Novel b0at1 inhibitor

Abstract

The purpose of the present invention is to provide a novel B0AT1 inhibitor. The present invention relates to a compound represented by formula (I): (the symbols in the formula are as described in the description) or a salt thereof. The present invention also relates to a B0AT1 inhibitor comprising said compound and a preventive and / or therapeutic agent for amino acid metabolism diseases such as phenylketonuria, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, non-ketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia that contains said compound.

Description

Novel B0AT1 inhibitors

[0001] The present invention relates to novel cinnamic acid glycinamide compounds that have an inhibitory effect on the neutral amino acid transporter B0AT1 and are useful for the prevention and / or treatment of amino acid metabolism disorders involving B0AT1.

[0002] The gene responsible for Hartnup disease, SLC6A19, is located at 5p15.33 and consists of 12 exons. Its gene product, the neutral amino acid transporter B0AT1, consists of 634 amino acids and has 12 transmembrane domains (Non-Patent Documents 1 and 2). B0AT1 is the primary transporter of neutral amino acids in the small intestine and kidney, responsible for the absorption of glycine, leucine, phenylalanine, and other amino acids in the small intestine and their reabsorption in the kidney (Non-Patent Documents 3-5). B0AT1 knockout mice are known to exhibit elevated urinary amino acid levels (Non-Patent Document 6), and clinically, B0AT1 dysfunction results in severe neutral amino aciduria, also known as Hartnup disease (Non-Patent Document 7). Therefore, it has been suggested that inhibiting B0AT1 may improve (alleviate) various diseases or pathologies involving neutral amino acids as transport substrates.

[0003] Furthermore, specific examples of the therapeutic effects of inhibiting the function of B0AT1 have also been reported, such as the improvement of the pathological condition of a phenylketonuria model mouse by congenitally deleting B0AT1 or by administering a nucleic acid compound that binds to mRNA to subsequently suppress its expression (Non-Patent Document 4).

[0004] In light of this background, compounds that inhibit B0AT1 have attracted attention as pharmaceuticals for preventing and / or treating various diseases or pathological conditions involving neutral amino acids, which are transport substrates, specifically amino acid metabolism disorders.

[0005] Examples of amino acid metabolism disorders include designated intractable diseases such as phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia, and continuous dietary therapy is the main known treatment for these disorders. Other than dietary therapy, known treatments include administering drugs that increase coenzymes or enzymes, and injecting enzymes, but neither of these is a fundamental treatment (e.g., Non-Patent Document 8, etc.).

[0006] Therefore, there is a need for the development of drugs for preventing and / or treating diseases, specifically amino acid metabolism disorders, whose symptoms can be alleviated by normalizing neutral amino acid metabolism through the inhibition of B0AT1.

[0007] Known compounds having B0AT1 inhibitory activity include, for example, nucleic acids having a sequence partially or completely identical to that of B0AT1 RNA (Non-Patent Document 4), the commercially available product nimesulide and its derivatives (Non-Patent Documents 9 and 10), the known compound cinromide (Non-Patent Document 11), and basic compounds discovered by library screening (Non-Patent Documents 12 and 13). However, it has not been reported that the cinnamic acid glycine amide compound according to the present invention exhibits B0AT1 inhibitory activity.

[0008] Nat. Genet., 2004; 36: pp.999-1002 Nat. Genet., 2004; 36: pp.1003-1007 The Journal of Biological Chemistry 2004; 279: pp.24467-24476 JCI Insight., 2018; 3(14): pp.e121762 IUBMB Life, 2009; 61(6): pp.591-599 MOLECULAR METABOLISM, 2015: pp.406-417 Biochem. J., 2005; 389: pp.745-751 Intractable Disease Information Center, Phenylketonuria (designated intractable disease 240) (http: / / www.nanbyou.or.jp / entry / 4747) Biochemical Phamracology, 2014; 89: p.422-430Bioorganic and Medicinal chemistry letters, 2021; 53: p.128421SLAS Discovery, 2019; 24(2): p.111-120British Journal of Pharmacology, 2017; 174: p.468-482Frontiers in Pharmacology, 2020; 11: p.140

[0009] An objective of the present invention is to provide a pharmaceutical agent that exhibits excellent B0AT1 inhibitory activity and can prevent and / or treat diseases, specifically amino acid metabolism disorders, whose symptoms can be alleviated by said activity.

[0010] As a result of extensive investigations to solve the above problems, the present inventors have discovered a compound represented by the following formula (I):

[0011]

[0012] [In the formula, R １ represents a halogen atom, an optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６alkylsulfanyl group, optionally substituted C ３－８ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C ６－１４ an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; n Xs each independently represent a fluorine atom or a chlorine atom; n represents an integer of 0 to 2; and R ２ is C optionally substituted with a substituent selected from the substituent group a １－６ represents an alkyl group, and R ３ is C optionally substituted with a substituent selected from the substituent group a １－６ C optionally substituted with an alkyl group or a substituent selected from the substituent group b ３－６ represents a cycloalkyl group, or R ２ and R ３ are bonded to each other and form, together with the nitrogen atom to which they are bonded, a nitrogen-containing non-aromatic heterocyclic group which may be substituted with a substituent selected from Substituent Group b. (Substituent Group a): A halogen atom; A hydroxy group; A cyano group; A carboxy group; A C optionally substituted with a halogen atom. １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; １－６ an alkylamino group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４an aryl group; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group c; and a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b. (Substituent group b): a halogen atom; a hydroxy group; a cyano group; a carboxy group; an oxo group; a thioxo group; C １－６ Alkyl group, C １－６ Alkyl-carbonyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; a halogen atom, a hydroxy group, and C １－６ C optionally substituted with a substituent selected from the group consisting of alkoxy groups １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ an alkylsulfonyl group; a C optionally substituted with a halogen atom; １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted with an alkyl group; a C １－６ Alkyl group, C ３－８ an aminosulfonyl group substituted with one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group; a tri-substituted silyl group; a tri-substituted silyloxy group; a C optionally substituted with 1 to 3 substituents selected from the group c of substituents; ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４ an aryl group; and a nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group c. (Substituent Group c): a halogen atom; a hydroxy group; a cyano group; a carboxy group; C １－６ Alkyl group and C １－６an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; a halogen atom, C １－６ Alkyl group and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups ６－１４ aryl groups; and halogen atoms, C １－６ Alkyl group and C １－６ and a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups.] (hereinafter, also abbreviated as "compound (I)"), or a pharmaceutically acceptable salt thereof has an excellent inhibitory effect on the neutral amino acid transporter B0AT1, leading to the completion of the present invention.

[0013] That is, the present invention is as follows: [1] Formula (I):

[0014]

[0015] [In the formula, R １ represents a halogen atom, an optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６ alkylsulfanyl group, optionally substituted C ３－８a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C ６－１４ an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; n Xs each independently represent a fluorine atom or a chlorine atom; n represents an integer of 0 to 2; and R ２ is C optionally substituted with a substituent selected from the substituent group a １－６ represents an alkyl group, and R ３ is C optionally substituted with a substituent selected from the substituent group a １－６ C optionally substituted with an alkyl group or a substituent selected from the substituent group b ３－６ represents a cycloalkyl group, or R ２ and R ３ are bonded to each other and form, together with the nitrogen atom to which they are bonded, a nitrogen-containing non-aromatic heterocyclic group which may be substituted with a substituent selected from Substituent Group b. (Substituent Group a): A halogen atom; A hydroxy group; A cyano group; A carboxy group; A C optionally substituted with a halogen atom. １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; １－６ an alkylamino group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４an aryl group; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group c; and a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b. (Substituent group b): a halogen atom; a hydroxy group; a cyano group; a carboxy group; an oxo group; a thioxo group; C １－６ Alkyl group, C １－６ Alkyl-carbonyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; a halogen atom, a hydroxy group, and C １－６ C optionally substituted with a substituent selected from the group consisting of alkoxy groups １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ an alkylsulfonyl group; a C optionally substituted with a halogen atom; １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted with an alkyl group; a C １－６ Alkyl group, C ３－８ an aminosulfonyl group substituted with one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group; a tri-substituted silyl group; a tri-substituted silyloxy group; a C optionally substituted with 1 to 3 substituents selected from the group c of substituents; ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４ an aryl group; and a nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group c. (Substituent Group c): a halogen atom; a hydroxy group; a cyano group; a carboxy group; C １－６ Alkyl group and C １－６an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; a halogen atom, C １－６ Alkyl group and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups ６－１４ aryl groups; and halogen atoms, C １－６ Alkyl group and C １－６ [2] A B0AT1 inhibitor comprising a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, wherein R １ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６[3] The B0AT1 inhibitor according to the above-mentioned [1], wherein R is a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group, and n is 0. １ But, Haro C １－４ [4] The B0AT1 inhibitor according to the above-mentioned [1] or [2], wherein R in formula (I) is an alkyl group. ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered monocyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 10-membered bridged cyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group, each of which is optionally substituted with 1 to 3 substituents selected from the substituent group b. [5] The B0AT1 inhibitor according to any one of the above-mentioned [1] to [3], ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, each optionally substituted with 1 to 3 substituents selected from the substituent group b, such as a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a 3,8-diazabicyclo[3.2.1]octyl group, a diazepanyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazo [6] The B0AT1 inhibitor according to any one of the above-mentioned [1] to [3], which forms a [1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 1,2,3,4-tetrahydroisoquinolyl group, a 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,7-naphthyridinyl group, or a 2,6-diazaspiro[3.3]heptyl group. ２ is substituted with 1 to 3 substituents selected from the substituent group a １－４ is an alkyl group, and R ３ C which is optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a １－４[7] The B0AT1 inhibitor according to any one of the above-mentioned [1] to [3], wherein R in formula (I) is an alkyl group. ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b,

[0016]

[0017] (wherein Y and Z each independently represent a carbon atom or a nitrogen atom;

[0018]

[0019] represents a single bond or a double bond; ring A represents a 5- to 8-membered non-aromatic heterocycle; ring B represents a 5- or 6-membered non-aromatic or aromatic heterocycle, or a benzene ring; m represents an integer of 0 to 3; and ＊ represents a bonding site with a carbonyl group.) The B0AT1 inhibitor according to any one of the above [1] to [3], which forms a group represented by the formula: [8] A pharmaceutical composition for preventing and / or treating a disease whose symptoms can be alleviated by B0AT1 inhibitory action, comprising the B0AT1 inhibitor according to any one of the above [1] to [7] and a pharmacologically acceptable carrier. [9] The pharmaceutical composition according to the above [8], wherein the disease whose symptoms can be alleviated by B0AT1 inhibitory action is an amino acid metabolism disorder.

[10] The pharmaceutical composition according to the above [9], wherein the amino acid metabolism disorder is phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, or isovaleric acidemia.

[11] The pharmaceutical composition according to the above [9], wherein the amino acid metabolism disorder is phenylketonuria.

[12] A compound represented by the formula (I'):

[0020]

[0021] [In the formula, R １’ is C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ n' X's each independently represent a fluorine atom or a chlorine atom; n' represents an integer of 0 to 2; and R ２’ is C substituted with a substituent selected from the substituent group a １－４ represents an alkyl group, and R ３’ is C optionally substituted with a substituent selected from the substituent group a １－４ C optionally substituted with an alkyl group or a substituent selected from the substituent group b ３－６ represents a cycloalkyl group, or R ２’ and R ３’ are combined with each other to form ‘ Together with the nitrogen atom to which they are bonded, they form a nitrogen-containing non-aromatic heterocyclic group which may be substituted with a substituent selected from Substituent Group b. (Substituent Group a): A halogen atom; A hydroxy group; A cyano group; A carboxy group; A C group which may be substituted with a halogen atom. １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; １－６an alkylamino group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４ an aryl group; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group c; and a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b. (Substituent group b): a halogen atom; a hydroxy group; a cyano group; a carboxy group; an oxo group; a thioxo group; C １－６ Alkyl group, C １－６ Alkyl-carbonyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; a halogen atom, a hydroxy group, and C １－６ C optionally substituted with a substituent selected from the group consisting of alkoxy groups １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ an alkylsulfonyl group; a C optionally substituted with a halogen atom; １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted with an alkyl group; a C １－６ Alkyl group, C ３－８ an aminosulfonyl group substituted with one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group; a tri-substituted silyl group; a tri-substituted silyloxy group; a C optionally substituted with 1 to 3 substituents selected from the group c of substituents; ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４an aryl group; and a nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group c. (Substituent Group c): a halogen atom; a hydroxy group; a cyano group; a carboxy group; C １－６ Alkyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; a halogen atom, C １－６ Alkyl group and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups ６－１４ aryl groups; and halogen atoms, C １－６ Alkyl group and C １－６ a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups, wherein the compound (hereinafter sometimes abbreviated as "compound (I')") represented by the following formula:

[0022]

[0023]

[13] In the formula (I′), R １’ But, Haro C １－４ The compound or salt thereof according to the above-mentioned

[12] , wherein R is an alkyl group, and n' is 0.

[14] In the formula (I'), ２’ and R ３’are bonded to each other and, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered monocyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 10-membered bridged ring nitrogen-containing non-aromatic heterocyclic group, a 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group, each of which is optionally substituted with 1 to 3 substituents selected from the substituent group b.

[15] The compound or salt thereof according to the above

[12] or

[13] , ２’ and R ３’ are bonded to each other and, together with the nitrogen atom to which they are bonded, each optionally substituted with 1 to 3 substituents selected from the substituent group b, such as a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a 3,8-diazabicyclo[3.2.1]octyl group, a diazepanyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazo The compound according to the above

[12] or

[13] , or a salt thereof, which forms a [1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 1,2,3,4-tetrahydroisoquinolyl group, a 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,7-naphthyridinyl group, or a 2,6-diazaspiro[3.3]heptyl group.

[16] Formula (I″):

[0024]

[0025] [In the formula, R １’’ represents a halogen atom, an optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６ alkylsulfanyl group, optionally substituted C ３－８ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C６－１４ an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; n" X" each independently represent a fluorine atom or a chlorine atom; n" represents an integer of 0 to 2; and R ２’’ is substituted with a group selected from the group consisting of: (i) a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group optionally substituted with a substituent selected from substituent group c, and (ii) a 5- or 6-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted with a substituent selected from substituent group b, and optionally further substituted with a substituent selected from substituent group a; １－４ represents an alkyl group, and R ３’’ is C substituted with a substituent selected from the substituent group a １－４ represents an alkyl group, or R ２’’ and R ３’’ are bonded to each other and form, together with the nitrogen atom to which they are bonded, a fused nitrogen-containing non-aromatic heterocyclic group (excluding a tetrahydroquinolyl group and a tetrahydroisoquinolyl group) which may be substituted with a substituent selected from Substituent Group b. (Substituent Group a): A halogen atom; A hydroxy group; A cyano group; A carboxy group; A C optionally substituted with a halogen atom １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; １－６ an alkylamino group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４an aryl group; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group c; and a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b. (Substituent group b): a halogen atom; a hydroxy group; a cyano group; a carboxy group; an oxo group; a thioxo group; C １－６ Alkyl group, C １－６ Alkyl-carbonyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; a halogen atom, a hydroxy group, and C １－６ C optionally substituted with a substituent selected from the group consisting of alkoxy groups １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ an alkylsulfonyl group; a C optionally substituted with a halogen atom; １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted with an alkyl group; a C １－６ Alkyl group, C ３－８ an aminosulfonyl group substituted with one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group; a tri-substituted silyl group; a tri-substituted silyloxy group; a C optionally substituted with 1 to 3 substituents selected from the group c of substituents; ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４ an aryl group; and a nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group c. (Substituent Group c): a halogen atom; a hydroxy group; a cyano group; a carboxy group; C １－６ Alkyl group and C １－６an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; a halogen atom, C １－６ Alkyl group and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups ６－１４ aryl groups; and halogen atoms, C １－６ Alkyl group and C １－６ a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups.] (hereinafter, also abbreviated as "compound (I")") or a salt thereof.

[17] A compound represented by the formula (I") (hereinafter, also abbreviated as "compound (I")") or a salt thereof. ２’’ and R ３’’ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b,

[0026]

[0027] (wherein Y′ and Z′ each independently represent a carbon atom or a nitrogen atom;

[0028]

[0029] represents a single bond or a double bond; ring A' represents a 5- to 8-membered non-aromatic heterocycle; ring B' represents a 5- or 6-membered non-aromatic heterocycle or aromatic heterocycle; m' represents an integer of 0 to 3; and ＊’represents a bonding site with a carbonyl group.) The compound according to the above-mentioned

[16] or a salt thereof, which forms a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[18] A pharmaceutical composition comprising the compound according to any of the above-mentioned

[12] to

[17] or a salt thereof, and a pharmacologically acceptable carrier.

[19] The pharmaceutical composition according to the above-mentioned

[18] , for use in the treatment and / or prevention of amino acid metabolism disorders.

[20] The pharmaceutical composition according to the above-mentioned

[18] , for use in the treatment and / or prevention of a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[21] The pharmaceutical composition according to the above-mentioned

[18] , for use in the treatment and / or prevention of phenylketonuria.

[22] The pharmaceutical composition according to any one of [8] to

[11] and

[18] to

[21] above, which is administered in combination with another drug.

[23] The pharmaceutical composition according to

[22] above, wherein the other drug is a B0AT1 inhibitor.

[24] The pharmaceutical composition according to

[22] above, wherein the other drug is a vitamin preparation, a drug for alleviating various symptoms of amino acid metabolism disorders, an antidepressant, an anti-anxiety drug, or a drug for treating ADHD.

[25] The pharmaceutical composition according to any one of [8] to

[11] and

[18] to

[21] above, wherein the pharmaceutical composition and the other drug are administered separately.

[26] The pharmaceutical composition according to any one of

[22] to

[24] above, wherein the pharmaceutical composition and the other drug are administered simultaneously or sequentially.

[27] The pharmaceutical composition according to any one of the above-mentioned

[22] to

[26] , for use in the treatment and / or prevention of an amino acid metabolism disorder.

[28] The pharmaceutical composition according to any one of the above-mentioned

[22] to

[26] , for use in the treatment and / or prevention of a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[29] A pharmaceutical composition comprising the pharmaceutical composition according to any one of [8] to

[11] and

[18] to

[21] above and another drug.

[30] The pharmaceutical composition according to

[29] above, for use in the treatment and / or prevention of amino acid metabolism disorders.

[31] The pharmaceutical composition according to

[29] above, for use in the treatment and / or prevention of a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[32] A method for preventing or treating amino acid metabolism disorders in a mammal, comprising administering to the mammal an effective amount of the B0AT1 inhibitor according to any one of [1] to [7] above.

[33] A method for preventing or treating a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia in a mammal, comprising administering to the mammal an effective amount of the B0AT1 inhibitor according to any one of [1] to [7] above.

[34] A method for preventing or treating an amino acid metabolism disorder in a mammal, comprising administering to the mammal an effective amount of the compound according to any one of

[12] to

[17] above or a salt thereof.

[35] A method for preventing or treating a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia, which comprises administering to a mammal an effective amount of the compound or salt thereof described in any of the above-mentioned

[12] to

[17] .

[36] A method for preventing or treating an amino acid metabolism disorder in a mammal, which comprises administering to the mammal an effective amount of the pharmaceutical composition described in any of the above-mentioned [8] to

[11] and

[18] to

[21] and another drug.

[37] A method for preventing or treating a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia, comprising administering to a mammal effective amounts of the pharmaceutical composition according to any of the above-mentioned [8] to

[11] and

[18] to

[21] and another drug simultaneously or sequentially.

[38] Use of the B0AT1 inhibitor according to any of the above-mentioned [1] to [7] for the manufacture of an agent for treating or preventing amino acid metabolism disorders.

[39] Use of the B0AT1 inhibitor according to any one of the above-mentioned [1] to [7] for the manufacture of a therapeutic or preventive agent for a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[40] Use of the compound according to any one of the above-mentioned

[12] to

[17] or a salt thereof for the manufacture of a therapeutic or preventive agent for an amino acid metabolism disorder.

[41] Use of the compound according to any one of the above-mentioned

[12] to

[17] or a salt thereof for the manufacture of a therapeutic or preventive agent for a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[42] The compound or salt thereof according to any one of the above-mentioned

[12] to

[17] for use in the prevention or treatment of amino acid metabolism disorders.

[43] The compound or salt thereof according to any one of the above-mentioned

[12] to

[17] for use in the prevention or treatment of a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[44] A method for producing the compound or salt thereof according to any one of the above-mentioned

[12] to

[17] .

[45] A prodrug of the compound or salt thereof according to any one of the above-mentioned

[12] to

[17] .

[0030] Compound (I) of the present invention or a pharmaceutically acceptable salt thereof has excellent inhibitory activity against B0AT1, and therefore, pharmaceutical compositions containing said compound are useful for treating and / or preventing diseases whose symptoms can be alleviated by B0AT1 inhibitory action. Examples of such diseases include amino acid metabolism disorders such as phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia. These amino acid metabolism disorders are designated intractable diseases that require long-term treatment, such as lifelong, very strict dietary therapy (amino acid-restricted diet). Therefore, compound (I) of the present invention or a pharmaceutically acceptable salt thereof can provide a novel and effective preventive and / or therapeutic agent.

[0031] The definitions of the terms and symbols used in this specification are explained below.

[0032] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0033] In the present specification, the term "alkyl (group)" refers to a linear or branched monovalent group having one or more carbon atoms formed by removing one hydrogen atom from any carbon atom of an alkane. When there is no particular limitation on the range of the carbon number, the term "alkyl (group)" refers to a C １－２０ alkyl groups, among which C １－６ Alkyl groups are preferred.

[0034] In this specification, "C １－２０ The term "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, and eicosyl.

[0035] In this specification, "C １－６The term "alkyl (group)" refers to 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, and 2-ethylbutyl.

[0036] In this specification, "C １－４ The term "alkyl (group)" refers to an alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0037] In the present specification, the term "haloalkyl (group)" refers to a group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms in the alkyl group have been substituted with halogen. Specific examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, and the like. Among these, "haloC １－６ Alkyl" is preferred, and "haloC １－４ Alkyl is more preferred.

[0038] In the present specification, the term "cycloalkyl (group)" refers to a cyclic alkyl group, and when there is no particular limitation on the range of the number of carbon atoms, it is preferably a C ３－８ It is a cycloalkyl group.

[0039] In this specification, "C ３－８The term "cycloalkyl (group)" refers to a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. ３－６ Cycloalkyl groups are preferred.

[0040] In this specification, "C ３－８ The term "cycloalkyloxy (group)" refers to the C ３－８ The cycloalkyl group means a group bonded to an oxygen atom, and specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.

[0041] In this specification, "C ３－８ The term "cycloalkylsulfanyl (group)" refers to the C ３－８ The cycloalkyl group means a group bonded to a sulfur atom, and specific examples include cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, cyclooctylsulfanyl, and the like.

[0042] In the present specification, the term "alkoxy (group)" refers to a group in which a linear or branched alkyl group is bonded to an oxygen atom, and when there is no particular limitation on the range of the carbon number, it is １－２０ is an alkoxy group, preferably C １－６ It is an alkoxy group.

[0043] In this specification, "C １－６ The term "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. １－４ Alkoxy groups are preferred.

[0044] As used herein, the term "haloalkoxy (group)" refers to an alkoxy group in which one or more hydrogen atoms have been substituted with halogen. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, and 6,6,6-trifluorohexyloxy. １－６ "Alkoxy" is preferred, and "haloC １－４ Alkoxy is more preferred.

[0045] In the present specification, the term "alkylsulfanyl (group)" refers to a group in which a linear or branched alkyl group is bonded to a sulfur atom, and preferably C １－６ It is an alkylsulfanyl group.

[0046] In this specification, "C １－６ The term "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.

[0047] In the present specification, the term "haloalkylsulfanyl (group)" refers to a group in which one or more hydrogen atoms in the alkylsulfanyl group have been substituted with halogen. Specific examples include fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 2-chloroethylsulfanyl, 2-bromoethylsulfanyl, 2-iodoethylsulfanyl, 2-fluoroethylsulfanyl, 2,2-difluoroethylsulfanyl, 2,2,2-trifluoroethylsulfanyl, pentafluoroethylsulfanyl, 2,2,3,3-tetrafluoropropylsulfanyl, 3,3,3-trifluoropropylsulfanyl, 4,4,4-trifluorobutylsulfanyl, 5,5,5-trifluoropentylsulfanyl, 6,6,6-trifluorohexylsulfanyl, and the like. Among these, "haloC １－６ Alkylsulfanyl is preferred.

[0048] In this specification, "C １－６ The term "alkylsulfonyl (group)" refers to a sulfonyl group (-S(=O) ２ -) to the above "C １－６ It means a group to which an "alkyl" group is attached, i.e., a straight-chain or branched-chain alkylsulfonyl group having 1 to 6 carbon atoms. １－６ Examples of the "alkylsulfonyl (group)" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, and the like.

[0049] In the present specification, the term "alkyl-carbonyl (group)" refers to a group in which the alkyl group is bonded to a carbonyl group, and the range of the number of carbon atoms is not particularly limited, but preferably, １－６ It is an alkyl-carbonyl group.

[0050] In the present specification, the term "alkoxy-carbonyl (group)" refers to a group in which the above-mentioned alkoxy group is bonded to a carbonyl group, and the range of the number of carbon atoms is not particularly limited, but preferably, １－６It is an alkoxy-carbonyl group.

[0051] In the present specification, "1 to 2 C １－６ The term "carbamoyl (group) optionally substituted with an alkyl group" refers to a carbamoyl group (-CONH ２ ) one or two hydrogen atoms are each independently selected from the group consisting of C １－６ It means a group which may be substituted with an alkyl group, and preferably mono- or di-C １－６ It is an alkyl-carbamoyl group.

[0052] In the present specification, the term "aryl (group)" refers to a monocyclic or polycyclic (fused) hydrocarbon group exhibiting aromaticity, and specifically includes, for example, C aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, and fluorenyl. ６－１４ Aryl groups include, among others, C ６－１０ Aryl groups are preferred.

[0053] In this specification, "C ６－１０ Examples of the "aryl (group)" include phenyl, 1-naphthyl, and 2-naphthyl, and among these, phenyl is preferred.

[0054] In the present specification, the term "aryl-carbonyl (group)" refers to a group in which the aryl group is bonded to a carbonyl group, and the range of the number of carbon atoms is not particularly limited, but preferably, ６－１４ It is an aryl-carbonyl group.

[0055] In this specification, "C ６－１４ The term "aryloxy (group)" refers to the C ６－１４ It means a group in which an aryl group is bonded to an oxygen atom, and specific examples include phenyloxy, 1-naphthyloxy, 2-naphthyloxy, biphenylyloxy, 2-anthryloxy, etc. Of these, the phenyloxy group is particularly preferred.

[0056] In this specification, "C ６－１４ The term "arylsulfonyl (group)" refers to the C ６－１４ The aryl group is a sulfonyl group (-S(=O) ２-) and examples thereof include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.

[0057] In this specification, "C ６－１４ The term "arylsulfonyloxy (group)" refers to the C ６－１４ The aryl group is a sulfonyloxy group (-S(=O) ２ and examples thereof include phenylsulfonyloxy, 1-naphthylsulfonyloxy, 2-naphthylsulfonyloxy, etc.

[0058] In this specification, "C ７－１８ The term "aralkyl (group)" refers to the C ６－１４ The aryl group is １－４ It means a group bonded to an alkyl group, and specific examples thereof include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl, etc. Among them, C ７－１０ An aralkyl group is preferred, and a benzyl group is particularly preferred.

[0059] In this specification, "C ７－１８ The term "aralkyloxy (group)" refers to the C ７－１８ It means an aralkyl group bonded to an oxygen atom, and specific examples include benzyloxy, phenethyloxy, naphthylmethyloxy, biphenylylmethyloxy, etc. Among these, the benzyloxy group is particularly preferred.

[0060] In the present specification, the term "acyl (group)" means a formyl group, a linear or branched alkyl-carbonyl group, or an aryl-carbonyl group. The carbon number range is not particularly limited, but preferably, a formyl group, C １－６ alkyl-carbonyl group, or C ６－１４ The aryl-carbonyl group is a preferred example of an acyl group, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl (pivaloyl), hexanoyl, heptanoyl, benzoyl, 1-naphthoyl, or 2-naphthoyl.

[0061] In the present specification, the term "acyloxy (group)" refers to a group in which the acyl group is bonded to an oxygen atom, and preferably C １－６ alkyl-carbonyloxy group, or C ６－１４ It is an aryl-carbonyloxy group.

[0062] In this specification, "C １－６ Alkyl group and C １－６ The term "amino (group) which may be substituted by 1 to 2 substituents selected from the group consisting of alkoxy-carbonyl groups" refers to an unsubstituted amino group, or an amino group in which 1 to 2 hydrogen atoms are substituted by the C １－６ Alkyl group and / or C １－６ It means a group substituted with an alkoxy-carbonyl group.

[0063] In the present specification, examples of the "heterocyclic ring (group)" include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, (iii) a 6- to 10-membered bridged cyclic non-aromatic heterocyclic group, and (iv) a 6- to 12-membered spirocyclic non-aromatic heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0064] In the present specification, examples of the "aromatic heterocyclic group" include 5- to 14-membered aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0065] Preferable examples of the "aromatic heterocyclic group" 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, thienopyridyl, furopyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, Examples thereof include 8- to 14-membered fused aromatic heterocyclic groups (fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups) such as pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0066] In the present specification, examples of the "non-aromatic heterocyclic group" include 3- to 14-membered non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0067] Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuryl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, and tetrahydroisoxazolyl. 3- to 10-membered monocyclic non-aromatic heterocyclic groups (preferably 5- to 8-membered monocyclic non-aromatic heterocyclic groups) such as piperidyl, piperazinyl, tetrahydropyridyl, dihydropyridyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl;Tetrahydrotriazolopyridyl, tetrahydrotriazolopyrazinyl, tetrahydropyrazolopyrazinyl, dihydropyrazolopyrrolyl, tetrahydropyrazolopyridyl, tetrahydroimidazolopyridyl, dihydroimidazolopyridyl, dihydroimidazolopyrrolyl, tetrahydroimidazolopyrazinyl, dihydropyrimidopyrrolyl, dihydropyridopyrrolyl, tetrahydropyridopyridyl, tetrahydrooxazolopyrazinyl, tetrahydropyridopyridyl, tetrahydrotriazolodiazepinyl, octahydro-1,4-oxazinopyrazinyl, dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl 9- to 14-membered fused non-aromatic heterocyclic groups (fused polycyclic (preferably bicyclic) non-aromatic heterocyclic groups) such as tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl;

[0068] More preferred examples of the "non-aromatic heterocyclic group" include pyrrolidinyl, piperidyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,7-naphthyridinyl and the like. Among these, fused non-aromatic heterocyclic groups such as 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, and 1,2,3,4-tetrahydro-2,7-naphthyridinyl are particularly preferred.

[0069] In the present specification, suitable examples of the "6- to 10-membered bridged non-aromatic heterocyclic group" include 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.2]octyl, 7-azabicyclo[2.2.1]heptanyl, quinuclidinyl and the like.

[0070] In the present specification, suitable examples of the "6- to 12-membered spirocyclic non-aromatic heterocyclic group" include 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.3]heptyl and the like.

[0071] As used herein, the term "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, which has at least one nitrogen atom as a ring-constituting atom.

[0072] In the present specification, "C optionally substituted with 1 to 3 substituents selected from substituent group c" is used. １－６ Alkyl group, C ３－８The term "aminosulfonyl (group) substituted with one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group" refers to an aminosulfonyl group (-S(=O) ２ -NH ２ wherein one hydrogen atom of each of the C groups may be substituted with 1 to 3 substituents selected from the substituent group c. １－６ Alkyl group, C ３－８ It means a group substituted with a cycloalkyl group or a non-aromatic heterocyclic group.

[0073] As used herein, the term "trisubstituted silyl (group)" refers to a silyl group having three identical or different substituents (e.g., C １－６ Alkyl group, C ６－１０ aryl group, etc.), and examples of the group include trialkylsilyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, and tert-butyldimethylsilyl group (preferably, triC １－６ alkylsilyl group), tert-butyldiphenylsilyl group, triphenylsilyl group, etc.

[0074] In the present specification, the term "trisubstituted silyloxy (group)" refers to a group in which a trisubstituted silyl group is bonded to an oxygen atom, and examples of the group include trialkylsilyloxy groups such as trimethylsilyloxy group, triethylsilyloxy group, triisopropylsilyloxy group, and tert-butyldimethylsilyloxy group (preferably, triC １－６ alkylsilyloxy group), tert-butyldiphenylsilyloxy group, triphenylsilyloxy group, etc.

[0075] In this specification, the term "optionally substituted" means unsubstituted or substituted with a specific substituent at any substitutable position (any hydrogen atom is replaced with a substituent). The "substituent" is not particularly limited, but examples include substituents selected from the group consisting of (substituent group a), (substituent group a'), (substituent group a''), (substituent group b), (substituent group c), and (substituent group d) below. When no particular substituent group is specified, it means that the group may be substituted with one or more substituents selected from (substituent group d) below. 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.

[0076] (Substituent group a): a halogen atom; a hydroxy group; a cyano group; a carboxy group; a C group optionally substituted with a halogen atom １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; １－６ an alkylamino group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４ an aryl group; a nitrogen-containing aromatic heterocyclic group (preferably a 5- or 6-membered nitrogen-containing aromatic heterocyclic group) optionally substituted with 1 to 3 substituents selected from Substituent Group c; and a non-aromatic heterocyclic group (preferably a 5- or 6-membered non-aromatic heterocyclic group) optionally substituted with 1 to 3 substituents selected from Substituent Group b.

[0077] (Substituent group a'): a hydroxy group; a carboxy group; a C group optionally substituted with a halogen atom１－６ Alkoxy group (e.g., methoxy group, ethoxy group); hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted with an alkyl group (e.g., a methylcarbamoyl group, a dimethylcarbamoyl group); a C optionally substituted with a halogen atom; １－６ alkylsulfonyl groups (e.g., methylsulfonyl groups); 5- to 6-membered nitrogen-containing aromatic heterocyclic groups optionally substituted by 1 to 3 substituents selected from Substituent Group c (e.g., pyridazinyl groups, pyrazolyl groups, thiazolyl groups, pyridyl groups, triazolyl groups, pyrimidinyl groups, oxadiazolyl groups, imidazolyl groups); and 5- to 6-membered non-aromatic heterocyclic groups optionally substituted by 1 to 3 substituents selected from Substituent Group b (e.g., tetrahydropyranyl groups, tetrahydrofuryl groups).

[0078] (Substituent group a″): a hydroxy group; a carboxy group; a C group optionally substituted with a halogen atom １－６ Alkoxy group (e.g., methoxy group, ethoxy group); hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted with an alkyl group (e.g., a methylcarbamoyl group, a dimethylcarbamoyl group); and a C optionally substituted with a halogen atom. １－６ Alkylsulfonyl groups (e.g., methylsulfonyl groups).

[0079] (Substituent group b): a halogen atom; a hydroxy group; a cyano group; a carboxy group; an oxo group; a thioxo group; C １－６ Alkyl group, C １－６ Alkyl-carbonyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; a halogen atom, a hydroxy group, and C １－６C optionally substituted with a substituent selected from the group consisting of alkoxy groups １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ an alkylsulfonyl group; a C optionally substituted with a halogen atom; １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted with an alkyl group; a C １－６ Alkyl group, C ３－８ an aminosulfonyl group substituted with one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group; a tri-substituted silyl group; a tri-substituted silyloxy group; a C optionally substituted with 1 to 3 substituents selected from the group c of substituents; ３－８ a cycloalkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４ an aryl group; and a nitrogen-containing aromatic heterocyclic group (preferably a 5- or 6-membered nitrogen-containing aromatic heterocyclic group) optionally substituted with 1 to 3 substituents selected from Substituent Group c.

[0080] (Substituent group c): a halogen atom; a hydroxy group; a cyano group; a carboxy group; C １－６ Alkyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; １－６ an alkyl group; a C group optionally substituted with a halogen atom; １－６ an alkoxy group; a C optionally substituted with a halogen atom; １－６ Alkylsulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; hydroxy group, diC１－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; a halogen atom, C １－６ Alkyl group and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups ６－１４ aryl groups; and halogen atoms, C １－６ Alkyl group and C １－６ a nitrogen-containing aromatic heterocyclic group (preferably a 5- or 6-membered nitrogen-containing aromatic heterocyclic group) which may be substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups;

[0081] (Substituent group d): a halogen atom; a hydroxy group; a carboxy group; a nitro group; a cyano group; C １－６ Alkyl group and C １－６ an amino group optionally substituted with 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; １－６ an alkyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group a １－６ Alkoxy group; C １－６ an alkoxy-carbonyl group; a C optionally substituted with 1 to 3 substituents selected from the substituent group a １－６ an alkylsulfonyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group b ３－８ a cycloalkyl group; an acyl group optionally substituted with 1 to 3 substituents selected from substituent group a; an acyloxy group optionally substituted with 1 to 3 substituents selected from substituent group b; a C group optionally substituted with 1 to 3 substituents selected from substituent group b; ６－１４ an aryl group; C optionally substituted with 1 to 3 substituents selected from the substituent group b ６－１４ an aryloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group b ６－１４an arylsulfonyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group b ６－１４ an arylsulfonyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group b ７－１８ an aralkyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group b ７－１８ Aralkyloxy group; hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted with an alkyl group; a hydroxy group, a diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyloxy group optionally substituted with an alkyl group; an oxo group; a thioxo group; a mono- or di-C １－６ an alkylamino group; an azido group; a tri-substituted silyl group; a tri-substituted silyloxy group; an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b; and a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group b, provided that (substituent group d) is not an "optionally substituted C １－６ "Alkyl group" or "optionally substituted C １－６ When representing an optional substituent of an alkoxy group, it is "C optionally substituted with a substituent selected from the substituent group a". １－６ alkyl group" and "C optionally substituted with a substituent selected from substituent group b ７－１８ The term "aralkyl group" refers to a substituent other than an "aralkyl group."

[0082] In the present specification, the term "a pharmaceutically acceptable salt thereof" means a salt that can be used as a medicine. When the compound (I) of the present invention has an acidic or basic group, it can be converted into a basic salt or an acid salt by reacting it with a base or an acid, and therefore the term refers to such a salt. The salt is preferably water-soluble.

[0083] Examples of the pharmaceutically acceptable "basic salt" of compound (I) of the present invention include 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., and the like, and alkali metal salts are preferred.

[0084] Examples of the pharmaceutically acceptable "acid salt" of compound (I) of the present invention include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate, etc.; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.; arylsulfonates such as benzenesulfonate, p-toluenesulfonate, etc.; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; and the like, and preferably hydrohalides (particularly hydrochloride).

[0085] In the present specification, "salts thereof" refers to all salts including the above-mentioned "pharmaceutically acceptable salts thereof".

[0086] As used herein, "prevention" includes preventing the onset of a disease, delaying the onset of a disease, and preventing the occurrence of a pathological condition. A "prophylactically effective amount" refers to a dose of an active ingredient sufficient to achieve the purpose of prevention.

[0087] As used herein, "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 a dose of an active ingredient sufficient to achieve the therapeutic purpose. Therefore, "improvement" is a concept encompassed by "treatment."

[0088] As used herein, the term "subject" refers to a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of an active ingredient is administered to prevent and / or treat (or improve) a disease or the pathology of a disease. The "subject" includes humans and non-human animals (particularly mammals (e.g., mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.)).

[0089] As used herein, the term "B0AT1 inhibitor" refers to a drug comprising a compound that inhibits B0AT1, a transporter responsible for the reabsorption of neutral amino acids such as phenylalanine in the kidney. In particular, compound (I) of the present invention, or a pharmaceutically 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): pp. 111-120) or the method described in the test examples below.

[0090] As used herein, the term "disease whose symptoms can be alleviated by inhibiting B0AT1" refers to a disease caused by increased levels of neutral amino acids in the blood due to mutations in genes involved in the amino acid metabolic pathway, etc. Specific examples of such diseases include amino acid metabolism disorders such as phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[0091] In this specification, the configuration of double bonds in formula (I) (including formula (I') and formula (I'')) and in the chemical formulas of the compounds in the examples is E-configuration, regardless of whether or not it is stated in the chemical formula.

[0092] (Compounds of the Present Invention (Compound (I), Compound (I') and Compound (I''))) Hereinafter, each group in the above formula (I) of Compound (I) will be explained.

[0093] R １ represents a halogen atom, an optionally substituted C １－６ alkyl group, optionally substituted C ３－８cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６ alkylsulfanyl group, optionally substituted C ３－８ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C ６－１４ It represents an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group.

[0094] R １ is preferably C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ A 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group, more preferably haloC １－４ It is an alkyl group.

[0095] The n Xs each independently represent a fluorine atom or a chlorine atom.

[0096] X is preferably a chlorine atom.

[0097] n represents an integer of 0 to 2;

[0098] n is preferably 0 or 1, and more preferably 0.

[0099] R ２ is C which may be substituted with a substituent selected from the above-mentioned substituent group a. １－６ represents an alkyl group.

[0100] R ２ is preferably C substituted with 1 to 3 substituents selected from the above-mentioned substituent group a. １－４ is an alkyl group, and more preferably a C substituted with 1 to 3 substituents selected from the above-mentioned substituent group a′. １－４ alkyl group, more preferably C substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″ １－４ It is an alkyl group.

[0101] R ３ is C which may be substituted with a substituent selected from the above-mentioned substituent group a. １－６ C optionally substituted with an alkyl group or a substituent selected from the above-mentioned substituent group b ３－６ represents a cycloalkyl group.

[0102] R ３ is preferably C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a. １－４ is an alkyl group, and more preferably C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a′. １－４ C is an alkyl group, and more preferably C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″. １－４ It is an alkyl group.

[0103] R ２ and R ３ may be bonded to each other to form, together with the nitrogen atom to which they are bonded, a nitrogen-containing non-aromatic heterocyclic group which may be substituted with a substituent selected from the above-mentioned substituent group b.

[0104] In such a case, R ２ and R ３preferably bond to each other and form, together with the nitrogen atom to which they are bonded, a 3- to 10-membered (preferably 5- to 8-membered) monocyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 10-membered bridged cyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group, each of which is optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group b; More preferably, each of the above-mentioned substituents is optionally substituted with 1 to 3 substituents selected from the substituent group b, such as a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a 3,8-diazabicyclo[3.2.1]octyl group, a diazepanyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, or a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group. , 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, 1,2,3,4-tetrahydroisoquinolyl group, 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, 1,2,3,4-tetrahydro-2,6-naphthyridinyl group, 1,2,3,4-tetrahydro-2,7-naphthyridinyl group or 2,6-diazaspiro[3.3]heptyl group, more preferably each substituted with 1 to 3 substituents selected from the substituent group b. optionally substituted pyrrolidinyl, piperidyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, phthalocyanine or 1,2,3,4-tetrahydro-2,7-naphthalene, and particularly preferred are 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, or 1,2,3,4-tetrahydro-2,7-naphthyridinyl.

[0105] In addition, preferred embodiments of the fused nitrogen-containing non-aromatic heterocyclic group include R ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b, and are represented by the following formula:

[0106]

[0107] (wherein Y and Z each independently represent a carbon atom or a nitrogen atom;

[0108]

[0109] represents a single bond or a double bond; ring A represents a 5- to 8-membered non-aromatic heterocycle; ring B represents a 5- or 6-membered non-aromatic or aromatic heterocycle, or a benzene ring; m represents an integer of 0 to 3; and ＊ represents a bonding site to a carbonyl group), a fused nitrogen-containing non-aromatic heterocyclic group (e.g., a group represented by the following formula:

[0110]

[0111] (In the formula, ＊ represents a bonding site with a carbonyl group.) In another preferred embodiment, R ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with a substituent selected from the substituent group b, and represent the following formula:

[0112]

[0113] (wherein Y and Z each independently represent a carbon atom or a nitrogen atom;

[0114]

[0115] represents a single bond or a double bond; ring A represents a 5- to 8-membered non-aromatic heterocycle; ring B represents a 5- or 6-membered non-aromatic heterocycle or aromatic heterocycle; m represents an integer of 0 to 3; and ＊ represents a bonding site to a carbonyl group), a fused nitrogen-containing non-aromatic heterocyclic group (e.g., a group represented by the following formula:

[0116]

[0117] (In the formula, ＊ represents the bonding site with the carbonyl group.

[0118] The following compound is suitable as compound (I): [Compound (IA)] R １ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with an alkyl group; n X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), and n is an integer of 0 to 2 (preferably 0 or 1); R ２ is substituted with 1 to 3 substituents selected from the substituent group a １－４ is an alkyl group; and R ３ C which is optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a１－４ Compound (I) or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group.

[0119] [Compound (IB)] R １ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with an alkyl group; n is 0; R ２ is substituted with 1 to 3 substituents selected from the substituent group a′ １－４ is an alkyl group; and R ３ C which is optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a′ １－４ Compound (I) or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group.

[0120] [Compound (IC)] R １ But, Haro C １－４ is an alkyl group; n is 0; R ２ is substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″ １－４ is an alkyl group; and R ３ C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″ １－４ Compound (I) or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group.

[0121] [Compound (ID)] R １ But C ２－６ Alkyl group, halo C１－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ n is an integer of 0 to 2 (preferably 0 or 1); and R is a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n is an integer of 0 to 2 (preferably 0 or 1); and ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, are optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group b, and are each a 3- to 10-membered (preferably 5- to 8-membered) monocyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 10-membered bridged ring nitrogen-containing non-aromatic heterocyclic group, a 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group (e.g., a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a 3,8-diazabicyclo[3.2.1]octyl group, a diazepanyl group), , 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, 1,2,3,4-tetrahydroisoquinolyl group, 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, 1,2,3,4-tetrahydro-2,6-naphthyridinyl group, 1,2,3,4-tetrahydro-2,7-naphthyridinyl group, 2,6-diazaspiro[3.3]heptyl group, etc.

[0122] [Compound (IE)] R １ But, Haro C １－４ is an alkyl group; n is 0; and R ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, are optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group b, and are each a 3- to 10-membered (preferably 5- to 8-membered) monocyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 10-membered bridged ring nitrogen-containing non-aromatic heterocyclic group, a 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group (e.g., a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a 3,8-diazabicyclo[3.2.1]octyl group, a diazepanyl group), , 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, 1,2,3,4-tetrahydroisoquinolyl group, 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, 1,2,3,4-tetrahydro-2,6-naphthyridinyl group, 1,2,3,4-tetrahydro-2,7-naphthyridinyl group, 2,6-diazaspiro[3.3]heptyl group, etc.

[0123] [Compound (IF)] R １ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４an aryl group, a halogen atom, or C １－６ n is an integer of 0 to 2 (preferably 0 or 1); and R is a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n is an integer of 0 to 2 (preferably 0 or 1); and ２ and R ３ are bonded to each other to form, together with the nitrogen atom to which they are bonded, a fused nitrogen-containing non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group b, or a pharmaceutically acceptable salt thereof.

[0124] [Compound (IG)] R １ But, Haro C １－４ is an alkyl group; n is 0; and R ２ and R ３ are bonded to each other to form, together with the nitrogen atom to which they are bonded, a fused 9- to 14-membered nitrogen-containing non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group b, or a pharmaceutically acceptable salt thereof.

[0125] [Compound (IH)] R １ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６n is an integer of 0 to 2 (preferably 0 or 1); and R is a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n is an integer of 0 to 2 (preferably 0 or 1); and ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b,

[0126]

[0127] (wherein Y and Z each independently represent a carbon atom or a nitrogen atom;

[0128]

[0129] represents a single bond or a double bond; ring A represents a 5- to 8-membered non-aromatic heterocycle; ring B represents a 5- or 6-membered non-aromatic or aromatic heterocycle, or a benzene ring; m represents an integer of 0 to 3; and ＊ represents a bonding site to a carbonyl group), a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group (e.g., a group represented by the following formula:

[0130]

[0131] (In the formula, ＊ represents a bonding site with a carbonyl group.) Compound (I) or a pharmaceutically acceptable salt thereof, wherein the compound (I) forms a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0132] [Compound (IJ)] R １ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC１－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ n is an integer of 0 to 2 (preferably 0 or 1); and R is a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n is an integer of 0 to 2 (preferably 0 or 1); and ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b,

[0133]

[0134] (wherein Y and Z each independently represent a carbon atom or a nitrogen atom;

[0135]

[0136] represents a single bond or a double bond; ring A represents a 5- to 8-membered non-aromatic heterocycle; ring B represents a 5- or 6-membered non-aromatic heterocycle or aromatic heterocycle; m represents an integer of 0 to 3; and ＊ represents a bonding site to a carbonyl group), a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group (e.g., a group represented by the following formula:

[0137]

[0138] (In the formula, ＊ represents a bonding site with a carbonyl group.) Compound (I) or a pharmaceutically acceptable salt thereof, wherein the compound (I) forms a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0139] [Compound (IK)] R １ But, Haro C １－４ is an alkyl group; n is 0; and R ２ and R ３are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b,

[0140]

[0141] (wherein Y and Z each independently represent a carbon atom or a nitrogen atom;

[0142]

[0143] represents a single bond or a double bond; ring A represents a 5- to 8-membered non-aromatic heterocycle; ring B represents a 5- or 6-membered non-aromatic or aromatic heterocycle, or a benzene ring; m represents an integer of 0 to 3; and ＊ represents a bonding site to a carbonyl group), a fused nitrogen-containing non-aromatic heterocyclic group (e.g., a group represented by the following formula:

[0144]

[0145] (In the formula, ＊ represents a bonding site with a carbonyl group.) Compound (I) or a pharmaceutically acceptable salt thereof, wherein the compound (I) forms a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0146] [Compound (IL)] R １ But, Haro C １－４ is an alkyl group; n is 0; and R ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b,

[0147]

[0148] (wherein Y and Z each independently represent a carbon atom or a nitrogen atom;

[0149]

[0150] represents a single bond or a double bond; ring A represents a 5- to 8-membered non-aromatic heterocycle; ring B represents a 5- or 6-membered non-aromatic heterocycle or aromatic heterocycle; m represents an integer of 0 to 3; and ＊ represents a bonding site to a carbonyl group), a fused nitrogen-containing non-aromatic heterocyclic group (e.g., a group represented by the following formula:

[0151]

[0152] (In the formula, ＊ represents a bonding site with a carbonyl group.) Compound (I) or a pharmaceutically acceptable salt thereof, wherein the compound (I) forms a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0153] [Compound (IM)] R １ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ n is an integer of 0 to 2 (preferably 0 or 1); and R is a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group; n Xs are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n is an integer of 0 to 2 (preferably 0 or 1); and ２ and R ３are bonded to each other and, together with the nitrogen atom to which they are bonded, each optionally substituted by 1 to 3 substituents selected from the substituent group b, such as a pyrrolidinyl group, a piperidyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 1,2,3,4-tetrahydroisoquinolyl group, a 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,6 -naphthyridinyl group or 1,2,3,4-tetrahydro-2,7-naphthyridinyl group (preferably 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl or 1,2,3,4-tetrahydro-2,7-naphthyridinyl).

[0154] [Compound (IN)] R １ But, Haro C １－４ is an alkyl group; n is 0; and R ２ and R ３are bonded to each other and, together with the nitrogen atom to which they are bonded, each optionally substituted by 1 to 3 substituents selected from the substituent group b, such as a pyrrolidinyl group, a piperidyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 1,2,3,4-tetrahydroisoquinolyl group, a 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,6 -naphthyridinyl group or 1,2,3,4-tetrahydro-2,7-naphthyridinyl group (preferably 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl or 1,2,3,4-tetrahydro-2,7-naphthyridinyl).

[0155] Among the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, the compounds represented by the formula (I′) and the formula (I″) (i.e., compound (I′) and compound (I″)) or salts thereof are novel compounds.

[0156] Each group in the formula (I') will be explained below.

[0157] R １’ is C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ It represents a 5- or 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted by an alkyl group.

[0158] R １’ is preferably haloC １－４ It is an alkyl group.

[0159] The n' X's each independently represent a fluorine atom or a chlorine atom.

[0160] X' is preferably a chlorine atom.

[0161] n' represents an integer of 0 to 2;

[0162] n' is preferably 0 or 1, and more preferably 0.

[0163] R ２’ is C substituted with a substituent selected from the above-mentioned substituent group a １－４ represents an alkyl group.

[0164] R ２’ is preferably C substituted with 1 to 3 substituents selected from the above-mentioned substituent group a′. １－４ It is an alkyl group.

[0165] R ３’ is C which may be substituted with a substituent selected from the above-mentioned substituent group a. １－４ C optionally substituted with an alkyl group or a substituent selected from the above-mentioned substituent group b ３－６ represents a cycloalkyl group.

[0166] R ３’ is preferably C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a′. １－４ is an alkyl group, and more preferably C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″. １－４ It is an alkyl group.

[0167] In another embodiment, R２’ and R ３’ are bonded to each other to form R ２’ and R ３’ may form, together with the nitrogen atom to which it is bonded, a nitrogen-containing non-aromatic heterocyclic group which may be substituted with a substituent selected from the above-mentioned substituent group b.

[0168] In such an embodiment, R ２’ and R ３’preferably bond to each other and form, together with the nitrogen atom to which they are bonded, a 3- to 10-membered (preferably 5- to 8-membered) monocyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 10-membered bridged ring nitrogen-containing non-aromatic heterocyclic group, a 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered fused non-aromatic heterocyclic group, each of which is optionally substituted with 1 to 3 substituents selected from the above-mentioned Substituent Group b; More preferably, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a 3,8-diazabicyclo[3.2.1]octyl group, a diazepanyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, or a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group, each of which is optionally substituted with 1 to 3 substituents selected from the substituent group b, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, 1,2,3,4-tetrahydroisoquinolyl group, 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, 1,2,3,4-tetrahydro-2,6-naphthyridinyl group, 1,2,3,4-tetrahydro-2,7-naphthyridinyl group or 2,6-diazaspiro[3.3]heptyl group, more preferably each of which is substituted with 1 to 3 substituents selected from the substituent group b. A pyrrolidinyl group, a piperidyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 1,2,3,4-tetrahydroisoquinolyl group, a 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2, and 1,6-naphthyridinyl or 1,2,3,4-tetrahydro-2,7-naphthyridinyl, and particularly preferred are 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, or 1,2,3,4-tetrahydro-2,7-naphthyridinyl.

[0169] The compound (I') is preferably the following compound: [Compound (I'A)] R １’ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group; n' X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), and n' is an integer of 0 to 2 (preferably 0 or 1); R ２’ is substituted with 1 to 3 substituents selected from the substituent group a １－４ is an alkyl group; and R ３’ C which is optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a １－４ Compound (I') or a salt thereof (wherein the compound (I') is a group represented by the following formula:

[0170]

[0171] excluding compounds represented by the formula:

[0172] [Compound (I'B)] R １’ But, Haro C １－４n' X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), and n' is an integer of 0 to 2 (preferably 0 or 1, more preferably 0); R ２’ is substituted with 1 to 3 substituents selected from the substituent group a′ １－４ is an alkyl group; and R ３’ C which is optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a′ １－４ Compound (I') or a salt thereof, wherein R is an alkyl group.

[0173] [Compound (I'C)] R １’ But, Haro C １－４ n' is an alkyl group; R ２’ is substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″ １－４ is an alkyl group; and R ３’ C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″ １－４ Compound (I') or a salt thereof, wherein R is an alkyl group.

[0174] [Compound (I'D)] R １’ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６n' X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n' is an integer of 0 to 2 (preferably 0 or 1); and R ２’ and R ３’ are bonded to each other to form R ２’ and R ３’ and a compound (I') or a salt thereof (wherein the compound (I') is represented by the following formula:

[0175]

[0176] excluding compounds represented by the formula:

[0177] [Compound (I'E)] R １’ But, Haro C １－４ n' X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), and n' is an integer of 0 to 2 (preferably 0 or 1, more preferably 0); R ２’ and R ３’ are bonded to each other and form, together with the nitrogen atom to which they are bonded, a 3- to 10-membered monocyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 10-membered bridged cyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group, each of which is optionally substituted with 1 to 3 substituents selected from the substituent group b.

[0178] [Compound (I'F)] R １’ But, Haro C １－４ n' X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), and n' is an integer of 0 to 2 (preferably 0 or 1, more preferably 0); R ２’ and R ３’are bonded to each other and, together with the nitrogen atom to which they are bonded, are optionally substituted with 1 to 3 substituents selected from the substituent group b, each of which is optionally substituted with 1 to 3 substituents selected from the substituent group b. Compound (I') or a salt thereof, which forms a 7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 1,2,3,4-tetrahydroisoquinolyl group, a 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,7-naphthyridinyl group, a 2,6-diazaspiro[3.3]heptyl group, or the like.

[0179] [Compound (I'G)] R １’ But, Haro C １－４ n' X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), and n' is an integer of 0 to 2 (preferably 0 or 1, more preferably 0); R ２’ and R ３’are bonded to each other and, together with the nitrogen atom to which they are bonded, are each optionally substituted by 1 to 3 substituents selected from the substituent group b, such as a pyrrolidinyl group, a piperidyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 1,2,3,4-tetrahydroisoquinolyl group, a 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,6- Compound (I') or a salt thereof, which forms a naphthyridinyl group or a 1,2,3,4-tetrahydro-2,7-naphthyridinyl group (preferably 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, or 1,2,3,4-tetrahydro-2,7-naphthyridinyl).

[0180] Next, each group in the formula (I'') will be explained.

[0181] R １’’ represents a halogen atom, an optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６ alkylsulfanyl group, optionally substituted C ３－８ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C ６－１４ It represents an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group.

[0182] R １’’ is preferably a halogen atom, an optionally substituted C１－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ a cycloalkyloxy group, a pentafluorosulfanyl group, or an optionally substituted C ６－１４ is an aryl group, more preferably haloC １－４ It is an alkyl group.

[0183] The n X's each independently represent a fluorine atom or a chlorine atom.

[0184] X'' is preferably a chlorine atom.

[0185] n'' represents an integer of 0 to 2.

[0186] n'' is preferably 0 or 1, and more preferably 0.

[0187] R ２’’ is substituted with a group selected from the group consisting of: (i) a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group optionally substituted with a substituent selected from the substituent group c; and (ii) a 5- or 6-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted with a substituent selected from the substituent group b, and optionally further substituted with a substituent selected from the substituent group a. １－４ represents an alkyl group.

[0188] R ２’’ is preferably substituted with a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (e.g., a pyridazinyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a triazolyl group, a pyrimidinyl group, an oxadiazolyl group, an imidazolyl group) optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group c, and optionally further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″, １－４ It is an alkyl group.

[0189] R ３’’ is C substituted with a substituent selected from the above-mentioned substituent group a １－４ represents an alkyl group.

[0190] R ３’’ is preferably C substituted with 1 to 3 substituents selected from the above-mentioned substituent group a′. １－４ is an alkyl group, and more preferably a C substituted with 1 to 3 substituents selected from the substituent group a″. １－４ It is an alkyl group.

[0191] In another embodiment, R ２’’ and R ３’’ may be bonded to each other to form, together with the nitrogen atom to which they are bonded, a fused nitrogen-containing non-aromatic heterocyclic group (excluding a tetrahydroquinolyl group and a tetrahydroisoquinolyl group) which may be substituted with a substituent selected from the aforementioned substituent group b.

[0192] In such an embodiment, R ２’’ and R ３’’ are preferably represented by the following formula:

[0193]

[0194] (wherein Y′ and Z′ each independently represent a carbon atom or a nitrogen atom;

[0195]

[0196] represents a single bond or a double bond; ring A' represents a 5- to 8-membered non-aromatic heterocycle; ring B' represents a 5- or 6-membered non-aromatic heterocycle or aromatic heterocycle; m' represents an integer of 0 to 3 (preferably 0 to 2); and ＊’ represents a bonding site with a carbonyl group, and more preferably, a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0197]

[0198] (In the formula, ＊ represents the bonding site with the carbonyl group.) to form a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0199] The compound (I″) is preferably the following compound: [Compound (I″A)] R １’’ is a halogen atom, optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６ alkylsulfanyl group, optionally substituted C ３－８ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C ６－１４ an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; n" X" are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), and n" is an integer of 0 to 2 (preferably 0 or 1); R ２’’ is substituted with a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (e.g., a pyridazinyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a triazolyl group, a pyrimidinyl group, an oxadiazolyl group, an imidazolyl group) optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group c, and optionally further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″, １－４ is an alkyl group; and R ３’’ is substituted with 1 to 3 substituents selected from the substituent group a′ １－４ Compound (I″) or a salt thereof, wherein: R is an alkyl group.

[0200] [Compound (I''B)] R １’’ is a halogen atom, optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ a cycloalkyloxy group, a pentafluorosulfanyl group, or an optionally substituted C ６－１４an aryl group; n" X" are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), and n" is an integer of 0 to 2 (preferably 0 or 1); R ２’’ is substituted with a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (e.g., a pyridazinyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a triazolyl group, a pyrimidinyl group, an oxadiazolyl group, an imidazolyl group) optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group c, and optionally further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″, １－４ is an alkyl group; and R ３’’ is substituted with 1 to 3 substituents selected from the substituent group a′ １－４ Compound (I″) or a salt thereof, wherein: R is an alkyl group.

[0201] [Compound (I''C)] R １’’ is a halogen atom, optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ a cycloalkyloxy group, a pentafluorosulfanyl group, or an optionally substituted C ６－１４ n" is 0; R ２’’ is substituted with a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (e.g., a pyridazinyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a triazolyl group, a pyrimidinyl group, an oxadiazolyl group, an imidazolyl group) optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group c, and optionally further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″, １－４ is an alkyl group; and R ３’’ is substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″ １－４ Compound (I″) or a salt thereof, wherein: R is an alkyl group.

[0202] [Compound (I''D)] R １’’ But, Haro C１－４ n'' is 0; R ２’’ is substituted with a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (e.g., a pyridazinyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a triazolyl group, a pyrimidinyl group, an oxadiazolyl group, an imidazolyl group) optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group c, and optionally further substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″, １－４ is an alkyl group; and R ３’’ is substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″ １－４ Compound (I″) or a salt thereof, wherein: R is an alkyl group.

[0203] [Compound (I''E)] R １’’ is a halogen atom, optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６ alkylsulfanyl group, optionally substituted C ３－８ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C ６－１４ an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; n" X" are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n" is an integer of 0 to 2 (preferably 0 or 1); and R ２’’ and R ３’’ are bonded to each other to form, together with the nitrogen atom to which they are bonded, a fused nitrogen-containing non-aromatic heterocyclic group (excluding a tetrahydroquinolyl group and a tetrahydroisoquinolyl group) optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group b, or a salt thereof.

[0204] [Compound (I''F)] R １’’ is a halogen atom, optionally substituted C１－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６ alkylsulfanyl group, optionally substituted C ３－８ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C ６－１４ an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; n" X" are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n" is an integer of 0 to 2 (preferably 0 or 1); and R ２’’ and R ３’’ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b,

[0205]

[0206] (wherein Y′ and Z′ each independently represent a carbon atom or a nitrogen atom;

[0207]

[0208] represents a single bond or a double bond; ring A' represents a 5- to 8-membered non-aromatic heterocycle; ring B' represents a 5- or 6-membered non-aromatic heterocycle or aromatic heterocycle; m' represents an integer of 0 to 3 (preferably 0 to 2); and ＊’ represents a bonding site with a carbonyl group.) Compound (I″) or a salt thereof,

[0209] [Compound (I''G)] R １’’ is a halogen atom, optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８a cycloalkyloxy group, a pentafluorosulfanyl group, or an optionally substituted C ６－１４ n" X" are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom), n" is an integer of 0 to 2 (preferably 0 or 1); and R ２’’ and R ３’’ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b,

[0210]

[0211] (wherein Y′ and Z′ each independently represent a carbon atom or a nitrogen atom;

[0212]

[0213] represents a single bond or a double bond; ring A' represents a 5- to 8-membered non-aromatic heterocycle; ring B' represents a 5- or 6-membered non-aromatic heterocycle or aromatic heterocycle; m' represents an integer of 0 to 3 (preferably 0 to 2); and ＊’ represents a bonding site with a carbonyl group.) Compound (I″) or a salt thereof,

[0214] [Compound (I''H)] R １’’ But, Haro C １－４ n'' is 0; and R ２’’ and R ３’’ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b,

[0215]

[0216] (In the formula, ＊ represents a bonding site with a carbonyl group.) Compound (I″) or a salt thereof,

[0217] Specific examples of suitable compound (I) include the compounds of Examples 1 to 283 (compounds (I-1) to (I-283)) described below, or pharmaceutically acceptable salts thereof (or salts thereof).

[0218] When the compound (I) of the present invention has an asymmetric carbon atom in the molecule, it can exist as a plurality of stereoisomers (i.e., diastereoisomers, optical isomers) based on the asymmetric carbon atom, and the present invention encompasses any one of these stereoisomers and a mixture containing these plurality of stereoisomers in any ratio. In addition, isomers may be produced due to conformation or tautomerism, and such isomers or mixtures thereof are also encompassed by the compound (I) of the present invention.

[0219] Compound (I) of the present invention may contain an isotope (e.g., ２ H. ３ H. １３ C. １４ C. １５ N. １８ F. ３２ P. ３５ S. １２５ The compound may be a compound labeled or substituted with an isotope (e.g., I), and a compound labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is useful in fields such as medical diagnosis.

[0220] The compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be crystalline, and may be in a single crystalline form or a mixture of multiple crystalline forms.

[0221] The compound (I) or a pharmaceutically acceptable salt thereof of the present invention may also include its intramolecular salts, adducts, and solvates thereof. These solvates are compounds in which solvent molecules are coordinated to compound (I) or a salt thereof, and also include hydrates. Examples of the solvates include hydrates, ethanol solvates, and dimethyl sulfoxide solvates of compound (I) or a salt thereof.

[0222] Compound (I) of the present invention may be a prodrug.

[0223] 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) is 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-(C-amino)-1, which may be substituted with an acyloxy group. １－６Examples of prodrugs other than the monoesters and diesters of the phosphate group include alkyl esters, phenyl esters, and benzyl esters (see Bioorganic Chemistry, 1984; 12: pp. 118-129). Examples of prodrugs other than the monoesters and diesters of the phosphate group include compounds having a group derived from a phosphate group, such as those described in Current Opinion in Investigational Drugs, 2006; 7: pp. 109-117, J. Med. Chem. 1994; 37: pp. 1857-1864, and J. Med. Chem. 2000; 43: pp. 4570-4574. Other embodiments of the prodrug of compound (I) include, for example, when compound (I) has an amino group, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, a compound in which the amino group of compound (I) is 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 is acylated, alkylated, phosphorylated or borated (for example, a compound in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated or pivaloylated). , succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); when compound (I) has a carboxy group, compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, methylamidated compounds, etc.). These compounds can be produced by methods known per se. Furthermore, the prodrug of compound (I) may be either a hydrate or a non-hydrate.Furthermore, 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, Hirokawa Publishing, 1990.

[0224] (Method for producing compound (I) of the present invention) Hereinafter, a method for producing compound (I) of the present invention or a pharmaceutically acceptable salt thereof will be described. Since compound (I) also encompasses compound (I), hereinafter, the methods for producing compound (I') and compound (I") will be referred to as the method for producing compound (I). As examples of the method for producing compound (I), representative production methods (A) to (E) will be described below, but the production method is not limited to these. In addition, the following production methods and steps may be combined with each other. Compound (I) (for example, compounds (I-1) to (I-283) described in the Examples below) can be produced by the following production methods (A) to (E), the Reference Examples and Examples below, or methods similar thereto.

[0225] Each starting compound may form a salt as long as it does not inhibit the reaction, and examples of such salts include the same as the salts of compound (I). Unless a specific production method is described, the starting compound may be a commercially available compound that is easily obtained and used, or may be produced according to a method known per se or a method similar thereto. In addition, intermediates produced in the following production methods may be isolated and purified by methods such as column chromatography, recrystallization, distillation, etc., or may be used in the next step without isolation.

[0226] The contents of all patent, non-patent, or literature references explicitly cited in this specification are hereby incorporated by reference in their entirety.

[0227] [Production Method (A)] This production method is a method for obtaining compound (Ia) by condensing compound (1-1) with compound (2-1). Compound (1-1) synthesized by a method known per se (see, for example, the specification of U.S. Pat. No. 10,836,736) can be suitably used.

[0228]

[0229] (The symbols in the formula have the same meanings as defined above.)

[0230] (Step A-1) This step is a step of producing compound (Ia) by condensing compound (1-1) and compound (2-1) in the presence of a condensing agent.

[0231] The amount of the compound (2-1) used is 1 to 5 moles, preferably 1 to 3 moles, per mole of the compound (1-1).

[0232] Condensing agents include o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (WSC hydrochloride), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBop), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU), and O-benzotriazole-N,N,N',N'-tetramethyluronium Examples of the condensing agent include hexafluoroborate (HBTU), and preferably HATU or WSC hydrochloride. The amount of the condensing agent used is usually 1 to 10 moles, and preferably 1 to 5 moles, per mole of compound (1-1).

[0233] The reaction may be carried out in the presence of a condensation additive such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (HOCt), 1-hydroxy-7-azabenzotriazole (HOAt), etc. The amount of the condensation additive used is usually 0 to 1.5 moles per mole of compound (1-1).

[0234] Examples of the base include organic bases such as triethylamine, pyridine, and N,N-diisopropylethylamine, and among these, triethylamine or N,N-diisopropylethylamine is preferred. The amount of the base used is usually 1 to 5 mol, preferably 1.5 mol, per 1 mol of compound (1-1).

[0235] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof 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.

[0236] The reaction temperature is usually −78° C. to room temperature, preferably 0° C. to room temperature, and the reaction time is usually 1 to 48 hours.

[0237] [Production Method (B)] This production method is a method for obtaining compound (Ia) by condensing compound (3-1) with compound (4-1). Compound (3-1) may be a commercially available product or one synthesized by a method known per se.

[0238]

[0239] (The symbols in the formula have the same meanings as defined above.)

[0240] (Step B-1) This step is a step of producing compound (Ia) by condensing compound (3-1) with compound (4-1) in the presence of a condensing agent. The amount of compound (4-1) used is 1 to 5 moles, preferably 1 to 3 moles, per mole of compound (3-1).

[0241] In step B-1, the reaction can be carried out under the same conditions as in step A-1, except that compound (3-1) is used instead of compound (1-1) and compound (4-1) is used instead of compound (2-1).

[0242] [Production Method (C)] In this production method, compound (1-1) and compound (2-2) are condensed in the presence of a condensing agent to obtain compound (Ib), and then a protecting group (P １ ) is deprotected to convert it to compound (Ic), and then reacted with R ４ This is a method for obtaining compound (Id) of the present invention by reductive amination with —CHO.

[0243]

[0244] (In the formula, P １ represents a protecting group, R ４ is a hydrogen atom, a halogen atom, a hydroxy group or C １－６ C optionally substituted with an alkoxy group ２－５ represents an alkyl group, ring A′ represents a nitrogen-containing non-aromatic heterocyclic group which may further have a heteroatom as a ring-constituting atom and which may be further substituted with a substituent selected from the above-mentioned substituent group b, and the other symbols are as defined above.

[0245] (Step C-1) This step is a step of producing compound (Ib) by condensing compound (1-1) and compound (2-2) in the presence of a condensing agent.

[0246] Step C-1 can be carried out under the same conditions as in Step A-1, except that compound (2-2) is used instead of compound (2-1). The amount of compound (2-2) used is 1 to 5 moles, preferably 1 to 3 moles, per mole of compound (1-1).

[0247] (Step C-2) This step is to remove the protecting group (P １ ) to obtain compound (Ic).

[0248] The deprotection step of step C-2 is to remove the protecting group (P １The deprotection reaction conditions can be selected depending on the type of the group. The deprotection reaction is carried out according to methods known per se, for example, the methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protective Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004, or the methods described in the Examples below.

[0249] (Step C-3) In this step, compound (Ic) is reacted with R ４ This is the step of reacting with —CHO (reductive amination reaction) to obtain compound (Id) of the present invention.

[0250] R ４ The amount of --CHO used is 1 to 3 moles, preferably 1 to 2 moles, per mole of compound (Ic).

[0251] Examples of the reducing agent include sodium triacetoxyborohydride, sodium borohydride, etc. The amount of the reducing agent used is 1 to 10 moles, preferably 1 to 3 moles, per mole of compound (Ic).

[0252] Examples of the acid include organic acids such as acetic acid, and Lewis acids such as titanium(IV) chloride and tetraisopropyl titanate. The amount of the acid used is 1 to 10 moles, preferably 1 to 3 moles, per mole of compound (Ic).

[0253] The reaction solvent is not particularly limited, but examples thereof 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.

[0254] The reaction temperature is usually from −10° C. to 100° C., preferably from 10° C. to 50° C., and the reaction time is usually from 1 hour to 48 hours.

[0255] [Production Method (D)] In this production method, the compound (1-1) is condensed with the compound (2-3) to obtain the compound (Ie), and then the protecting group (P ２ ) is converted into compound (If) of the present invention by deprotection.

[0256]

[0257] (In the formula, P ２ represents a protecting group, and Q １ is an oxygen atom or C(=O)O ＊ ( ＊ Is, P ２ represents a bonding site with (Ring A" represents a nitrogen-containing non-aromatic heterocyclic group which may further have a heteroatom as a ring-constituting atom and which may be further substituted with a substituent selected from the above-mentioned substituent group b, and the other symbols are as defined above.

[0258] (Step D-1) This step is a step of producing compound (Ie) by condensing compound (1-1) and compound (2-3) in the presence of a condensing agent.

[0259] Step D-1 can be carried out under the same conditions as in Step A-1, except that compound (2-3) is used instead of compound (2-1). The amount of compound (2-3) used is 1 to 5 moles, preferably 1 to 3 moles, per mole of compound (1-1).

[0260] (Step D-2) This step is to remove the protecting group (P ２ ) to obtain compound (If).

[0261] The deprotection step of step D-2 is to remove the protecting group (P ２The deprotection reaction conditions can be selected depending on the type of the group. The deprotection reaction is carried out according to methods known per se, for example, the methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protective Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004, or the methods described in the Examples below.

[0262] [Production Method (E)] This production method is a method for obtaining compound (Ih) of the present invention by a cross-coupling reaction between compound (Ig) and compound (5-1) in the presence of a metal catalyst and a base.

[0263]

[0264] (In the formula, X ０ represents a halogen atom, Ar １ is an optionally substituted C ６－１４ represents an aryl group, R ５ and R ６ each independently represents a hydrogen atom or an alkyl group, or R ５ and R ６ may be bonded to each other to form a cyclic boronic acid ester such as a pinacol ester of boronic acid together with the boron atom, and the other symbols are as defined above.

[0265] [Step E-1] This step can be carried out by a cross-coupling reaction (Suzuki coupling reaction) between compound (Ig) and an arylboronic acid or arylboronic acid ester (e.g., a pinacol ester of arylboronic acid, etc.) (compound (5-1)) in the presence of a metal catalyst (e.g., a palladium catalyst) and a base in a solvent that does not influence the reaction. Compound (Ig) can be produced by the above-mentioned production method (A) or (B), or a method analogous thereto. Compound (5-1) can be a commercially available product, or can be produced by a method known per se [e.g., the method described in "Advanced Organic Chemistry, 4th Ed." (Jerry March) or "Comprehensive Organic Transformations, 2nd Ed." (Richard C. Larock)] or a method analogous thereto. The amount of compound (5-1) used is usually 1 to 4 moles per mole of compound (Ig).

[0266] Metal catalysts include palladium(II) acetate, palladium(II) chloride, dichlorobis(tricyclohexylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and bis(dibenzylideneacetone)palladium(0) (Pd ２ (dba) ３ ), tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride.diphenylphosphinoferrocene (PdCl ２ (dppf)), PdCl ２Examples of suitable catalysts include palladium catalysts such as (dppf) dichloromethane complex, palladium carbon(0), and bis(triphenylphosphine)palladium dichloride; copper catalysts such as copper iodide(I), copper bromide(I), copper chloride(I), and copper chloride(II); iron catalysts such as iron(III) acetylacetonate; nickel catalysts such as bis(1,5-cyclooctadiene)nickel(0) and bis(acetylacetonate)nickel(II); and ruthenium catalysts such as dichloro(p-cymene)ruthenium(II) dimer and ruthenium alumina. Palladium catalysts are preferred, and dichlorobis(tricyclohexylphosphine)palladium(II) is more preferred. 1'-Bis(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 3,6-dimethoxy-2-dicyclohexylphosphino-2',4',6' Phosphine ligands such as 1-triisopropylbiphenyl (BrettPhos), tri-t-butylphosphine, tricyclohexylphosphine, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (AmPhos), (S)-1-[(RP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (JosiPhos), etc.; phenanthroline, etc. may also be added. The amount of the metal catalyst used is usually 0.01 mol to 1 mol, preferably 0.05 mol to 0.1 mol, relative to 1 mol of compound (Ig). The amount of the ligand used is usually 0.05 mol to 1 mol, preferably 0.1 mol to 0.4 mol, relative to 1 mol of compound (Ig).

[0267] Examples of the base include alkali metal amides such as lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.; alkali metal phosphates such as sodium phosphate, potassium phosphate, etc.; and amines such as triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, etc. The amount of the base used is usually 1 mol to 5 mol, preferably 2 mol to 4.5 mol, per mol of compound (Ig).

[0268] This step can be carried out in the presence or absence of an additive. Examples of the additive include alkali metal halides such as potassium fluoride. The amount of the additive used is usually 1 mol to 5 mol, preferably 1.5 mol to 2.5 mol, per mol of compound (Ig).

[0269] The reaction solvent is not particularly limited, but examples thereof include amides such as N,N-dimethylformamide, N-methylpyrrolidone, etc.; ethers such as tetrahydrofuran, 1,4-dioxane, etc.; halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as toluene, xylene, etc.; nitriles such as acetonitrile, etc.; water; or a mixture thereof.

[0270] The reaction temperature is usually −78° C. to 200° C., preferably −78° C. to 120° C. The reaction time is usually 0.5 to 12 hours.

[0271] The compound (I) or a pharmaceutically acceptable salt thereof obtained by the above-mentioned production method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.

[0272] When compound (I) of the present invention or a pharmaceutically 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). Alternatively, optical isomers can be synthesized using optically pure starting materials. Furthermore, optical isomers can also be synthesized by stereoselectively carrying out each reaction using an asymmetric auxiliary group or an asymmetric catalyst.

[0273] (Medicine (Pharmaceutical Composition) of the Present Invention) The medicine of the present invention is a medicine for preventing and / or treating a disease whose symptoms can be alleviated by B0AT1 inhibitory action, which contains, as an active ingredient, compound (I) or a pharmaceutically acceptable salt thereof, or a B0AT1 inhibitor consisting of compound (I) or a pharmaceutically acceptable salt thereof. Note that compound (I') and compound (I"), which are novel compounds, are also included in compound (I), and therefore medicines containing compound (I') or compound (I") as an active ingredient are also included in medicines containing compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0274] The pharmaceutical of the present invention may be either a pharmaceutical consisting solely of compound (I) or a pharmaceutically acceptable salt thereof (or a B0AT1 inhibitor consisting of compound (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, etc. The pharmaceutical of the present invention can be administered to a subject (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.) in a prophylactically effective amount or a therapeutically effective amount.

[0275] Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethylcellulose, talc, etc.), solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.), 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 stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; polyvinyl alcohol hydrophilic polymers such as cellulose acetate, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like), isotonic agents (for example, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and the like), buffers (for example, buffer solutions such as phosphates, acetates, carbonates, and citrates, and the like), soothing agents (for example, benzyl alcohol, and the like), preservatives (for example, parahydroxybenzoates, , chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbates, etc.), coloring agents (e.g., water-soluble food tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide), etc.), sweeteners (e.g., saccharin sodium, dipotassium glycyrrhizinate, stevia, etc.), and the like.

[0276] The medicament (pharmaceutical composition) of the present invention can be prepared by mixing the above-mentioned components and then processing the mixture according to known means into preparations for oral administration such as tablets, fine granules, granules, capsules, dry syrup, etc., or 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. Among these, oral preparations such as tablets are preferred as the medicament of the present invention.

[0277] The content of compound (I) of the present invention or a pharmaceutically acceptable salt thereof in the medicament (pharmaceutical composition) of the present invention varies depending on the form of the preparation, but 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.

[0278] The dosage of compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, can be appropriately selected depending on the subject of administration (such as the subject's age, body weight, general health condition, sex, and severity of the condition), the administration route, the type of disease, and the type of concomitant medication. For example, in the case of humans, when orally administered to an adult patient (body weight approximately 60 kg), the daily dosage of compound (I) or a pharmaceutically acceptable salt thereof is generally 0.001 mg to 1000 mg, preferably 0.01 mg to 100 mg, calculated as the active ingredient, of compound (I), and 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.

[0279] Compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, is particularly effective for the prophylaxis or treatment of diseases whose symptoms can be alleviated by B0AT1 inhibitory action, particularly amino acid metabolism disorders such as phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[0280] Compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, can be administered (concomitantly used) in combination with other drugs (concomitant drugs) as 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.

[0281] Specifically, when compound (I) of the present invention or a pharmaceutically acceptable salt thereof is used for the treatment and / or prevention of amino acid metabolism disorders such as phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, isovaleric acidemia, etc., concomitant drugs include, for example, vitamin preparations (e.g., folic acid (vitamin B9), nicotinamide (vitamin B3), thiamin (vitamin B4), thiamin (vitamin B5), thiamin (vitamin B6), thiamin (vitamin B7), thiamin (vitamin B8), thiamin (vitamin B9), thiamin (vitamin B1), thiamin (vitamin B10), thiamin (vitamin B11), thiamin (vitamin B12), thiamin (vitamin B13), thiamin (vitamin B14), thiamin (vitamin B15), thiamin (vitamin B16), thiamin (vitamin B17), thiamin (vitamin B18), thiamin (vitamin B19), thiamin (vitamin B20), thiamin (vitamin B21), thiamin (vitamin B22), thiamin (vitamin B23), thiamin (vitamin B24), thiamin (vitamin B25), thiamin (vitamin B26), thiamin (vitamin B27), thiamin (vitamin B28), thiamin (vitamin B29), thiamin (vitamin B30), thiamin (vitamin B31), thiamin (vitamin B32), thiamin (vitamin B33 (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-adenosylmethionine, betaine, aspirin, dipyridamole, sodium benzoate, dextromethorphan, ketamine, antidepressants, anti-anxiety drugs, drugs for treating ADHD, etc.).

[0282] When a concomitant drug is used, the administration timing is not limited, and they may be administered to the subject simultaneously or at staggered times. Staggered administration may involve administering the medicament of the present invention first and the concomitant drug later, or the concomitant drug first and the medicament of the present invention later. The respective administration methods may be the same or different. Furthermore, compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be administered in combination with the concomitant drug as a single formulation.

[0283] The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The compounding ratio of the compound of the present invention or a pharmaceutically acceptable salt thereof to the concomitant drug can be appropriately selected depending on the subject (the subject's age, body weight, general health condition, sex, severity of disease, etc.), administration route, type of disease, type of concomitant drug, etc.

[0284] The mass ratio of compound (I) or a pharmaceutically acceptable salt thereof to the concomitant drug is not particularly limited.

[0285] Furthermore, concomitant drugs that complement and / or enhance the therapeutic effect of compound (I) or a pharmaceutically acceptable salt thereof also include those that have not been discovered so far but will be discovered in the future, based on the above-mentioned mechanism.

[0286] Furthermore, in order to complement and / or enhance the therapeutic effect of compound (I) or a pharmaceutically acceptable salt thereof, it is also effective to use it in combination with a dietary therapy that avoids the intake of specific amino acids or enzyme replacement therapy.

[0287] The medicament or pharmaceutical composition of the present invention may be provided in the form of a kit together with instructions for administration and the like. The drugs contained in the kit are supplied in a container made of a material that 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 alter the components. For example, 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 instructions for use. The instructions 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.

[0288] The present invention will be described in detail below based on Reference Examples, Examples, and Test Examples, but the present invention is not limited to the Examples and Test Examples and may be modified within the scope of the present invention. Furthermore, reagents, devices, and materials used in the present invention are commercially available unless otherwise specified.

[0289] % indicates mol / mol% for yield, and % by weight for other values ​​unless otherwise specified. Furthermore, unless otherwise specified, room temperature indicates a temperature between 15°C and 30°C. Below, * in structural formulas indicates racemic carbon. Other abbreviations used in the text have the following meanings. THF: tetrahydrofuran DMF: N,N-dimethylformamide HATU: o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate WSC: 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide DABSO: bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct HOBt: 1-hydroxybenzotriazole

[0290] Unless otherwise specified, the raw material compounds used in the following Reference Examples and Examples are known compounds, and were synthesized and identified according to methods known per se (e.g., U.S. Pat. No. 10,836,736; Bioorganic & Medicinal Chemistry Letters, 2017, 27(21), 4805-4811; J. Med. Chem., 2014, 57, 3687-3706; WO 2013 / 067274), or methods equivalent thereto.

[0291] Reference Example 1: Preparation of tert-butyl (3R)-3-(5-methyl-1,3,4-oxadiazolo-2-yl)piperazine-1-carboxylate

[0292]

[0293] (1) To a solution of (2R)-1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2-carboxylic acid (28.9 g) in chloroform (160 ml), acetylhydrazine (7.05 g), WSC hydrochloride (22.8 g), 1-hydroxybenzotriazole monohydrate (18.2 g), and triethylamine (16 g) were added sequentially, and the reaction mixture was stirred at room temperature for 3 hours and 40 minutes. 180 ml of water was added to the reaction mixture, and the organic layer was extracted with chloroform. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain O1-benzyl-O4-tert-butyl(2R)-2-(acetamidocarbamoyl)piperazine-1,4-dicarboxylate (35.3 g; yield 100%) as a pale yellow amorphous solid. MS (ESI) m / z: 421.1 [M+H] ＋

[0294] (2) To the O1-benzyl-O4-tert-butyl (2R)-2-(acetamidocarbamoyl)piperazine-1,4-dicarboxylate (35.3 g) obtained in (1) above in THF (150 ml), methyl N-(triethylammoniumsulfonyl)carbamate (19.1 g) was added and stirred at 70°C for 1 hour. Subsequently, methyl N-(triethylammoniumsulfonyl)carbamate (1.70 g) was added and stirred at 70°C for 40 minutes. Further, methyl N-(triethylammoniumsulfonyl)carbamate (1.89 g) was added and stirred at 70°C for 50 minutes. After cooling, the solvent was distilled off under reduced pressure, ethyl acetate and saturated brine were added to the residue, and the organic layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 100 / 0 to 99 / 1) to give O1-benzyl-O4-tert-butyl(2R)-2-(5-methyl-1,3,4-oxadiazolo-2-yl)piperazine-1,4-dicarboxylate (29.6 g; yield 93%) as a pale yellow oil. MS (ESI) m / z: 403.3 [M+H] ＋

[0295] (3) To a solution of O1-benzyl-O4-tert-butyl (2R)-2-(5-methyl-1,3,4-oxadiazolo-2-yl)piperazine-1,4-dicarboxylate (29.6 g) obtained in (2) above in ethanol (250 ml), 5% palladium on carbon (2.96 g) was added to water to prepare a 54% aqueous suspension (6.4 g), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 6.5 hours. After purging the flask with nitrogen, the reaction mixture was filtered through Celite and washed three times with ethanol (50 ml). The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 50 / 1 to 40 / 1, followed by chloroform / methanol containing 1% aqueous ammonia = 40 / 1 to 10 / 1). The impure fractions were concentrated, and the residue was purified again by silica gel column chromatography (solvent: chloroform / methanol = 99 / 1 to 97 / 3). The fraction containing the target compound and the high-purity fraction obtained from the first column chromatography were mixed and concentrated under reduced pressure. The resulting residue was purified again by silica gel column chromatography (solvent: chloroform / methanol = 99 / 1 to 97 / 3 to 95 / 5) to give the title compound (6.6 g; yield 34%) as colorless crystals. MS (ESI) m / z: 269.2 [M+H] ＋

[0296] Reference Example 2: Preparation of (E)-3-[4-(5-methyl-1,2,4-oxadiazolo-3-yl)phenyl]prop-2-enecarboxylic acid

[0297]

[0298] Malonic acid (610 mg) and pyridine (0.12 ml) were added to a solution of 4-(5-methyl-1,2,4-oxadiazolo-3-yl)benzaldehyde (1 g) in ethanol (12 ml), and the mixture was stirred under reflux for 5 hours. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (520 mg; yield 43%) as a white solid. MS (ESI) m / z: 231.1 [M+H] ＋

[0299] Reference Example 3: Preparation of 4-methoxy-3-(2-methoxyethylamino)butanoic acid methyl ester hydrochloride

[0300]

[0301] A solution of 4-methoxy-3-oxobutanoic acid methyl ester (885 μL), 2-methoxyethanamine (590 μL), and acetic acid (390 μL) in chloroform (20 mL) was stirred at room temperature for 10 minutes, after which sodium triacetoxyborohydride (1.73 g) was added, and the reaction mixture was stirred at room temperature for 50 minutes. The reaction mixture was cooled to 0°C, and hydrochloric acid (4 mol / L ethyl acetate solution) (15 mL) was slowly added. After stirring at room temperature for a while, the reaction mixture was concentrated, and diisopropyl ether was added and sonicated. This solution was concentrated, ethyl acetate was added, and sonicated. This solution was further concentrated, and diethyl ether was added and sonicated. The precipitated solid was collected by filtration, washed with diethyl ether, and dried in vacuo at 60°C to obtain 1.17 g (71% yield) of the title compound as a yellow solid. MS (ESI) m / z: 205.9 [M+H] ＋

[0302] Reference Example 4: Preparation of 3-[tert-butoxycarbonyl(2-methoxyethyl)amino]-4-methoxybutanoic acid methyl ester

[0303]

[0304] To a dichloromethane (5 ml) solution of 4-methoxy-3-(2-methoxyethylamino)butanoic acid methyl ester hydrochloride (240 mg) obtained in Reference Example 3, tert-butoxycarbonyl tert-butyl carbonate (467 mg) and triethylamine (650 μl) were added, and the reaction mixture was stirred at room temperature for 70 minutes. To this was further added tert-butoxycarbonyl tert-butyl carbonate (265 mg), and the reaction mixture was stirred at room temperature for 1.5 hours. Water was added, and the aqueous layer was extracted with chloroform. The combined organic layers were filtered through a phase separator and then concentrated. The residue was purified by silica gel column chromatography to give 3-[tert-butoxycarbonyl(2-methoxyethyl)amino]-4-methoxybutanoic acid methyl ester (127 mg; yield 42%) as a colorless oil. MS (ESI) m / z: 206.2 [M+H-Boc]＋

[0305] Reference Example 5: Preparation of N-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide

[0306]

[0307] (1) To a solution of 5-phenylmethoxycarbonyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-carboxylic acid (200 mg) in DMF (4 ml), aqueous methylamine solution (9.5 mol / l, 1 ml), HATU (253 mg), and N,N-diisopropylethylamine (0.35 ml) were added, and the reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure to give crude benzyl 2-(methylcarbamoyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (208.6 mg).

[0308] (2) To a solution of the crude product (208.6 mg) of benzyl 2-(methylcarbamoyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate obtained in (1) above in ethanol (5 ml), 10% palladium / carbon (200 mg) was added under a nitrogen atmosphere, and after replacing the atmosphere with hydrogen, the reaction mixture was stirred at room temperature for 3 hours. After replacing the atmosphere in the flask with nitrogen, the reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure and dried under reduced pressure to give the crude product (119.6 mg) of the title compound.

[0309] Reference Example 6: Preparation of (8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine hydrochloride

[0310]

[0311] (1) To a solution of (2R)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (503 mg) and formamidine hydrochloride (235 mg) in DMF (15 ml), HATU (1.24 g) and N,N-diisopropylethylamine (1.4 ml) were added, and the reaction mixture was stirred at room temperature for 20 minutes. Acetic acid (1.55 ml) and 2-hydrazinoethanol (0.36 ml) were added, and the reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate, and saturated aqueous sodium bicarbonate was slowly added at 0°C. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl N-[(1R)-1-[2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]ethyl]carbamate (515 mg; yield 29%) as a yellow oil. MS (ESI) m / z: 257.1 [M+H] ＋

[0312] (2) To a solution of tert-butyl N-[(1R)-1-[2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]ethyl]carbamate (408 mg) obtained in (1) above in 1,4-dioxane (12 ml), cyanomethylenetributylphosphorane (0.82 ml) was added, and the reaction mixture was heated to 150°C in a microwave reactor under a nitrogen atmosphere and stirred for 60 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl (8R)-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carboxylate (291 mg; yield 158%) as a yellow viscous oil. MS (ESI) m / z: 239.0 [M+H] ＋

[0313] (3) To a solution of tert-butyl (8R)-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carboxylate (290 mg) obtained in (2) above in ethyl acetate, a hydrogen chloride-ethyl acetate solution (4 mol / ml) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a crude product (135 mg).

[0314] Reference Example 7: Preparation of N-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

[0315]

[0316] (1) To a solution of ethyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxylate (500 mg) in THF (12 ml), N,N-diisopropylethylamine (1.4 ml) and benzyl chloroformate (0.54 ml) were added, and the reaction mixture was stirred at room temperature overnight. Aqueous ammonium chloride solution was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7-O-benzyl 2-O-ethyl 6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-2,7-dicarboxylate (910 mg; yield 108.1%) as a colorless viscous substance. MS (ESI) m / z: 331.1 [M+H] ＋

[0317] (2) To a solution of 7-O-benzyl 2-O-ethyl 6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-2,7-dicarboxylate (857 mg) obtained in (1) above in ethanol (6 mL) was added aqueous sodium hydroxide (1 mol / L, 4 mL), and the reaction mixture was stirred at room temperature for 3 hours. Hydrochloric acid was added to the reaction mixture to neutralize it, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain 7-phenylmethoxycarbonyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid (620 mg; yield 79.1%) as a colorless viscous oil. MS (ESI) m / z: 303.1 [M+H] ＋

[0318] (3) To a DMF (4 ml) solution of 7-phenylmethoxycarbonyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid (200 mg) obtained in (2) above and HATU (377 mg), aqueous methylamine solution (9.5 mol / l, 1.67 ml) and N,N-diisopropylethylamine (0.4 ml) were added, and the reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure to give crude benzyl 2-(methylcarbamoyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carboxylate (209 mg).

[0319] (4) To a solution of the crude product (209 mg) of benzyl 2-(methylcarbamoyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carboxylate obtained in (3) above in ethanol (5 ml), 10% palladium / carbon (100 mg) was added under a nitrogen atmosphere, and after replacing the atmosphere with hydrogen, the reaction mixture was stirred at room temperature for 3 hours. After replacing the atmosphere in the flask with nitrogen, the reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure and dried under reduced pressure to give the crude product (119.9 mg) of the title compound.

[0320] Reference Example 8: Preparation of N,N-dimethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

[0321]

[0322] (1) To a DMF (4 ml) solution of 7-phenylmethoxycarbonyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid (200 mg) obtained in Reference Example 7(2) and HATU (377 mg), aqueous dimethylamine solution (9.5 mol / l, 0.35 ml) and N,N-diisopropylethylamine (0.35 ml) were added, and the reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure to give crude benzyl 2-(dimethylcarbamoyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carboxylate (217.9 mg).

[0323] (2) To a solution of the crude product (217.9 mg) of benzyl 2-(dimethylcarbamoyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carboxylate obtained in (1) above in ethanol (4 ml), 10% palladium / carbon (150 mg) was added under a nitrogen atmosphere, and after replacing the atmosphere with hydrogen, the reaction mixture was stirred at room temperature for 3 hours. After replacing the atmosphere in the flask with nitrogen, the reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure and dried under reduced pressure to give the crude product (129.1 mg) of the title compound.

[0324] Reference Example 9: Preparation of spiro[6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-8,1'-cyclopropane]hydrochloride

[0325]

[0326] (1) To a solution of 1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopropane-1-carboxylic acid (965 mg) and formamidine hydrochloride (435 mg) in DMF (30 ml), HATU (2.20 g) and N,N-diisopropylethylamine (2.5 ml) were added, and the reaction mixture was stirred at room temperature for 70 minutes. To this was added acetic acid (2.75 ml) and 2-hydrazinoethanol (0.65 ml), and the reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate, and saturated aqueous sodium bicarbonate was slowly added at 0°C. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl N-[1-[2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]cyclopropyl]carbamate (1.12 g; yield 39.2%) as a yellow oil. MS (ESI) m / z: 269.2 [M+H] ＋

[0327] (2) To a solution of tert-butyl N-[1-[2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]cyclopropyl]carbamate (1.12 g) obtained in (1) above in 1,4-dioxane (30 ml), cyanomethylenetributylphosphorane (2.6 ml) was added, and the reaction mixture was heated to 150°C in a microwave reactor under a nitrogen atmosphere and stirred for 60 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl spiro[5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-8,1'-cyclopropane]-7-carboxylate (280 mg; yield 59.6%) as a brown oil. MS (ESI) m / z: 251.1 [M+H] ＋

[0328] (3) To the tert-butyl spiro[5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-8,1'-cyclopropane]-7-carboxylate (275 mg) obtained in (2) above, a hydrogen chloride-ethyl acetate solution (4 mol / 1.37 ml) was added, and the reaction mixture was stirred at room temperature for 5 days. The precipitated solid was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure at 50°C to obtain a crude product (189 mg) of the title compound.

[0329] Reference Example 10: Preparation of 1-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethanol trifluoroacetate

[0330]

[0331] (1) A solution of tert-butyl 2-formyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (346 mg) in THF (6 ml) was cooled to −78°C, and a solution of methylmagnesium bromide in diethyl ether (3 mol / l, 0.5 ml) was added. The reaction mixture was stirred overnight while naturally warming. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl 2-(1-hydroxyethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (240 mg; yield 71.1%) as a colorless amorphous solid. MS (ESI) m / z: 268.4 [M+H] ＋

[0332] (2) To a suspension of tert-butyl 2-(1-hydroxyethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (250 mg) obtained in (1) above in dichloromethane (4 ml) was added trifluoroacetic acid (4 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain a crude product of the title compound (263 mg).

[0333] Reference Example 11: Preparation of N-[(1-fluorocyclopropyl)methyl]-1-(5-methyl-1,3,4-oxadiazol-2-yl)methanamine

[0334]

[0335] (1) To a solution of (1-fluorocyclopropyl)methanamine hydrochloride (250 mg) in dichloromethane (10 ml), triethylamine (0.83 ml) and 2-nitrobenzenesulfonyl chloride (662 mg) were added under ice cooling, and the reaction mixture was stirred at room temperature overnight. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain N-[(1-fluorocyclopropyl)methyl]-2-nitrobenzenesulfonamide (291 mg; yield 53.3%) as a pale yellow solid. MS (ESI) m / z: 273.0 [M-H] －

[0336] (2) To a solution of N-[(1-fluorocyclopropyl)methyl]-2-nitrobenzenesulfonamide (290 mg) obtained in (1) above in DMF (6 ml), sodium hydride (approximately 60% w / w, 64 mg) and 2-(bromomethyl)-5-methyl-1,3,4-oxadiazole (281 mg) were added under ice cooling, and the reaction mixture was stirred at 80°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography to give a crude product of N-[(1-fluorocyclopropyl)methyl]-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-nitrobenzenesulfonamide (240 mg).

[0337] (3) To a solution of the crude N-[(1-fluorocyclopropyl)methyl]-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-nitrobenzenesulfonamide (240 mg) obtained in (2) above in acetonitrile (6 ml), 4-ethylbenzenethiol (0.22 ml) and cesium carbonate (448 mg) were added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and then dried under reduced pressure to obtain the title compound (196 mg) as a crude product.

[0338] Reference Example 12: Preparation of 1-methoxy-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]propan-2-amine

[0339]

[0340] To a solution of (5-methyl-1,3,4-oxadiazol-2-yl)methanamine hydrochloride (300 mg) in dichloromethane (10 ml), triethylamine (0.31 ml), 1-methoxypropan-2-one (180 mg), acetic acid (0.11 ml), and sodium triacetoxyborohydride (640 mg) were added, and the reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then dried under reduced pressure to give the title compound as a crude product (371 mg).

[0341] Reference Examples 13-14: The corresponding starting compounds were treated in the same manner as in Reference Example 12 to give crude products of the compounds listed in Table 1-1 below.

[0342]

[0343] Reference Example 15: Preparation of 1-[[(3S)-pyrrolidin-3-yl]methyl]pyrazole trifluoroacetate

[0344]

[0345] (1) tert-Butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (202 mg), cyanomethylenetributylphosphorane (0.47 ml), and 1H-pyrazole (68 mg) were added sequentially to a solution of 1,4-dioxane (10 ml), and the reaction mixture was stirred at an external temperature of 125°C for 2 hours. The reaction solution was concentrated to dryness, and toluene was added to the resulting residue, followed by distillation of the solvent. The residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 70 / 30 to 40 / 60) to obtain tert-butyl (3S)-3-(pyrazol-1-ylmethyl)pyrrolidine-1-carboxylate (145 mg; yield 57%) as an orange amorphous solid. MS (ESI) m / z: 364.4 [M+H-tBu] ＋

[0346] (2) To a solution of tert-butyl (3S)-3-(pyrazol-1-ylmethyl)pyrrolidine-1-carboxylate (146 mg) obtained in (1) above in dichloromethane (2 ml) was added trifluoroacetic acid (0.2 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and toluene was added to the resulting residue and the solvent was evaporated to give the title compound as a crude product (154.1 mg).

[0347] Reference Example 16: The corresponding starting compounds were treated in the same manner as in Reference Example 15 to give crude products of the compounds listed in Table 1-2 below.

[0348]

[0349] Reference Example 17: Preparation of (2R,4S)-N-methyl-4-pyrazol-1-ylpyrrolidine-2-carboxamide trifluoroacetate

[0350]

[0351] (1) 1-O-tert-butyl 2-O-methyl(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (302 mg), cyanomethylenetributylphosphorane (0.54 ml), and 1H-pyrazole (85 mg) were added sequentially to dioxane (6 ml), and the reaction mixture was stirred at an external temperature of 110°C for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 70 / 30 to 40 / 60) to obtain 1-O-tert-butyl 2-O-methyl(2R,4S)-4-pyrazol-1-ylpyrrolidine-1,2-dicarboxylate (251 mg; yield 69%) as a yellow amorphous solid. MS (ESI) m / z: 196.1 [M+H] ＋

[0352] (2) To a solution of 1-O-tert-butyl 2-O-methyl(2R,4S)-4-pyrazol-1-ylpyrrolidine-1,2-dicarboxylate (247 mg) obtained in (1) above in methanol (5.5 ml) was added 1 mol / l aqueous sodium hydroxide solution (1.6 ml), and the reaction mixture was stirred at room temperature for 2 hours. 1 mol / l hydrochloric acid (1.6 ml) was added to the reaction mixture, and the mixture was concentrated to dryness. The residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 100 / 0 to 70 / 30) to obtain (2R,4S)-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-pyrazol-1-ylpyrrolidine-2-carboxylic acid (162 mg; yield 69%) as colorless crystals. MS (ESI) m / z: 282.1 [M+H] ＋

[0353] (3) To a solution of (2R,4S)-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-pyrazol-1-ylpyrrolidine-2-carboxylic acid (75 mg) obtained in (2), methanamine hydrochloride (18 mg), and HATU (111 mg) in DMF (1.5 ml), N,N-diisopropylethylamine (0.14 ml) was added, and the reaction mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was evaporated, and the residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate / acetonitrile = 80 / 20 to 50 / 50) to obtain tert-butyl (2R,4S)-2-(methylcarbamoyl)-4-pyrazol-1-ylpyrrolidine-1-carboxylate (37 mg; yield 47%) as a colorless amorphous solid. MS (ESI) m / z: 295.1 [M+H] ＋

[0354] (4) To a solution of tert-butyl (2R,4S)-2-(methylcarbamoyl)-4-pyrazol-1-ylpyrrolidine-1-carboxylate (34 mg) obtained in (3) above in dichloromethane (1 ml) was added trifluoroacetic acid (0.1 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and toluene was added to the resulting residue and the solvent was evaporated to give the title compound as a crude product (36 mg).

[0355] Reference Example 19: Preparation of 6-bromo-4-methoxy-1,2,3,4-tetrahydroisoquinoline

[0356]

[0357] (1) To a solution of 6-bromo-2-(2-nitrophenyl)sulfonyl-3,4-dihydro-1H-isoquinolin-4-ol (300 mg) in toluene (2 ml), tetrabutylammonium hydrogen sulfate (25 mg), iodomethane (206 mg), and potassium hydroxide (50% w / v, 2 ml) were added, and the reaction mixture was stirred at 50°C for 1 hour. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue after concentration under reduced pressure was purified by silica gel column chromatography to obtain 6-bromo-4-methoxy-2-(2-nitrophenyl)sulfonyl-3,4-dihydro-1H-isoquinoline (295 mg; yield 95%) as a colorless viscous substance. MS (ESI) m / z: 397.1 / 399.1 [M+H] ＋

[0358] (2) To a DMF (2 ml) solution of 6-bromo-4-methoxy-2-(2-nitrophenyl)sulfonyl-3,4-dihydro-1H-isoquinoline (295 mg) obtained in (1) above, potassium carbonate (191 mg) and phenylmethanethiol (172 mg) were added, and the reaction mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then dried under reduced pressure to obtain the crude product of the title compound (167 mg; yield 99%) as a brown viscous oil.

[0359] Reference Example 20: Preparation of 6-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine

[0360]

[0361] (1) To a solution of 6-bromo-[1,2,4]triazolo[1,5-a]pyrazine (500 mg), cesium carbonate (1.6 g), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (580 mg) in 1,4-dioxane (4 ml), water (1 ml) was added, and the reaction mixture was heated to 140°C in a microwave reactor and stirred for 60 minutes. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure. The residue after vacuum concentration was purified by silica gel column chromatography to obtain 6-ethenyl-[1,2,4]triazolo[1,5-a]pyrazine (238 mg; yield 65%) as a yellow solid. １ H-NMR (400MHz, CDCl ３ ): δ 9.27 (d, 1H), 8.50-8.41 (m, 2H), 6.79 (dd, 1H), 6.40 (dd, 1H), 5.59 (dd, 1H).

[0362] (2) To a solution of 6-ethenyl-[1,2,4]triazolo[1,5-a]pyrazine (238 mg) obtained in (1) above in ethanol (2 ml) were added acetic acid (1 ml) and palladium hydroxide (25 mg). The reaction mixture was heated to 50°C under a hydrogen atmosphere and stirred for 4 hours. The reaction mixture was filtered through Celite and neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue after concentration under reduced pressure was purified by silica gel column chromatography to obtain 6-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (172 mg; yield 49%) as a yellow viscous material. MS (ESI) m / z: 152.9 [M+H] ＋

[0363] Reference Example 21: Preparation of 6-(methoxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine

[0364]

[0365] (1) To a solution of 6-bromo-[1,2,4]triazolo[1,5-a]pyrazine (250 mg) in THF (1 ml), tributyl(methoxymethyl)tin (605 mg) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (106 mg) were added, and the reaction mixture was heated to 80°C and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure. The residue after vacuum concentration was purified by silica gel column chromatography to obtain 6-(methoxymethyl)-[1,2,4]triazolo[1,5-a]pyrazine (52 mg; yield 19%) as a white solid. MS (ESI) m / z: 165.1 [M+H] ＋

[0366] (2) To a solution of 6-(methoxymethyl)-[1,2,4]triazolo[1,5-a]pyrazine (52 mg) obtained in (1) above in ethanol (2.4 ml) were added acetic acid (4.7 ml) and palladium hydroxide (10 mg). The reaction mixture was heated to 70°C under a hydrogen atmosphere and stirred for 3 hours. The reaction mixture was filtered through Celite and neutralized with saturated aqueous sodium bicarbonate. The aqueous layer was then extracted with a 4:1 mixture of chloroform and methanol. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6-(methoxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (38 mg; yield 94%) as a brown viscous substance. MS (ESI) m / z: 168.9 [M+H] ＋

[0367] Reference Example 22: Preparation of 1,2,3,4-tetrahydroisoquinoline-6-sulfonamide

[0368]

[0369] (1) To a solution of benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (300 mg) in 2-propanol (3 ml), DABSO (210 mg), N-cyclohexyl-N-methylcyclohexanamine (2.8 mmol, 600 μl), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (31 mg) were added, and the reaction mixture was heated to 110°C in a microwave reactor and stirred for 60 minutes. After cooling the reaction mixture on ice, sodium hypochlorite (10% w / v, 1.4 ml) and ammonia (9.8 mol / l methanol solution, 0.18 ml) were added, and the mixture was stirred for 30 minutes. Further sodium hypochlorite (10% w / v, 1.4 ml) was added, and the mixture was warmed to room temperature and stirred for 30 minutes. Saturated aqueous sodium thiosulfate was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue after concentration under reduced pressure was purified by silica gel column chromatography to obtain benzyl 6-sulfamoyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (58 mg; yield 19%) as a yellow viscous oil. MS (ESI) m / z: 345.2 [M-H] －

[0370] (2) To a solution of benzyl 6-sulfamoyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (58 mg) obtained in (1) above in methanol (1 ml) was added palladium hydroxide (20 mg), and the reaction mixture was stirred under a hydrogen atmosphere at 60° C. for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (36 mg) as a crude product in the form of a colorless viscous substance.

[0371] Reference Example 23: Preparation of N-methyl-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide

[0372]

[0373] (1) To a solution of benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (200 mg) in 2-propanol (2 ml), DABSO (140 mg), N-cyclohexyl-N-methylcyclohexanamine (2.8 mmol, 370 μl), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (21 mg) were added, and the reaction mixture was heated to 110°C in a microwave reactor and stirred for 60 minutes. After cooling the reaction mixture on ice, sodium hypochlorite (10% w / v, 1 ml) and methylamine (9.8 mol / l methanol solution, 0.11 ml) were added, and the mixture was stirred for 30 minutes. Saturated aqueous sodium thiosulfate was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain benzyl 6-(methylsulfamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (64 mg; yield 31%) as a yellow oil. MS (ESI) m / z: 359.3 [M−H] －

[0374] (2) To a solution of benzyl 6-methylsulfamoyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (64 mg) obtained in (1) above in methanol (1 ml) was added palladium hydroxide (10 mg), and the reaction mixture was stirred under a hydrogen atmosphere at 60° C. for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (40 mg) as a crude product in the form of a brown viscous oil.

[0375] Reference Example 24: Preparation of pyrrolidin-1-yl(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)methanone hydrochloride

[0376]

[0377] (1) To a solution of 5-[(2-methylpropan-2-yl)oxycarbonyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-carboxylic acid (90 mg) in acetonitrile (1.1 ml), HOBt (55 mg), N,N-diisopropylethylamine (70 μl), pyrrolidine (30 μl), and WSC hydrochloride (76 mg) were added, and the reaction mixture was stirred at room temperature for 60 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude tert-butyl 3-(pyrrolidine-1-carbonyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (108 mg) as a colorless oil.

[0378] (2) To a solution of tert-butyl 3-(pyrrolidine-1-carbonyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (108 mg) obtained in (1) above in ethyl acetate (1 ml) was added hydrogen chloride (4 mol / l ethyl acetate solution, 1 ml), and the mixture was stirred at room temperature for 60 minutes. The reaction mixture was concentrated under reduced pressure, and diisopropyl ether was added to the residue. The precipitated solid was collected by filtration to obtain the title compound (70 mg; yield 69%) as a white solid. MS (ESI) m / z: 221.2 [M+H] ＋

[0379] Reference Examples 25 to 28: The corresponding starting compounds were treated in the same manner as in Reference Example 24 to give the compounds listed in Tables 1 to 3 below.

[0380]

[0381] Reference Example 29: Preparation of tert-butyl 5-fluoro-1,2,3,4-tetrahydroisoquinoline-6-carboxylate

[0382]

[0383] (1) 6-Bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline (1 g) was dissolved in 1,4-dioxane (15 ml) and water (7.5 ml), and sodium bicarbonate (730 mg) and benzyl chloroformate (930 mg) were added. The mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100 / 0 to 65 / 35) to obtain benzyl 6-bromo-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.4 g; 84%) as a colorless oil. MS (ESI) m / z: 363.8 / 365.8 [M+H] ＋

[0384] (2) Benzyl 6-bromo-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.4 g) obtained in (1) above was dissolved in acetonitrile (6 ml) and methanol (3 ml), and bis(tri-tert-butylphosphine)palladium (98 mg), molybdenum hexacarbonyl (1.1 g), and diazabicycloundecene (1.2 ml) were added. The mixture was stirred at 150 ° C. for 30 minutes in a microwave reactor. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100 / 0 to 75 / 25) to obtain 2-O-benzyl 6-O-methyl 5-fluoro-3,4-dihydro-1H-isoquinoline-2,6-dicarboxylate (992 mg; 66%) as a gray oil. MS (ESI) m / z: 344.1 [M + H] ＋

[0385] (3) 2-O-benzyl 6-O-methyl 5-fluoro-3,4-dihydro-1H-isoquinoline-2,6-dicarboxylate (992 mg) obtained in (2) above was dissolved in methanol (8.5 ml), and 4 M lithium hydroxide solution (2.5 ml) was added, followed by stirring at room temperature for 3 hours. The reaction solution was neutralized with 1 M hydrochloric acid and then concentrated. The residue was azeotroped with toluene and then dried under reduced pressure to obtain a crude product of 5-fluoro-2-phenylmethoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (837 mg).

[0386] (4) The crude product (837 mg) of 5-fluoro-2-phenylmethoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid obtained in (3) above was dissolved in toluene (8.5 ml), and 1,1-di-tert-butoxy-N,N-dimethyl-methanamine (44 ml) was added and stirred at 120°C for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain 2-O-benzyl 6-O-tert-butyl 5-fluoro-3,4-dihydro-1H-isoquinoline-2,6-dicarboxylate (238 mg; 22%) as a colorless oil. MS (ESI) m / z: 386.2 [M+H] ＋

[0387] (5) 2-O-benzyl 6-O-tert-butyl 5-fluoro-3,4-dihydro-1H-isoquinoline-2,6-dicarboxylate (238 mg) obtained in (4) above was dissolved in ethanol (2 ml), and dihydroxypalladium (24 mg) was added thereto, followed by stirring at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was concentrated to give the title compound as a crude product (155 mg).

[0388] Reference Examples 30 to 32: The corresponding starting compounds were treated in the same manner as in Reference Example 29 to give crude products of the compounds listed in Tables 1 to 4 below.

[0389]

[0390] Reference Example 33: Preparation of tert-butyl 3-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

[0391]

[0392] (1) To a mixture of ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (1.0 g) and dichloromethane (20 ml), triethylamine (0.8 ml) and benzyl chloroformate (0.76 ml) were added and stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product of 5-O-benzyl 2-O-ethyl 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate.

[0393] (2) To a mixture of the crude product of 5-O-benzyl 2-O-ethyl 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate obtained in (1) above and ethanol (20 ml) was added 4N aqueous sodium hydroxide solution (1.5 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude product of 5-phenylmethoxycarbonyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-carboxylic acid.

[0394] (3) To a mixed solution of the crude 5-phenylmethoxycarbonyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-carboxylic acid obtained in (2) above and toluene (15 ml), N,N-dimethylformamide di-tert-butyl acetal (6 ml) was added, and the mixture was stirred at 120°C for 30 minutes under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 65 / 35 to 45 / 55) to obtain 5-O-benzyl 2-O-tert-butyl 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate (1.46 g; yield 80%) as a yellow oil. MS (ESI) m / z: 302.2 [M-tBu+2H]+

[0395] (4) To a mixture of 5-O-benzyl 2-O-tert-butyl 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate (480 mg) obtained in (3) above and acetonitrile (7 ml), N-bromosuccinimide (270 mg) was added and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium thiosulfate and a 1N aqueous solution of potassium carbonate were added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 67 / 33 to 52 / 48) to obtain 5-O-benzyl 2-O-tert-butyl 3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate (490 mg; yield 84%) as a colorless oil. MS (ESI) m / z: 380.1 / 382.1 [M-tBu+2H]+

[0396] (5) To a mixture of 5-O-benzyl 2-O-tert-butyl 3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate (110 mg) obtained in (4) above and 1,4-dioxane (1.8 ml), 4-(trifluoromethyl)phenyl pinacol boronic acid (112 mg), [4-(di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonic acid (17 mg), and 2N aqueous sodium carbonate solution (0.9 ml) were added, and the mixture was stirred at 140°C for 1 hour in a microwave reactor. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 60 / 40 to 40 / 60) to give 5-O-benzyl 2-O-tert-butyl 3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate (123 mg; yield 97%) as a yellow oil. MS (ESI) m / z: 446.4 [M-tBu+2H]+

[0397] (6) To a mixture of 5-O-benzyl 2-O-tert-butyl 3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate (123 mg) obtained in (5) above, methanol (1.5 ml), and THF (0.5 ml), 20% palladium hydroxide (20 mg) was added, and the mixture was stirred at 50°C under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite and then concentrated under reduced pressure to obtain a crude product of the title compound (90 mg) as a yellow oil. MS (ESI) m / z: 368.06 [M+H] ＋

[0398] Reference Examples 34 to 36: The corresponding starting compounds were treated in the same manner as in Reference Example 33 to give crude products of the compounds listed in Tables 1 to 5 below.

[0399]

[0400] Reference Example 37: Preparation of tert-butyl 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

[0401]

[0402] To a mixture of palladium acetate (12 mg) and dichloromethane (6 ml) under a nitrogen atmosphere were added triethylamine (0.03 ml), triethylsilane (0.2 ml), and 5-O-benzyl 2-O-tert-butyl 3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate (490 mg) obtained in Reference Example 33(4), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to obtain the title compound (90 mg; yield 27%) as a pale yellow solid. MS (ESI) m / z: 246.1 / 248.1 [M-tBu+2H]+

[0403] Reference Example 38: Preparation of 7-bromo-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin-6-one hydrochloride

[0404]

[0405] (1) 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0 to 40 / 60) to obtain tert-butyl 7-bromo-6-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (42.2 mg; yield 18%) as a colorless amorphous substance. MS (ESI) m / z: 329.2 / 331.2 [M+H] ＋

[0406] (2) To the tert-butyl 7-bromo-6-oxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (42.2 mg) obtained in (1) above, a 4N hydrochloric acid-ethyl acetate solution (0.8 ml) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (33.2 mg; yield 98%) as a white solid. MS (ESI) m / z: 229.0 / 231.0 [M+H] ＋

[0407] Reference Example 39: Preparation of 6-bromo-1-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline

[0408]

[0409] (1) 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. The organic layer was washed successively with 1N hydrochloric acid and 1N aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude N-[2-(3-bromophenyl)ethyl]-2-methoxyacetamide (1.36 g) as a yellow oil.

[0410] (2) To a toluene (17 ml) solution of the crude N-[2-(3-bromophenyl)ethyl]-2-methoxyacetamide (1.36 g) obtained in (1) above, phosphorus(V) oxide was added, and the mixture was stirred at 140°C for 2 hours. After cooling to 0°C, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude 6-bromo-1-(methoxymethyl)-3,4-dihydroisoquinoline (1.27 g) as a brown oil.

[0411] (3) Sodium borohydride (756 mg) was added to a solution of the crude 6-bromo-1-(methoxymethyl)-3,4-dihydroisoquinoline (1.27 g) obtained in (2) above in methanol (17 ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (64.1 mg; yield 5.0%) as an orange oil. MS (ESI) m / z: 256.1 / 258.1 [M+H] ＋

[0412] Example 1: Preparation of (E)-N-[2-oxo-2-(3-oxopiperazin-1-yl)ethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-1))

[0413]

[0414] To a solution of 2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetic acid (2.00 g) in DMF (25 ml) was added piperazin-2-one (770 mg), N,N-diisopropylethylamine (1.5 ml), and HATU (3.36 g) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was stirred at room temperature for a while. The aqueous layer was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered through a cotton plug. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 100 / 0 to 96 / 4). Fractions containing the target product were combined and concentrated, and the residue was suspended and washed with diisopropyl ether and ethyl acetate. It was then dried under reduced pressure at 60°C to obtain the title compound (1.90 g; yield 73%) as a white solid. MS (ESI) m / z: 356.3 [M+H] ＋

[0415] Examples 2 to 102: The corresponding starting compounds were treated in the same manner as in Example 1 to obtain the compounds listed in Tables 2-1 to 2-21 below.

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437] Example 103: Preparation of (E)-N-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-3-(4-phenylphenyl)prop-2-enamide (compound (I-103))

[0438]

[0439] N,N-Diisopropylethylamine (0.23 ml) was added to a solution of (E)-3-(4-phenylphenyl)prop-2-enecarboxylic acid (50 mg), 2-amino-1-(4-methylpiperazin-1-yl)ethanone hydrochloride (56 mg), and HATU (110 mg) in DMF (3 ml), and the reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate and chloroform were added to the reaction mixture, which was then stirred and filtered through a phase separator. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate / acetonitrile = 70 / 30 to 40 / 60) to give the title compound (62 mg; yield 77%) as a pale yellow solid. MS (ESI) m / z: 364.4 [M+H] ＋

[0440] Examples 104 to 118: The corresponding starting compounds were treated in the same manner as in Example 103 to obtain the compounds listed in Tables 3-1 to 3-3 below.

[0441]

[0442]

[0443]

[0444] Example 119: Preparation of (E)-N-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-119))

[0445]

[0446] (1) To a solution of 3-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-carboxylic acid tert-butyl ester (453 mg) obtained in Example 152 below in acetonitrile (2 mL) was added hydrochloric acid (4 mol / L ethyl acetate solution) (3 mL), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give crude (E)-N-[2-(2-methylpiperazin-1-yl)-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide hydrochloride (400 mg) as an orange amorphous solid.

[0447] (2) To a dichloromethane (3.5 ml) solution of the crude (E)-N-[2-(2-methylpiperazin-1-yl)-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide hydrochloride (400 mg) obtained in (1) above, formaldehyde (37 wt % methanol solution) (150 μl), acetic acid (500 μl), and sodium triacetoxyborohydride (330 mg) were added, and the reaction mixture was stirred at room temperature for 1 hour. A 0.5 mol / l aqueous NaOH solution was added to the reaction mixture, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered through a cotton plug. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 98 / 2 to 91 / 9) to give the title compound (240 mg; yield 64%) as a white amorphous solid. MS (ESI) m / z: 370.2 [M+H] ＋

[0448] Examples 120 to 122: The corresponding compounds of Examples 153 to 155 (compound (I-153) to compound (I-155)) were treated in the same manner as in Example 119 to obtain the compounds listed in Table 4 below.

[0449]

[0450] Example 123: Preparation of (2S)-4-methyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid (compound (I-123))

[0451]

[0452] To a solution of (2S)-4-methyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid methyl ester (compound (I-156)) (318 mg) obtained in Example 156 described below in methanol (1.6 ml) was added 1 mol / L aqueous sodium hydroxide solution (1.6 ml), and the reaction mixture was stirred at room temperature for 3 hours. 1 mol / L hydrochloric acid (1.6 ml) and 1 mol / L aqueous sodium hydroxide solution (1 ml) were added to the reaction mixture, and the solution was purified by reverse-phase HPLC (solvent: 10 mmol / L aqueous ammonium carbonate / acetonitrile = 80 / 20 to 65 / 35) to obtain the title compound (169 mg; yield 55%) as a white powder. MS (ESI) m / z: 400.1 [M+H] ＋

[0453] Examples 124 to 125: The compounds of Examples 157 to 158 described below (compound (I-157) to compound (I-158)) were treated in the same manner as in Example 123 to obtain the compounds listed in Table 5 below.

[0454]

[0455] Example 126: Preparation of (E)-3-[4-(4-fluorophenyl)phenyl]-N-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]prop-2-enamide (compound (I-126))

[0456]

[0457] (E)-3-(4-bromophenyl)-N-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]prop-2-enamide (100 mg), (4-fluorophenyl)boronic acid (57 mg), dichlorobis(tricyclohexylphosphine)palladium(II) (20 mg), and tripotassium phosphate (174 mg) were suspended in toluene (3 ml) and water (0.3 ml), and the reaction mixture was stirred at 110°C for 5 hours. The reaction mixture was allowed to cool, then filtered through Celite while washing with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (solvent: 10 mmol / l aqueous ammonium carbonate / acetonitrile = 70 / 30 to 40 / 60) to give the title compound (91 mg; yield 87%) as a white solid. MS (ESI) m / z: 382.2 [M+H] ＋

[0458] Examples 127-128: The corresponding starting compounds were treated in the same manner as in Example 126 to give the compounds listed in Table 6 below.

[0459]

[0460] Example 129: Preparation of (E)-N-[2-[2-(1-hydroxy-1-methylethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-129))

[0461]

[0462] (1) To a solution of O5-benzyl O2-ethyl 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2,5-dicarboxylate (150 mg) in THF (5 ml), methylmagnesium bromide (3 mol / l THF solution) (0.5 ml) was added at −78°C, and the mixture was stirred at −78°C for 1 hour, then gradually warmed to room temperature and stirred overnight. Water was added to the reaction solution, which was then concentrated under reduced pressure to obtain crude 2-(1-hydroxy-1-methyl-ethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine.

[0463] (2) To the crude 2-(1-hydroxy-1-methyl-ethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine obtained in (1) above, DMF (5 ml), [[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetic acid (130 mg), HATU (226 mg), and N,N-diisopropylethylamine (0.4 ml) were added in that order, and the reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the aqueous layer was separated with ethyl acetate. The combined organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: ethyl acetate / methanol = 100 / 0 to 95 / 5) to give the title compound (25 mg; yield 13%) as a colorless solid. MS (ESI) m / z: 437.3 [M+H] ＋

[0464] Example 130: Preparation of 4-methoxy-3-[2-methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]-N-methylbutanamide (compound (I-130))

[0465]

[0466] (1) To a solution of 3-[tert-butoxycarbonyl(2-methoxyethyl)amino]-4-methoxybutanoic acid methyl ester (127 mg) obtained in Reference Example 4 in THF (4 ml) was added 1 mol / l aqueous sodium hydroxide solution (500 μl), and the reaction mixture was stirred at room temperature for 16 hours. 1 mol / l hydrochloric acid (500 μl) was added to the reaction mixture, which was then concentrated under reduced pressure and azeotroped twice with toluene to give crude 3-[tert-butoxycarbonyl(2-methoxyethyl)amino]-4-methoxybutanoic acid.

[0467] (2) The crude product of 3-[tert-butoxycarbonyl(2-methoxyethyl)amino]-4-methoxybutanoic acid obtained in (1) above was dissolved in DMF (4 ml), and 2 ml of this solution was taken. To this solution, monomethylamine (310 μl) and HATU (94.9 mg) were added, and the reaction solution was stirred at room temperature for 40 minutes. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to give crude product of tert-butyl N-(2-methoxyethyl)-N-[1-(methoxymethyl)-3-(methylamino)-3-oxopropyl]carbamate (130 mg).

[0468] (3) To the crude product (130 mg) of tert-butyl N-(2-methoxyethyl)-N-[1-(methoxymethyl)-3-(methylamino)-3-oxopropyl]carbamate obtained in (2) above, hydrochloric acid (4 mol / L 1,4-dioxane solution) (2 ml) was added, and the reaction mixture was stirred at room temperature for 80 minutes. The reaction solution was concentrated to obtain a crude product of 4-methoxy-3-(2-methoxyethylamino)-N-methylbutanamide hydrochloride.

[0469] (4) The crude product of 4-methoxy-3-(2-methoxyethylamino)-N-methylbutanamide hydrochloride obtained in (3) above and 2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetic acid (57.9 mg) were treated in the same manner as in Example 1 to give the title compound (29.8 mg; total yield 31%) as a colorless amorphous substance. MS (ESI) m / z: 460.1 [M+H] ＋

[0470] Example 131 Preparation of (E)-N-[2-[(3R)-4-methyl-3-(5-methyl-1,3,4-oxadiazolo-2-yl)piperazin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-131))

[0471]

[0472] (E)-N-[2-[(3R)-3-(5-methyl-1,3,4-oxadiazol-2-yl)piperazin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-167)) (103 mg) obtained in Example 167 described below was treated in the same manner as in (2) of Example 119 to give the title compound (88 mg; yield 92%) as a colorless amorphous substance. MS (ESI) m / z: 438.2 [M+H] ＋

[0473] Example 132: Preparation of (2R)-1-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid (compound (I-132))

[0474]

[0475] (2R)-1-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid methyl ester (compound (I-171)) obtained in Example 171 described below was treated in the same manner as in Example 119(2) to obtain the title compound (83 mg; yield 21%) as a white powder. MS (ESI) m / z: 400.1 [M+H] ＋

[0476] Example 133: Preparation of (E)-N-(2-oxo-2-piperazin-1-ylethyl)-3-[4-(trifluoromethyl)phenyl]prop-2-enamide hydrochloride (compound (I-133))

[0477]

[0478] To a solution of 600 mg of 4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-carboxylic acid tert-butyl ester (compound (I-160)) obtained in Example 160 described below in methanol (5 ml), hydrochloric acid (4 mol / l 1,4-dioxane solution) (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and acetonitrile was added to the resulting residue, followed by suspension washing and filtration under reduced pressure. The resulting solid was dried by heating to obtain the title compound (410 mg; yield 80%) as a white solid. MS (ESI) m / z: 342.1 [M+H] ＋

[0479] Example 134: Preparation of N-ethyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-carboxamide (compound (I-134))

[0480]

[0481] To a dichloromethane (5 ml) solution of (E)-N-(2-oxo-2-piperazin-1-ylethyl)-3-[4-(trifluoromethyl)phenyl]prop-2-enamide hydrochloride (compound (I-133)) (150 mg) obtained in Example 133, triethylamine (0.15 ml) and ethyl isocyanate (0.04 ml) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the resulting residue, and the mixture was suspended and washed, followed by filtration under reduced pressure. The resulting solid was dried by heating to give the title compound (137 mg; yield 84%) as a white solid. MS (ESI) m / z: 413.2 [M+H] ＋

[0482] Example 135: Preparation of 2-[2-methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]acetic acid (compound (I-135))

[0483]

[0484] To a solution of 3 ml of 2-[2-methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]acetic acid ethyl ester (compound (I-161)) (350 mg) obtained in Example 161 described below in methanol (3 ml), 1 mol / l aqueous sodium hydroxide solution (2.5 ml) was added, and the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture, 2.5 ml of 1 mol / l hydrochloric acid and 10 ml of water were added, and the mixture was stirred overnight. The precipitated solid was collected by filtration, washed by suspension in diisopropyl ether, and then dried under reduced pressure to obtain the title compound (253 mg; yield 78%) as a white solid. MS (ESI) m / z: 389.1 [M+H] ＋

[0485] Examples 136 and 137: Preparation of both enantiomers of (E)-N-[2-oxo-2-[3-oxo-5-phenylpiperazin-1-yl]ethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-136) and compound (I-137))

[0486]

[0487] The racemic (E)-N-[2-oxo-2-(3-oxo-5-phenylpiperazin-1-yl)ethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-12)) (166 mg) prepared in Example 12 was optically resolved by chiral HPLC to give two enantiomers of the title compound, as shown in Table 7 below.

[0488]

[0489] Example 138: Preparation of (2R)-N,N,4-trimethyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxamide (compound (I-138))

[0490]

[0491] To a DMF (0.5 ml) solution of (2R)-4-methyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid (compound (I-169)) (30 mg) obtained in Example 169 described below, a 9.5 mol / l aqueous dimethylamine solution (12 μl), N,N-diisopropylethylamine (20 μl), and HATU (43 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water and DMSO were added to the reaction mixture, and the mixture was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate / acetonitrile = 70 / 30 to 40 / 60) to obtain the title compound (17 mg; yield 54%) as a white viscous substance. MS (ESI) m / z: 427.3 [M+H] ＋

[0492] Example 139: Preparation of (2R)-N,4-dimethyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxamide (compound (I-139))

[0493]

[0494] To a DMF (0.5 ml) solution of (2R)-4-methyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid (compound (I-169)) (30 mg) obtained in Example 169 described below, a 9.5 mol / l aqueous dimethylamine solution (10 μl), N,N-diisopropylethylamine (18 μl), and HATU (40 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water and DMSO were added to the reaction mixture, and the mixture was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate / acetonitrile = 80 / 20 to 50 / 50) to obtain the title compound (18 mg; yield 58%) as a white viscous substance. MS (ESI) m / z: 413.2 [M+H] ＋

[0495] Example 140: Preparation of 7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-2-carboxylic acid (compound (I-140))

[0496]

[0497] To a solution of 500 mg of 7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (compound (I-162)) obtained in Example 162 described below in methanol (4 ml), 1 mol / L aqueous sodium hydroxide solution (1.2 ml) was added, and the reaction mixture was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid (1.2 ml) was added to the reaction mixture, and the precipitated solid was collected by filtration and suspended and washed with diisopropyl ether. The resulting solid was purified by reverse-phase HPLC (solvent: 10 mmol / L aqueous ammonium carbonate / acetonitrile = 90 / 10 to 60 / 40), and the resulting solid was suspended in 1 mol / L hydrochloric acid, collected by filtration, suspended and washed with diisopropyl ether, and dried under reduced pressure to obtain the title compound (120 mg; yield 26%) as a white powder. MS (ESI) m / z: 423.2 [M+H] ＋

[0498] Example 141: Preparation of (E)-N-[2-[(2R,4R)-4-hydroxy-2-phenylpyrrolidin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-141))

[0499]

[0500] To a THF (2 ml) solution of the crude product of (E)-N-[2-[(2R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-phenylpyrrolidin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (Compound (I-163)) obtained in Example 163 described below, a 1 mol / l tetra-n-butylammonium fluoride-THF solution (0.6 ml) was added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 50 / 50 to 0 / 100), and the fractions containing the target product were concentrated under reduced pressure. The resulting solid was washed with ethyl acetate and filtered to give the title compound (75 mg; yield 30%) as a white solid. MS (ESI) m / z: 419.2 [M+H] ＋

[0501] Example 142: Preparation of (E)-N-[2-[(3S)-3-[acetyl(methyl)amino]pyrrolidin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-142))

[0502]

[0503] (1) tert-Butyl N-methyl-N-[(3S)-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidin-3-yl]carbamate (Compound (I-164)) (79 mg) obtained in Example 164 described below was dissolved in dichloromethane (3 ml), and 2,2,2-trifluoroacetic acid (0.05 ml) was added, followed by stirring at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and toluene was added to the resulting residue for azeotropy, to obtain a crude product of (E)-N-[2-[(3S)-3-(methylamino)pyrrolidin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide 2,2,2-trifluoroacetate as a pale yellow solid.

[0504] (2) The crude product of (E)-N-[2-[(3S)-3-(methylamino)pyrrolidin-1-yl]-2-oxo-ethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide 2,2,2-trifluoroacetate obtained in (1) above was dissolved in dichloromethane (1 ml), and triethylamine (0.07 ml) and acetyl chloride (17 mg) were added and stirred at room temperature for 1 hour. Methanol was added to the reaction solution to terminate the reaction, and the solvent was concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (solvent: 10 mmol / l aqueous ammonium carbonate / acetonitrile = 80 / 20 to 50 / 50) to give the title compound (62.5 mg; yield 94%) as a colorless viscous material. MS (ESI) m / z: 398.2 [M+H] ＋

[0505] Example 143: Preparation of (E)-N-[2-[(3S)-3-acetamidopyrrolidin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-143))

[0506]

[0507] (1) tert-Butyl N-[(3S)-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidin-3-yl]carbamate (Compound (I-165)) (68 mg) obtained in Example 165 described below was dissolved in dichloromethane (3 ml), and 2,2,2-trifluoroacetic acid (0.1 ml) was added, followed by stirring at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and toluene was added to the resulting residue for azeotropy, to obtain a crude product of (E)-N-[2-[(3S)-3-aminopyrrolidin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide 2,2,2-trifluoroacetate as a pale yellow solid.

[0508] (2) The crude product of (E)-N-[2-[(3S)-3-aminopyrrolidin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide 2,2,2-trifluoroacetate obtained in (1) above was dissolved in dichloromethane (1 ml), and triethylamine (0.07 ml) and acetyl chloride (15 mg) were added, followed by stirring at room temperature for 1 hour. Methanol was added to the reaction solution to terminate the reaction, and the solvent was concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (solvent: 10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 80 / 20 to 50 / 50) to obtain the title compound (42 mg; yield 71%) as a colorless solid. MS (ESI) m / z: 384.2 [M+H] ＋

[0509] Example 144: Preparation of (3S)-N-methyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-3-carboxamide (compound (I-144))

[0510]

[0511] (3S)-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-3-carboxylic acid methyl ester (compound (I-158)) (42 mg) obtained in Example 158 described below was dissolved in methylamine (2 mol / L THF solution) (3 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC (solvent: 10 mmol / L aqueous ammonium carbonate / acetonitrile = 70 / 30 to 40 / 60) to obtain the title compound (38 mg; yield 91%) as a colorless powder. MS (ESI) m / z: 384.2 [M+H] ＋

[0512] Example 145: Preparation of (3S)-N,N-dimethyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-3-carboxamide (compound (I-145))

[0513]

[0514] To a solution of 40 mg of (3S)-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-3-carboxylic acid (compound (I-125)) obtained in Example 125 in DMF (1 ml), methylamine hydrochloride (9 mg) and HATU (45 mg) were added, and N,N-diisopropylethylamine (0.056 ml) was added dropwise, followed by stirring at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (solvent: 10 mmol / l aqueous ammonium carbonate / acetonitrile = 70 / 30 to 40 / 60) to give the title compound (42 mg; yield 98%) as a colorless powder. MS (ESI) m / z: 398.2 [M+H] ＋

[0515] Example 146: Preparation of (3S)-N,N-dimethyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-3-carboxamide (compound (I-146))

[0516]

[0517] To a solution of 50 mg of 7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-2-carboxylic acid (compound (I-140)) prepared in Example 140 in DMF (0.5 ml), 9.5 mol / l aqueous dimethylamine solution (15 μl), N,N-diisopropylethylamine (25 μl), and HATU (68 mg) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 10% aqueous potassium carbonate solution, and the mixture was extracted with a mixed solvent of chloroform:methanol (90:10). The organic layers were combined and dried over anhydrous magnesium sulfate, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase HPLC (10 mmol / L aqueous ammonium carbonate / acetonitrile = 70 / 30 to 40 / 60) to give the title compound (36 mg; yield 68%) as a white powder. MS (ESI) m / z: 450.2 [M+H]+

[0518] Example 147: Preparation of (E)-N-[2-[2-methoxyethyl-[2-[2-methoxyethyl(methyl)amino]-2-oxoethyl]amino]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-147))

[0519]

[0520] To a solution of 2-[2-methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]acetic acid (50 mg) (compound (I-135)) prepared in Example 135 in DMF (0.6 ml), 2-methoxy-N-methylethanamine (18 mg), N,N-diisopropylethylamine (33 μl), and HATU (73 mg) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and purified by reverse phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 70 / 30 to 40 / 60) to obtain the title compound (49 mg; yield 83%) as a colorless viscous material. MS (ESI) m / z: 460.1 [M+H]+

[0521] Example 148: Preparation of (E)-N-[2-[[2-[2-hydroxyethyl(methyl)amino]-2-oxoethyl]-(2-methoxyethyl)amino]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-148))

[0522]

[0523] To a solution of 50 mg of 2-[2-methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]acetic acid (compound (I-135)) prepared in Example 135) in DMF (0.6 ml), 2-(methylamino)ethanol (15 mg), N,N-diisopropylethylamine (33 μl), and HATU (73 mg) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 80 / 20 to 50 / 50) to obtain the title compound (43 mg; yield 75%) as a colorless viscous material. MS (ESI) m / z: 446.1 [M+H]+

[0524] Example 149: Preparation of (E)-N-[2-[[2-(dimethylamino)-2-oxoethyl]-(2-methoxyethyl)amino]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-149))

[0525]

[0526] To a solution of 50 mg of 2-[2-methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]acetic acid (compound (I-135)) prepared in Example 135) in DMF (0.6 ml), 9.5 mol / l aqueous dimethylamine solution (22 μl), N,N-diisopropylethylamine (33 μl), and HATU (73 mg) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 70 / 30 to 40 / 60) to obtain the title compound (47 mg; yield 88%) as a colorless viscous material. MS (ESI) m / z: 416.1 [M+H]+

[0527] Example 150: Preparation of (2R,4R)-4-hydroxy-N,N-dimethyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-2-carboxamide (compound (I-150))

[0528]

[0529] To a DMF (1 ml) solution of (2R,4R)-4-hydroxy-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-2-carboxylic acid (compound (I-170)) (70 mg) obtained in Example 170 described below, a 9.5 mol / l aqueous dimethylamine solution (21 μl), N,N-diisopropylethylamine (40 μl), and HATU (84 mg) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and purified by reverse phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 80 / 20 to 50 / 50) to obtain the title compound (50 mg; yield 67%) as a white solid. MS (ESI) m / z: 414.2 [M+H]+

[0530] Example 151: Preparation of (2R,4R)-4-hydroxy-N-(2-hydroxyethyl)-N-methyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-2-carboxamide (compound (I-151))

[0531]

[0532] To a DMF (1 ml) solution of (2R,4R)-4-hydroxy-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-2-carboxylic acid (compound (I-170)) (70 mg) obtained in Example 170 described below, 2-(methylamino)ethanol (16 μl), N,N-diisopropylethylamine (40 μl), and HATU (84 mg) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 80 / 20 to 50 / 50) to obtain the title compound (57 mg; yield 71%) as a colorless viscous material. MS (ESI) m / z: 444.3 [M+H]+

[0533] Preparation of Examples 152 to 166: The corresponding starting compounds were treated in the same manner as in Example 1 to give the compounds listed in Tables 8-1 to 8-3 below.

[0534]

[0535]

[0536]

[0537] Example 167: Preparation of (E)-N-[2-[(3R)-3-(5-methyl-1,3,4-oxadiazol-2-yl)piperazin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-167))

[0538]

[0539] (1) Trifluoroacetic acid (0.1 ml) was added to a dichloromethane (1 ml) solution of tert-butyl (3R)-3-(5-methyl-1,3,4-oxadiazolo-2-yl)piperazine-1-carboxylate (150 mg) obtained in Reference Example 1, and the reaction mixture was stirred at room temperature for 1 hour. Further trifluoroacetic acid (0.1 ml) was added, and the reaction mixture was stirred at room temperature overnight, and then at 50°C for 3 hours. After allowing the reaction mixture to cool, toluene was added and the mixture was concentrated to obtain crude 2-methyl-5-[(2R)-piperazin-2-yl]-1,3,4-oxadiazole trifluoroacetate as pale yellow crystals.

[0540] (2) The crude product of 2-methyl-5-[(2R)-piperazin-2-yl]-1,3,4-oxadiazole trifluoroacetate obtained in (1) above and 2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetic acid (100 mg) were treated in the same manner as in Example 1 to give the title compound (103 mg; yield 43%) as a colorless solid. MS (ESI) m / z: 424.2 [M+H] ＋

[0541] Example 168: Preparation of (2R)-4-methyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid methyl ester (compound (I-168))

[0542]

[0543] (1) 2,2,2-trifluoroacetic acid (3 ml) was added to a solution of O1-tert-butyl O2-methyl (2R)-4-methylpiperazine-1,2-dicarboxylate (1.34 g) in dichloromethane (7 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness, and the resulting solid was collected by filtration and dried under reduced pressure at 60°C to give a crude product of (2R)-4-methylpiperazine-2-carboxylic acid methyl ester 2,2,2-trifluoroacetate (1.50 g).

[0544] (2) The crude product (1.07 g) of (2R)-4-methylpiperazine-2-carboxylic acid methyl ester 2,2,2-trifluoroacetate obtained in (1) above and 2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetic acid (1.0 g) were treated in the same manner as in Example 1 to obtain the title compound (350 mg; yield 23%) as a colorless oil. MS (ESI) m / z: 414.6 [M+H] ＋

[0545] Example 169: Preparation of (2R)-4-methyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid (compound (I-169))

[0546]

[0547] (2R)-4-methyl-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid methyl ester (compound (I-168)) (350 mg) obtained in Example 168 was treated in the same manner as in Example 123 to give the title compound (75 mg; yield 22%) as a white solid. MS (ESI) m / z: 400.1 [M+H] ＋

[0548] Example 170: Preparation of (2R,4R)-4-hydroxy-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-2-carboxylic acid (compound (I-170))

[0549]

[0550] (2R,4R)-4-hydroxy-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-2-carboxylic acid methyl ester (compound (I-166)) (488 mg) obtained in Example 166 was treated in the same manner as in Example 123 to give the title compound (422 mg; yield 90%) as a white solid. MS (ESI) m / z: 387.1 [M+H]+

[0551] Example 171: Preparation of (2R)-1-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-2-carboxylic acid methyl ester (compound (I-171))

[0552]

[0553] 1O-tert-butyl 2O-methyl (2R)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1,2-dicarboxylate (compound (I-159)) (416 mg) obtained in Example 159 was treated in the same manner as in Example 119 to give the title compound (416 mg; yield 98%) as a pale yellow amorphous substance. MS (ESI) m / z: 414.1 [M+H] ＋

[0554] Examples 172 to 260: The corresponding starting compounds were treated in the same manner as in Example 1 to obtain the compounds listed in Tables 9-1 to 9-18 below.

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573] Example 261: Preparation of 5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (compound (I-261))

[0574]

[0575] 5-Fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-3,4-dihydro-1H-isoquinoline-6-carboxylic acid tert-butyl ester (139.4 mg) was dissolved in a hydrogen chloride-ethyl acetate solution (4 mol / L, 0.6 mL) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure again. Diisopropyl ether was added to the resulting residue, and the precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (88.5 mg; yield 71.4%) as a colorless solid. MS (ESI) m / z: 451.2 [M+H] ＋

[0576] Examples 262 to 275: The corresponding starting compounds were treated in the same manner as in Example 261 to give the compounds listed in Tables 10-1 to 10-3 below.

[0577]

[0578]

[0579]

[0580] Example 276: Preparation of 2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]amino]acetyl]-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (compound (I-276))

[0581]

[0582] 2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]amino]acetyl]-3,4-dihydro-1H-isoquinoline-6-carboxylic acid methyl ester (147 mg) was dissolved in methanol (2 ml) and THF (2 ml), and an aqueous lithium hydroxide solution (4 mol / l; 0.23 ml) was added and stirred at room temperature for 3 hours. The reaction mixture was neutralized and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (28.6 mg; yield 22.1%) as a colorless solid. MS (ESI) m / z: 491.2 [M+H] ＋

[0583] Example 277: The corresponding starting compounds were treated in the same manner as in Example 276 to give the compounds listed in Table 11-1 below.

[0584]

[0585] Example 278: Preparation of N-(2-methylpropyl)-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-3,4-dihydro-1H-isoquinoline-4-carboxamide (compound (I-278))

[0586]

[0587] To a solution of N-(2-methylpropyl)-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-3,4-dihydro-1H-isoquinoline-4-carboxylic acid (50 mg) in DMF (1.5 ml), N,N-diisopropylethylamine (0.04 ml), HATU (62 mg), and 2-methylpropan-1-amine (17 mg) were added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (48.3 mg; yield 85.7%) as a colorless solid. MS (ESI) m / z: 488.4 [M+H] ＋

[0588] Examples 279 to 281: The corresponding starting compounds were treated in the same manner as in Example 278 to give the compounds listed in Table 12-1 below.

[0589]

[0590] Example 282: Preparation of (E)-N-[2-[2-(difluoromethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-282))

[0591]

[0592] Dess-Martin periodinane (312 mg) was added to a dichloromethane (5 ml) solution of (E)-N-[2-[2-(hydroxymethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-2-oxo-ethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (200 mg) prepared in Example 173, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the layers were separated. The organic layer was washed successively with 10% aqueous sodium carbonate and saturated brine, dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and bis(2-methoxyethyl)aminosulfur trifluoride (0.3 ml) was added to a chloroform (5 ml) solution of the resulting crude product under ice-cooling, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 50 / 50 to 0 / 100). The fractions containing the target compound were concentrated under reduced pressure to give the title compound (102 mg; yield 49%) as a white solid. MS (ESI) m / z: 429.2 [M+H] ＋

[0593] Example 283: Preparation of (6R)-5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-6-carboxylic acid (compound (I-283))

[0594]

[0595] (1) To a solution of 1H-pyrazole-3-carbaldehyde (192 mg) in acetonitrile (10 ml), (2R)-3-hydroxy-2-(1H-pyrazol-3-ylmethylamino)propanoic acid tert-butyl ester (847 mg) and N,N-diisopropylethylamine (0.35 ml) were added, followed by sequential addition of acetic acid (0.011 ml) and sodium triacetoxyborohydride (25 mg), and the mixture was stirred overnight at room temperature. Methanol and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate / acetonitrile = 90 / 10 to 60 / 40) to give (2R)-3-hydroxy-2-(1H-pyrazol-3-ylmethylamino)propanoic acid tert-butyl ester (350 mg; yield 73%) as a pale yellow amorphous solid. MS (ESI) m / z: 242.1 [M+H] ＋

[0596] (2) To a solution of (2R)-3-hydroxy-2-(1H-pyrazol-3-ylmethylamino)propanoic acid tert-butyl ester (345 mg) obtained in (1) in acetonitrile (7.5 ml), benzaldehyde (152 mg), acetic acid (0.01 ml), and sodium triacetoxyborohydride (606 mg) were added sequentially, and the mixture was stirred overnight at room temperature. Methanol and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate / acetonitrile = 60 / 40 to 30 / 70) to give (2R)-2-[benzyl(1H-pyrazol-3-ylmethyl)amino]-3-hydroxy-propanoic acid tert-butyl ester (364 mg; yield 77%) as a colorless amorphous solid. MS (ESI) m / z: 332.2 [M+H] ＋

[0597] (3) To a dioxane (6 ml) solution of (2R)-2-[benzyl(1H-pyrazol-3-ylmethyl)amino]-3-hydroxy-propanoic acid tert-butyl ester (360 mg) obtained in (2), cyanomethylenetributylphosphorane (393 mg) was added, and the mixture was stirred at an external temperature of 110°C for 7 hours. Toluene was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 50 / 50 to 20 / 80) to give (6R)-5-benzyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (133 mg; yield 39%) as a yellow amorphous solid. MS (ESI) m / z: 314.2 [M+H] ＋

[0598] (4) To a solution of (6R)-5-benzyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (130 mg) obtained in (3) in ethanol (5 ml), 10% palladium / carbon (393 mg) was added, and the mixture was stirred under a hydrogen atmosphere at an external temperature of 60°C for 3 hours. After purging the reaction mixture with nitrogen, chloroform was added, and the mixture was filtered through Celite. The filtrate was evaporated under reduced pressure to give (6R)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (85 mg; yield 93%) as a colorless amorphous solid. MS (ESI) m / z: 224.2 [M+H] ＋

[0599] (5) To a dichloromethane (1.2 ml) solution of (6R)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (55 mg) obtained in (4), a 1N solution of 2-azidoacetyl chloride in 2-methoxy-2-methylpropane (0.25 ml) was added and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure, and the resulting residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate / acetonitrile = 70 / 30 to 40 / 60) to give (6R)-5-(2-azidoacetyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (72 mg; yield 95%) as a yellow amorphous solid. MS (ESI) m / z: 307.1 [M+H] ＋

[0600] (6) To a solution of (6R)-5-(2-azidoacetyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (72 mg) obtained in (5) in a mixture of THF (1 ml) and water (0.05 ml), triphenylphosphine (93 mg) was added and the mixture was stirred at an external temperature of 50°C for 2 hours. Toluene was added to the reaction mixture, and the solvent was evaporated under reduced pressure to obtain a crude product. DMF (1.2 ml) was added to the obtained crude product, and (E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoic acid (51 mg), HATU (98 mg), and N,N-diisopropylethylamine (0.13 ml) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile=60 / 40 to 30 / 70) to give (6R)-5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (46.3 mg; yield 41%) as a colorless amorphous solid. MS (ESI) m / z: 479.2 [M+H] ＋

[0601] (7) To a dichloromethane (1 ml) solution of (6R)-5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (40 mg) obtained in (6), trifluoroacetic acid (0.1 ml) was added, and the mixture was stirred at room temperature for 2 hours and then at an external temperature of 50°C for 4 hours. Further trifluoroacetic acid (0.1 ml) was added, and the mixture was stirred at an external temperature of 50°C for 2 hours. Further trifluoroacetic acid (0.1 ml) was added, and the mixture was stirred at an external temperature of 50°C for 2 hours. Further trifluoroacetic acid (0.1 ml) was added, and the mixture was stirred at an external temperature of 50°C for 2 hours. The reaction mixture was evaporated under reduced pressure, toluene was added, and the resulting crude product was crystallized by adding diethyl ether. The crystalline compound was collected by filtration to give the title compound (20 mg; yield 57%) as a colorless amorphous substance. MS (ESI) m / z: 423.0 [M+H] ＋

[0602] Test Example 1: hB0AT1 Inhibition Test

[0603] Experimental Method: Test compounds dissolved in dimethyl sulfoxide (DMSO) were added at 0.5 μl per well to a 96-well plate for solid-phase radioactivity measurement containing a scintillator in the bottom of the wells. DMSO alone was added as a control, and DMSO containing N-(4-bromophenyl)-3,5-dichloro-2-hydroxybenzamide (final concentration 10 μM) was added at 0.5 μl per well to measure nonspecific B0AT1 uptake. Human B0AT1-stably expressing CHO cells suspended in buffer (96 mM sodium chloride, 2 mM potassium chloride, 1.8 mM calcium chloride, 1 mM magnesium chloride, 0.01% bovine serum albumin, 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid, pH 7.0) were added at 90 μl to a concentration of 75,000 cells per well. After leaving the plates at room temperature for 30 minutes or more, the plates were subjected to a phenylalanine uptake experiment. 10 μl of a buffer solution containing L-phenylalanine and [3,4,5-3H]-L-phenylalanine was added per well (final concentration of phenylalanine: 0.25 mM). Radioactivity on the bottom of the plate at room temperature was measured over time using a scintillation counter, and the radioactivity values ​​after 100-200 minutes were analyzed. The results were calculated by subtracting non-specific B0AT1 uptake from the control uptake, which was set to 100%, and the concentration of each test compound at which it was inhibited by 50% (IC ５０ The values ​​were calculated by nonlinear regression using a logistic model.

[0604] The results are shown in Tables 13-1 to 13-8 below.

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613] The efficacy of the B0AT1 inhibitor discovered in the present invention in a living body can be measured, for example, as follows.

[0614] Test Example 2: Evaluation test of urinary phenylalanine excretion in mice

[0615] (1) Preparation of Compound and Phenylanine Dosage Solutions. The test compound was weighed, and 200 μl of 0.5% carboxymethylcellulose sodium salt (Sigma-Aldrich) and saline solution (for intraperitoneal administration) or aqueous solution (for oral administration) was added. The compound was then ground and suspended using a mixer mill (Retsch) to the optimal concentration. The suspension was then sonicated for 10 minutes using an ultrasonic homogenizer (Nihonsei). The administration solution was prepared on the day of administration of the test compound. L-phenylalanine (Sigma-Aldrich) was dissolved in saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory) using sonication to prepare a 25 mg / ml solution. The administration solution was prepared on the day of phenylalanine administration.

[0616] (2) Compound Administration and Urine Sample Collection. Male C57BL / 6J (Charles River Japan, Inc.) weighing 20-30 g (8-11 weeks old) were used as test animals. They were group-housed in PC cages until two days before the test. Two days before the test, the animals were confirmed to be in good general condition. After weighing, the animals were individually housed in stainless steel metabolic cages for mice (Shinano Seisakusho Co., Ltd.) with free access to tap water and food. On the morning of the test compound administration, the animals were weighed, and the grouping program GPR3 ​​ver. 3.0.2 was used to assign the animals to groups using a simulation method to ensure that the weights on the test day and the weight changes from two days before the test were uniform across groups. Test compounds were administered intraperitoneally or orally and housed in clean metabolic cages. Thirty minutes after test compound administration, phenylalanine was administered intraperitoneally at 500 mg / 20 ml / kg. Urine was collected 4 hours, 6 hours, or 24 hours after administration of the test compound, and the urine weight was measured. When collecting urine 4 hours and 6 hours after administration, the mice were restrained and allowed to void urine from the bladder. The urine was separated from impurities by centrifugation, and the supernatant was collected. Glucose, occult blood, and leukocyte counts were measured using LifeSticks urine test strips (Siemens Healthcare Diagnostics). The collected urine was stored at -20°C or below and used to measure phenylalanine concentrations.

[0617] (3) Measurement of urinary phenylalanine by LC-MS / MS 190 μl of IS solution (d5-phenylalanine dissolved in acetonitrile / methanol = 7 / 3 at a concentration of 1 μg / ml) was added to 10 μl of urine sample and mixed, and then centrifuged. 3 μl of the supernatant was analyzed by LC-MS / MS. As a calibration standard, 10 μl of a standard solution containing IS solution and 180 μl of IS solution were added to 10 μl of physiological saline and mixed. After centrifugation, 3 μl of the supernatant was analyzed by LC-MS / MS under the following conditions. <Measurement conditions> MS: Quattro Premier XE LC: ACQUITY UPLC Column: ACQUITY UPLC HSS C18 Column, 100 Å, 1.8 μm, 2.1 mm × 100 mm Mobile phase A: 0.025% heptafluorobutyric acid aqueous solution Mobile phase B: acetonitrile Gradient (B%): 2-2-98-98-2 (0.00-0.50-3.50-4.25-5.00 min) Column temperature: 50°C Flow rate: 0.40 ml / min

[0618] As shown in Tables 13-1 to 13-8, compound (I) of the present invention or a salt thereof was confirmed to have excellent inhibitory activity against B0AT1. The above results suggest that compound (I) of the present invention or a salt thereof exhibits preventive and / or therapeutic effects against amino acid metabolism disorders such as phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[0619] Since compound (I) of the present invention or a pharmaceutically acceptable salt thereof has excellent inhibitory activity against B0AT1, a pharmaceutical composition containing the same can be used for the treatment and / or prevention of diseases whose symptoms can be alleviated by B0AT1 inhibitory action, specifically, for example, amino acid metabolism disorders such as phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, isovaleric acidemia, etc. These amino acid metabolism disorders are designated intractable diseases that require long-term treatment, such as lifelong, very strict dietary therapy (amino acid-restricted diet), and therefore compound (I) of the present invention or a pharmaceutically acceptable salt thereof can provide a novel and effective preventive and / or therapeutic agent.

[0620] This application is based on Japanese Patent Application No. 2022-011030 filed on January 27, 2022 in Japan, the contents of which are incorporated in their entirety herein.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R １ represents a halogen atom, an optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６ alkylsulfanyl group, optionally substituted C ３－８ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C ６－１４ an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; n X's each independently represent a fluorine atom or a chlorine atom; n represents an integer from 0 to 2; and R ２ is C optionally substituted with a substituent selected from the substituent group a １－６ represents an alkyl group, and R ３ is C optionally substituted with a substituent selected from the substituent group a １－６ C optionally substituted with an alkyl group or a substituent selected from the substituent group b ３－６ represents a cycloalkyl group, or R ２ and R ３ are bonded to each other to form, together with the nitrogen atom to which they are bonded, a nitrogen-containing non-aromatic heterocyclic group which may be substituted with a substituent selected from Substituent group b. (Substituent group a): halogen atoms; hydroxy group; cyano group; Carboxy group; C optionally substituted with a halogen atom １－６ an alkoxy group; C optionally substituted with a halogen atom １－６ alkylsulfonyl group; C １－６ alkyl-carbonyl group; C １－６ Alkoxy-carbonyl groups; Hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; JiC １－６ alkylamino group; C optionally substituted with 1 to 3 substituents selected from substituent group c ３－８ cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from substituent group c ６－１４ aryl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from Substituent Group c; and a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from Substituent Group b; (Substituent group b): halogen atoms; hydroxy group; cyano group; Carboxy group; oxo group; Thioxo group; C １－６ Alkyl group, C １－６ Alkyl-carbonyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of alkoxy-carbonyl groups; Halogen atoms, hydroxy groups and C １－６ C optionally substituted with a substituent selected from the group consisting of alkoxy groups １－６ alkyl groups; C optionally substituted with a halogen atom １－６ an alkoxy group; C optionally substituted with a halogen atom １－６ alkylsulfonyl group; C optionally substituted with a halogen atom １－６ alkyl-carbonyl group; C １－６ Alkoxy-carbonyl groups; Hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; C, each of which may be substituted with 1 to 3 substituents selected from substituent group c; １－６ Alkyl group, C ３－８ an aminosulfonyl group substituted by one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group; trisubstituted silyl group; trisubstituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from substituent group c ３－８ cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from substituent group c ６－１４ an aryl group; and a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group c; (Substituent group c): halogen atoms; hydroxy group; cyano group; Carboxy group; C １－６ Alkyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of alkoxy-carbonyl groups; C optionally substituted with a halogen atom １－６ alkyl groups; C optionally substituted with a halogen atom １－６ an alkoxy group; C optionally substituted with a halogen atom １－６ alkylsulfonyl group; C １－６ alkyl-carbonyl group; C １－６ Alkoxy-carbonyl groups; Hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; Halogen atoms, C １－６ Alkyl group and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups ６－１４ an aryl group; and Halogen atoms, C １－６ Alkyl group and C １－６ a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups. A B0AT1 inhibitor comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

2. In formula (I), R １ But C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, a halogen atom, or C １－６ a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group, and The B0AT1 inhibitor of claim 1, wherein n is 0.

3. In formula (I), R １ But, Haro C １－４ The B0AT1 inhibitor according to claim 1 or 2, which is an alkyl group.

4. In formula (I), R ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, form a 3- to 10-membered monocyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 10-membered bridged cyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group, each of which is optionally substituted with 1 to 3 substituents selected from Substituent group b.

5. In formula (I), R ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, each optionally substituted with 1 to 3 substituents selected from the substituent group b, such as a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a 3,8-diazabicyclo[3.2.1]octyl group, a diazepanyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin ... The B0AT1 inhibitor according to claim 1 or 2, which forms a riazolo[1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 1,2,3,4-tetrahydroisoquinolyl group, a 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,7-naphthyridinyl group, or a 2,6-diazaspiro[3.3]heptyl group.

6. In formula (I), R ２ is substituted with 1 to 3 substituents selected from the substituent group a １－４ is an alkyl group, and R ３ C optionally substituted with 1 to 3 substituents selected from the substituent group a １－４ The B0AT1 inhibitor according to claim 1 or 2, which is an alkyl group.

7. In formula (I), R ２ and R ３ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b, 【Chemistry 2】 (wherein Y and Z each independently represent a carbon atom or a nitrogen atom; 【Transformation 3】 represents a single bond or a double bond; ring A represents a 5- to 8-membered non-aromatic heterocycle; ring B represents a 5- or 6-membered non-aromatic or aromatic heterocycle, or a benzene ring; m represents an integer of 0 to 3; and ＊ represents the bonding site with the carbonyl group.) The B0AT1 inhibitor according to claim 1 or 2, which forms a group represented by the formula:

8. A pharmaceutical composition for preventing and / or treating amino acid metabolism disorders, comprising the B0AT1 inhibitor according to claim 1 or 2 and a pharmacologically acceptable carrier.

9. 9. The pharmaceutical composition according to claim 8, wherein the amino acid metabolism disorder is phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, or isovaleric acidemia.

10. The pharmaceutical composition according to claim 8, wherein the amino acid metabolism disorder is phenylketonuria.

11. Formula (I'): 【Chemistry 4】 [In the formula, R １’ is C ２－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, halo C ２－６ Alkoxy group, C ３－６ cycloalkyloxy group, C ３－６ Cycloalkyl-C １－４ Alkoxy group, C ２－６ Alkylsulfanyl group, haloC １－６ Alkylsulfanyl group, C ３－６ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, a C group optionally substituted with a halogen atom, ６－１４ an aryl group, or C １－６ a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group; n' number of X's represent fluorine atoms; n' represents an integer from 0 to 2; and R ２’ is C substituted with a substituent selected from the substituent group a １－４ represents an alkyl group, and R ３’ is C optionally substituted with a substituent selected from the substituent group a １－４ C optionally substituted with an alkyl group or a substituent selected from the substituent group b ３－６ represents a cycloalkyl group, or R ２’ and R ３’ are bonded to each other to form, together with the nitrogen atom to which they are bonded, a nitrogen-containing non-aromatic heterocyclic group which may be substituted with a substituent selected from Substituent group b. (Substituent group a): halogen atoms; hydroxy group; cyano group; Carboxy group; C optionally substituted with a halogen atom １－６ an alkoxy group; C optionally substituted with a halogen atom １－６ alkylsulfonyl group; C １－６ alkyl-carbonyl group; C １－６ Alkoxy-carbonyl groups; Hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; JiC １－６ alkylamino group; C optionally substituted with 1 to 3 substituents selected from substituent group c ３－８ cycloalkyl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from Substituent Group c; and a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from Substituent Group b; (Substituent group b): halogen atoms; hydroxy group; cyano group; Carboxy group; oxo group; Thioxo group; C １－６ Alkyl group, C １－６ Alkyl-carbonyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of alkoxy-carbonyl groups; Halogen atoms, hydroxy groups and C １－６ C optionally substituted with a substituent selected from the group consisting of alkoxy groups １－６ alkyl groups; C optionally substituted with a halogen atom １－６ an alkoxy group; C optionally substituted with a halogen atom １－６ alkylsulfonyl group; C optionally substituted with a halogen atom １－６ alkyl-carbonyl group; C １－６ Alkoxy-carbonyl groups; Hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; C, each of which may be substituted with 1 to 3 substituents selected from substituent group c; １－６ Alkyl group, C ３－８ an aminosulfonyl group substituted by one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group; trisubstituted silyl group; trisubstituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from substituent group c ３－８ cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from substituent group c ６－１４ an aryl group; and a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group c; (Substituent group c): halogen atoms; hydroxy group; cyano group; Carboxy group; C １－６ Alkyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of alkoxy-carbonyl groups; C optionally substituted with a halogen atom １－６ alkyl groups; C optionally substituted with a halogen atom １－６ an alkoxy group; C optionally substituted with a halogen atom １－６ alkylsulfonyl group; C １－６ alkyl-carbonyl group; C １－６ Alkoxy-carbonyl groups; Hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; Halogen atoms, C １－６ Alkyl group and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups ６－１４ an aryl group; and Halogen atoms, C １－６ Alkyl group and C １－６ a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups. or a salt thereof, provided that the compound is represented by the following formula: 【Transformation 5】 Excluding compounds represented by the formula:

12. In formula (I'), R １’ But, Haro C １－４ is an alkyl group, and 12. The compound or salt thereof according to claim 11, wherein n' is 0.

13. In formula (I'), R ２’ and R ３’ are bonded to each other and, together with the nitrogen atom to which they are bonded, represent a 3- to 10-membered monocyclic nitrogen-containing non-aromatic heterocyclic group, a 6- to 10-membered bridged ring nitrogen-containing non-aromatic heterocyclic group, a 6- to 12-membered spirocyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group, each of which is optionally substituted with 1 to 3 substituents selected from Substituent group b.

14. In formula (I'), R ２’ and R ３’ are bonded to each other and, together with the nitrogen atom to which they are bonded, are each optionally substituted by 1 to 3 substituents selected from the substituent group b, such as a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a 3,8-diazabicyclo[3.2.1]octyl group, a diazepanyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin ... The compound or salt thereof according to claim 11 or 12, which forms a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 1,2,3,4-tetrahydroisoquinolyl group, a 5,6,7,8-tetrahydro-1,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,6-naphthyridinyl group, a 1,2,3,4-tetrahydro-2,7-naphthyridinyl group, or a 2,6-diazaspiro[3.3]heptyl group.

15. Formula (I″): 【Transformation 6】 [In the formula, R １’’ represents a halogen atom, an optionally substituted C １－６ alkyl group, optionally substituted C ３－８ cycloalkyl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－８ cycloalkyloxy group, optionally substituted C １－６ alkylsulfanyl group, optionally substituted C ３－８ a cycloalkylsulfanyl group, a pentafluorosulfanyl group, an optionally substituted C ６－１４ an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; n X's each independently represent a fluorine atom or a chlorine atom; n″ represents an integer from 0 to 2; and R ２’’ teeth, (i) a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group optionally substituted with a substituent selected from Substituent Group c, and (ii) a 5- or 6-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted with a substituent selected from Substituent Group B and optionally further substituted with a substituent selected from the substituent group a; １－４ represents an alkyl group, and R ３’’ is C substituted with a substituent selected from the substituent group a １－４ represents an alkyl group, or R ２’’ and R ３’’ are bonded to each other and form, together with the nitrogen atom to which they are bonded, a fused nitrogen-containing non-aromatic heterocyclic group (excluding fused nitrogen-containing non-aromatic heterocycles having a spiro structure and excluding an indoline group, a tetrahydrothienopyridine group, a tetrahydroquinolyl group, and a tetrahydroisoquinolyl group) which may be substituted with a substituent selected from substituent group b. (Substituent group a): halogen atoms; hydroxy group; cyano group; Carboxy group; C optionally substituted with a halogen atom １－６ an alkoxy group; C optionally substituted with a halogen atom １－６ alkylsulfonyl group; C １－６ alkyl-carbonyl group; C １－６ Alkoxy-carbonyl groups; Hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; JiC １－６ alkylamino group; C optionally substituted with 1 to 3 substituents selected from substituent group c ３－８ cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from substituent group c ６－１４ aryl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from Substituent Group c; and a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from Substituent Group b; (Substituent group b): halogen atoms; hydroxy group; cyano group; Carboxy group; oxo group; Thioxo group; C １－６ Alkyl group, C １－６ Alkyl-carbonyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of alkoxy-carbonyl groups; Halogen atoms, hydroxy groups and C １－６ C optionally substituted with a substituent selected from the group consisting of alkoxy groups １－６ alkyl groups; C optionally substituted with a halogen atom １－６ an alkoxy group; C optionally substituted with a halogen atom １－６ alkylsulfonyl group; C optionally substituted with a halogen atom １－６ alkyl-carbonyl group; C １－６ Alkoxy-carbonyl groups; Hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; C, each of which may be substituted with 1 to 3 substituents selected from substituent group c; １－６ Alkyl group, C ３－８ an aminosulfonyl group substituted by one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group; trisubstituted silyl group; trisubstituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from substituent group c ３－８ cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from substituent group c ６－１４ an aryl group; and a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from substituent group c; (Substituent group c): halogen atoms; hydroxy group; cyano group; Carboxy group; C １－６ Alkyl group and C １－６ an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of alkoxy-carbonyl groups; C optionally substituted with a halogen atom １－６ alkyl groups; C optionally substituted with a halogen atom １－６ an alkoxy group; C optionally substituted with a halogen atom １－６ alkylsulfonyl group; C １－６ alkyl-carbonyl group; C １－６ Alkoxy-carbonyl groups; Hydroxy group, diC １－６ Alkylamino group and C １－６ 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group １－６ a carbamoyl group optionally substituted by an alkyl group; Halogen atoms, C １－６ Alkyl group and C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups ６－１４ an aryl group; and Halogen atoms, C １－６ Alkyl group and C １－６ a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups. A compound represented by the formula (I) or a salt thereof.

16. In formula (I″), R ２’’ and R ３’’ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the substituent group b, 【Transformation 7】 (wherein Y′ and Z′ each independently represent a carbon atom or a nitrogen atom; 【Transformation 8】 represents a single bond or a double bond; ring A' represents a 5- to 8-membered non-aromatic heterocycle; ring B' represents a 5- or 6-membered non-aromatic heterocycle or aromatic heterocycle; m' represents an integer of 0 to 3; and ＊’ represents the bonding site with the carbonyl group.) The compound or salt thereof according to claim 15 , which forms a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

17. A compound represented by formula (I-260) or a salt thereof: 【Chemistry 9】

18. A pharmaceutical composition comprising the compound or salt thereof according to any one of claims 11, 12, and 15 to 17, and a pharmacologically acceptable carrier.

19. 19. The pharmaceutical composition according to claim 18 for use in the treatment and / or prevention of amino acid metabolism disorders.

20. The pharmaceutical composition according to claim 18, for use in the treatment and / or prevention of a disease selected from the group consisting of phenylketonuria, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

21. 19. The pharmaceutical composition according to claim 18 for use in the treatment and / or prevention of phenylketonuria.

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