New pharmaceutical use of cinnamoylglycinamide compounds

Abstract

To provide a novel B0AT1 inhibitor.SOLUTION: The present invention relates to a pharmaceutical composition containing a compound represented by formula (I) in the figure, where each symbol is as described in the specification, or a pharmaceutically acceptable salt thereof. The present invention particularly relates to a B0AT1 inhibitor comprising the compound, and a pharmaceutical composition containing the compound for the prophylaxis and / or treatment of amino acid metabolism disorders such as phenylketonuria, tyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a novel medicinal use of a cinnamic acid glycine amide compound which has an inhibitory effect on the neutral amino acid transporter B0AT1 and is useful for the prevention and / or treatment of amino acid metabolic disorders involving B0AT1. [Background technology]

[0002] The causative gene of Hartnup disease, SLC6A19, is localized at 5p15.33 and consists of 12 exons. The gene product, the neutral amino acid transporter B0AT1, consists of 634 amino acids and has 12 transmembrane sites (Non-Patent Documents 1 and 2). B0AT1 is the main transporter of neutral amino acids in the small intestine and kidney, and is responsible for the absorption of glycine, leucine, phenylalanine, etc. in the small intestine and their reabsorption in the kidney (Non-Patent Documents 3 to 5). B0AT1 knockout mice are known to show high levels of amino acids in urine (Non-Patent Document 6), and in clinical practice, B0AT1 dysfunction results in severe neutral aminoaciduria, known as the aforementioned Hartnup disease (Non-Patent Document 7). Therefore, it has been thought that various diseases or pathological conditions involving neutral amino acids, which are transport substrates, may be improved (alleviated) by inhibiting B0AT1.

[0003] In addition, specific examples of the therapeutic effect of disease by suppressing the function of B0AT1 have also been reported, such as the improvement of the pathology of a phenylketonuria model mouse by congenitally deleting B0AT1 or by administering a nucleic acid compound that binds to mRNA to suppress its expression laterally (Non-Patent Document 4).

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

[0005] Examples of amino acid metabolic 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 the main known treatment for these diseases is continuous dietary therapy. Other than dietary therapy, administration of drugs that increase coenzymes or enzymes, and injection of enzymes are also known, but none of these are fundamental treatments (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 metabolic disorders, whose symptoms can be alleviated by normalizing neutral amino acid metabolism through inhibition of B0AT1.

[0007] To date, compounds having B0AT1 inhibitory activity have been known, for example, nucleic acids having a sequence partially or completely identical to the RNA of B0AT1 (Non-Patent Document 4), nimesulide and its derivatives (Non-Patent Documents 9 and 10), a known compound, cinromide (Non-Patent Document 11), and basic compounds found by library screening (Non-Patent Documents 12 and 13), etc. However, it has not been reported that the cinnamic acid glycine amide compound according to the present invention exhibits a B0AT1 inhibitory effect. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Nat. Genet., 2004; 36: p.999-1002 [Non-Patent Document 2] Nat. Genet., 2004; 36: p.1003-1007 [Non-Patent Document 3] The Journal of Biological Chemistry 2004; 279: p.24467-24476 [Non-Patent Document 4] JCI Insight., 2018; 3(14): p.e121762 [Non-Patent Document 5] IUBMB Life, 2009; 61(6): p.591-599 [Non-Patent Document 6] MOLECULAR METABOLISM, 2015: p.406-417 [Non-Patent Document 7] Biochem. J., 2005; 389: p.745-751 [Non-Patent Document 8] Intractable Disease Information Center, Phenylketonuria (designated intractable disease 240) (http: / / www.nanbyou.or.jp / entry / 4747) [Non-Patent Document 9] Biochemical Phamracology, 2014; 89: p.422-430 [Non-Patent Document 10] Bioorganic and Medicinal chemistry letters, 2021; 53: p.128421 [Non-Patent Document 11] SLAS Discovery, 2019; 24(2): p.111-120 [Non-Patent Document 12] British Journal of Pharmacology, 2017; 174: p.468-482 [Non-Patent Document 13] Frontiers in Pharmacology, 2020; 11: p.140 Summary of the Invention [Problem to be solved by the invention]

[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 whose symptoms can be alleviated by said activity, specifically, amino acid metabolic disorders. [Means for solving the problem]

[0010] As a result of intensive research aimed at solving the above problems, the present inventors have discovered a compound represented by the following formula (I):

[0011] [ka]

[0012] [In the formula, R 1 is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkyloxy group, optionally substituted C 1-6 Alkylsulfanyl group, optionally substituted C 3-8 Cycloalkylsulfanyl group, pentafluorosulfanyl group, 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 C may be substituted with a substituent selected from the substituent group a 1-6 represents an alkyl group, and R 3 C may be substituted with a substituent selected from the substituent group a 1-6 C which may be 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 halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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; JC 1-6 Alkylamino groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the substituent group c; and A non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; Halogen atoms, hydroxyl groups and C 1-6 C, which may be substituted with a substituent selected from the group consisting of alkoxy groups 1-6 Alkyl groups; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C optionally substituted with halogen atoms 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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 may be substituted with 1 to 3 substituents selected from the 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; Tri-substituted silyl groups; Tri-substituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; and a nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the substituent group c. (substituent group c): Halogen atoms; Hydroxy group; Cyano group; Carboxy group; C 1-6 Alkyl groups and C 1-6 an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; C optionally substituted with halogen atoms 1-6 Alkyl groups; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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 groups and C 1-6 C, which may be 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 groups and C 1-6 a nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of an alkoxy group.] The present invention has been completed based on the discovery that a compound represented by the following formula (hereinafter sometimes abbreviated as "compound (I)"), or a pharma- ceutically acceptable salt thereof, has an excellent inhibitory effect on the neutral amino acid transporter B0AT1 and is useful for the prophylaxis and / or treatment of amino acid metabolic disorders involving B0AT1.

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

[0014] [ka]

[0015] [In the formula, R 1 is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6Alkoxy group, optionally substituted C 3-8 Cycloalkyloxy group, optionally substituted C 1-6 Alkylsulfanyl group, optionally substituted C 3-8 Cycloalkylsulfanyl group, pentafluorosulfanyl group, 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 C may be substituted with a substituent selected from the substituent group a 1-6 represents an alkyl group, and R 3 C may be substituted with a substituent selected from the substituent group a 1-6 C which may be 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 halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups and C 1-6 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group; 1-6A carbamoyl group optionally substituted by an alkyl group; JC 1-6 Alkylamino groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the substituent group c; and A non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; Halogen atoms, hydroxyl groups and C 1-6 C, which may be substituted with a substituent selected from the group consisting of alkoxy groups 1-6 Alkyl groups; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C optionally substituted with halogen atoms 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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 may be substituted with 1 to 3 substituents selected from the 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; Tri-substituted silyl groups; Tri-substituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; and a nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the substituent group c. (substituent group c): Halogen atoms; Hydroxy group; Cyano group; Carboxy group; C 1-6 Alkyl groups and C 1-6 an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; C optionally substituted with halogen atoms 1-6 Alkyl groups; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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 groups and C 1-6C, which may be 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 groups and C 1-6 a nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of an alkoxy group.] A B0AT1 inhibitor comprising a compound represented by the formula: [2] In formula (I), R 1 But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, halogen atom or C 1-6 a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with an alkyl group, The B0AT1 inhibitor according to the above-mentioned [1], wherein n is 0. [3] In formula (I), R 1 But, HaroC 1-4 The B0AT1 inhibitor according to the above [1] or [2], which is an alkyl group. [4] In formula (I), R 2 and R 3are 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 spiro cyclic 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 by 1 to 3 substituents selected from the 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, may each be substituted with 1 to 3 substituents selected from the above-mentioned 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 B0AT1 inhibitor according to any one of the above [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. [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 may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a. 1-4 The B0AT1 inhibitor according to any one of the above-mentioned [1] to [3], which is an alkyl group. [7] In formula (I), 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 above-mentioned substituent group b,

[0016] [ka]

[0017] (In the formula, Y and Z each independently represent a carbon atom or a nitrogen atom;

[0018] [ka]

[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- to 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 any one of the above-mentioned [1] to [3], which forms a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula: [8] A pharmaceutical composition for preventing and / or treating a disease whose symptoms can be alleviated by the B0AT1 inhibitory effect, comprising the B0AT1 inhibitor according to any one of the above [1] to [7] and a pharma- ceutical acceptable carrier. [9] The pharmaceutical composition according to the above [8], wherein the disease whose symptoms can be alleviated by the B0AT1 inhibitory effect is amino acid metabolic disorder.

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

[12] Formula (I'):

[0020] [ka]

[0021] [In the formula, R 1’ is C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, halogen atom or C 1-6 a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group; Each of the n' X' independently represents a fluorine atom or a chlorine atom; 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’ C may be substituted with a substituent selected from the substituent group a 1-4 C which may be 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): Halogen atoms; Hydroxy group; Cyano group; Carboxy group; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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; JC 1-6 Alkylamino groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the substituent group c; and A non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; Halogen atoms, hydroxyl groups and C 1-6 C, which may be substituted with a substituent selected from the group consisting of alkoxy groups 1-6 Alkyl groups; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C optionally substituted with halogen atoms 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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 may be substituted with 1 to 3 substituents selected from the 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; Tri-substituted silyl groups; Tri-substituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; and a nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the substituent group c. (substituent group c): Halogen atoms; Hydroxy group; Cyano group; Carboxy group; C 1-6 Alkyl groups and C 1-6 an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; C optionally substituted with halogen atoms 1-6 Alkyl groups; C optionally substituted with halogen atoms1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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 groups and C 1-6 C, which may be 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 groups and C 1-6 a nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of an alkoxy group.] or a pharma- ceutically acceptable salt thereof (wherein the formula is the formula:

[0022] [ka]

[0023] or a salt thereof, and a pharma- ceutical composition comprising the compound represented by the formula (I):

[13] In formula (I'), R 1’ But, HaroC 1-4 is an alkyl group, and The pharmaceutical composition according to the above

[12] , wherein n' is 0.

[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, 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 spiro cyclic 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] 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 each be substituted by 1 to 3 substituents selected from the above-mentioned 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 pharmaceutical composition according to the above

[12] or

[13] , which forms an azolo[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] [ka]

[0025] [In the formula, R 1’’ is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8Cycloalkyloxy group, optionally substituted C 1-6 Alkylsulfanyl group, optionally substituted C 3-8 Cycloalkylsulfanyl group, pentafluorosulfanyl group, 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 by 1 to 3 substituents selected from the substituent group c, and (ii) a 5- or 6-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents 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, 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, together with the nitrogen atom to which they are bonded, form 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): Halogen atoms; Hydroxy group; Cyano group; Carboxy group; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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; JC 1-6 Alkylamino groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the substituent group c; and A non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; Halogen atoms, hydroxyl groups and C 1-6 C, which may be substituted with a substituent selected from the group consisting of alkoxy groups 1-6 Alkyl groups; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C optionally substituted with halogen atoms 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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 may be substituted with 1 to 3 substituents selected from the 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; Tri-substituted silyl groups; Tri-substituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; and a nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the substituent group c. (substituent group c): Halogen atoms; Hydroxy group; Cyano group; Carboxy group; C 1-6 Alkyl groups and C 1-6 an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; C optionally substituted with halogen atoms 1-6 Alkyl groups; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups and C 1-61 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 groups and C 1-6 C, which may be 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 groups and C 1-6 a nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of an alkoxy group.] (hereinafter, also abbreviated as "compound (I'')") or a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition comprising a pharma- ceutically acceptable carrier.

[17] 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 above-mentioned substituent group b,

[0026] [ka]

[0027] (In the formula, Y′ and Z′ each independently represent a carbon atom or a nitrogen atom;

[0028] [ka]

[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- to 6-membered non-aromatic or aromatic heterocycle; m' represents an integer from 0 to 3; and *’ represents the bonding site with the carbonyl group.) The pharmaceutical composition according to the above-mentioned

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

[18] The pharmaceutical composition according to any one of

[12] to

[17] above for use in treating and / or preventing amino acid metabolic disorders.

[19] The pharmaceutical composition according to any of the above

[12] to

[17] 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.

[20] The pharmaceutical composition according to

[19] above for use in the treatment and / or prevention of phenylketonuria.

[21] The pharmaceutical composition according to any one of the above [8] to

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

[22] The pharmaceutical composition according to

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

[23] The pharmaceutical composition according to

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

[24] The pharmaceutical composition according to any one of

[21] to

[23] above, wherein the pharmaceutical composition according to any one of [8] to

[20] above and the other drug are administered separately.

[25] The pharmaceutical composition according to any one of

[21] to

[23] above, wherein the pharmaceutical composition according to any one of [8] to

[20] above and another drug are administered simultaneously or sequentially.

[26] The pharmaceutical composition according to any one of

[21] to

[25] above for use in treating and / or preventing amino acid metabolic disorders.

[27] The pharmaceutical composition according to any of

[21] to

[25] 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.

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

[20] and another drug.

[29] The pharmaceutical composition according to

[28] above for use in the treatment and / or prevention of amino acid metabolic disorders.

[30] The pharmaceutical composition according to

[28] 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.

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

[32] A method for preventing or treating a disease in a mammal 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 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 amino acid metabolic disorders in a mammal, comprising administering to the mammal an effective amount of the pharmaceutical composition according to any one of

[12] to

[17] above.

[34] A method for preventing or treating a disease in a mammal 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 the mammal an effective amount of the pharmaceutical composition according to any one of

[12] to

[17] above.

[35] A method for preventing or treating amino acid metabolic disorders in a mammal, comprising administering to the mammal effective amounts of the pharmaceutical composition according to any one of [8] to

[20] above and another drug simultaneously or sequentially.

[36] 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 an effective amount of the pharmaceutical composition according to any one of [8] to

[20] above and another drug simultaneously or sequentially.

[37] Use of the B0AT1 inhibitor according to any one of the above [1] to [7] for the manufacture of an agent for treating or preventing amino acid metabolic disorders.

[38] Use of the B0AT1 inhibitor according to any of the above [1] to [7] for the manufacture of an agent for the treatment 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.

[39] Use of the pharmaceutical composition according to any one of

[12] to

[17] above for the manufacture of an agent for treating or preventing amino acid metabolic disorders.

[40] Use of the pharmaceutical composition according to any one of

[12] to

[17] above for the manufacture of an agent for the treatment 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.

[41] The pharmaceutical composition according to any one of

[12] to

[17] above, for use in the prevention or treatment of amino acid metabolic disorders.

[42] The pharmaceutical composition according to any of the above

[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.

[43] A method for producing the pharmaceutical composition according to any one of

[12] to

[17] above. Effect of the Invention

[0030] Since the compound (I) of the present invention or a pharma- ceutical acceptable salt thereof has excellent inhibitory activity against B0AT1, a pharmaceutical composition containing the compound is useful for treating and / or preventing diseases whose symptoms can be alleviated by the 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 a very strict dietary therapy (amino acid restricted diet) that continues for the rest of one's life, and therefore a pharmaceutical composition containing the compound (I) of the present invention or a pharma-ceutical acceptable salt thereof can provide a novel and effective prophylactic and / or therapeutic agent for the amino acid metabolism disorders. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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, chlorine atom, bromine atom or 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 linear or branched monovalent group having one or more carbon atoms. 1-20 Alkyl groups, among which C 1-6 Alkyl groups are preferred.

[0034] In this specification, "C 1-20The 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 1-6 The term "alkyl (group)" means an alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, sec-pentyl (pentan-2-yl), 3-pentyl (pentan-3-yl), tert-pentyl (1,1-dimethylpropyl), hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0036] In this specification, "C 1-4 The term "alkyl (group)" means 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 are 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 them, "haloC1-6 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 carbon number range, it is preferably C 3-8 It is a cycloalkyl group.

[0039] In this specification, "C 3-8 The 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 above-mentioned 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 above-mentioned 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 unless otherwise specified, the term "alkoxy (group)" refers to any group having a carbon number of 1 to 3, preferably 1 to 3, more ... 1-20 is an alkoxy group, preferably 1-6 It is an alkoxy group.

[0043] In this specification, "C 1-6The term "alkoxy (group)" refers to 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, and hexyloxy. 1-4 Alkoxy groups are preferred.

[0044] In the present specification, the term "haloalkoxy (group)" refers to a group in which one or more hydrogen atoms in the alkoxy group are 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, 6,6,6-trifluorohexyloxy, and the like. Among them, "haloC 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, 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 are 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, and 6,6,6-trifluorohexylsulfanyl. Among them, "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-) having the above-mentioned "C 1-6 The term "C" refers to a group having an "alkyl" group bonded thereto, 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. 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. The range of the number of carbon atoms is not particularly limited, but preferably, 1-6 It 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 (-CONH2) in which one or two hydrogen atoms are independently selected from the group represented by the above C 1-6 It means a group which may be substituted with an alkyl group, and preferably a 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 (condensed) 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 preferable.

[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. The carbon number range is not particularly limited, but preferably is 6-14 It is an aryl-carbonyl group.

[0055] In this specification, "C 6-14 The term "aryloxy (group)" refers to the above 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. Among them, the phenyloxy group is particularly preferred.

[0056] In this specification, "C 6-14 The term "arylsulfonyl (group)" refers to the above-mentioned C 6-14 It means a group in which an aryl group is bonded to the sulfur atom of a sulfonyl group (-S(=O)2-), and examples thereof include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0057] In this specification, "C 6-14 The term "arylsulfonyloxy (group)" refers to the above-mentioned C 6-14 It means a group in which an aryl group is bonded to the sulfur atom of a sulfonyloxy group (-S(=O)2-O-), and examples thereof include phenylsulfonyloxy, 1-naphthylsulfonyloxy, and 2-naphthylsulfonyloxy.

[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. 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 above C 7-18 An aralkyl group means a group bonded to an oxygen atom, and specific examples include benzyloxy, phenethyloxy, naphthylmethyloxy, biphenylylmethyloxy, etc. Among these, a 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 6-14Aryl-carbonyl group. Specific preferred examples of acyl (group) include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl (pivaloyl), hexanoyl, heptanoyl, benzoyl, 1-naphthoyl, 2-naphthoyl, and the like.

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

[0062] In this specification, "C 1-6 Alkyl groups 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 selected from the group consisting of 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 of such 8- to 14-membered fused aromatic heterocyclic groups (fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups) include 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. , piperidyl, piperazinyl, tetrahydropyridyl, dihydropyridyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, and other 3- to 10-membered monocyclic non-aromatic heterocyclic groups (preferably 5- to 8-membered monocyclic non-aromatic heterocyclic groups); 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 and 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" means 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 1-6 Alkyl group, C 3-8 The term "aminosulfonyl (group) substituted by one substituent selected from the group consisting of a cycloalkyl group and a non-aromatic heterocyclic group" refers to the above-mentioned C in which one hydrogen atom of the aminosulfonyl group (-S(=O)2-NH2) may be substituted by one to three substituents selected from the group consisting of 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 "tri-substituted 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, and the like.

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

[0075] In the present specification, "optionally substituted" means that the group is 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 thereof 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, each substituent may be the same or different. may also be different.

[0076] (substituent group a): Halogen atoms; Hydroxy group; Cyano group; Carboxy group; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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; JC 1-6 Alkylamino groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; a nitrogen-containing aromatic heterocyclic group (preferably a 5- or 6-membered nitrogen-containing aromatic heterocyclic group) which may be substituted by 1 to 3 substituents selected from the 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 the substituent group b.

[0077] (substituent group a'): Hydroxy group; Carboxy group; C optionally substituted with halogen atoms 1-6 Alkoxy groups (e.g., methoxy and ethoxy groups); Hydroxy group, diC 1-6 Alkylamino groups 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 (e.g., a methylcarbamoyl group, a dimethylcarbamoyl group); C optionally substituted with halogen atoms 1-6 Alkylsulfonyl groups (e.g., methylsulfonyl groups); a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the substituent group c (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); and A 5- or 6-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the substituent group b (e.g., a tetrahydropyranyl group, a tetrahydrofuryl group).

[0078] (substituent group a''): Hydroxy group; Carboxy group; C optionally substituted with halogen atoms 1-6 Alkoxy groups (e.g., methoxy and ethoxy groups); Hydroxy group, diC 1-6 Alkylamino groups and C 1-6 1 to 2 C optionally substituted with a substituent selected from the group consisting of an alkoxy group;1-6 Carbamoyl groups optionally substituted with alkyl groups (e.g., methylcarbamoyl groups, dimethylcarbamoyl groups); and C optionally substituted with halogen atoms 1-6 Alkylsulfonyl groups (e.g., methylsulfonyl groups).

[0079] (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 an alkoxy-carbonyl group; Halogen atoms, hydroxyl groups and C 1-6 C, which may be substituted with a substituent selected from the group consisting of alkoxy groups 1-6 Alkyl groups; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C optionally substituted with halogen atoms 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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 may be substituted with 1 to 3 substituents selected from the 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; Tri-substituted silyl groups; Tri-substituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group c 3-8 Cycloalkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group c 6-14 Aryl groups; and 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 substituent group c.

[0080] (substituent group c): Halogen atoms; Hydroxy group; Cyano group; Carboxy group; C 1-6 Alkyl groups and C 1-6 an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; C optionally substituted with halogen atoms 1-6 Alkyl groups; C optionally substituted with halogen atoms 1-6 Alkoxy groups; C optionally substituted with halogen atoms 1-6 Alkylsulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Hydroxy group, diC 1-6 Alkylamino groups 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 groups and C 1-6 C, which may be substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups. 6-14 Aryl groups; and Halogen atoms, C 1-6Alkyl groups 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): Halogen atoms; Hydroxy group; Carboxy group; Nitro group; Cyano group; C 1-6 Alkyl groups and C 1-6 an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of an alkoxy-carbonyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 Alkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 Alkoxy groups; C 1-6 Alkoxy-carbonyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 Alkylsulfonyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group b 3-8 Cycloalkyl groups; an acyl group optionally substituted by 1 to 3 substituents selected from substituent group a; an acyloxy group optionally substituted by 1 to 3 substituents selected from substituent group a; C optionally substituted with 1 to 3 substituents selected from the substituent group b 6-14 Aryl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group b 6-14 Aryloxy groups; C optionally substituted with 1 to 3 substituents selected from the substituent group b 6-14 Arylsulfonyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group b6-14 Arylsulfonyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group b 7-18 Aralkyl groups; C optionally substituted with 1 to 3 substituents selected from the substituent group b 7-18 Aralkyloxy group; Hydroxy group, diC 1-6 Alkylamino groups 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; Hydroxy group, diC 1-6 Alkylamino groups 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 by an alkyl group; oxo group; Thioxo group; Mono- or di-C 1-6 Alkylamino groups; Azide group; Tri-substituted silyl groups; Tri-substituted silyloxy group; an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the substituent group b; and A non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the substituent group b. However, (substituent group d) is "optionally substituted C 1-6 "Alkyl group" or "Optionally substituted C 1-6 When expressing an optional substituent of "alkoxy group", "C optionally substituted with a substituent selected from the substituent group a" is used, 1-6 "Alkyl group" and "C optionally substituted with a substituent selected from the 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 pharma- ceutically 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 acidic salt by reacting it with a base or an acid, and thus the term refers to such a salt. The salt is preferably water-soluble.

[0083] Examples of the pharma- ceutically 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 preferably alkali metal salts.

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

[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 prevention of disease onset, delay of disease onset, and prevention of pathology. 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 (severity). A "therapeutically effective amount" refers to a dose of an active ingredient sufficient to achieve a therapeutic purpose. Therefore, "improvement" is a concept that is included in "treatment".

[0088] In the present specification, the term "subject" refers to a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of an active ingredient required for preventing and / or treating (or ameliorating) a disease or a pathological condition of a disease is administered. The "subject" includes humans and non-human animals, particularly mammals (e.g., humans, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).

[0089] In this specification, the term "B0AT1 inhibitor" refers to a drug consisting of a compound having an effect of inhibiting 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 pharma- ceutical acceptable salt thereof, exhibits excellent inhibitory activity against B0AT1. The inhibitory activity of B0AT1 can be measured, for example, by the method described in Non-Patent Document 11 (SLAS Discovery, 2019; 24(2): p.111-120) or the method described in the test example described below.

[0090] In the present specification, the term "disease whose symptoms can be alleviated by inhibiting B0AT1" refers to a disease caused by an increase in the level of neutral amino acids in the blood due to a mutation in a gene related to the amino acid metabolic pathway, etc. Specific examples of such diseases include amino acid metabolic 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 formulae of each example compound is all 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'')) Each group in the above formula (I) of compound (I) will be explained below.

[0093] R 1 is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkyloxy group, optionally substituted C 1-6 Alkylsulfanyl group, optionally substituted C 3-8 Cycloalkylsulfanyl group, pentafluorosulfanyl group, 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, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, halogen atom or C 1-6 a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl group, More preferably, halo C1-4 It is an alkyl group.

[0095] Each of the n Xs independently represents 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 C 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, More preferably, C substituted with 1 to 3 substituents selected from the substituent group a′. 1-4 is an alkyl group, More preferably, C is substituted with 1 to 3 substituents selected from the above-mentioned substituent group a″. 1-4 It is an alkyl group.

[0101] R 3 C may be substituted with a substituent selected from the above-mentioned substituent group a. 1-6 C which may be 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 which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a. 1-4 is an alkyl group, More preferably, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a′ 1-4 is an alkyl group, More preferably, C may be 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 is optionally substituted with a substituent selected from the aforementioned substituent group b.

[0104] In such a case, R 2 and R 3 preferably bonded to each other to 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 spiro cyclic 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 substituent group b may be substituted with 1 to 3 substituents selected from 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[1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl group, a 5,6,7,8-tetrahydropyrazolo ... ]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, each of which may be substituted by 1 to 3 substituents selected from the above-mentioned substituent group b, is more preferably pyrrolidinyl, piperidyl, 5,6,7,8-tetrahydro-[1,2,4]triazoloyl group, [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, and particularly preferably each of them is substituted with 1 to 3 substituents selected from the substituent group b. and 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, optionally substituted.

[0105] In addition, preferred embodiments of the fused nitrogen-containing non-aromatic heterocyclic group include R 2 and R3 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 above-mentioned substituent group b, and each of them represents the following formula:

[0106] [ka]

[0107] (In the formula, Y and Z each independently represent a carbon atom or a nitrogen atom;

[0108] [ka]

[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- to 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.) (e.g., a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0110] [ka]

[0111] (In the formula, * represents the bonding site with the carbonyl group.) A condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula: 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 above-mentioned substituent group b, and are represented by the following formula:

[0112] [ka]

[0113] (In the formula, Y and Z each independently represent a carbon atom or a nitrogen atom;

[0114] [ka]

[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- to 6-membered non-aromatic or aromatic heterocycle; m represents an integer from 0 to 3; and * represents the bonding site with the carbonyl group.) (e.g., a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0116] [ka]

[0117] (In the formula, * represents the bonding site with the carbonyl group.) and forming a condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula:

[0118] As compound (I), the following compounds are preferred: [Compound (IA)] R 1 But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 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 3-6Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, 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 each independently represent a fluorine atom or a chlorine atom (preferably a chlorine atom); n is an integer from 0 to 2 (preferably 0 or 1); R 2 is substituted with 1 to 3 substituents selected from the substituent group a 1-4 is an alkyl group; and R 3 C may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a. 1-4 is an alkyl group, Compound (I) or a pharma- ceutically acceptable salt thereof.

[0119] [Compound (IB)] R 1 But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, halogen atom or C 1-6 a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 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 may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a'. 1-4 is an alkyl group, Compound (I) or a pharma- ceutically acceptable salt thereof.

[0120] [Compound (IC)] R 1 But, HaroC 1-4 is 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 may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a'' 1-4 is an alkyl group, Compound (I) or a pharma- ceutically acceptable salt thereof.

[0121] [Compound (ID)] R 1 But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, 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 each independently represent a fluorine atom or a chlorine atom (preferably a chlorine atom); n is an integer from 0 to 2 (preferably 0 or 1); and R 2 and R 3 are bonded to each other and, together with the nitrogen atom to which they are bonded, are each optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group b, 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 spiro cyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered condensed 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. Compound (I) or a pharma- ceutically acceptable salt thereof.

[0122] [Compound (IE)] R 1 But, HaroC 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, are each optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group b, 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 spiro cyclic nitrogen-containing non-aromatic heterocyclic group, or a 9- to 14-membered condensed 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. Compound (I) or a pharma- ceutically acceptable salt thereof.

[0123] [Compound (IF)] R 1 But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, 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 each independently represent a fluorine atom or a chlorine atom (preferably a chlorine atom); n is an integer from 0 to 2 (preferably 0 or 1); and R 2 and R 3 are bonded 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. Compound (I) or a pharma- ceutically acceptable salt thereof.

[0124] [Compound (IG)] R 1 But, HaroC 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. Compound (I) or a pharma- ceutically acceptable salt thereof.

[0125] [Compound (IH)] R 1 But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, 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 each independently represent a fluorine atom or a chlorine atom (preferably a chlorine atom); n is an integer from 0 to 2 (preferably 0 or 1); and R 2 and R 3 are bonded 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 above-mentioned substituent group b,

[0126] [ka]

[0127] (In the formula, Y and Z each independently represent a carbon atom or a nitrogen atom;

[0128] [ka]

[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- to 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.) A 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, each of which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group b):

[0130] [ka]

[0131] (In the formula, * represents the bonding site with the carbonyl group.) (a condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula: Forming Compound (I) or a pharma- ceutically acceptable salt thereof.

[0132] [Compound (IJ)] R 1 But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, 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 each independently represent a fluorine atom or a chlorine atom (preferably a chlorine atom); n is an integer from 0 to 2 (preferably 0 or 1); and R 2 and R 3 are bonded 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 above-mentioned substituent group b,

[0133] [ka]

[0134] (In the formula, Y and Z each independently represent a carbon atom or a nitrogen atom;

[0135] [ka]

[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- to 6-membered non-aromatic or aromatic heterocycle; m represents an integer from 0 to 3; and * represents the bonding site with the carbonyl group.) A 9- to 14-membered fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula (for example, each of which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group b):

[0137] [ka]

[0138] (In the formula, * represents the bonding site with the carbonyl group.) A condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula: Compound (I) or a pharma- ceutically acceptable salt thereof.

[0139] [Compound (IK)] R 1 But, HaroC 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 above-mentioned substituent group b,

[0140] [ka]

[0141] (In the formula, Y and Z each independently represent a carbon atom or a nitrogen atom;

[0142] [ka]

[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- to 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.) (e.g., a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0144] [ka]

[0145] (In the formula, * represents the bonding site with the carbonyl group.) (a condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula: Forming Compound (I) or a pharma- ceutically acceptable salt thereof.

[0146] [Compound (IL)] R 1 But, HaroC 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 above-mentioned substituent group b,

[0147] [ka]

[0148] (In the formula, Y and Z each independently represent a carbon atom or a nitrogen atom;

[0149] [ka]

[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- to 6-membered non-aromatic or aromatic heterocycle; m represents an integer from 0 to 3; and * represents the bonding site with the carbonyl group.) (e.g., a fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula:

[0151] [ka]

[0152] (In the formula, * represents the bonding site with the carbonyl group.) A condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula: Compound (I) or a pharma- ceutically acceptable salt thereof.

[0153] [Compound (IM)] R 1 But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, 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 each independently represent a fluorine atom or a chlorine atom (preferably a chlorine atom); n is an integer from 0 to 2 (preferably 0 or 1); and R 2 and R 3 are bonded 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, 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), Compound (I) or a pharma- ceutically acceptable salt thereof.

[0154] [Compound (IN)] R 1 But, HaroC 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, 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), Compound (I) or a pharma- ceutically acceptable salt thereof.

[0155] Among the compound (I) of the present invention or a pharma- ceutically 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, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, halogen atom or C 1-6 It represents a 5- or 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with an alkyl group.

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

[0159] Each of the n' X' independently represents 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 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’ C may be substituted with a substituent selected from the above-mentioned substituent group a. 1-4 C which may be 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, 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, R 2’ and R 3’ are combined with 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 aforementioned substituent group b.

[0168] In such embodiments, R 2’ and R 3’ preferably bonded to each other to 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, each of the above-mentioned substituent group b may be substituted with 1 to 3 substituents selected from 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[1,5-a]pyrazinyl group, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl group, a 5,6,7,8-tetrahydropyrazolo ... a pyrrolidinyl group, a piperidyl group, a 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 or 1,2,3,4-tetrahydro-2,7-naphthyridinyl group, and particularly preferably 1 to 3 substituents selected from the substituent group b. and optionally substituted 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] As compound (I'), the following compounds are preferable. [Compound (I'A)] R 1’ But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms 6-14 Aryl group, 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); n' is an integer from 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 may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a. 1-4 is an alkyl group, Compound (I') or a salt thereof (wherein the compound has the following formula:

[0170] [ka]

[0171] (Excluding compounds represented by the formula:

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

[0173] [Compound (I'C)] R 1’ But, HaroC 1-4 is 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 may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a'' 1-4 is an alkyl group, Compound (I') or a salt thereof.

[0174] [Compound (I'D)] R 1’ But, C 2-6 Alkyl group, haloC 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkoxy group, haloC 2-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 3-6 Cycloalkyl-C 1-4 Alkoxy group, C 2-6 Alkylsulfanyl group, haloC 1-6 Alkylsulfanyl group, C 3-6 Cycloalkylsulfanyl group, pentafluorosulfanyl group, C optionally substituted with halogen atoms6-14 Aryl group, 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); n' is an integer from 0 to 2 (preferably 0 or 1); and R 2’ and R 3’ are combined together to form R 2’ and R 3’ is bonded to form, together with the nitrogen atom, a nitrogen-containing non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group b. Compound (I') or a salt thereof (wherein the compound has the following formula:

[0175] [ka]

[0176] (Excluding compounds represented by the formula:

[0177] [Compound (I'E)] R 1’ But, HaroC 1-4 is an alkyl group; n' X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom); n' is an integer from 0 to 2 (preferably 0 or 1, more preferably 0); R 2’ and R 3’ are bonded to each other to 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 spiro cyclic 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; Compound (I') or a salt thereof.

[0178] [Compound (I'F)] R 1’ But, HaroC 1-4 is an alkyl group; n' X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom); n' is an integer from 0 to 2 (preferably 0 or 1, more preferably 0); R 2’ and R 3’ are bonded to each other and, together with the nitrogen atom to which they are bonded, may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group b. 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. Compound (I') or a salt thereof.

[0179] [Compound (I'G)] R 1’ But, HaroC 1-4 is an alkyl group; n' X's are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom); n' is an integer from 0 to 2 (preferably 0 or 1, more preferably 0); R 2’ and R 3’are bonded to each other and, together with the nitrogen atom to which they are bonded, each of which may be 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- forming 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), Compound (I') or a salt thereof.

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

[0181] R 1’’ is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkyloxy group, optionally substituted C 1-6 Alkylsulfanyl group, optionally substituted C 3-8 Cycloalkylsulfanyl group, pentafluorosulfanyl group, 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, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 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] Each of the n X's independently represents 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’’ teeth, (i) a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the above-mentioned substituent group c, and (ii) a 5- or 6-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the above-mentioned 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 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, More preferably, C substituted with 1 to 3 substituents selected from the above-mentioned 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 is optionally substituted with a substituent selected from the aforementioned substituent group b.

[0192] In such embodiments, R 2’’ and R 3’’ are preferably represented by the following formula, which may be 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 above-mentioned substituent group b:

[0193] [ka]

[0194] (In the formula, Y′ and Z′ each independently represent a carbon atom or a nitrogen atom;

[0195] [ka]

[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- to 6-membered non-aromatic heterocycle or aromatic heterocycle; m' represents an integer of 0 to 3 (preferably 0 to 2); and *’ represents the bonding site with the carbonyl group.) and forming a condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula: More preferably, the compound represented by the following formula, each of which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group b:

[0197] [ka]

[0198] (In the formula, * represents the bonding site with the carbonyl group.) The fused nitrogen-containing non-aromatic heterocyclic group represented by the following formula is formed.

[0199] As compound (I″), the following compounds are preferable. [Compound (I''A)] R 1’’ is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkyloxy group, optionally substituted C 1-6 Alkylsulfanyl group, optionally substituted C 3-8 Cycloalkylsulfanyl group, pentafluorosulfanyl group, optionally substituted C 6-14an 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 from 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 is further optionally 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 is an alkyl group, Compound (I'') or a salt thereof.

[0200] [Compound (I''B)] R 1’’ is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 A cycloalkyloxy group, a pentafluorosulfanyl group, or an optionally substituted C 6-14 is an aryl group; n" X" are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom); n'' is an integer from 0 to 2 (preferably 0 or 1); R 2’’is 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 is further optionally 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 is an alkyl group, Compound (I'') or a salt thereof.

[0201] [Compound (I''C)] R 1’’ is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 A cycloalkyloxy group, a pentafluorosulfanyl group, or an optionally substituted C 6-14 is an aryl group; 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 is further optionally 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 is an alkyl group, Compound (I'') or a salt thereof.

[0202] [Compound (I''D)] R1’’ But, HaroC 1-4 is an alkyl group; 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 is further optionally 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 is an alkyl group, Compound (I'') or a salt thereof.

[0203] [Compound (I''E)] R 1’’ is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkyloxy group, optionally substituted C 1-6 Alkylsulfanyl group, optionally substituted C 3-8 Cycloalkylsulfanyl group, pentafluorosulfanyl group, 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 from 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 which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group b (excluding a tetrahydroquinolyl group and a tetrahydroisoquinolyl group). Compound (I'') or a salt thereof.

[0204] [Compound (I''F)] R 1’’ is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkyloxy group, optionally substituted C 1-6 Alkylsulfanyl group, optionally substituted C 3-8 Cycloalkylsulfanyl group, pentafluorosulfanyl group, 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 from 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 above-mentioned substituent group b,

[0205] [ka]

[0206] (In the formula, Y′ and Z′ each independently represent a carbon atom or a nitrogen atom;

[0207] [ka]

[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- to 6-membered non-aromatic heterocycle or aromatic heterocycle; m' represents an integer of 0 to 3 (preferably 0 to 2); and *’ represents the bonding site with the carbonyl group.) Forming a condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula: Compound (I'') or a salt thereof.

[0209] [Compound (I''G)] R 1’’ is a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 A cycloalkyloxy group, a pentafluorosulfanyl group, or an optionally substituted C 6-14 is an aryl group; n" X" are each independently a fluorine atom or a chlorine atom (preferably a chlorine atom); n'' is an integer from 0 to 2 (preferably 0 or 1); and R 2’’ and R 3’’ are bonded 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 above-mentioned substituent group b,

[0210] [ka]

[0211] (In the formula, Y′ and Z′ each independently represent a carbon atom or a nitrogen atom;

[0212] [ka]

[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- to 6-membered non-aromatic heterocycle or aromatic heterocycle; m' represents an integer of 0 to 3 (preferably 0 to 2); and *’ represents the bonding site with the carbonyl group.) Forming a condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula: Compound (I'') or a salt thereof.

[0214] [Compound (I''H)] R 1’’ But, HaroC 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 above-mentioned substituent group b,

[0215] [ka]

[0216] (In the formula, * represents the bonding site with the carbonyl group.) Forming a condensed nitrogen-containing non-aromatic heterocyclic group represented by the formula: Compound (I'') or a salt thereof.

[0217] Suitable specific examples of compound (I) include the compounds of Examples 1 to 283 (compound (I-1) to compound (I-283)) described below, or pharma- ceutically acceptable salts thereof (or salts thereof).

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

[0219] The compound (I) of the present invention may contain isotopes (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 used in positron emission tomography (PET) (PET tracer), and is useful in fields such as medical diagnosis.

[0220] The compound (I) of the present invention or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof of the present invention may include its intramolecular salt, adduct, and solvate thereof. These solvates are compounds in which the molecules of a solvent are coordinated to the compound (I) or a salt thereof, and also include hydrates. For example, hydrates, ethanol solvates, dimethylsulfoxide solvates, etc. of the compound (I) or a salt thereof may be mentioned.

[0222] The 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, for example, C, which may be substituted with an acyloxy group. 1-6 Examples of the prodrug other than the monoester or diester of the phosphate group include the compounds having a group derived from the phosphate group described in Current opinion in investigational drugs, 2006; 7: p.109-117, J. Med. Chem. 1994; 37: p.1857-1864, and J. Med. Chem. 2000; 43: p.4570-4574. 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 has been acylated, alkylated or phosphorylated (for example, a compound in which the amino group of compound (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated or tert-butylated); when compound (I) has a hydroxyl group, a compound in which the hydroxyl group has been acylated, alkylated, phosphorylated or borated (for example, a compound in which the hydroxyl group of compound (I) has been acetylated, palmitoylated, 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. In addition, the prodrug of compound (I) may be one that changes into a compound represented by compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, "Molecular Design," pp. 163-198, published by Hirokawa Shoten in 1990.

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

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

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

[0227] [Manufacturing method (A)] This production method is a method for obtaining compound (Ia) by condensing compound (1-1) and compound (2-1). Compound (1-1) that can be suitably used is one synthesized by a method known per se (see, for example, the specification of US Pat. No. 10,836,736, etc.).

[0228] [ka]

[0229] (The symbols in the formula are as defined above.)

[0230] (Process 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 mol, preferably 1 to 3 mol, per 1 mol of the compound (1-1).

[0232] Condensation agents include o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) (WSC hydrochloride), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBop), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU), and O-benzotriazole-N,N,N',N'-tetramethyluronium Examples thereof include hexafluoroborate (HBTU), and preferably HATU or WSC hydrochloride. The amount of the condensing agent used is usually 1 to 10 mol, and preferably 1 to 5 mol, per 1 mol 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), or 1-hydroxy-7-azabenzotriazole (HOAt). The amount of the condensation additive used is usually 0 to 1.5 mol per 1 mol of the compound (1-1).

[0234] The base includes organic bases such as triethylamine, pyridine, and N,N-diisopropylethylamine, and among these, triethylamine or N,N-diisopropylethylamine is preferable. The amount of the base used is usually 1 to 5 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 from −78° C. to room temperature, preferably from 0° C. to room temperature, and the reaction time is usually from 1 to 48 hours.

[0237] [Manufacturing method (B)] This production method is a method for obtaining compound (Ia) by condensing compound (3-1) and compound (4-1). As the compound (3-1), a commercially available product or one synthesized by a method known per se can be suitably used.

[0238] [ka]

[0239] (The symbols in the formula are as defined above.)

[0240] (Process B-1) This step is a step of producing compound (Ia) by condensing compound (3-1) and compound (4-1) in the presence of a condensing agent. The amount of the compound (4-1) used is 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of the 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] [Manufacturing 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 converted to compound (Ic) by deprotection, and then reacted with R 4 This is a method for obtaining compound (Id) of the present invention by reductive amination with --CHO.

[0243] [ka]

[0244] (In the formula, P 1 represents a protecting group, R 4 is a hydrogen atom, a halogen atom, a hydroxyl 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 further be substituted with a substituent selected from the above-mentioned substituent group b, and the other symbols are as defined above.

[0245] (Process 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] In step C-1, the reaction 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 the compound (2-2) used is 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of the compound (1-1).

[0247] (Process C-2) This step is to convert the amino group protecting group (P 1 ) is deprotected to obtain compound (Ic).

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

[0249] (Process C-3) In this step, compound (Ic) is reacted with R 4 -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] The reducing agent includes, for example, sodium triacetoxyborohydride, sodium borohydride, and the like. The amount of the reducing agent used is 1 to 10 mol, preferably 1 to 3 mol, relative to 1 mol of compound (Ic).

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

[0253] The reaction solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc.; alcohols such as methanol, ethanol, etc.; ethers such as tetrahydrofuran, etc.; halogenated hydrocarbons such as chloroform, dichloromethane, etc., and mixtures thereof.

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

[0255] [Manufacturing method (D)] In this production method, compound (1-1) and compound (2-3) are condensed to obtain compound (Ie), and then a protecting group (P 2 ) is deprotected to convert it into compound (If) of the present invention.

[0256] [ka]

[0257] (In the formula, P 2 represents a protecting group, Q 1 is an oxygen atom or C(=O)O * ( * , 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 further be substituted with a substituent selected from the above-mentioned substituent group b; and the other symbols are as defined above.

[0258] (Process 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] In step D-1, the reaction 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 the compound (2-3) used is 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of the compound (1-1).

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

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

[0262] [Manufacturing 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] [ka]

[0264] (In the formula, X 0 represents a halogen atom, and 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 6may be bonded to each other to form a cyclic boronic acid ester such as a pinacol ester of a boronic acid together with the boron atom, and the other symbols are as defined above.

[0265] [Process E-1] This step can be carried out by a cross-coupling reaction (Suzuki coupling reaction) between compound (Ig) and an arylboronic acid or an 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) may be a commercially available product or may 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), bis(dibenzylideneacetone)palladium(0) (Pd2(dba)3), tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride·diphenylphosphinoferrocene (PdCl2(dppf)), PdCl2(dppf) dichloromethane complex, palladium on carbon(0), and bis(triphenylphosphine). Examples of suitable catalysts include palladium catalysts such as 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. Among these, palladium catalysts are preferred, and dichlorobis(tricyclohexylphosphine)palladium(II) is more preferred. In addition, 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 3,6-dimethoxy-2-dicyclohexylphosphino-2',4',6' -Phosphine ligands such as 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, and 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, per mol of compound (Ig).

[0267] Examples of the base include alkali metal amides such as lithium diisopropylamide, sodium amide, and lithium bistrimethylsilylamide; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; alkali metal phosphates such as sodium phosphate and potassium phosphate; and amines such as triethylamine, N,N-diisopropylethylamine, pyridine, and N-methylmorpholine. The amount of the base used is usually 1 mol to 5 mol, preferably 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, such as an alkali metal halide, 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 from -78°C to 200°C, preferably from -78°C to 120°C. The reaction time is usually 0.5 to 12 hours.

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

[0272] When the compound (I) of the present invention or a pharma- ceutical acceptable salt thereof exists as an optical isomer based on an asymmetric carbon, it can be separated into individual optical isomers by a conventional optical resolution method (e.g., fractional crystallization, resolution using a chiral column). Optical isomers can also 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 pharma- ceutical acceptable salt thereof, or a B0AT1 inhibitor consisting of compound (I) or a pharma- ceutical acceptable salt thereof. In addition, since the novel compounds (I') and (I'') are also included in compound (I), a medicine containing compound (I') or compound (I'') as an active ingredient is also included in a medicine containing compound (I) or a pharma- ceutically acceptable salt thereof as an active ingredient.

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

[0275] Examples of pharma- ceutically acceptable carriers include excipients (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethylcellulose, talc, etc.), solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cotton fruit 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 stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; polyvinyl alcohol hydrophilic polymers such as cellulose acetate, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, etc.), isotonicity agents (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.), buffers (e.g., buffer solutions such as phosphates, acetates, carbonates, citrates, etc.), soothing agents (e.g., benzyl alcohol, etc.), preservatives (e.g., paraoxybenzoic acid esters, , chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbate salts, etc.), coloring agents (e.g., water-soluble edible 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 edible tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide), etc.), sweeteners (e.g., sodium saccharin, dipotassium glycyrrhizinate, stevia, etc.), etc.

[0276] The medicament (pharmaceutical composition) of the present invention can be prepared by mixing the above-mentioned components and then treating the mixture in a manner known per se to prepare preparations for oral administration such as tablets, fine granules, granules, capsules, dry syrups, etc., or preparations for parenteral administration such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, etc.), topical preparations (e.g., transdermal preparations, ointments, lotions, patches), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, liposome preparations, etc. Of the pharmaceutical agents of the present invention, preparations for oral administration such as tablets are preferred.

[0277] The content of the compound (I) of the present invention or a pharma- ceutical 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 the compound (I) of the present invention or a pharma- ceutically acceptable salt thereof can be appropriately selected depending on the subject of administration (subject's age, body weight, general health condition, sex, degree of illness, etc.), administration route, type of disease, type of concomitant medication, etc. The daily dosage of the compound (I) or a pharma-ceutically acceptable salt thereof, for example, in the case of humans, when orally administered to an adult patient (body weight about 60 kg), is usually 0.001 mg to 1000 mg, preferably 0.01 mg to 100 mg, calculated as the active ingredient 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 pharma- ceutically 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] The compound (I) of the present invention or a pharma- ceutically acceptable salt thereof can be administered (concomitantly) 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 that have been conventionally used in the treatment of the above-mentioned "diseases whose symptoms can be alleviated by the B0AT1 inhibitory action" can be suitably used.

[0281] Specifically, when the compound (I) of the present invention or a pharma- ceutically acceptable salt thereof is used for the treatment and / or prevention of amino acid metabolism disorders such as phenylketonuria, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia, examples of concomitant drugs include vitamin preparations (e.g., folic acid (vitamin B9), nicotinamide (vitamin B3), thiamine (vitamin B4), niacin (vitamin B5), niacinamide (vitamin B6), niacinamide (vitamin B7), niacinamide (vitamin B8), niacinamide (vitamin B9), niacinamide (vitamin B10), niacinamide (vitamin B11), niacinamide (vitamin B12), niacinamide (vitamin B13), niacinamide (vitamin B14), niacinamide (vitamin B15), niacinamide (vitamin B16), niacinamide (vitamin B17), niacinamide (vitamin B18), niacinamide (vitamin B19), niacinamide (vitamin B20), niacinamide (vitamin B21), niacinamide (vitamin B22), niacinamide (vitamin B23), niacinamide (vitamin B24), niacinamide (vitamin B25), niacinamide (vitamin B26), niacinamide (vitamin B27), niacinamide (vitamin B28), niacinamide (vitamin B29), niacinamide (vitamin B30), niacinamide (vitamin B31), niacinamide (vitamin B32), niacinamide (vitamin B33), niacinamide (vitamin Examples of such therapeutic agents include drugs for alleviating various symptoms of amino acid metabolism disorders (e.g., L-dopa, LNAAs such as 5-hydroxytryptophan, sapropterin hydrochloride, pegvaliase, nicotinic acid, nitisinone, S-adenosylmethionine, betaine, aspirin, dipyridamole, sodium benzoate, dextromethorphan, ketamine, antidepressants, anti-anxiety drugs, ADHD treatment drugs, etc.).

[0282] When using a concomitant drug, the administration time is not limited, and they may be administered to the subject at the same time or at a time lag. In the administration at a time lag, the medicament of the present invention may be administered first and the concomitant drug may be administered later, or the concomitant drug may be administered first and the medicament of the present invention may be administered later. The administration method of each may be the same or different. In addition, the compound (I) of the present invention or a pharma- ceutical acceptable salt thereof may be administered in combination with the concomitant drug as a single preparation.

[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 its pharma- ceutically acceptable salt, etc., to the concomitant drug can be appropriately selected depending on the subject of administration (the subject's age, body weight, general health condition, sex, degree of disease, etc.), administration route, type of disease, type of concomitant drug, etc.

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

[0285] In addition, the concomitant drugs that complement and / or enhance the therapeutic effect of compound (I) or a pharma- ceutically acceptable salt thereof include those that have not been found so far but will be found 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 pharma- ceutical acceptable salt thereof, it is also effective to use the compound in combination with a dietary therapy that avoids the intake of specific amino acids or with 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 on the administration method, etc. The drug contained in the kit is supplied in a container made of a material that effectively maintains the activity of the components of the medicament or pharmaceutical composition for a long period of time, does not adsorb to the inside of the container, and does not deteriorate the components. 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 an instruction manual. The instruction manual for use of the kit may be provided to the user in the form of a printed document, or may be stored on an electromagnetically readable medium, such as a CD-ROM or DVD-ROM. EXAMPLES

[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, the reagents, devices, and materials used in the present invention are commercially available unless otherwise specified.

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

[0290] The raw material compounds used in the following Reference Examples and Examples are known compounds unless otherwise specified, 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; International Publication No. WO 2013 / 067274) or methods equivalent thereto.

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

[0292] [ka]

[0293] (1) (2R)-1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2-carboxylic acid (28.9 g) in chloroform (160 ml) was successively added with acetylhydrazine (7.05 g), WSC hydrochloride (22.8 g), 1-hydroxybenzotriazole monohydrate (18.2 g), and triethylamine (16 g), 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 saline, 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) Methyl N-(triethylammonium sulfonyl)carbamate (19.1 g) was added to THF (150 ml) of O1-benzyl-O4-tert-butyl (2R)-2-(acetamidocarbamoyl)piperazine-1,4-dicarboxylate (35.3 g) obtained in (1) above, and the mixture was stirred at 70°C for 1 hour. Subsequently, methyl N-(triethylammonium sulfonyl)carbamate (1.70 g) was added and the mixture was stirred at 70°C for 40 minutes. Further, methyl N-(triethylammonium sulfonyl)carbamate (1.89 g) was added and the mixture was stirred at 70°C for 50 minutes. After cooling, the solvent was distilled off under reduced pressure, ethyl acetate and saturated saline were added to the residue, and the organic layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, 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 obtain O1-benzyl-O4-tert-butyl (2R)-2-(5-methyl-1,3,4-oxadiazol-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-oxadiazol-2-yl)piperazine-1,4-dicarboxylate (29.6 g) obtained in (2) above in ethanol (250 ml), 5% palladium / carbon (2.96 g) was added to water to prepare a 54% water suspension (6.4 g), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 6.5 hours. After replacing the flask with nitrogen, the reaction solution was filtered through Celite and washed three times with ethanol (50 ml). The obtained 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% ammonia water = 40 / 1 to 10 / 1). The fraction containing impurities was 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 substance and the high-purity fraction obtained by the first column chromatography were mixed and concentrated under reduced pressure, and the resulting residue was purified again by silica gel column chromatography (solvent: chloroform / methanol = 99 / 1 to 97 / 3 to 95 / 5) to obtain 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-oxadiazol-3-yl)phenyl]prop-2-enecarboxylic acid

[0297] [ka]

[0298] Malonic acid (610 mg) and pyridine (0.12 ml) were added to a solution of 4-(5-methyl-1,2,4-oxadiazol-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 obtain 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] [ka]

[0301] A solution of 4-methoxy-3-oxobutanoic acid methyl ester (885μl), 2-methoxyethanamine (590μl), and acetic acid (390μl) in chloroform (20ml) was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (1.73g) was added, and the reaction mixture was stirred at room temperature for 50 minutes. The reaction mixture was cooled to 0℃, and hydrochloric acid (4mol / l ethyl acetate solution) (15ml) was slowly added. After stirring at room temperature for a while, the reaction mixture was concentrated, diisopropyl ether was added, and sonication was performed. This solution was concentrated, ethyl acetate was added, and sonication was performed. This solution was further concentrated, and diethyl ether was added, and sonication was performed. The precipitated solid was collected by filtration, washed with diethyl ether, and then vacuum dried at 60℃ to obtain 1.17g (yield 71%) 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] [ka]

[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. Thereto, tert-butoxycarbonyl tert-butyl carbonate (265 mg) was further added, 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, and the residue was purified by silica gel column chromatography to obtain the title compound (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] [ka]

[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), methylamine aqueous 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 sodium bicarbonate water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain a crude product of 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 the reaction mixture was stirred at room temperature for 3 hours after replacing with hydrogen. After replacing the flask with nitrogen, the reaction solution was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain a 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] [ka]

[0311] (1) (2R)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (503 mg) and formamidine hydrochloride (235 mg) were added to a solution of DMF (15 ml) with HATU (1.24 g) and N,N-diisopropylethylamine (1.4 ml), 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 thereto, and the reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate, and saturated sodium bicarbonate water was slowly added at 0°C, after which the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the residue after vacuum concentration was purified by silica gel column chromatography to obtain 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) in 1,4-dioxane (12 ml), cyanomethylenetributylphosphorane (0.82 ml) was added, and the reaction mixture was heated to 150° C. in a microwave reaction apparatus 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 the ethyl acetate 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, 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 obtain the crude product of the title compound (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] [ka]

[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. An aqueous solution of ammonium chloride was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, 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 liquid. 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), an aqueous sodium hydroxide solution (1 mol / l, 4 ml) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, 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 solution of 7-phenylmethoxycarbonyl-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid (200 mg) obtained in (2) and HATU (377 mg) in DMF (4 ml), a methylamine aqueous 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 sodium bicarbonate water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain a crude product of 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 the mixture was stirred at room temperature for 3 hours after replacing with hydrogen. After replacing the atmosphere in the flask with nitrogen, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 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] [ka]

[0322] (1) To a 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) in DMF (4 ml), dimethylamine aqueous 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 sodium bicarbonate water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain a crude product of 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 the mixture was stirred at room temperature for 3 hours after replacing with hydrogen. After replacing the atmosphere in the flask with nitrogen, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain a 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] [ka]

[0326] (1) HATU (2.20 g) and N,N-diisopropylethylamine (2.5 ml) were added 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), and the reaction mixture was stirred at room temperature for 70 minutes. Acetic acid (2.75 ml) and 2-hydrazinoethanol (0.65 ml) were added thereto, and the reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate, and saturated sodium bicarbonate water was slowly added at 0°C, after which the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the residue after vacuum concentration was purified by silica gel column chromatography to obtain 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) in 1,4-dioxane (30 ml), cyanomethylenetributylphosphorane (2.6 ml) was added, and the reaction mixture was heated to 150° C. in a microwave reaction apparatus 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, 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 dried under reduced pressure at 50°C to obtain the 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] [ka]

[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 saline, 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), trifluoroacetic acid (4 ml) was added, 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 (263 mg) of the title compound.

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

[0334] [ka]

[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. An aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, 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[MH] -

[0336] (2) To a solution of N-[(1-fluorocyclopropyl)methyl]-2-nitrobenzenesulfonamide (290 mg) obtained in (1) above in DMF (6 ml), sodium hydride (about 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 saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product of N-[(1-fluorocyclopropyl)methyl]-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-nitrobenzenesulfonamide (240 mg).

[0337] (3) 4-ethylbenzenethiol (0.22 ml) and cesium carbonate (448 mg) were added to an acetonitrile (6 ml) solution of the crude product (240 mg) of N-[(1-fluorocyclopropyl)methyl]-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-nitrobenzenesulfonamide obtained in (2) above, 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 a crude product (196 mg) of the title compound.

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

[0339] [ka]

[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 sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then dried under reduced pressure to obtain a crude product of the title compound (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 shown in Table 1-1 below.

[0342] [Table 1-1]

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

[0344] [ka]

[0345] (1) tert-Butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (202 mg), cyanomethylenetributylphosphorane (0.47 ml), and 1H-pyrazole (68 mg) were added in sequence to a 1,4-dioxane (10 ml) solution, 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 to distill off 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) Trifluoroacetic acid (0.2 ml) was added to a dichloromethane (2 ml) solution of tert-butyl (3S)-3-(pyrazol-1-ylmethyl)pyrrolidine-1-carboxylate (146 mg) obtained in (1) above, 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 to distill off the solvent, thereby obtaining a crude product (154.1 mg) of the title compound.

[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 shown in Table 1-2 below.

[0348] [Table 1-2]

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

[0350] [ka]

[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 successively 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 / 30-40 / 60) to obtain 1-O-tert-butyl 2-O-methyl (2R,4S)-4-(pyrazol-1-yl)pyrrolidine-1,2-dicarboxylate (251 mg; yield 69%) as a yellow amorphous solid. MS(ESI)m / z:196.1[M+H] +

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

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

[0354] (4) Trifluoroacetic acid (0.1 ml) was added to a dichloromethane (1 ml) solution of tert-butyl (2R,4S)-2-(methylcarbamoyl)-4-(pyrazol-1-yl)pyrrolidine-1-carboxylate (34 mg) obtained in (3) above, 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 to distill off the solvent, thereby obtaining a crude product (36 mg) of the title compound.

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

[0356] [ka]

[0357] (1) Tetrabutylammonium hydrogen sulfate (25 mg), iodomethane (206 mg), and potassium hydroxide (50% w / v, 2 ml) were added to a solution of 6-bromo-2-(2-nitrophenyl)sulfonyl-3,4-dihydro-1H-isoquinolin-4-ol (300 mg) in toluene (2 ml), 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 saline, 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 liquid. MS(ESI)m / z:397.1 / 399.1[M+H] +

[0358] (2) To a solution of 6-bromo-4-methoxy-2-(2-nitrophenyl)sulfonyl-3,4-dihydro-1H-isoquinoline (295 mg) obtained in (1) above in DMF (2 ml), 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 saline, 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] [ka]

[0361] (1) 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) were added with water (1 ml), 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 the concentration under reduced pressure 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, CDCl3): 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) Acetic acid (1 ml) and palladium hydroxide (25 mg) were added to a solution of 6-ethenyl-[1,2,4]triazolo[1,5-a]pyrazine (238 mg) obtained in (1) in ethanol (2 ml), and 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 sodium bicarbonate water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, 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 the title compound (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] [ka]

[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 the concentration under reduced pressure 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) Acetic acid (4.7 ml) and palladium hydroxide (10 mg) were added to a solution of 6-(methoxymethyl)-[1,2,4]triazolo[1,5-a]pyrazine (52 mg) obtained in (1) in ethanol (2.4 ml), and 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 sodium bicarbonate water, and the aqueous layer was extracted with a mixed solution of chloroform / methanol = 4:1. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (38 mg; yield 94%) as a brown viscous liquid. MS(ESI)m / z:168.9[M+H] +

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

[0368] [ka]

[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. After further addition of sodium hypochlorite (10% w / v, 1.4 ml), 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 saline, 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[MH] -

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

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

[0372] [ka]

[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 saline, 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[MH] -

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

[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 ammonium chloride water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (108 mg) of tert-butyl 3-(pyrrolidine-1-carbonyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate 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), hydrogen chloride (4 mol / l ethyl acetate solution, 1 ml) was added and stirred at room temperature for 60 minutes. The reaction mixture was concentrated under reduced pressure, diisopropyl ether was added to the residue, and 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 25~28: The corresponding starting compounds were treated in the same manner as in Reference Example 24 to obtain the compounds shown in Table 1-3 below.

[0380] [Table 1-3]

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

[0382] [ka]

[0383] (1) 6-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline (1g) was dissolved in 1,4-dioxane (15ml) and water (7.5ml), sodium bicarbonate (730mg) and benzyl chloroformate (930mg) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, 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 (1.4g; 84%) as a colorless oil. MS(ESI)m / z:363.8 / 365.8[M+H] +

[0384] (2) The 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 and stirred in a microwave reaction apparatus at 150 ° C. for 30 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100 / 0 ~ 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) The 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), 4M lithium hydroxide solution (2.5 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with 1M hydrochloric acid and then concentrated. The residue was azeotroped with toluene and 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-ditert-butoxy-N,N-dimethyl-methanamine (44 ml) was added and stirred for 1 hour at 120° C. 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) The 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), dihydroxypalladium (24 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was concentrated to obtain a crude product (155 mg) of the title compound.

[0388] Reference examples 30~32: The corresponding starting compounds were treated in the same manner as in Reference Example 29 to give crude products of the compounds shown in Table 1-4 below.

[0389] [Table 1-4]

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

[0391] [ka]

[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) 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 with 4N aqueous sodium hydroxide solution (1.5 ml) and 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 saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product of 5-phenylmethoxycarbonyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-carboxylic acid.

[0394] (3) N,N-dimethylformamide di-tert-butyl acetal (6 ml) was added to a mixture of the crude product of 5-phenylmethoxycarbonyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-carboxylic acid obtained in (2) above and toluene (15 ml), 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, and the mixture was 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)phenylboronic acid pinacol (112 mg), [4-(di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonic acid (17 mg) and 2N-sodium carbonate aqueous solution (0.9 ml) were added, and the mixture was stirred at 140°C for 1 hour in a microwave reaction apparatus. 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 saline, 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 obtain 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) 20% palladium hydroxide (20 mg) was added 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), and the mixture was stirred for 2 hours at 50° C. under a hydrogen atmosphere. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the title compound (90 mg) as a crude product as a yellow oil. MS(ESI)m / z:368.06[M+H] +

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

[0399] [Table 1-5]

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

[0401] [ka]

[0402] A mixture of palladium acetate (12 mg) and dichloromethane (6 ml) was added under a nitrogen atmosphere with 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 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] [ka]

[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 saline, 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) 4N hydrochloric acid-ethyl acetate solution (0.8 ml) was added 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, 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] [ka]

[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 solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crude product of N-[2-(3-bromophenyl)ethyl]-2-methoxyacetamide (1.36 g) as a yellow oil.

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

[0411] (3) Sodium borohydride (756 mg) was added to a solution of the crude product (1.27 g) of 6-bromo-1-(methoxymethyl)-3,4-dihydroisoquinoline 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 saline, 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: (E) Production of -N-[2-oxo-2-(3-oxopiperazin-1-yl)ethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (Compound (I-1))

[0413] [ka]

[0414] To a solution of 2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetic acid (2.00 g) in DMF (25 ml), piperazine-2-one (770 mg), N,N-diisopropylethylamine (1.5 ml), and HATU (3.36 g) were added 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 stirred at room temperature for a while, and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered through a cotton plug. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 100 / 0 to 96 / 4). The fractions containing the target product were combined and concentrated, and the residue was suspended and washed with diisopropyl ether and ethyl acetate, and 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 2-102: The corresponding starting compounds were treated in the same manner as in Example 1 to obtain the compounds shown in Tables 2-1 to 2-21 below.

[0416] [Table 2-1]

[0417] [Table 2-2]

[0418] [Table 2-3]

[0419]

Table 2-4

[0420]

Table 2-5

[0421]

Table 2-6

[0422]

Table 2-7

[0423]

Table 2-8

[0424]

Table 2-9

[0425]

Table 2-10

[0426]

Table 2-11

[0427]

Table 2-12

[0428]

Table 2-13

[0429] [Table 2-14]

[0430] [Table 2-15]

[0431] [Table 2-16]

[0432] [Table 2-17]

[0433] [Table 2-18]

[0434] [Table 2-19]

[0435] [Table 2-20]

[0436] [Table 2-21]

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

[0438] [ka]

[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 sodium bicarbonate water 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 solution / acetonitrile = 70 / 30-40 / 60) to obtain 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 shown in Tables 3-1 to 3-3 below.

[0441] [Table 3-1]

[0442] [Table 3-2]

[0443] [Table 3-3]

[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] [ka]

[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 described below in acetonitrile (2 ml), hydrochloric acid (4 mol / l ethyl acetate solution) (3 ml) was added, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain a crude product (400 mg) of (E)-N-[2-(2-methylpiperazin-1-yl)-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide hydrochloride as an orange amorphous solid.

[0447] (2) To a dichloromethane (3.5 ml) solution of the crude product (400 mg) of (E)-N-[2-(2-methylpiperazin-1-yl)-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide hydrochloride obtained in (1) above, formaldehyde (37% by weight solution in methanol) (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 NaOH aqueous 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 distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 98 / 2 to 91 / 9) to obtain the title compound (240 mg; yield 64%) as a white amorphous substance. 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] [Table 4]

[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] [ka]

[0452] A 1 mol / l aqueous sodium hydroxide solution (1.6 ml) was added to a methanol (1.6 ml) 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 later, and the reaction mixture was stirred at room temperature for 3 hours. After adding 1 mol / l hydrochloric acid (1.6 ml) and 1 mol / l aqueous sodium hydroxide solution (1 ml) to the reaction mixture, the solution was purified by reverse phase HPLC (solvent: 10 mmol / l aqueous ammonium carbonate solution / 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 124-125: The compounds of Examples 157 to 158 (compound (I-157) to compound (I-158)) described below were treated in the same manner as in Example 123 to obtain the compounds listed in Table 5 below.

[0454] [Table 5]

[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] [ka]

[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. After cooling, the reaction mixture was 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 solution / acetonitrile = 70 / 30-40 / 60) to obtain 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 obtain the compounds listed in Table 6 below.

[0459] [Table 6]

[0460] Example 129: (E) Preparation of -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] [ka]

[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, and then stirred overnight while gradually warming to room temperature. Water was added to the reaction solution, and the mixture was concentrated under reduced pressure to obtain a crude product of 2-(1-hydroxy-1-methyl-ethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine.

[0463] (2) 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 to the crude product of 2-(1-hydroxy-1-methyl-ethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine obtained in (1) above, in that order, and the reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate water was added to the reaction solution, and the aqueous layer was separated with ethyl acetate. The combined organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: ethyl acetate / methanol = 100 / 0 to 95 / 5) to obtain 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] [ka]

[0466] (1) 1 mol / l aqueous sodium hydroxide solution (500 μl) was added to a THF (4 ml) solution of 3-[tert-butoxycarbonyl(2-methoxyethyl)amino]-4-methoxybutanoic acid methyl ester (127 mg) obtained in Reference Example 4, 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 obtain a crude product of 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 was taken from this. Monomethylamine (310 μl) and HATU (94.9 mg) were added thereto, 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 layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a 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 obtain 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-oxadiazol-2-yl)piperazin-1-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide (compound (I-131))

[0471] [ka]

[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 later was treated in the same manner as in (2) of Example 119 to obtain 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] [ka]

[0475] The title compound (83 mg; yield 21%) was obtained as a white powder by treating (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 later in the same manner as in Example 119(2). 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] [ka]

[0478] Hydrochloric acid (4 mol / l 1,4-dioxane solution) (10 ml) was added to a methanol (5 ml) solution of 4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-carboxylic acid tert-butyl ester (compound (I-160)) (600 mg) obtained in Example 160 described below, 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, which was suspended and washed, and then filtered 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] [ka]

[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 stirred at room temperature for 2 hours. Water was added to the reaction solution, and then the solution was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue, which was suspended and washed, and then filtered under reduced pressure. The obtained solid was dried by heating to obtain 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] [ka]

[0484] A 1 mol / l aqueous sodium hydroxide solution (2.5 ml) was added to a methanol (3 ml) solution 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, and the reaction mixture was stirred at room temperature for 1 hour. 1 mol / l hydrochloric acid (2.5 ml) and water (10 ml) were added to the reaction mixture and stirred overnight. The precipitated solid was collected by filtration, suspended and washed with 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: (E) Preparation of both enantiomers of -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] [ka]

[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 obtain two enantiomers of the title compound as shown in Table 7 below.

[0488] [Table 7]

[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] [ka]

[0491] A 9.5 mol / l dimethylamine aqueous solution (12 μl), N,N-diisopropylethylamine (20 μl), and HATU (43 mg) were added 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, and the mixture was stirred at room temperature for 1 hour. Water and DMSO were added to the reaction mixture, and the title compound (17 mg; yield 54%) was obtained as a white viscous substance by purifying it with reverse phase HPLC (10 mmol / l ammonium carbonate aqueous solution / acetonitrile = 70 / 30 to 40 / 60). 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] [ka]

[0494] A 9.5 mol / l dimethylamine aqueous solution (10 μl), N,N-diisopropylethylamine (18 μl), and HATU (40 mg) were added 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, and the mixture was stirred at room temperature for 1 hour. Water and DMSO were added to the reaction mixture, and the title compound (18 mg; yield 58%) was obtained as a white viscous substance by purifying it with reverse phase HPLC (10 mmol / l ammonium carbonate aqueous solution / acetonitrile = 80 / 20 to 50 / 50). 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] [ka]

[0497] 1 mol / l aqueous sodium hydroxide solution (1.2 ml) was added to a methanol (4 ml) solution 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)) (500 mg) obtained in Example 162 described later, 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 solid obtained by purifying the obtained solid by reverse phase HPLC (solvent: 10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 90 / 10 to 60 / 40) 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] [ka]

[0500] A 1 mol / l tetra-n-butylammonium fluoride-THF solution (0.6 ml) was added 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 later, 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 saline 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 fraction containing the target product was concentrated under reduced pressure. The resulting solid was washed with ethyl acetate and filtered to obtain 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] [ka]

[0503] (1) N-methyl-N-[(3S)-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidin-3-yl]carbamic acid tert-butyl (compound (I-164)) (79 mg) obtained in Example 164 described later was dissolved in dichloromethane (3 ml), 2,2,2-trifluoroacetic acid (0.05 ml) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and toluene was added to the obtained residue to perform azeotropy, thereby obtaining 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 salt as a light 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), triethylamine (0.07 ml) and acetyl chloride (17 mg) were added, and the mixture was stirred at room temperature for 1 hour. After adding methanol to the reaction solution to stop the reaction, the solvent was concentrated under reduced pressure, and 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 (62.5 mg; yield 94%) as a colorless viscous substance. 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] [ka]

[0507] (1) N-[(3S)-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidin-3-yl]carbamic acid tert-butyl (compound (I-165)) (68 mg) obtained in Example 165 described later was dissolved in dichloromethane (3 ml), 2,2,2-trifluoroacetic acid (0.1 ml) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and toluene was added to the obtained residue to perform azeotropy, thereby obtaining 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 salt as a light 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), triethylamine (0.07 ml) and acetyl chloride (15 mg) were added, and the mixture was stirred at room temperature for 1 hour. After adding methanol to the reaction solution to stop the reaction, the solvent was concentrated under reduced pressure, and 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] [ka]

[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 later 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 ammonium carbonate aqueous solution / 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] [ka]

[0514] Methylamine hydrochloride (9 mg), HATU (45 mg) were added to a DMF (1 ml) solution of (3S)-1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]pyrrolidine-3-carboxylic acid (compound (I-125)) (40 mg) obtained in Example 125, and N,N-diisopropylethylamine (0.056 ml) was added dropwise and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution 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, and the resulting residue was purified by reverse phase HPLC (solvent: 10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 70 / 30 to 40 / 60) to obtain 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] [ka]

[0517] 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)) (50 mg) prepared in Example 140 was dissolved in DMF (0.5 ml), and 9.5 mol / l dimethylamine aqueous solution (15 μl), N,N-diisopropylethylamine (25 μl), and HATU (68 mg) were added and stirred at room temperature for 1 hour. A 10% potassium carbonate aqueous solution was added to the reaction mixture, and it was extracted with a mixed solvent of chloroform:methanol (90:10). The organic layers were combined, 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 solution / acetonitrile=70 / 30 to 40 / 60) to obtain the title compound (36 mg; yield 68%) as a white powder. MS(ESI)m / z:450.2[M+H]+

[0518] Example 147: (E) Preparation of -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] [ka]

[0520] 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 was added to a DMF (0.6 ml) solution of 2-methoxy-N-methylethanamine (18 mg), N,N-diisopropylethylamine (33 μl), and HATU (73 mg), 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 ammonium carbonate aqueous solution / acetonitrile = 70 / 30 to 40 / 60) to obtain the title compound (49 mg; yield 83%) as a colorless viscous substance. MS(ESI)m / z:460.1[M+H]+

[0521] Example 148: (E) Preparation of -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] [ka]

[0523] 2-(methylamino)ethanol (15 mg), N,N-diisopropylethylamine (33 μl), and HATU (73 mg) were added to a DMF (0.6 ml) solution of 2-[2-methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]acetic acid (compound (I-135)) (50 mg) prepared in Example 135, 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 substance. MS(ESI)m / z:446.1[M+H]+

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

[0525] [ka]

[0526] 2-[2-Methoxyethyl-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]amino]acetic acid (compound (I-135)) (50 mg) prepared in Example 135 was added to a DMF (0.6 ml) solution of 9.5 mol / l dimethylamine aqueous solution (22 μl), N,N-diisopropylethylamine (33 μl), and HATU (73 mg), 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 ammonium carbonate aqueous solution / acetonitrile = 70 / 30 to 40 / 60) to obtain the title compound (47 mg; yield 88%) as a colorless viscous substance. 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] [ka]

[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, 9.5 mol / l dimethylamine aqueous 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 ammonium carbonate aqueous 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] [ka]

[0532] To a 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 in DMF (1 ml), 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 substance. MS(ESI)m / z:444.3[M+H]+

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

[0534] [Table 8-1]

[0535] [Table 8-2]

[0536] [Table 8-3]

[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] [ka]

[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-oxadiazole-2-yl)piperazine-1-carboxylate (150 mg) obtained in Reference Example 1, and the reaction mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid (0.1 ml) was further added, and the reaction mixture was stirred at room temperature overnight, and then stirred at 50° C. for 3 hours. After cooling the reaction mixture, toluene was added and the mixture was concentrated to obtain a crude product of 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 obtain 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] [ka]

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

[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] [ka]

[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 obtain 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] [ka]

[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 obtain 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] [ka]

[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 obtain 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 shown in Tables 9-1 to 9-18 below.

[0555] [Table 9-1]

[0556] [Table 9-2]

[0557] [Table 9-3]

[0558] [Table 9-4]

[0559]

Table 9-5

[0560]

Table 9-6

[0561]

Table 9-7

[0562]

Table 9-8

[0563]

Table 9-9

[0564]

Table 9-10

[0565]

Table 9-11

[0566]

Table 9-12

[0567]

Table 9-13

[0568]

Table 9-14

[0569] [Table 9-15]

[0570] [Table 9-16]

[0571] [Table 9-17]

[0572] [Table 9-18]

[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] [ka]

[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 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 obtained 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 obtain the compounds shown in Tables 10-1 to 10-3 below.

[0577] [Table 10-1]

[0578] [Table 10-2]

[0579] [Table 10-3]

[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] [ka]

[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) solution, and lithium hydroxide aqueous solution (4 mol / l; 0.23 ml) was added and stirred at room temperature for 3 hours. After neutralization of the reaction mixture, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100 / 0-0 / 100) to obtain 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] [Table 11-1]

[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] [ka]

[0587] 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) was added with N,N-diisopropylethylamine (0.04 ml), HATU (62 mg), and 2-methylpropan-1-amine (17 mg), 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 with water and saturated saline solution in that order, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (48.3 mg; yield 85.7%) as a colorless solid. MS(ESI)m / z:488.4[M+H] +

[0588] Examples 279-281: 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] [Table 12-1]

[0590] Example 282: (E) Preparation of -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] [ka]

[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 sodium bicarbonate water was added to the reaction mixture to separate the layers, and the organic layer was washed successively with 10% aqueous sodium carbonate solution and saturated saline, dried over sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and bis(2-methoxyethyl)aminosulfur trifluoride (0.3 ml) was added to a chloroform (5 ml) solution of the obtained crude product under ice cooling, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and filtered. The solvent was removed 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 product were concentrated under reduced pressure to obtain 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] [ka]

[0595] (1) (2R)-2-amino-3-hydroxypropanoic acid tert-butyl ester (847 mg) and N,N-diisopropylethylamine (0.35 ml) were added to a solution of 1H-pyrazole-3-carbaldehyde (192 mg) in acetonitrile (10 ml), followed by the addition of acetic acid (0.011 ml) and sodium triacetoxyborohydride (25 mg) in that order, and the mixture was stirred overnight at room temperature. Methanol and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture, the solvent was removed under reduced pressure, and the resulting residue was purified by reversed-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 90 / 10 to 60 / 40) to obtain (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) (1) (2R)-3-hydroxy-2-(1H-pyrazol-3-ylmethylamino)propanoic acid tert-butyl ester (345 mg) obtained in (1) was dissolved in acetonitrile (7.5 ml) and successively added with benzaldehyde (152 mg), acetic acid (0.01 ml), and sodium triacetoxyborohydride (606 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 removed under reduced pressure. The residue obtained was purified by reversed-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 60 / 40 to 30 / 70) to obtain (2R)-2-[benzyl(1H-pyrazol-3-ylmethyl)amino]-3-hydroxypropanoic acid tert-butyl ester (364 mg; yield 77%) as a colorless amorphous solid. MS(ESI)m / z:332.2[M+H] +

[0597] (3) (2R)-2-[benzyl(1H-pyrazol-3-ylmethyl)amino]-3-hydroxypropanoic acid tert-butyl ester (360 mg) obtained in (2) was added to a dioxane (6 ml) solution of cyanomethylenetributylphosphorane (393 mg) and stirred for 7 hours at an external temperature of 110° C. Toluene was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting residue was purified by reversed-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile=50 / 50-20 / 80) to obtain (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 substance. MS(ESI)m / z:314.2[M+H] +

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

[0599] (5) (4) (6R)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (55 mg) obtained in (4) was dissolved in dichloromethane (1.2 ml), and 1N 2-azidoacetyl chloride in 2-methoxy-2-methylpropane (0.25 ml) and triethylamine (0.05 ml) were added and 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 distilled off under reduced pressure, and the resulting residue was purified by reversed-phase HPLC (10 mmol / l aqueous ammonium carbonate / acetonitrile = 70 / 30 to 40 / 60) to obtain (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) (5) (6R)-5-(2-azidoacetyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-6-carboxylic acid tert-butyl ester (72 mg) obtained in (5) was mixed in THF (1 ml) and water (0.05 ml) to add triphenylphosphine (93 mg) and stirred at an external temperature of 50 ° C. for 2 hours. Toluene was added to the reaction mixture, and the solvent was distilled off 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, and the mixture was stirred 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 substance. MS(ESI)m / z:479.2[M+H] +

[0601] (7) (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) was added to a dichloromethane (1 ml) solution of trifluoroacetic acid (0.1 ml), stirred at room temperature for 2 hours, and then stirred at an external temperature of 50°C for 4 hours. Trifluoroacetic acid (0.1 ml) was added and stirred at an external temperature of 50°C for 2 hours. Trifluoroacetic acid (0.1 ml) was further added and stirred at an external temperature of 50°C for 2 hours. Trifluoroacetic acid (0.1 ml) was further added and stirred at an external temperature of 50°C for 2 hours. Trifluoroacetic acid (0.1 ml) was further added and stirred at an external temperature of 50°C for 2 hours. The reaction mixture was evaporated under reduced pressure, toluene was added, and the crude product obtained by evaporation under reduced pressure was crystallized by adding diethyl ether, and the crystalline compound was collected by filtration to obtain 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> A test compound dissolved in dimethyl sulfoxide (DMSO) was added at 0.5 μl per well to a 96-well plate for solid-phase radioactivity measurement containing a scintillator on the bottom of the well (final concentration of DMSO: 0.5%). 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 the amount of B0AT1 nonspecific uptake. Human B0AT1 stably expressing CHO cells suspended in a buffer (buffer containing 96 mM sodium chloride, 2 mM potassium chloride, 1.8 mM calcium chloride, 1 mM magnesium chloride, 0.01% bovine serum albumin, and 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid, pH 7.0) were added at 90 μl so that the number of cells per well was 75,000. After leaving the plate at room temperature for 30 minutes or more, the plate was subjected to a phenylalanine uptake experiment. 10 μl of a buffer solution containing L-phenylalanine and [3,4,5-3H]-L-phenylalanine was added to each well (final concentration of phenylalanine: 0.25 mM), and the radioactivity on the bottom surface 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 the non-specific B0AT1 uptake from the control uptake, which was set to 100%, and the concentration at which each test compound inhibited it by 50% (IC 50 The mean mean (p < 0.05) was calculated by nonlinear regression using a logistic model.

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

[0605] [Table 13-1]

[0606] [Table 13-2]

[0607] [Table 13-3]

[0608] [Table 13-4]

[0609] [Table 13-5]

[0610] [Table 13-6]

[0611] [Table 13-7]

[0612] [Table 13-8]

[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: Mouse urinary phenylalanine excretion evaluation test

[0615] (1) Preparation of compound and phenylalanine dosing solutions The test compound was weighed, and 0.5% carboxymethylcellulose sodium salt (Sigma-Aldrich), 200 μl of saline solution (for intraperitoneal administration) or water (for oral administration) was added, and then the mixture was ground and suspended using a mixer mill (Retsch) to adjust the optimum concentration. Then, the mixture was sonicated for 10 minutes using an ultrasonic crusher (Nihonseiki). 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) by sonication, and adjusted to 25 mg / ml. The administration solution was prepared on the day of administration of phenylalanine.

[0616] (2) Compound administration and urine sample collection Male C57BL / 6J (Charles River Japan, Inc.) weighing 20-30g (8-11 weeks old) were used as test animals. They were group-housed in PC cages until 2 days before the test, and the animals were confirmed to be in good general condition 2 days before the test. The test animals were individually housed in stainless metabolic cages for mice (Shinano Seisakusho Co., Ltd.) and were allowed to freely consume tap water and food. The animals were weighed on the morning of the day of administration of the test compound, and the animals were assigned to groups by simulation using the grouping program GPR3 ​​ver.3.0.2 so that the weight on the day of the test and the weight change from 2 days before the test were uniform among the groups. The test compound was administered intraperitoneally or orally, and the animals were housed in clean metabolic cages. 30 minutes after administration of the test compound, phenylalanine was administered intraperitoneally at 500mg / 20ml / kg. Urine was collected 4, 6, or 24 hours after administration of the test compound, and the urine weight was measured. When collecting urine 4 and 6 hours after administration, the mice were restrained and allowed to urinate in the bladder. The urine was separated from impurities by centrifugation, and the supernatant was collected. Glucose, occult blood, and white blood cells were measured using urine test strips LifeSticks (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 (1 μg / ml d5-phenylalanine dissolved in acetonitrile / methanol = 7 / 3) was added to 10 μl of urine sample, mixed, centrifuged, and 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 saline, mixed, centrifuged, and 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, 100Å, 1.8μm, 2.1mm × 100mm Mobile phase A: 0.025% heptafluorobutyric acid in water 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℃ Flow rate: 0.40ml / min

[0618] As shown in Tables 13-1 to 13-8, it was confirmed that compound (I) of the present invention or a salt thereof has excellent inhibitory activity against B0AT1. From the above results, it was suggested 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. [Industrial Applicability]

[0619] Since the compound (I) of the present invention or a pharma- ceutical acceptable salt thereof has excellent inhibitory activity against B0AT1, a pharmaceutical composition containing the compound can be used for treating and / or preventing diseases whose symptoms can be alleviated by the 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 medical treatment such as a very strict dietary therapy (amino acid restricted diet) that continues for the rest of one's life, so the compound (I) of the present invention or a pharma-ceutical acceptable salt thereof can provide a novel and effective preventive and / or therapeutic agent.

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 Alkoxy group, optionally substituted C ３－８ Cycloalkyloxy group, optionally substituted C １－６ Alkylsulfanyl group, optionally substituted C ３－８ Cycloalkylsulfanyl group, pentafluorosulfanyl group, 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 C may be substituted with a substituent selected from the substituent group a １－６ represents an alkyl group, and R ３ C may be substituted with a substituent selected from the substituent group a １－６ C which may be 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 Alkoxy group; 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; JC １－６ Alkylamino group; C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ cycloalkyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４ Aryl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the substituent group c; and a non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; Halogen atoms, hydroxy groups and C １－６ C, which may be 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 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 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; C may be substituted with 1 to 3 substituents selected from the 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; Tri-substituted silyl group; Tri-substituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ cycloalkyl group; 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 which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; C optionally substituted with a halogen atom １－６ Alkyl groups; C optionally substituted with a halogen atom １－６ Alkoxy group; 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; Halogen atom, C １－６ Alkyl group and C １－６ C, which may be substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups. ６－１４ An aryl group; and Halogen atom, C １－６ Alkyl group and C １－６ a nitrogen-containing aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of an alkoxy group. or a pharma- ceutically acceptable salt thereof.

2. In formula (I), R １ But, C ２－６ Alkyl group, haloC １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, haloC ２－６ Alkoxy group, C ３－６ 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, or 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, The B0AT1 inhibitor of claim 1, wherein n is 0.

3. In formula (I), R １ But, HaroC １－４ The B0AT1 inhibitor of claim 1 , 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 spiro cyclic 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. 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 above-mentioned 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 any one of claims 1 to 3, which forms a pyrazolo[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 may be substituted with 1 to 3 substituents selected from the substituent group a １－４ The B0AT1 inhibitor according to any one of claims 1 to 3, 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】 (In the formula, Y and Z each independently represent a carbon atom or a nitrogen atom; 【Chemistry 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- to 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 any one of claims 1 to 3, which forms a fused nitrogen-containing non-aromatic heterocyclic group represented by the formula:

8. A pharmaceutical composition for preventing and / or treating a disease whose symptoms can be alleviated by the B0AT1 inhibitory effect, comprising the B0AT1 inhibitor according to claim 1 and a pharma- ceutical acceptable carrier.

9. The pharmaceutical composition according to claim 8, wherein the disease whose symptoms can be alleviated by inhibiting B0AT1 is an amino acid metabolic disorder.

10. The pharmaceutical composition according to claim 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 claim 9, wherein the amino acid metabolism disorder is phenylketonuria.

12. Formula (I'): 【Chemistry 4】 [In the formula, R １’ is C ２－６ Alkyl group, haloC １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkoxy group, haloC ２－６ Alkoxy group, C ３－６ 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, or a C group optionally substituted with a halogen atom; ６－１４ An aryl group, a halogen atom, or C １－６ represents a 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by an alkyl 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 substituted with a substituent selected from the substituent group a １－４ represents an alkyl group, and R ３’ C may be substituted with a substituent selected from the substituent group a １－４ C which may be 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 Alkoxy group; 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; JC １－６ Alkylamino group; C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ cycloalkyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４ Aryl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the substituent group c; and a non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; Halogen atoms, hydroxy groups and C １－６ C, which may be 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 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 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; C may be substituted with 1 to 3 substituents selected from the 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; Tri-substituted silyl group; Tri-substituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ cycloalkyl group; 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 which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; C optionally substituted with a halogen atom １－６ Alkyl groups; C optionally substituted with a halogen atom １－６ Alkoxy group; 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; Halogen atom, C １－６ Alkyl group and C １－６ C, which may be substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups. ６－１４ An aryl group; and Halogen atom, C １－６ Alkyl group and C １－６ a nitrogen-containing aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of an alkoxy group. or a pharma- ceutically acceptable salt thereof (provided that the compound is represented by the following formula: 【Chemistry 5】 or a salt thereof, and a pharma- ceutical composition comprising the compound represented by the formula (I):

13. In formula (I'), R １’ But, HaroC １－４ is an alkyl group, and The method of claim 12, wherein n' is 0.

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, 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 spiro cyclic 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. 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 each be substituted by 1 to 3 substituents selected from the above-mentioned 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[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. The pharmaceutical composition according to claim 12.

16. Formula (I″): 【Chemistry 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 Alkoxy group, optionally substituted C ３－８ Cycloalkyloxy group, optionally substituted C １－６ Alkylsulfanyl group, optionally substituted C ３－８ Cycloalkylsulfanyl group, pentafluorosulfanyl group, optionally substituted C ６－１４ an aryl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; n" X" each independently represents a fluorine atom or a chlorine atom; n″ represents an integer from 0 to 2; and R ２’’ teeth, (i) a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the substituent group c, and (ii) a 5- or 6-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents 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, 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 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 substituent group b. (Substituent group a): Halogen atoms; Hydroxy group; Cyano group; Carboxy group; C optionally substituted with a halogen atom １－６ Alkoxy group; 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; JC １－６ Alkylamino group; C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ cycloalkyl group; C optionally substituted with 1 to 3 substituents selected from the substituent group c ６－１４ Aryl groups; a nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from the substituent group c; and a non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; Halogen atoms, hydroxy groups and C １－６ C, which may be 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 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 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; C may be substituted with 1 to 3 substituents selected from the 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; Tri-substituted silyl group; Tri-substituted silyloxy group; C optionally substituted with 1 to 3 substituents selected from the substituent group c ３－８ cycloalkyl group; 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 which may be substituted with 1 to 3 substituents selected from the 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 an alkoxy-carbonyl group; C optionally substituted with a halogen atom １－６ Alkyl groups; C optionally substituted with a halogen atom １－６ Alkoxy group; 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; Halogen atom, C １－６ Alkyl group and C １－６ C, which may be substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups. ６－１４ An aryl group; and Halogen atom, C １－６ Alkyl group and C １－６ a nitrogen-containing aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of an alkoxy group. or a pharma- ceutically acceptable salt thereof, and a pharma- ceutical composition comprising a compound represented by the formula:

17. 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 7】 (In the formula, Y′ and Z′ each independently represent a carbon atom or a nitrogen atom; 【Chemistry 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- to 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 pharmaceutical composition according to claim 16, which forms a fused nitrogen-containing non-aromatic heterocyclic group represented by the formula:

18. The pharmaceutical composition according to any one of claims 12 to 17 for use in the treatment and / or prevention of amino acid metabolic disorders.

19. The pharmaceutical composition according to any one of claims 12 to 17, 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.

20. A pharmaceutical composition according to any one of claims 12 to 17 for use in the treatment and / or prevention of phenylketonuria.

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