example 47 to give the compounds shown in Table 4 below as crude products.
  • Trifluoroacetic acid (0.3 ml) was added to a dichloromethane (2 ml) solution of tert-butyl 7-chloro-6-(2-methoxy-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (63.4 mg) obtained in (1) above, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a crude product (66 mg).
  • potassium hexacyanidoferrate(II) trihydrate 400 mg
  • chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) 300 mg
  • potassium acetate 280 mg
  • 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), and the mixture was stirred at room temperature for 3 hours. Aqueous sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, 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. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.
  • Reference Examples 61 to 99 The corresponding starting compounds were treated in the same manner as in Reference Example 60 to obtain the compounds shown in Tables 5-1 to 5-8 below.
  • 1,2-dichloroethane (7 ml) was added to the obtained crude product, followed by tert-butyl 3-oxopiperidine-1-carboxylate (268 mg) and N,N'-diisopropylethylamine (0.23 mL) in that order, and the mixture was stirred at room temperature. After confirming that the reaction mixture had become a solution, acetic acid (0.3 ml) and sodium triacetoxyborohydride (569 mg) were added, and the mixture was stirred overnight at room temperature. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with chloroform.
  • Reference examples 102 to 104 The corresponding starting compounds were treated in the same manner as in Reference Example 101 to give the crude products of the compounds shown in Table 6 below.
  • Reference Example 105 The corresponding starting compounds were treated in the same manner as in Reference Example 47 to give the compounds shown in Table 7 below as crude products.
  • Triethylamine (0.78 ml) and di-tert-butyl dicarbonate (217 mg) were added to a dichloromethane solution (19 ml) of (2S,5R)-1-benzyl-5-methyl-2-phenylpiperazine (990 mg) at room temperature, and the mixture was stirred overnight.
  • a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with chloroform, and the organic layer was concentrated under reduced pressure.
  • Reference Example 107 The corresponding starting compounds were treated in the same manner as in Reference Example 41 to give the compounds shown in Table 8 below.
  • the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and methanol (63 ml) and an aqueous sodium hydroxide solution (1 mol/l, 30 ml) were added, and the reaction mixture was stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, and extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Reference examples 110 to 113 The corresponding starting compounds were treated in the same manner as in Reference Example 109 to give the compounds shown in Table 9 below as crude products.
  • Reference Example 115 The corresponding starting compounds were treated in the same manner as in Reference Example 114 to give the compounds shown in Table 10 below as crude products.
  • Reference examples 117 to 124 The corresponding starting compounds were treated in the same manner as in Reference Example 116 to give the compounds shown in Tables 11-1 and 11-2 below as crude products.
  • Reference examples 126 to 128 The corresponding starting compounds were treated in the same manner as in Reference Example 125 to give the compounds shown in Table 12 below as crude products.
  • Reference examples 129 to 135 The corresponding starting compounds were treated in the same manner as in Reference Example 60 to obtain the compounds shown in Tables 13-1 and 13-2 below.
  • Reference Example 139 The corresponding starting compounds were treated in the same manner as in Reference Example 116 to give the compounds shown in Table 14 below as crude products.
  • Reference examples 140 to 143 The corresponding starting compounds were treated in the same manner as in Reference Example 125 to give the compounds shown in Table 15 below as crude products.
  • Reference Example 145 The corresponding starting compounds were treated in the same manner as in Reference Example 116 to give the compounds shown in Table 16 below.
  • O1-tert-butyl O3-methyl piperazine-1,3-dicarboxylate (5.0 g) was dissolved in 1,4-dioxane (20.5 ml) and cooled to 0°C. Then, 2N aqueous sodium hydroxide solution (22.5 ml) and di-tert-butyl dicarbonate (5.4 g) were added and stirred at room temperature for 20 hours. The reaction mixture was washed with diisopropyl ether and water. Ethyl acetate and 1N hydrochloric acid were added to the aqueous layer, followed by extraction.
  • Reference examples 148 to 151 The corresponding starting compounds were treated in the same manner as in Reference Example 60 to give the compounds shown in Table 17 below.
  • O1-tert-butyl O3-methyl (3R)-piperazine-1,3-dicarboxylate (581 mg) was dissolved in DMF (10 ml), and diisopropylethylamine (1.0 ml), HATU (797 mg), and 2-[[2-[[(E)-3-[2-fluoromethyl-4-(trifluoromethyl)phenyl]prop-2-enoylamino acid were added and stirred at room temperature for 1 hour. Ethyl acetate and aqueous ammonium chloride were added to the reaction mixture, followed by extraction with ethyl acetate.
  • Examples 2-82 The corresponding starting compounds were treated in the same manner as in Example 1 to obtain the compounds shown in Tables 18-1 to 18-16 below.
  • Examples 84 to 104 The corresponding starting compounds were treated in the same manner as in Example 83 to obtain the compounds shown in Tables 19-1 to 19-4 below.
  • Examples 105 to 108 The corresponding starting compounds were treated in the same manner as in Example 104 to obtain the compounds shown in Table 20 below.
  • Examples 110 to 126 The corresponding starting compounds were treated in the same manner as in Example 109 to obtain the compounds shown in Tables 21-1 to 21-4 below.
  • Example 127 Production of tert-butyl 2-[8-cyano-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-3,4-dihydro-1H-isoquinolin-6-yl]acetate (compound (I-127))
  • Examples 128 to 133 The corresponding starting compounds were treated in the same manner as in Example 127 to give the compounds shown in Table 22 below.
  • Example 135 The corresponding starting compounds were treated in the same manner as in Example 134 to give the compounds shown in Table 23 below.
  • Example 137 The corresponding starting compounds were treated in the same manner as in Example 136 to give the compounds shown in Table 24 below.
  • Example 138 Production of tert-butyl 3-[3-bromo-5-[2-[[(E)-3-[4-(pentafluoro- ⁇ 6-sulfanyl)phenyl]prop-2-enoyl]amino]acetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl]propanoate (compound (I-138))
  • N-bromosuccinimide (45 mg) was added to a solution of tert-butyl 3-[5-[2-[[(E)-3-[4-(pentafluoro- ⁇ 6-sulfanyl)phenyl]prop-2-enoyl]amino]acetyl]-6,7-dihydro-4H-pyrazolo[1,5a]pyrazin-2-yl]propanoate (104 mg) in chloroform (1.2 ml), and the mixture was stirred at an external temperature of 60°C for 1 hour. After allowing the reaction mixture to cool, an aqueous solution of sodium thiosulfate and an aqueous solution of potassium carbonate were added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product of the title compound as a yellow oil.
  • Example 139 The corresponding starting compounds were treated in the same manner as in Example 138 to give crude products of the compounds shown in Table 25 below.
  • Example 140 Production of 2-[3-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-1,2,4,5-tetrahydro-3-benzazepin-7-yl]acetic acid (compound (I-140))
  • Examples 141-199 The corresponding starting compounds were treated in the same manner as in Example 140 to obtain the compounds shown in Tables 26-1 to 26-12 below.

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