Novel B0AT1 inhibitors

Abstract

The purpose of the present invention is to provide a novel B0AT1 inhibitor.　The present invention pertains to a compound, or a salt thereof, having an inhibitory action on B0AT1, the compound being represented by formula (I) [the symbols in the formula are as defined in the description]. The present invention also pertains to: a B0AT1 inhibitor containing the compound; and a pharmaceutical composition containing the compound. One embodiment of the present invention is a medical drug that is suitable for preventing and / or treating, for example, amino acid metabolism disorders such as phenylketonuria, urea cycle disorders, hypertyrosinemia (type 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemias, and isovaleric acidemia.

Description

[Technical Field]

[0001] This invention relates to a novel compound that has inhibitory activity on the neutral amino acid transporter B0AT1. [Background technology]

[0002] The causative gene for Hartnup disease, SLC6A19, is localized at 5p15.33 and consists of 12 exons. Its gene product, the neutral amino acid transporter B0AT1, is composed of 634 amino acids and has 12 transmembrane regions (Non-Patent Literature 1, 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 Literature 3-5). B0AT1 knockout mice are known to exhibit elevated levels of amino acids in their urine (Non-Patent Literature 6), and clinically, B0AT1 dysfunction presents with severe neutral amino aciduria, known as Hartnup disease (Non-Patent Literature 7). Therefore, it was thought that inhibiting B0AT1 could potentially improve (alleviate) various diseases or conditions involving neutral amino acids, which are transport substrates.

[0003] Furthermore, specific examples of the therapeutic effects of inhibiting B0AT1 function on diseases have been reported, such as the improvement of the disease state in phenylketonuria model mice by either congenitally deficient in B0AT1 or by suppressing its expression acquiredly by administering nucleic acid compounds that bind to mRNA (Non-Patent Literature 4).

[0004] Against this backdrop, compounds that inhibit B0AT1 have attracted attention as pharmaceuticals for the prevention and / or treatment of various diseases or conditions involving neutral amino acids, which are transport substrates, specifically amino acid metabolic disorders.

[0005] Examples of amino acid metabolism disorders include designated intractable diseases such as phenylketonuria, urea cycle disorders, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia. The main treatment for these conditions is known to be continuous dietary therapy. In addition to dietary therapy, the administration of drugs that increase coenzymes and enzymes, and therapies involving enzyme injections are also known, but none of these are fundamental treatments (for example, Non-Patent Document 8, etc.).

[0006] Therefore, there is a need for the development of drugs that can normalize neutral amino acid metabolism by inhibiting B0AT1, thereby alleviating symptoms of diseases, specifically amino acid metabolic disorders, in order to prevent and / or treat them.

[0007] To date, compounds possessing B0AT1 inhibitory activity have been known, for example, nucleic acids having sequences that partially or completely match those of B0AT1 RNA (Non-Patent Document 4), existing marketed products such as nimeslides and their derivatives (Non-Patent Documents 9 and 10), the known compound synlomid (Non-Patent Document 11), and basic compounds discovered through library screening (Non-Patent Documents 12 and 13). Cinnamic acid glycinamide compounds (Patent Document 1) are also known. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2023 / 145804 [Non-patent literature]

[0009] [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] National Center for Intractable Diseases Information, 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 [Overview of the project] [Problems that the invention aims to solve]

[0010] This invention provides a novel compound having excellent B0AT1 inhibitory activity, and a pharmaceutical product containing the same as an active ingredient. [Means for solving the problem]

[0011] As a result of diligent research, the inventors of this invention have found the following formula (I):

[0012] [ka]

[0013] [In the formula, R may be substituted with C 6-10 Represents an aryl-ethenyl group; R 1 represents a carboxyl group, or a group that is biologically equivalent to a carboxyl group; L may be further substituted, C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 Represents a divalent organic group comprising an alkynylene group and a group selected from the group consisting of 3 to 14-membered divalent non-aromatic heterocyclic groups; and A represents a divalent nitrogen-containing heterocyclic group that may be further substituted. We discovered that the compound represented by (hereinafter sometimes abbreviated as "Compound (I)"), or a pharmaceutically acceptable salt thereof, has excellent inhibitory activity against the neutral amino acid transporter B0AT1, and thus completed the present invention.

[0014] In other words, one embodiment of the present invention is as follows: [1] Equation (I):

[0015] [ka]

[0016] [In the formula, R represents an optionally substituted C 6-10 aryl-ethenyl group; R 1 represents a carboxy group or a group biologically equivalent to the carboxy group; L represents a divalent organic group containing a group selected from the group consisting of an optionally further substituted C 1-6 alkylene group, C 6-10 arylene group, C 3-14 cycloalkylene group, C 2-6 alkenylene group, C 2-6 alkynylene group, and a divalent non-aromatic heterocyclic group having 3 to 14 members; and A represents an optionally further substituted divalent nitrogen-containing heterocyclic group.] A compound represented by the formula or a pharmaceutically acceptable salt thereof. [2] In the formula (I), R is a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-8 cycloalkyloxy group, an optionally substituted C 1-6 alkylsulfanyl group, an optionally substituted C 3-8 cycloalkylsulfanyl group, and a 2-phenylethenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a pentafluorosulfanyl group; R 1 is a carboxy group or a group biologically equivalent to the carboxy group; L is -NR 2 -(wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group.), -O-, -S-, -C(=O)-, C 1-6 alkylene group, C 6-10 arylene group, C 3-14 cycloalkylene group, C 2-6 alkenylene group, C 2-6The C may each have an alkynylene group and one or more divalent groups selected from the group consisting of 3 to 14 membered divalent non-aromatic heterocyclic groups, either internally or at its terminal, and each may be further substituted with one to three substituents selected from substituent group a. 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 An alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group; and A may be further substituted with one to three substituents selected from substituent group a, as shown in the following formula:

[0017] [ka]

[0018] (In the formula, ** This represents the bonding site with the carbonyl group. *** This represents the bonding site with group L, and ring A 1 This represents a monoring of 3 to 10 members, a fused ring of 8 to 14 members, a spiroring of 6 to 16 members, or a bridging ring of 6 to 14 members, and may include, in addition to nitrogen and carbon atoms, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by The compounds described in [1] above or pharmaceutically acceptable salts thereof. (substituent group a): halogen atom; Hydroxyl group; Cyano group; Oxo group; Halogen atom, hydroxyl group, cyano group, C 1-6 Alkoxy group, C 6-14 Aryl group, carboxyl group, C 1-6 Alkoxy-carbonyl group, 1 or 2 C 1-6 A carbamoyl group which may be substituted with an alkyl group, and C 6-14C may be substituted with substituents selected from the group consisting of aryloxy groups. 1-6 alkyl group; C that can be substituted with halogen atoms 1-6 Alkoxy group; C that can be substituted with halogen atoms 1-6 Alkyl sulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Halogen atom, hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyl groups that may be substituted with alkyl groups; Ji C 1-6 Alkylamino group; Tri-substituted silyl group; Tri-substituted silyloxy group; C may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'. 6-14 Hydrocarbon ring group; A 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and A 3- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'. (substituent group b): halogen atom; Hydroxyl group; Cyano group; Oxo group; Carboxy group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 1-6 alkyl group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 3-8 Cycloalkyl groups; Halogen atom, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 6-10 Aryl group; Halogen atom, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 A 5- to 14-membered aromatic heterocyclic group which may be substituted with substituents selected from the group consisting of alkoxy groups; Halogen atom, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 A 3- to 14-membered non-aromatic heterocyclic group which may be substituted with substituents selected from the group consisting of alkoxy groups; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 1-6 Alkoxy group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 1-6 Alkyl sulfanyl group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 3-8 Cycloalkyloxy group; C that can be substituted with halogen atoms 1-6 Alkyl sulfonyl group; C that can be substituted with halogen atoms 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Halogen atom, hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyl groups that may be substituted with alkyl groups; Halogen atoms, hydroxyl groups, cyano groups, and C1-6 C which may be each substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups 1-6 alkyl group, C 3-8 a sulfamoyl group substituted with 1 substituent selected from the group consisting of cycloalkyl groups and non-aromatic heterocyclic groups; and pentafluorosulfanyl group. (Substituent group b'): halogen atom; hydroxy group; cyano group; oxo group; carboxy group; halogen atom, hydroxy group, cyano group and C 1-6 alkyl group which may be substituted with a substituent selected from the group consisting of alkoxy groups 1-6 alkyl group; halogen atom, hydroxy group, cyano group and C 1-6 cycloalkyl group which may be substituted with a substituent selected from the group consisting of alkoxy groups 3-8 cycloalkyl group; halogen atom, hydroxy group, cyano group and C 1-6 alkoxy group which may be substituted with a substituent selected from the group consisting of alkoxy groups 1-6 alkoxy group; halogen atom, hydroxy group, cyano group and C 1-6 alkylsulfanyl group which may be substituted with a substituent selected from the group consisting of alkoxy groups 1-6 alkylsulfanyl group; halogen atom, hydroxy group, cyano group and C 1-6 cycloalkyloxy group which may be substituted with a substituent selected from the group consisting of alkoxy groups 3-8 cycloalkyloxy group; alkylsulfonyl group which may be substituted with a halogen atom 1-6 alkylsulfonyl group; alkyl-carbonyl group which may be substituted with a halogen atom 1-6 alkyl-carbonyl group; C 1-6 alkoxy-carbonyl group; halogen atom, hydroxy group, diC 1-6A substituent selected from the group consisting of an alkylamino group and a C 1-6 alkyl group which may be substituted with 1 or 2 substituents selected from the group consisting of an alkoxy group; 1-6 a carbamoyl group which may be substituted with an alkyl group; a sulfamoyl group substituted with 1 substituent selected from the group consisting of a halogen atom, a hydroxy group, a cyano group and a C 1-6 alkyl group, which may be further substituted with 1 to 3 substituents each selected from the group consisting of an alkoxy group; 1-6 an alkyl group, a C 3-8 cycloalkyl group and a non-aromatic heterocyclic group; and a pentafluorosulfanyl group. [3] In formula (I), R is a 2-(E)-phenylethenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, an alkyl group which may be substituted with a halogen atom, and a pentafluorosulfanyl group; 1-6 R is a carboxy group or a group biologically equivalent to the carboxy group; 1 L is -NR 2 -(wherein R 2 represents a hydrogen atom or a C 1-6 alkyl group.), -O-, -S-, -C(=O)-, C 6-10 arylene group, C 3-10 cycloalkylene group, C 2-6 alkynylene group, and one or more divalent groups selected from the group consisting of a 3- to 8-membered divalent non-aromatic heterocyclic group, which may have at the interior or the terminus thereof, and which may be further substituted with 1 to 3 substituents selected from the substituent group a, a C 1-6 alkylene group, 6-10 an arylene group which may be further substituted with 1 to 3 substituents selected from the substituent group a, a cycloalkylene group which may be further substituted with 1 to 3 substituents selected from the substituent group a, 3-10 a cycloalkylene group which may be further substituted with 1 to 3 substituents selected from the substituent group a, a cycloalkylene group which may be further substituted with 1 to 3 substituents selected from the substituent group a, 2-4 a cycloalkylene group which may be further substituted with 1 to 3 substituents selected from the substituent group a, C may be further substituted with 1 to 3 substituents selected from the substituent group a. 2-4 Alkynylene group, or A 3 to 8-membered divalent non-aromatic heterocyclic group which may be further substituted with 1 to 3 substituents selected from the substituent group a above. and A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula:

[0019] [ka]

[0020] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0021] [ka]

[0022] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by The compounds described in [1] above or pharmaceutically acceptable salts thereof. [3'] In equation (I), R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups; R 1 However, it is a carboxyl group, or a group that is biologically equivalent to a carboxyl group; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 6-10 Allirene group, C 3-10 Cycloalkylene group, C 2-6 C may have one or more divalent groups selected from the group consisting of an alkynylene group and a 3- to 8-membered divalent non-aromatic heterocyclic group, either internally or at its terminal, and may be further substituted with one to three substituents selected from the substituent group a. 1-6 Alkylene group, C may be further substituted with 1 to 3 substituents selected from the substituent group a. 6-10 Arylene group, C may be further substituted with 1 to 3 substituents selected from the substituent group a. 3-10 Cycloalkylene group, C may be further substituted with 1 to 3 substituents selected from the substituent group a. 2-4 Alkynylene group, or A 3 to 8-membered divalent non-aromatic heterocyclic group which may be further substituted with 1 to 3 substituents selected from the substituent group a above. and A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula:

[0023] [ka]

[0024] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0025] [ka]

[0026] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by The compounds described in [1] above or pharmaceutically acceptable salts thereof. [4] In equation (I), L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ), -O-, -S-, C 3-10C may have one or more divalent groups selected from the group consisting of cycloalkylene groups and 3 to 8-membered divalent non-aromatic heterocyclic groups, either internally or at its terminal, and may be further substituted with one to three substituents selected from the substituent group a. 1-6 Alkylene group, C may be further substituted with 1 to 3 substituents selected from the substituent group a. 3-10 Cycloalkylene group, or A 3 to 8-membered divalent non-aromatic heterocyclic group which may be further substituted with 1 to 3 substituents selected from the substituent group a above. The compounds described in [3] or [3'] above, or pharmaceutically acceptable salts thereof. [5] In equation (I), L may be further substituted with 1 to 3 substituents selected from the substituent group a. 1-6 It is an alkylene group. The compounds described in [3] or [3'] above, or pharmaceutically acceptable salts thereof. [6] In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula:

[0027] [ka]

[0028] (The definitions of each symbol in the formula are the same as those given above.) A compound described in [5] above or a pharmaceutically acceptable salt thereof, which is a divalent nitrogen-containing non-aromatic heterocyclic group represented by . [7] In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula:

[0029] [ka]

[0030] (The definitions of each symbol in the formula are the same as above. However, Z is CR 5 R 6 If this is the case, the substituents that may be further substituted may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b' among the substituents of substituent group a. 6-14 Selected from the group consisting of hydrocarbon ring groups; 5- to 14-membered aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and 3- to 14-membered non-aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'. A compound described in [5] above or a pharmaceutically acceptable salt thereof, which is a divalent nitrogen-containing non-aromatic heterocyclic group represented by . [8] In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula:

[0031] [ka]

[0032] (The definitions of each symbol in the formula are the same as those given above.) A compound described in [5] above or a pharmaceutically acceptable salt thereof, which is a divalent nitrogen-containing non-aromatic heterocyclic group represented by . [9] In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula:

[0033] [ka]

[0034] (The definitions of each symbol in the formula are the same as those given above.) A compound described in [5] above or a pharmaceutically acceptable salt thereof, which is a divalent nitrogen-containing non-aromatic heterocyclic group represented by . [9'] In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula:

[0035] [ka]

[0036] (The definitions of each symbol in the formula are the same as those given above.) A compound described in [5] above or a pharmaceutically acceptable salt thereof, which is a divalent nitrogen-containing non-aromatic heterocyclic group represented by .

[10] In equation (I), R 1 However, the carboxyl group may be substituted. 1-6 A compound according to any of the above [1] to [9], [3'] and [9'], or a pharmaceutically acceptable salt thereof, wherein the compound is an alkoxy-carbonyl group or an optionally substituted carbamoyl group.

[11] 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 3-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; N,N-dimethyl-3-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl]propanamide; 1-[7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,8-dihydro-5H-2,7-naphthyridine-3-yl]piperidine-4-carboxylic acid; 3-[3-bromo-5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl]propanoic acid; 2-[[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]oxy]acetic acid; 2-[2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; (1R*,2R*)-2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]cyclopropane-1-carboxylic acid and both enantiomers; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[7-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,8-dihydro-5H-2,7-naphthyridine-3-yl]acetic acid; 3-[3-bromo-5-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl]propanoic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]aminoacetic acid; 2-[2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-cyano-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-(2-fluoro-4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-yl]sulfanyl]acetic acid; 2-[7-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-cyano-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; (E)-N-[2-[6-(2-amino-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide; 2-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-[1,3]thiazolo[4,5-c]pyridine-2-yl]acetic acid; (E)-N-[2-[6-[2-(methylamino)-2-oxoethyl]-3,4-dihydro-1H-isoquinoline-2-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide; 4-[4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3-phenylpiperazine-1-yl]butanoic acid and both enantiomers; 2-[[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2,3-dihydroindole-4-yl]oxy]acetic acid; 1-[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperidine-3-yl]bicyclo[2.1.1]hexane-5-carboxylic acid; 2-[[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]oxy]-2-methylpropanoic acid; 3-[[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]oxy]-2,2-dimethylpropanoic acid; 4-[4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(3-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 3-[[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]methyl]cyclobutane-1-carboxylic acid and both enantiomers; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]-2,2-dimethylbutanoic acid; 4-[3-(3-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid and both enantiomers; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chloro-3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-2-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]2-methyl-5-phenylpiperazine-1-yl]-2,2-dimethylbutanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[12] 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 3-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; N,N-dimethyl-3-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl]propanamide; 2-[2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; (1R*,2R*)-2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]cyclopropane-1-carboxylic acid and both enantiomers; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[7-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-cyano-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-(2-fluoro-4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[7-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-[1,3]thiazolo[4,5-c]pyridine-2-yl]acetic acid; 4-[(3S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3-phenylpiperazine-1-yl]butanoic acid; 1-[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperidine-3-yl]bicyclo[2.1.1]hexane-5-carboxylic acid; 4-[(3S)-3-(4-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(3-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 3-[[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]methyl]cyclobutane-1-carboxylic acid and both enantiomers; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid and both enantiomers; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chloro-3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-2-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]2-methyl-5-phenylpiperazine-1-yl]-2,2-dimethylbutanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[13] 2-[7-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[7-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 4-[(3S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3-phenylpiperazine-1-yl]butanoic acid; 1-[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperidine-3-yl]bicyclo[2.1.1]hexane-5-carboxylic acid; 4-[(3S)-3-(4-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(3-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-2-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]2-methyl-5-phenylpiperazine-1-yl]-2,2-dimethylbutanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[14] 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 3-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; N,N-dimethyl-3-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl]propanamide; 2-[2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 4-[(3R)-3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(triflu Oromethyl)phenyl]prop-2-enoyl]aminoacetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[15] A B0AT1 inhibitor comprising any of the compounds described in [1] to

[14] , [3'] and [9'] above or a pharmaceutically acceptable salt thereof. [15'] A B0AT1 inhibitor as described in

[15] above, which is a prophylactic and / or therapeutic agent for amino acid metabolic disorders. [15''] A B0AT1 inhibitor as described above [15'], wherein the amino acid metabolic disorder is phenylketonuria, urea cycle disorder, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, or isovaleric acidemia.

[16] A pharmaceutical composition comprising a compound described in any of [1] to

[14] , [3'] and [9'] above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[17] The pharmaceutical composition according to

[16] above for the prevention and / or treatment of a disease whose symptoms can be alleviated by B0AT1 inhibitory action.

[18] The pharmaceutical composition according to

[17] above, wherein the disease whose symptoms can be alleviated by B0AT1 inhibitory action is an amino acid metabolic disorder.

[19] The pharmaceutical composition according to

[18] above, wherein the amino acid metabolic disorder is phenylketonuria, urea cycle disorder, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, or isovaleric acidemia.

[20] The pharmaceutical composition according to

[18] above, wherein the amino acid metabolic disorder is phenylketonuria.

[21] A pharmaceutical composition according to any one of

[16] to

[20] above, characterized by being administered in combination with other drugs.

[22] The pharmaceutical composition according to

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

[23] The pharmaceutical composition of the above

[21] , wherein the other drugs are vitamins, drugs for relieving various symptoms of amino acid metabolic disorders, antidepressants, anxiolytics, or drugs for treating ADHD.

[24] A pharmaceutical composition according to any one of

[16] to

[20] above, characterized in that the pharmaceutical composition and other drugs are administered separately.

[25] A pharmaceutical composition according to any one of

[16] to

[20] above, characterized in that the pharmaceutical composition and other drugs are administered simultaneously or sequentially.

[26] A method for preventing or treating an amino acid metabolic disorder in a mammal, characterized by administering an effective amount of any of the compounds described in [1] to

[14] , [3'] and [9'] above or a pharmaceutically acceptable salt thereof to the mammal.

[27] A method for preventing or treating a disease selected from the group consisting of phenylketonuria, urea cycle disorders, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia in a mammal, characterized by administering an effective amount of any of the compounds described in [1] to

[14] , [3'] and [9'] above or a pharmaceutically acceptable salt thereof to the mammal.

[28] A method for preventing or treating an amino acid metabolic disorder in a mammal, characterized by administering an effective amount of the pharmaceutical composition described in any of

[16] to

[20] above and another drug to the mammal simultaneously or sequentially.

[29] A method for preventing or treating a disease selected from the group consisting of phenylketonuria, urea cycle disorders, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia in a mammal, characterized by administering an effective amount of the pharmaceutical composition described in any of

[16] to

[20] above and another drug simultaneously or sequentially to the mammal.

[30] Use of any of the compounds described in [1] to

[14] , [3'] and [9'] above or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for amino acid metabolic disorders.

[31] Use of any of the compounds described in [1] to

[14] , [3'] and [9'] above or a pharmaceutically acceptable salt thereof for the manufacture of therapeutic or prophylactic agents for diseases selected from the group consisting of phenylketonuria, urea cycle disorders, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia and isovaleric acidemia.

[32] A compound or a pharmaceutically acceptable salt thereof described in any of [1] to

[14] , [3'] and [9'] above, for use in the prevention or treatment of amino acid metabolic disorders.

[33] A compound or a pharmaceutically acceptable salt thereof described in any of [1] to

[14] , [3'] and [9'] above, for use in the prevention or treatment of a disease selected from the group consisting of phenylketonuria, urea cycle disorders, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia and isovaleric acidemia.

[34] A method for producing any of the compounds described in [1] to

[14] , [3'] and [9'] above, or a pharmaceutically acceptable salt thereof.

[35] A prodrug of any of the compounds described in [1] to

[14] , [3'] and [9'] above, or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0037] Compound (I) of the present invention or a pharmaceutically acceptable salt thereof has excellent inhibitory activity against B0AT1. Therefore, pharmaceutical compositions containing this compound are useful for the treatment and / or prevention of diseases whose symptoms can be alleviated by B0AT1 inhibitory action. [Modes for carrying out the invention]

[0038] The definitions of terms and symbols used in this specification are explained below.

[0039] In this specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0040] In this specification, "alkyl(group)" means a monovalent group having one or more carbon atoms, either linear or branched, obtained by removing one hydrogen atom from any carbon atom of an alkane, and unless otherwise specified regarding the range of carbon atoms, C 1-20 It is an alkyl group, and among them, C 1-6 Alkyl alkyl groups are preferred.

[0041] In this specification, "C 1-20 "Alkyl (group)" refers to alkyl groups with 1 to 20 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, eicosyl, etc.

[0042] In this specification, "C 1-6 "Alkyl (group)" refers to an alkyl group having 1 to 6 carbon atoms. Examples 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.

[0043] In this specification, "C 1-4 "Alkyl (group)" refers to an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0044] In this specification, "C which may be substituted with halogen atoms" 1-6 "Alkyl (group)" refers to the unsubstituted C 1-6 Alkyl alkyl group, or the C 1-6 C in an alkyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with halogens. 1-6This refers to alkyl groups. Specifically, examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, etc. Among these, "C which may be substituted with a halogen atom" is also included. 1-4 Alkyl (group) is more preferred.

[0045] In this specification, "C which may be substituted with substituents selected from the group" 1-6 "Alkyl (group)" refers to the unsubstituted C 1-6 Alkyl alkyl group, or the C 1-6 This 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 the same or different substituents selected from the group of substituents. In particular, "C which may be substituted with the same or different substituents selected from the group" 1-4 Alkyl (group) is more preferred.

[0046] In this specification, "cycloalkyl(group)" means a cyclic alkyl group, and unless otherwise specified regarding the carbon number range, preferably C 3-14 It is a cycloalkyl group, more preferably C 3-8 It is a cycloalkyl group.

[0047] In this specification, "C 3-14 "Cycloalkyl(group)" refers to a cyclic alkyl group having 3 to 14 carbon atoms, and may be monocyclic, fused, spirocyclic, or bridging. 3-14 Specific examples of "cycloalkyl(group)" include monocyclic C groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-14Cycloalkyl; condensed ring C such as 1-decalinyl and 2-decalinyl 5-14 Cycloalkyl; spirocyclic C such as spiro[3.4]octyl, spiro[4.5]decyl, and spiro[3.6]decyl. 6-14 Cycloalkyl; cross-linked C such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. 5-14 Examples include cycloalkyls. In particular, C 3-8 Cycloalkyl groups are preferred.

[0048] In this specification, "C 3-8 A "cycloalkyl(group)" refers to a cyclic alkyl group with 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Among these, C 3-6 Cycloalkyl groups are preferred.

[0049] In this specification, "C which may be substituted with substituents selected from the group" 3-8 "Cycloalkyl(group)" refers to the unsubstituted C 3-8 Cycloalkyl group, or the C 3-8 This refers to a cycloalkyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with the same or different substituents selected from the group of substituents.

[0050] In this specification, "C 3-8 "Cycloalkyloxy (group)" refers to the above C 3-8 A cycloalkyl group refers to a group bonded to an oxygen atom. Specifically, examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0051] In this specification, "C which may be substituted with substituents selected from the group" 3-8 "Cycloalkyloxy (group)" refers to the unsubstituted C 3-8 Cycloalkyloxy group, or the C 3-8This refers to a cycloalkyloxy group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with the same or different substituents selected from the group of substituents.

[0052] In this specification, "C 3-8 "Cycloalkylsulfanyl (group)" refers to the C 3-8 A cycloalkyl group refers to a group bonded to a sulfur atom. Specifically, examples include cyclopropylsulfanil, cyclobutylsulfanil, cyclopentylsulfanil, cyclohexylsulfanil, cycloheptylsulfanil, and cyclooctylsulfanil.

[0053] In this specification, "alkoxy(group)" means a group in which a linear or branched alkyl group is bonded to an oxygen atom, and unless otherwise specified regarding the range of carbon atoms, C 1-20 It is an alkoxy group, preferably C 1-6 It is an alkoxy group.

[0054] In this specification, "C 1-6 "Alkoxy(group)" refers to an alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc. Among them, C 1-4 An alkoxy group is preferred.

[0055] In this specification, "C which may be substituted with halogen atoms" 1-6 "Alkoxy(group)" refers to the unsubstituted C 1-6 Alkoxy group, or the C 1-6This refers to a group in which one or more hydrogen atoms in the alkoxy group are substituted with a halogen. Specifically, examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, 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, etc. Among these, "C may be substituted with a halogen atom" is also included. 1-4 Alkoxy(group) is more preferred.

[0056] In this specification, "C which may be substituted with substituents selected from the group" 1-6 "Alkoxy(group)" refers to the unsubstituted C 1-6 Alkoxy group, or the C 1-6 This refers to a group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms in the alkoxy group are substituted with the same or different substituents selected from the group of substituents. In particular, "C may be substituted with the same or different substituents selected from the group" 1-4 Alkoxy(group) is more preferred.

[0057] In this specification, "alkylsulfanil (group)" means a group in which a linear or branched alkyl group is bonded to a sulfur atom, preferably C 1-6 It is an alkylsulfanil group.

[0058] In this specification, "C 1-6"Alkyl sulfanyl (group)" refers to an alkyl sulfanyl group having 1 to 6 carbon atoms. Examples include methyl sulfanyl, ethyl sulfanyl, propyl sulfanyl, isopropyl sulfanyl, butyl sulfanyl, isobutyl sulfanyl, sec-butyl sulfanyl, tert-butyl sulfanyl, pentyl sulfanyl, isopentyl sulfanyl, neopentyl sulfanyl, and hexyl sulfanyl.

[0059] In this specification, "C which may be substituted with substituents selected from the group" 1-6 "Alkyl sulfanyl (group)" refers to the unsubstituted C 1-6 Alkyl sulfanyl group, or the C 1-6 This refers to a group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms in an alkylsulfanil group are substituted with the same or different substituents selected from the group of substituents.

[0060] In this specification, "C 1-6 "Alkylsulfonyl (group)" refers to a group where the sulfur atom of the sulfonyl group (-S(=O)2-) is the aforementioned "C 1-6 This refers to a group to which an alkyl group is attached, that is, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms. 1-6 Examples of alkylsulfonyl (groups) include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, and hexylsulfonyl.

[0061] In this specification, "C which may be substituted with halogen atoms" 1-6 "Alkylsulfonyl (group)" refers to the unsubstituted C 1-6 Alkyl sulfonyl group, or the C 1-6This refers to an alkylsulfonyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with halogens. Specifically, examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-chloroethylsulfonyl, 2-bromoethylsulfonyl, 2-iodoethylsulfonyl, 2-fluoroethylsulfonyl, 2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, pentafluoroethylsulfonyl, 2,2,3,3-tetrafluoropropylsulfonyl, 3,3,3-trifluoropropylsulfonyl, 4,4,4-trifluorobutylsulfonyl, 5,5,5-trifluoropentylsulfonyl, 6,6,6-trifluorohexylsulfonyl, and the like.

[0062] In this specification, "C 1-6 "Alkyl-carbonyl (group)" refers to the aforementioned C 1-6 This refers to a group in which an alkyl group is bonded to a carbonyl group. Specifically, examples include acetyl, ethyl carbonyl, propyl carbonyl, butyl carbonyl, pentyl carbonyl, and hexyl carbonyl.

[0063] In this specification, "C which may be substituted with halogen atoms" 1-6 "Alkyl-carbonyl (group)" refers to the unsubstituted C 1-6 Alkyl-carbonyl group, or the C 1-6This refers to an alkyl-carbonyl group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are substituted with halogens. Specifically, examples include acetyl, ethyl carbonyl, propyl carbonyl, butyl carbonyl, pentyl carbonyl, hexyl carbonyl, fluoromethyl carbonyl, difluoromethyl carbonyl, trifluoromethyl carbonyl, 2-chloroethyl carbonyl, 2-bromoethyl carbonyl, 2-iodoethyl carbonyl, 2-fluoroethyl carbonyl, 2,2-difluoroethyl carbonyl, 2,2,2-trifluoroethyl carbonyl, pentafluoroethyl carbonyl, 2,2,3,3-tetrafluoropropyl carbonyl, 3,3,3-trifluoropropyl carbonyl, 4,4,4-trifluorobutyl carbonyl, 5,5,5-trifluoropentyl carbonyl, 6,6,6-trifluorohexyl carbonyl, and the like.

[0064] In this specification, "C 1-6 "Alkoxy-carbonyl (group)" refers to the C 1-6 This refers to a group in which an alkoxy group is bonded to a carbonyl group. Specifically, examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

[0065] In this specification, "optionally substituted carbamoyl(group)" means a carbamoyl group (-CONH2) in which one or two hydrogen atoms may be independently substituted with other substituents (mono- or di-substituted carbamoyl group). Di-substituted carbamoyl groups also include 1-pyrrolidinylcarbonyl groups and 1-piperidylcarbonyl groups.

[0066] In this specification, "halogen atom, hydroxyl group, diC" refers to a halogen atom, a hydroxyl group, or diC. 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6A carbamoyl (group) which may be substituted with an alkyl group means that one or two hydrogen atoms of the carbamoyl group (-CONH2) are independently substituted with a halogen atom, a hydroxyl group, or diC. 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 This refers to a group that may be substituted with an alkyl group, preferably mono- or di-C. 1-6 It is an alkyl-carbamoyl group.

[0067] In this specification, "C 2-6 The "alkenyl group" is C 2-6 This refers to a monovalent group with 2 to 6 carbon atoms in a linear or branched chain, obtained by removing one hydrogen atom from any carbon atom of an alkene. Specifically, examples include vinyl, 1-propenyl, allyl, isopropenyl, butenyl, and isobutenyl.

[0068] In this specification, "C 2-6 The term "alkynyl group" refers to C 2-6 This refers to a monovalent group with 2 to 6 carbon atoms in a linear or branched chain, obtained by removing one hydrogen atom from any carbon atom of an alkyne. Specifically, examples include ethynyl, propargyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl.

[0069] In this specification, "aryl(group)" means a monocyclic or polycyclic (condensed) hydrocarbon group exhibiting aromaticity. In particular, C 6-14 An aryl group is preferred, C 6-10 An aryl group is more preferable.

[0070] In this specification, "C 6-14 Examples of "aryl (group)" include phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, phenanthryl, 2-anthuryl, and fluorenyl.

[0071] In this specification, "C 6-10Examples of "aryl(group)" include phenyl, 1-naphthyl, and 2-naphthyl, with phenyl being preferred.

[0072] In this specification, "aryl-carbonyl (group)" means a group in which the aryl group is bonded to a carbonyl group, and the range of carbon atoms is not particularly limited, but preferably C 6-14 It is an aryl-carbonyl group.

[0073] In this specification, "C 6-14 "Aryloxy (group)" refers to the above C 6-14 An aryl group refers to a group bonded to an oxygen atom. Specifically, examples include phenyloxy, 1-naphthyloxy, 2-naphthyloxy, biphenylyloxy, phenanthryloxy, and 2-anthryloxy. Among these, C 6-10 An aryloxy group is preferred, and a phenyloxy group is particularly preferred.

[0074] In this specification, "C 6-14 A "hydrocarbon ring (or group)" refers to a monovalent, saturated or partially unsaturated aliphatic hydrocarbon ring (or group) with 6 to 14 carbon atoms, or a monovalent aromatic hydrocarbon ring (or group) with 6 to 14 carbon atoms.

[0075] In this specification, "C 6-14 "Aryl sulfonyl (group)" refers to the C 6-14 An aryl group refers to a group in which an aryl group is bonded to the sulfur atom of a sulfonyl group (-S(=O)2-), and examples include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0076] In this specification, "C 6-14 "Aryl sulfonyl oxy (group)" refers to the above C 6-14 This refers to a group in which an aryl group is bonded to the sulfur atom of a sulfonyloxy group (-S(=O)2-O-), such as phenylsulfonyloxy, 1-naphthylsulfonyloxy, and 2-naphthylsulfonyloxy.

[0077] In this specification, "C 6-10The term "aryl-ethenyl group" refers to a group where the terminal hydrogen atom of the ethenyl group (-CH=CH2) is the same as the C group. 6-10 This refers to a group substituted with an aryl group, of which the 2-phenylethenyl group is preferred, and the 2-(E)-phenylethenyl group is particularly preferred.

[0078] In this specification, "(E)" in the chemical formula of each example compound or "(E)-" in the compound name indicates that the double bond configuration is the E configuration.

[0079] In this specification, "C 7-18 "Aralkyl (group)" refers to the aforementioned C 6-14 The aryl group is the C 1-4 This refers to a group bonded to an alkyl group, specifically, benzyl, phenethyl, naphthylmethyl, biphenylylmethyl, etc. Among these, C 7-10 Aralkyl groups are preferred, and benzyl groups are particularly preferred.

[0080] In this specification, "C 7-18 "Aralkyloxy (group)" refers to the above C 7-18 An aralkyl group refers to a group bonded to an oxygen atom. Specifically, examples include benzyloxy, phenethyloxy, naphthylmethyloxy, and biphenylylmethyloxy. Among these, the benzyloxy group is particularly preferred.

[0081] In this specification, "acyl(group)" means a formyl group, a linear or branched alkyl-carbonyl group, or an aryl-carbonyl group, and the carbon number range is not particularly limited, but preferably a formyl group, C 1-6 Alkyl-carbonyl group, or C 6-14 It is an aryl-carbonyl group. Suitable specific examples of acyl(groups) include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl (pivaloyl), hexanoyl, heptanol, benzoyl, 1-naphthoyl, 2-naphthoyl, and the like.

[0082] In this specification, "acyloxy(group)" means a group in which the acyl group is bonded to an oxygen atom, preferably C 1-6 Alkyl-carbonyloxy group, or C 6-14 It is an aryl-carbonyloxy group.

[0083] In this specification, "Di C 1-6 "Alkylamino (group)" refers to a group in which two hydrogen atoms of the amino group are the same or different. 1-6 This refers to a group substituted with an alkyl group.

[0084] In this specification, "C 1-6 "Alkylene (group)" refers to the above C 1-6 This refers to a divalent group formed by removing one hydrogen atom from an alkyl group. 1-6 Examples of alkylene groups include, for example, methylene, dimethylethylene, methylmethylene, dimethylmethylene, trimethylene, propane-1,2-diyl, tetramethylene, pentamethylene, isopentane-2,4-diyl, and hexamethylene.

[0085] In this specification, "C 6-10 "Arylene (group)" refers to the aforementioned "C 6-10 This refers to a divalent group formed by removing one hydrogen atom from an "aryl group". 6-10 Examples of allerene (groups) include 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene group, and 2,6-naphthylene.

[0086] In this specification, "C 2-6 "Alkenylene (group)" refers to the aforementioned "C 2-6 It refers to a divalent group obtained by removing one hydrogen atom from an "alkenyl group". In particular, C 2-3 Alkenylenes are preferred. 2-3 Examples of alkenylene groups include etenylene (-CH=CH-) and propenylene (-CH=CHCH2-).

[0087] In this specification, "C2-6 "Alkynylene (group)" refers to the above "C 2-6 It refers to a divalent group obtained by removing one hydrogen atom from an "alkynyl group". In particular, C 2-3 Alkynylene is preferred. 2-3 Examples of alkynylene (groups) include ethynylene (-C≡C-) and propynylene (-C≡C-CH2-).

[0088] In this specification, "C 3-14 "Cycloalkylene (group)" refers to the aforementioned "C 3-14 This refers to a divalent group obtained by removing one hydrogen atom from a "cycloalkyl group". In particular, C 3-8 Cycloalkylene is preferred. 3-8 Examples of cycloalkylene (groups) include, for example, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,3-diyl, bicyclo[2.1.1]hexane-1,2-diyl, and bicyclo[1.1.1]pentane-1,3-diyl.

[0089] In this specification, "3- to 14-membered divalent non-aromatic heterocycle (group)" means a divalent group obtained by removing one hydrogen atom from the "3- to 14-membered non-aromatic heterocycle (group)" described later. Among these, 3- to 8-membered divalent non-aromatic heterocycles are preferred. Specific examples of 3- to 8-membered divalent non-aromatic heterocycles (groups) include aziridine-1,2-diyl, oxetane-2,4-diyl, azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,2-diyl, piperidine-1,3-diyl, and piperidine-1,4-diyl.

[0090] In this specification, "C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 "An alkylylene group, or a divalent organic group comprising a 3- to 14-membered divalent non-aromatic heterocyclic group" refers to the above "C 1-6 Alkylene group, C 6-10 Allirene group, C3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 This refers to a divalent group having an alkynylene group or a 3- to 14-membered divalent non-aromatic heterocyclic group, and "C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 "Organic groups having an alkynylene group or a 3- to 14-membered divalent non-aromatic heterocyclic group" in the phrase "C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 The parts other than the "alkynylene group or the 3- to 14-membered divalent non-aromatic heterocyclic group" can be arbitrarily set. 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 A preferred example of a divalent organic group containing an alkynylene group or a 3- to 14-membered divalent non-aromatic heterocyclic group is, for example, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 C may each have an alkynylene group and one or more divalent groups selected from the group consisting of 3 to 14 membered divalent non-aromatic heterocyclic groups, either internally or at its terminal, and may each be further substituted with one to three substituents selected from the substituent group a. 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6Examples include an alkynylene group or a 3- to 14-membered divalent non-aromatic heterocyclic group. Here, the two bonds of the divalent (organic) group may originate from the same carbon atom or different carbon atoms in the (organic) group, or from the heteroatoms constituting the (organic) group. Also, in this specification, "C 3-10 Cycloalkylene group, C 2-4 "Alkenylene group" and "C 2-4 The term "alkynylene group" refers to the aforementioned "C 3-14 Cycloalkylene group, C 2-6 "Alkenylene group" and "C 2-6 It is synonymous with "alkylylene group" except for the difference in the range of carbon atoms.

[0091] In this specification, "heterocyclic group" refers to, for example, (i) aromatic heterocyclic groups and (ii) non-aromatic heterocyclic groups, each containing one to four heteroatoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms as ring constituent atoms, wherein (i) aromatic heterocyclic groups include 5 or 6-membered monocyclic aromatic heterocyclic groups and 8 to 14-membered fused aromatic heterocyclic groups, and (ii) non-aromatic heterocyclic groups include 3 to 10-membered monocyclic non-aromatic heterocyclic groups, 9 to 14-membered fused non-aromatic heterocyclic groups, 6 to 14-membered bridging cyclic non-aromatic heterocyclic groups and 6 to 16-membered spirocyclic non-aromatic heterocyclic groups.

[0092] In this specification, "aromatic heterocyclic group" refers, for example, to a 5- to 14-membered aromatic heterocyclic group containing, as ring constituent atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms.

[0093] Suitable 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, pyridadinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyridyl, phlopyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyradinyl, imidazopyrimidinyl, thienopyrimidinyl, phlopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl Examples include 8 to 14-membered condensed aromatic heterocyclic groups (condensed polycyclic (preferably 2 or 3-cyclic) aromatic heterocyclic groups) such as pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, prinyl, isoquinolyl, quinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, sinnolinyl, carbazolyl, β-carbolinyl, phenanthiinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0094] In this specification, "non-aromatic heterocyclic group" refers, for example, to a 3- to 14-membered non-aromatic heterocyclic group containing, as ring constituent atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms.

[0095] Suitable examples of the "non-aromatic heterocyclic group" include azilidinyl, oxyranil, thyranil, azetidinil, oxetanil, thietanil, tetrahydrothienyl, tetrahydrofuryl, pyrrolinil, pyrrolidinyl, imidazolinil, imidazolidinyl, oxazolinil, oxazolidinil, pyrazolidinil, pyrazolidinil, thiazolinil, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, and tetrahydroisoxazolyl. , piperidyl, piperazinyl, tetrahydropyridyl, dihydropyridyl, dihydrothiopyranil, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranil, tetrahydropyranil, tetrahydrothiopyranil, morpholinil, thiomorpholinil, azepanil, diazepanil, azepinyl, oxepanil, azocanil, diazocanil, etc. (preferably 5 to 8 membered monocyclic non-aromatic heterocyclic groups); Tetrahydrotriazolopyridyl, tetrahydrotriazolopyradinyl, tetrahydropyrazolopyrazinyl, dihydropyrazolopyraryl, dihydropyrazolopyrazinyl, tetrahydropyrazolopyrazinyl, tetrahydroimidazolopyrazinyl, dihydroimidazolopyrazinyl, dihydroimidazolopyraryl, dihydroimidazolopyraryl, tetrahydroimidazolopyrazinyl, dihydropyridopyraryl, dihydropyridopyraryl, tetrahydropyridopyrazinyl, tetrahydrooxazolopyradinyl, tetrahydropyridopyrazinyl, tetrahydrotriazolodiazepinyl, octahydro-1,4-oxazinopyrazinyl, dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzimidazolyl, dihydrobenzioxazolyl, dihydrobenziisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, dihydroisoquinolyl Examples include 8 to 14-membered condensed non-aromatic heterocyclic groups (condensed polycyclic (preferably bicyclic) non-aromatic heterocyclic groups) such as tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridyl, dihydrothiazolo[4,5-c]pyridyl, dihydrothiazolo[5,4-c]pyridyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenantridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthilidinyl, dihydronaphthilidinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0096] More preferred examples of the "non-aromatic heterocyclic group" include pyrrolidinyl, piperidyl, tetrahydrotriazolopyradinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyradinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyradinyl), tetrahydropyrazolopyrazinyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyradinyl), tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydroisoquinolyl), tetrahydronaphthilidinyl (e.g., 5,6,7,8-tetrahydro-1,6-naphthilidinyl, 1,2,3,4-tetrahydro-2,6-naphthilidinyl Examples include dinyl (1,2,3,4-tetrahydro-2,7-naphthilidinyl), dihydropyrazolopyrazinyl (e.g., dihydro-4H-pyrazolo[1,5-a]pyradinyl), dihydronaphthilidinyl (e.g., 6,8-dihydro-5H-2,7-naphthilidinyl), dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl), dihydrothiazolo[5,4-c]pyridyl (e.g., 6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridyl), dihydrothiazolo[4,5-c]pyridyl (e.g., 6,7-dihydro-4H-[1,3]thiazolo[4,5-c]pyridyl), and indolinyl (e.g., 2,3-dihydroindolyl).

[0097] Other preferred examples of the “non-aromatic heterocyclic group” include 6 to 14-membered cross-linked non-aromatic heterocyclic groups such as 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.2]octyl, 7-azabicyclo[2.2.1]heptanyl, and quinuclidinyl; and Examples include 6- to 16-membered spirocyclic non-aromatic heterocyclic groups such as 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[3.5]nonyl, and 2,6-diazaspiro[3.3]heptyl.

[0098] In this specification, "nitrogen-containing heterocyclic groups" include nitrogen-containing aromatic heterocyclic groups and nitrogen-containing non-aromatic heterocyclic groups.

[0099] In this specification, "nitrogen-containing aromatic heterocyclic group" or "nitrogen-containing non-aromatic heterocyclic group" means a group among the aromatic heterocyclic group or non-aromatic heterocyclic group that has at least one nitrogen atom as a ring constituent atom.

[0100] In this specification, "divalent nitrogen-containing aromatic heterocyclic group" means a divalent group obtained by removing one hydrogen atom from the "nitrogen-containing aromatic heterocyclic group".

[0101] In this specification, "divalent nitrogen-containing non-aromatic heterocyclic group" means a divalent group obtained by removing one hydrogen atom from the "nitrogen-containing non-aromatic heterocyclic group".

[0102] In this specification, "may be further substituted with one to three substituents selected from substituent group a (or substituent group b)" means that, in addition to the two bonds in the divalent group, one to three hydrogen atoms may be independently further substituted with one to three substituents selected from substituent group a (or substituent group b). If substituent group a' (or substituent group b') is adopted instead of substituent group a, this definition applies similarly, with substituent group a (or substituent group b) being read as substituent group a' (or substituent group b').

[0103] In this specification, “trisubstituted silyl(group)” means three identical or different substituents (e.g., C 1-6 Alkyl alkyl group, C 6-10 This refers to a silyl group substituted with an aryl group, and such groups include, for example, trialkylsilyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, and tert-butyldimethylsilyl (preferably triC 1-6 Examples include alkylsilyl groups, tert-butyldiphenylsilyl groups, and triphenylsilyl groups.

[0104] In this specification, "tri-substituted silyloxy (group)" means a group in which a tri-substituted silyl group is bonded to an oxygen atom, and such groups include, for example, trialkylsilyloxy groups such as trimethylsilyloxy group, triethylsilyloxy group, triisopropylsilyloxy group, and tert-butyldimethylsilyloxy group (preferably tri-C 1-6 Examples include alkylsilyloxy groups, tert-butyldiphenylsilyloxy groups, and triphenylsilyloxy groups.

[0105] In this specification, "biologically equivalent group" means, in the field of medicinal chemistry, a "functional group that exhibits broadly similar biological effects and has chemical and physical similarities," as proposed by Thornber in 1979. Examples of "biologically equivalent groups to carboxyl groups" include, for example, a substituted C 1-6 Alkoxy-carbonyl group, optionally substituted carbamoyl group, cyano group, the following formula:

[0106] [ka]

[0107] (In the formula, the dashed line represents the bonding site of the group represented by the above chemical formula, and * (This indicates the bonding position with L.) A group selected from the group consisting of the above, or its tautomer groups, etc., is an example, among which C may be substituted. 1-6 An alkoxy-carbonyl group or an optionally substituted carbamoyl group is preferred.

[0108] In this specification, “may be substituted” means either unsubstituted or substituted with a specific substituent at any substituted position (any hydrogen atom is replaced by a substituent). The “substituents” are not particularly limited, but include substituents selected from (substituent group a), (substituent group a'), (substituent group b), or (substituent group b') below. If no substituent group is specifically specified, it means that the substituent may be substituted with one or more substituents selected from (substituent group c) or (substituent group c') below. The number of substituents is not particularly limited as long as it is substituted, but is usually 1 to 5, preferably 1 to 3. If multiple substituents are present, each substituent may be identical or different.

[0109] (substituent group a): halogen atom; Hydroxyl group; Cyano group; Oxo group; Halogen atom, hydroxyl group, cyano group, C 1-6 Alkoxy group, C 6-14 Aryl group, carboxyl group, C 1-6 Alkoxy-carbonyl group, 1 or 2 C 1-6 A carbamoyl group which may be substituted with an alkyl group, and C 6-14 C may be substituted with substituents selected from the group consisting of aryloxy groups. 1-6 alkyl group; C that can be substituted with halogen atoms 1-6 Alkoxy group; C that can be substituted with halogen atoms 1-6 Alkyl sulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Halogen atom, hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyl groups that may be substituted with alkyl groups; Ji C 1-6 Alkylamino group; Tri-substituted silyl group; Tri-substituted silyloxy group; C may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'. 6-14 Hydrocarbon ring group; A 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and A 3- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'.

[0110] (substituent group a'): halogen atom; Hydroxyl group; Cyano group; Oxo group; Halogen atom, hydroxyl group, cyano group, C 1-6 Alkoxy group, C 6-14 Aryl group, and C 6-14 C may be substituted with substituents selected from the group consisting of aryloxy groups. 1-6 alkyl group; C that can be substituted with halogen atoms 1-6 Alkoxy group; C that can be substituted with halogen atoms 1-6 Alkyl sulfonyl group; C 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Halogen atom, hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyl groups that may be substituted with alkyl groups; Ji C 1-6 Alkylamino group; Tri-substituted silyl group; Tri-substituted silyloxy group; C may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'. 6-14 Hydrocarbon ring group; A 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and A 3- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'.

[0111] (substituent group b): halogen atom; Hydroxyl group; Cyano group; Oxo group; Carboxy group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 1-6 alkyl group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 3-8 Cycloalkyl groups; Halogen atom, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 6-10 Aryl group; Halogen atom, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 A 5- to 14-membered aromatic heterocyclic group which may be substituted with substituents selected from the group consisting of alkoxy groups; Halogen atom, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 A 3- to 14-membered non-aromatic heterocyclic group which may be substituted with substituents selected from the group consisting of alkoxy groups; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 1-6 Alkoxy group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 1-6 Alkyl sulfanyl group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 3-8 Cycloalkyloxy group; C that can be substituted with halogen atoms 1-6 Alkyl sulfonyl group; C that can be substituted with halogen atoms 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Halogen atom, hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyl groups that may be substituted with alkyl groups; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 Each of the C atoms may be substituted with one to three substituents selected from the group consisting of alkoxy groups. 1-6 Alkyl alkyl group, C 3-8 A sulfamoyl group substituted with one substituent selected from the group consisting of cycloalkyl groups and non-aromatic heterocyclic groups; and Pentafluorosulfanyl group.

[0112] (substituent group b'): halogen atom; Hydroxyl group; Cyano group; Oxo group; Carboxy group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 1-6 alkyl group; Halogen atoms, hydroxyl groups, cyano groups, and C1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 3-8 Cycloalkyl groups; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 1-6 Alkoxy group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 1-6 Alkyl sulfanyl group; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 C may be substituted with substituents selected from the group consisting of alkoxy groups. 3-8 Cycloalkyloxy group; C that can be substituted with halogen atoms 1-6 Alkyl sulfonyl group; C that can be substituted with halogen atoms 1-6 Alkyl-carbonyl group; C 1-6 Alkoxy-carbonyl group; Halogen atom, hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyl groups that may be substituted with alkyl groups; Halogen atoms, hydroxyl groups, cyano groups, and C 1-6 Each of the C atoms may be substituted with one to three substituents selected from the group consisting of alkoxy groups. 1-6 Alkyl alkyl group, C 3-8 A sulfamoyl group substituted with one substituent selected from the group consisting of cycloalkyl groups and non-aromatic heterocyclic groups; and Pentafluorosulfanyl group.

[0113] (substituent group c): halogen atom; Hydroxyl group; Carboxy group; Nitro group; Cyano group; C 1-6 Alkyl and C 1-6 An amino group which may be substituted with one or two substituents selected from the group consisting of alkoxy-carbonyl groups; C may be substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 alkyl group; C may be substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 Alkoxy group; C 1-6 Alkoxy-carbonyl group; C may be substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 Alkyl sulfonyl group; C may be substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-8 Cycloalkyl groups; An acyl group which may be substituted with one to three substituents selected from substituent group a or substituent group a'; An acyloxy group which may be substituted with one to three substituents selected from substituent group a or substituent group a'; C may be substituted with 1 to 3 substituents selected from substituent group b. 6-14 Aryl group; C may be substituted with 1 to 3 substituents selected from substituent group b. 6-14 Aryloxy group; C may be substituted with 1 to 3 substituents selected from substituent group b. 6-14 Aryl sulfonyl group; C may be substituted with 1 to 3 substituents selected from substituent group b. 6-14 Aryl sulfonyl oxy group; C may be substituted with 1 to 3 substituents selected from substituent group b. 7-18 Aralkyl group; C may be substituted with 1 to 3 substituents selected from substituent group b. 7-18 Aralkyloxy group; Hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyl groups that may be substituted with alkyl groups; Hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyloxy groups that may be substituted with alkyl groups; Oxo group; Thioxo group; Mono- or di-C 1-6 Alkylamino group; Azide group; Tri-substituted silyl group; Tri-substituted silyloxy group; Aromatic heterocyclic groups which may be substituted with one to three substituents selected from substituent group b; and A non-aromatic heterocyclic group which may be substituted with one to three substituents selected from substituent group b.

[0114] (substituent group c'): halogen atom; Hydroxyl group; Carboxy group; Nitro group; Cyano group; C 1-6 Alkyl and C 1-6 An amino group which may be substituted with one or two substituents selected from the group consisting of alkoxy-carbonyl groups; C may be substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 alkyl group; C may be substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 Alkoxy group; C 1-6 Alkoxy-carbonyl group; C may be substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 Alkyl sulfonyl group; C may be substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-8 Cycloalkyl groups; An acyl group which may be substituted with one to three substituents selected from substituent group a or substituent group a'; An acyloxy group which may be substituted with one to three substituents selected from substituent group a or substituent group a'; C may be substituted with 1 to 3 substituents selected from substituent group b. 6-14 Aryl group; C may be substituted with 1 to 3 substituents selected from substituent group b'. 6-14 Aryloxy group; C may be substituted with 1 to 3 substituents selected from substituent group b'. 6-14 Aryl sulfonyl group; C may be substituted with 1 to 3 substituents selected from substituent group b'. 6-14 Aryl sulfonyl oxy group; C may be substituted with 1 to 3 substituents selected from substituent group b'. 7-18 Aralkyl group; C may be substituted with 1 to 3 substituents selected from substituent group b'. 7-18 Aralkyloxy group; Hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyl groups that may be substituted with alkyl groups; Hydroxyl group, diC 1-6 Alkylamino group and C 1-6 1 to 2 C atoms which may be substituted with substituents selected from the group consisting of alkoxy groups 1-6 Carbamoyloxy groups that may be substituted with alkyl groups; Oxo group; Thioxo group; Mono- or di-C 1-6 Alkylamino group; Azide group; Tri-substituted silyl group; Tri-substituted silyloxy group; Aromatic heterocyclic groups which may be substituted with one to three substituents selected from substituent group b'; and A non-aromatic heterocyclic group which may be substituted with one to three substituents selected from substituent group b'.

[0115] In this specification, "pharmaceutically acceptable salt" means a salt that can be used as a medicine. When compound (I) of the present invention has an acidic group or a basic group, it can be reacted with a base or an acid to form a basic salt or an acidic salt, and the salt is indicated accordingly. The salt is preferably water-soluble.

[0116] Examples of pharmaceutically acceptable "basic salts" of compound (I) of the present invention include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salts such as ammonium salt and tetramethylammonium salt; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, and picoline salt; and basic amino acid salts such as lysine salt and arginine salt. Preferably, alkali metal salts (especially sodium salt or potassium salt) and basic amino acid salts are used.

[0117] Examples of pharmaceutically acceptable "acidic salts" of compound (I) of the present invention include hydrohalides such as hydrofluoric acid, hydrochloride, hydrobromide, and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates, and phosphates; lower alkanesulfonates such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; arylsulfonates such as benzenesulfonates and p-toluenesulfonates; organic salts such as acetates, malates, fumarates, succinates, citrates, ascorbic acid, tartrates, oxalates, and maleates. Preferably, hydrohalides (especially hydrochlorides) are used.

[0118] In this specification, “the salt” means all salts, including “the pharmaceutically acceptable salt” as defined above.

[0119] In this specification, “prevention” includes the prevention of disease onset, the delay of disease onset, and the prevention of disease development. “Prophylactic effective dose” means a dose of the active ingredient sufficient to achieve the preventive purpose.

[0120] In this specification, “treatment” includes the cure of a disease, the improvement of the pathology of a disease (e.g., one or more symptoms), and the suppression of the progression of a disease (or its severity). “Therapeutic effective dose” means a dose of the active ingredient sufficient to achieve the therapeutic objective. Therefore, “improvement” is a concept encompassed within “treatment.”

[0121] In this specification, “Subject” means a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of an active ingredient necessary to prevent and / or treat (or improve) a disease or the pathophysiology of a disease is administered. Such “Subject” may be a human or a non-human animal, and in particular a mammal (e.g., a human, mouse, rat, guinea pig, hamster, rabbit, cat, dog, cattle, sheep, monkey, etc.).

[0122] In this specification, "B0AT1 inhibitor" means a drug comprising a compound that inhibits B0AT1, a transporter responsible for the reabsorption of neutral amino acids such as phenylalanine in the kidney. In particular, compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, exhibits excellent inhibitory activity against B0AT1. The inhibitory activity against B0AT1 can be measured, for example, by the method described in Non-Patent Document 11 (SLAS Discovery, 2019; 24(2): p.111-120) or by the method described in the test examples below.

[0123] In this specification, "diseases whose symptoms can be alleviated by B0AT1 inhibition" means diseases caused by elevated levels of neutral amino acids in the blood due to mutations in genes related to amino acid metabolic pathways, etc. Specifically, such diseases include amino acid metabolic disorders such as phenylketonuria, urea cycle disorders, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[0124] (The compound of the present invention (compound (I))) The following describes each group in formula (I) of compound (I).

[0125] R 1 This represents a carboxyl group, or a group that is biologically equivalent to a carboxyl group.

[0126] R 1 Preferably, a carboxyl group, or a substituted C 1-6 An alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or the following formula:

[0127] [ka]

[0128] (In the formula, the dashed line represents the bonding site of the group represented by the above chemical formula, and * (This indicates the bonding position with L.) A group selected from the group consisting of the following, or a tautomer group thereof, More preferably, a carboxyl group, or a substituted C 1-6 This is an alkoxy-carbonyl group, or a carbamoyl group which may be substituted.

[0129] L may be further substituted, C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 This represents a divalent organic group containing an alkynylene group and a group selected from the group consisting of 3 to 14-membered divalent non-aromatic heterocyclic groups.

[0130] L is preferably -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 C may each have one or more divalent groups selected from the group consisting of an alkynylene group and a 3 to 14-membered divalent non-aromatic heterocyclic group, either internally or at its terminal, and may each be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 An alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group, More preferably, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 6-10Arylene group (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene), C 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), C 2-6 C may have an alkynylene group and one or more divalent non-aromatic heterocyclic groups of 3 to 8 members selected from the group consisting of azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepane-1,2-diyl, and may be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 6-10 Arylene group (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene), C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 2-4 Alkynylene group, or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. And, More preferably, -NR2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ), -O-, -S-, C 3-10 C may have one or more divalent groups selected from the group consisting of cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3 to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) internally or at its terminal, and may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepane-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a', Particularly preferably, C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 It is an alkylene group.

[0131] A represents a divalent nitrogen-containing heterocyclic group that may be further substituted.

[0132] A may preferably be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown below:

[0133] [ka]

[0134] (In the formula, ** This represents the bonding site with the carbonyl group. *** This represents the bonding site with group L, and ring A 1 This represents a monoring of 3 to 10 members, a fused ring of 8 to 14 members, a spiroring of 6 to 16 members, or a bridging ring of 6 to 14 members, and may include, in addition to nitrogen and carbon atoms, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by , In one more preferred embodiment, the following formula may be further substituted with one to three substituents selected from substituent group a or substituent group a':

[0135] [ka]

[0136] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0137] [ka]

[0138] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0139] [ka]

[0140] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by , In another, more preferred embodiment, the following formula may be further substituted with one to three substituents selected from substituent group a or substituent group a':

[0141] [ka]

[0142] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0143] [ka]

[0144] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0145] [ka]

[0146] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by , More preferably, the following formula may be further substituted with one to three substituents selected from substituent group a or substituent group a':

[0147] [ka]

[0148] (The definitions of each symbol in the formula are the same as those given above.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0149] [ka]

[0150] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by , More preferably, the following formula may be further substituted with one to three substituents selected from substituent group a or substituent group a':

[0151] [ka]

[0152] (The definitions of each symbol in the formula are the same as those given above.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0153] [ka]

[0154] (The definitions of each symbol in the formula are the same as above. However, Z is CR 5 R 6 If this is the case, the substituents that may be further substituted may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b' among the substituents of substituent group a or substituent group a'. 6-14 Selected from the group consisting of hydrocarbon ring groups; 5- to 14-membered aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and 3- to 14-membered non-aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by , Particularly preferably, the following formula may be further substituted with one to three substituents selected from substituent group a or substituent group a':

[0155] [ka]

[0156] (The definitions of each symbol in the formula are the same as those given above.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (preferably further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0157] [ka]

[0158] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by .

[0159] R may be substituted with C 6-10 This represents an aryl-ethenyl group.

[0160] R is preferably a halogen atom, and C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, may be substituted C 3-8 Cycloalkyloxy group, may be substituted C 1-6 Alkylsulfanyl group, may be substituted C 3-8 A 2-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of cycloalkylsulfanyl groups and pentafluorosulfanyl groups, More preferably, a halogen atom, or a C atom which may be substituted with a halogen atom. 1-6The 2-(E)-phenylethenyl group may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups.

[0161] The following compounds are preferred as compound (I): [Compound (IA)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or the following formula:

[0162] [ka]

[0163] (In the formula, the dashed line represents the bonding site of the group represented by the above chemical formula, and * (This indicates the bonding position with L.) A group selected from the group consisting of the following, or a tautomer group thereof; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 C may each have one or more divalent groups selected from the group consisting of an alkynylene group and a 3 to 14-membered divalent non-aromatic heterocyclic group, either internally or at its terminal, and may each be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 An alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0164] [ka]

[0165] (In the formula, ** This represents the bonding site with the carbonyl group. *** This represents the bonding site with group L, and ring A 1 This represents a monoring of 3 to 10 members, a fused ring of 8 to 14 members, a spiroring of 6 to 16 members, or a bridging ring of 6 to 14 members, and may include, in addition to nitrogen and carbon atoms, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, may be substituted C 3-8 Cycloalkyloxy group, may be substituted C 1-6 Alkylsulfanyl group, may be substituted C 3-8 A 2-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of cycloalkylsulfanyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0166] [Compound (IB)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 C may each have one or more divalent groups selected from the group consisting of an alkynylene group and a 3 to 14-membered divalent non-aromatic heterocyclic group, either internally or at its terminal, and may each be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 An alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0167] [ka]

[0168] (In the formula, ** This represents the bonding site with the carbonyl group. *** This represents the bonding site with group L, and ring A 1 This represents a monoring of 3 to 10 members, a fused ring of 8 to 14 members, a spiroring of 6 to 16 members, or a bridging ring of 6 to 14 members, and may include, in addition to nitrogen and carbon atoms, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, may be substituted C 3-8 Cycloalkyloxy group, may be substituted C 1-6 Alkylsulfanyl group, may be substituted C3-8 A 2-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of cycloalkylsulfanyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0169] [Compound (IC)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or the following formula:

[0170] [ka]

[0171] (In the formula, the dashed line represents the bonding site of the group represented by the above chemical formula, and * (This indicates the bonding position with L.) A group selected from the group consisting of the following, or a tautomer group thereof; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 6-10 Arylene group (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene), C 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), C 2-6C may have an alkynylene group and one or more divalent non-aromatic heterocyclic groups of 3 to 8 members selected from the group consisting of azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepane-1,2-diyl, and may be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 6-10 Arylene group (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene), C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 2-4 Alkynylene group, or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. and; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0172] [ka]

[0173] (In the formula, **This represents the bonding site with the carbonyl group. *** This represents the bonding site with group L, and ring A 1 This represents a monoring of 3 to 10 members, a fused ring of 8 to 14 members, a spiroring of 6 to 16 members, or a bridging ring of 6 to 14 members, and may include, in addition to nitrogen and carbon atoms, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, may be substituted C 3-8 Cycloalkyloxy group, may be substituted C 1-6 Alkylsulfanyl group, may be substituted C 3-8 A 2-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of cycloalkylsulfanyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0174] [Compound (ID)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or the following formula:

[0175] [ka]

[0176] (In the formula, the dashed line represents the bonding site of the group represented by the above chemical formula, and * (This indicates the bonding position with L.) A group selected from the group consisting of the following, or a tautomer group thereof; L, -NR 2 -(Here, R2 is a hydrogen atom or C 1-6 Represents alkyl groups. ), -O-, -S-, C 3-10 C may have one or more divalent groups selected from the group consisting of cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3 to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) internally or at its terminal, and may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 The alkylene group may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. and; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0177] [ka]

[0178] (In the formula, ** This represents the bonding site with the carbonyl group. ***This represents the bonding site with group L, and ring A 1 This represents a monoring of 3 to 10 members, a fused ring of 8 to 14 members, a spiroring of 6 to 16 members, or a bridging ring of 6 to 14 members, and may include, in addition to nitrogen and carbon atoms, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, may be substituted C 3-8 Cycloalkyloxy group, may be substituted C 1-6 Alkylsulfanyl group, may be substituted C 3-8 A 2-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of cycloalkylsulfanyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0179] [Compound (IE)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or the following formula:

[0180] [ka]

[0181] (In the formula, the dashed line represents the bonding site of the group represented by the above chemical formula, and * (This indicates the bonding position with L.) A group selected from the group consisting of the following, or a tautomer group thereof; L may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 It is an alkylene group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0182] [ka]

[0183] (In the formula, ** This represents the bonding site with the carbonyl group. *** This represents the bonding site with group L, and ring A 1 This represents a monoring of 3 to 10 members, a fused ring of 8 to 14 members, a spiroring of 6 to 16 members, or a bridging ring of 6 to 14 members, and may include, in addition to nitrogen and carbon atoms, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, may be substituted C 3-8 Cycloalkyloxy group, may be substituted C 1-6 Alkylsulfanyl group, may be substituted C 3-8 A 2-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of cycloalkylsulfanyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0184] [Compounds (IF)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or the following formula:

[0185] [ka]

[0186] (In the formula, the dashed line represents the bonding site of the group represented by the above chemical formula, and * (This indicates the bonding position with L.) A group selected from the group consisting of the following, or a tautomer group thereof; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 C may each have one or more divalent groups selected from the group consisting of an alkynylene group and a 3 to 14-membered divalent non-aromatic heterocyclic group, either internally or at its terminal, and may each be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 An alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0187] [ka]

[0188] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0189] [ka]

[0190] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0191] [ka]

[0192] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 1-6 Alkoxy group, may be substituted C 3-8 Cycloalkyloxy group, may be substituted C 1-6 Alkylsulfanyl group, may be substituted C 3-8A 2-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of cycloalkylsulfanyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0193] [Compounds (IF')] A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0194] [ka]

[0195] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0196] [ka]

[0197] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0198] [ka]

[0199] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and The definitions of the other symbols are the same as those for [Compound (IF)] above. Compound (I) or a pharmaceutically acceptable salt thereof.

[0200] [Compound (IG)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or the following formula:

[0201] [ka]

[0202] (In the formula, the dashed line represents the bonding site of the group represented by the above chemical formula, and * (This indicates the bonding position with L.) A group selected from the group consisting of the following, or a tautomer group thereof; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6C may each have one or more divalent groups selected from the group consisting of an alkynylene group and a 3 to 14-membered divalent non-aromatic heterocyclic group, either internally or at its terminal, and may each be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 An alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0203] [ka]

[0204] (In the formula, ** This represents the bonding site with the carbonyl group. *** This represents the bonding site with group L, and ring A 1 This represents a monoring of 3 to 10 members, a fused ring of 8 to 14 members, a spiroring of 6 to 16 members, or a bridging ring of 6 to 14 members, and may include, in addition to nitrogen and carbon atoms, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0205] [Compound (IH)] R 1 However, the carboxyl group may be substituted. 1-6An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 6-10 Arylene group (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene), C 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), C 2-6 C may have an alkynylene group and one or more divalent non-aromatic heterocyclic groups of 3 to 8 members selected from the group consisting of azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepane-1,2-diyl, and may be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 6-10 Arylene group (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene), C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 2-4 Alkynylene group, or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. and; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0206] [ka]

[0207] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0208] [ka]

[0209] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0210] [ka]

[0211] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0212] [Compound (IH')] A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0213] [ka]

[0214] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0215] [ka]

[0216] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0217] [ka]

[0218] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and The definitions of the other symbols are the same as those for [compound (IH)] above. Compound (I) or a pharmaceutically acceptable salt thereof.

[0219] [Compound (IJ)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ), -O-, -S-, C 3-10C may have one or more divalent groups selected from the group consisting of cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3 to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) internally or at its terminal, and may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 The alkylene group may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), or 3 to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. and; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0220] [ka]

[0221] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0222] [ka]

[0223] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0224] [ka]

[0225] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0226] [Compound (IJ')] A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0227] [ka]

[0228] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0229] [ka]

[0230] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0231] [ka]

[0232] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and The definitions of the other symbols are the same as those for [compound (IJ)] above. Compound (I) or a pharmaceutically acceptable salt thereof.

[0233] [Compounds (IK)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 It is an alkylene group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0234] [ka]

[0235] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0236] [ka]

[0237] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0238] [ka]

[0239] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0240] [Compound (IK')] A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0241] [ka]

[0242] (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.)

[0243] [ka]

[0244] The bonds indicated by represent single or double bonds, and Y independently represents either a nitrogen atom or a CR. 3 (Here, R 3 is a hydrogen atom or C 1-6 It represents an alkyl group. Z represents an oxygen atom, a sulfur atom, and NR. 4 or CR 5 R 6 (Here, R 4 , R 5 and R 6 Each of these is independently a hydrogen atom or C 1-6 Represents an alkyl group. ) where n represents an integer from 0 to 2, and m represents an integer from 0 to 2, n 1 and n 2 Each of these independently represents an integer between 0 and 2, and m 1 and m 2 Each of these independently represents an integer between 0 and 2. ** represents the bonding site with the carbonyl group, and *** (This represents the binding site with group L.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0245] [ka]

[0246] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and The definitions of the other symbols are the same as those for [compound (IK)] above. Compound (I) or a pharmaceutically acceptable salt thereof.

[0247] [Compound (IL)] R 1However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 6-10 Arylene group (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene), C 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), C 2-6 C may have an alkynylene group and one or more divalent non-aromatic heterocyclic groups of 3 to 8 members selected from the group consisting of azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepane-1,2-diyl, and may be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 6-10 Arylene group (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene), C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), C may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 2-4 Alkynylene group, or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. and; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0248] [ka]

[0249] (The definitions of each symbol in the formula are the same as those given above.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0250] [ka]

[0251] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0252] [Compounds (IM)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ), -O-, -S-, C 3-10 C may have one or more divalent groups selected from the group consisting of cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3 to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) internally or at its terminal, and may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 The alkylene group may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0253] [ka]

[0254] (The definitions of each symbol in the formula are the same as those given above.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0255] [ka]

[0256] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0257] [Compounds (IN)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 It is an alkylene group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0258] [ka]

[0259] (The definitions of each symbol in the formula are the same as those given above.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0260] [ka]

[0261] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0262] [Compound (IP)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ) -O-, -S-, -C(=O)-, C 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 C may each have one or more divalent groups selected from the group consisting of an alkynylene group and a 3 to 14-membered divalent non-aromatic heterocyclic group, either internally or at its terminal, and may each be further substituted with one to three substituents selected from substituent group a or substituent group a'. 1-6 Alkylene group, C 6-10 Allirene group, C 3-14 Cycloalkylene group, C 2-6 Alkenylene group, C 2-6 An alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0263] [ka]

[0264] (The definitions of each symbol in the formula are the same as those given above.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0265] [ka]

[0266] (The definitions of each symbol in the formula are the same as above. However, Z is CR 5 R 6 If this is the case, the substituents that may be further substituted may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b' among the substituents of substituent group a or substituent group a'. 6-14 Selected from the group consisting of hydrocarbon ring groups; 5- to 14-membered aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and 3- to 14-membered non-aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0267] [Compounds (IQ)] R 1 However, the carboxyl group may be substituted. 1-6An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ), -O-, -S-, C 3-10 C may have one or more divalent groups selected from the group consisting of cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3 to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) internally or at its terminal, and may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 The alkylene group may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. and; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0268] [ka]

[0269] (The definitions of each symbol in the formula are the same as those given above.) A divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula (e.g., may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'):

[0270] [ka]

[0271] (The definitions of each symbol in the formula are the same as above. However, Z is CR 5 R 6 If this is the case, the substituents that may be further substituted may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b' among the substituents of substituent group a or substituent group a'. 6-14 Selected from the group consisting of hydrocarbon ring groups; 5- to 14-membered aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'; and 3- to 14-membered non-aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b or substituent group b'. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0272] [Compounds (IR)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L, -NR 2 -(Here, R 2 is a hydrogen atom or C1-6 Represents alkyl groups. ), -O-, -S-, C 3-10 C may have one or more divalent groups selected from the group consisting of cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3 to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) internally or at its terminal, and may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 The alkylene group may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. and; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0273] [ka]

[0274] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R is a 2-(E)-phenylethenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group which may be substituted with a halogen atom, and a pentafluorosulfanyl group; Compound (I) or a pharmaceutically acceptable salt thereof.

[0275] [Compound (IS)] R 1 is a carboxy group, a C 1-6 alkoxy-carbonyl group which may be substituted, or a carbamoyl group which may be substituted; L is a C 1-6 alkylene group which may be further substituted with 1 to 3 substituents selected from the group a or group a'; A is a divalent nitrogen-containing non-aromatic heterocyclic group represented by the following formula, which may be further substituted with 1 to 3 substituents selected from the group a or group a':

[0276] [Chemical formula]

[0277] (The definitions of each symbol in the formula are the same as those described above.) and; R is a 2-(E)-phenylethenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group which may be substituted with a halogen atom, and a pentafluorosulfanyl group; Compound (I) or a pharmaceutically acceptable salt thereof.

[0278] [Compound (IT)] R 1 is a carboxy group, a C 1-6 alkoxy-carbonyl group which may be substituted, or a carbamoyl group which may be substituted; L is -NR 2 -(where R2 is a hydrogen atom or C 1-6 Represents alkyl groups. ), -O-, -S-, C 3-10 C may have one or more divalent groups selected from the group consisting of cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3 to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) internally or at its terminal, and may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 The alkylene group may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. and; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0279] [ka]

[0280] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0281] [Compound (IU)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 It is an alkylene group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0282] [ka]

[0283] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0284] [Compound (IV)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L, -NR 2 -(Here, R 2 is a hydrogen atom or C 1-6 Represents alkyl groups. ), -O-, -S-, C 3-10 C may have one or more divalent groups selected from the group consisting of cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl) and 3 to 8-membered divalent non-aromatic heterocyclic groups (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) internally or at its terminal, and may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 The alkylene group may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 3-10 Cycloalkylene groups (e.g., cyclobutane-1,3-diyl, cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,2-diyl, cyclohexane-1,2-diyl, bicyclo[2.1.1]hexane-1,2-diyl), or A 3 to 8-membered divalent non-aromatic heterocyclic group (e.g., azetidine-1,3-diyl, pyrrolidine-1,3-diyl, pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,4-diyl, azepan-1,2-diyl) which may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. and; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0285] [ka]

[0286] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0287] [Compound (IW)] R 1 However, the carboxyl group may be substituted. 1-6 An alkoxy-carbonyl group, or a carbamoyl group which may be substituted; L may be further substituted with 1 to 3 substituents selected from substituent group a or substituent group a'. 1-6 It is an alkylene group; A may be further substituted with one to three substituents selected from substituent group a or substituent group a', as shown in the following formula:

[0288] [ka]

[0289] (The definitions of each symbol in the formula are the same as those given above.) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by; and R may be a halogen atom, or C may be substituted with a halogen atom. 1-6 A 2-(E)-phenylethenyl group which may be substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups. Compound (I) or a pharmaceutically acceptable salt thereof.

[0290] Specific examples of suitable compound (I) are the compounds of Examples 1 to 403 described later (compounds (I-1) to (I-403)), or pharmaceutically acceptable salts thereof. In particular, 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 3-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; N,N-dimethyl-3-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl]propanamide; 1-[7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,8-dihydro-5H-2,7-naphthyridine-3-yl]piperidine-4-carboxylic acid; 3-[3-bromo-5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl]propanoic acid; 2-[[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]oxy]acetic acid; 2-[2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; (1R*,2R*)-2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]cyclopropane-1-carboxylic acid and both enantiomers; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[7-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,8-dihydro-5H-2,7-naphthyridine-3-yl]acetic acid; 3-[3-bromo-5-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl]propanoic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]aminoacetic acid; 2-[2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-cyano-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-(2-fluoro-4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-yl]sulfanyl]acetic acid; 2-[7-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-cyano-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; (E)-N-[2-[6-(2-amino-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide; 2-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-[1,3]thiazolo[4,5-c]pyridine-2-yl]acetic acid; (E)-N-[2-[6-[2-(methylamino)-2-oxoethyl]-3,4-dihydro-1H-isoquinoline-2-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide; 4-[4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3-phenylpiperazine-1-yl]butanoic acid and both enantiomers; 2-[[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2,3-dihydroindole-4-yl]oxy]acetic acid; 1-[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperidine-3-yl]bicyclo[2.1.1]hexane-5-carboxylic acid; 2-[[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]oxy]-2-methylpropanoic acid; 3-[[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]oxy]-2,2-dimethylpropanoic acid; 4-[4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(3-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 3-[[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]methyl]cyclobutane-1-carboxylic acid and both enantiomers; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]-2,2-dimethylbutanoic acid; 4-[3-(3-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid and both enantiomers; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chloro-3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-2-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(triflu Oromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]2-methyl-5-phenylpiperazine-1-yl]-2,2-dimethylbutanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, More preferably, 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 3-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; N,N-dimethyl-3-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl]propanamide; 2-[2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; (1R*,2R*)-2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]cyclopropane-1-carboxylic acid and both enantiomers; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[7-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-cyano-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-(2-fluoro-4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[7-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-[1,3]thiazolo[4,5-c]pyridine-2-yl]acetic acid; 4-[(3S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3-phenylpiperazine-1-yl]butanoic acid; 1-[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperidine-3-yl]bicyclo[2.1.1]hexane-5-carboxylic acid; 4-[(3S)-3-(4-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(3-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 3-[[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]methyl]cyclobutane-1-carboxylic acid and both enantiomers; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid and both enantiomers; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chloro-3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-4-[2-[[(E)-3-[2-F Luoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-2-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]pipette Radin-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine- 1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(triflu Oromethyl)phenyl]prop-2-enoyl]aminoacetyl]-5-phenylpiperazi [n-1-yl]butanoic acid; and 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]2-methyl-5-phenylpiperazine-1-yl]-2,2-dimethylbutanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, More preferably, 2-[7-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[7-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 4-[(3S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3-phenylpiperazine-1-yl]butanoic acid; 1-[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperidine-3-yl]bicyclo[2.1.1]hexane-5-carboxylic acid; 4-[(3S)-3-(4-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(3-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-2-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]2-methyl-5-phenylpiperazine-1-yl]-2,2-dimethylbutanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, Particularly preferred is 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 3-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; N,N-dimethyl-3-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl]propanamide; 2-[2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 4-[(3R)-3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[0291] Compound (I) of the present invention, if it has a chiral carbon atom in its molecule, may exist as multiple stereoisomers (i.e., diastereomers, optical isomers) based on that chiral carbon atom. However, the present invention encompasses either any one of these stereoisomers, or a mixture containing any multiple stereoisomers in any proportion. Furthermore, isomers may be generated by conformation or tautomerism, and such isomers or mixtures thereof are also included in Compound (I) of the present invention.

[0292] Compound (I) of the present invention contains isotopes (for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 F, 32 P, 35 S, 123 I, 125 I, 131 Compounds labeled or substituted with isotopes such as I can be used, for example, as tracers (PET tracers) in single-photon emission computed tomography (SPECT) and positron emission tomography (PET), and are useful in fields such as medical diagnosis.

[0293] Compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be crystalline, and may be a single crystalline form or a mixture of multiple crystalline forms.

[0294] Compound (I) of the present invention, or its pharmaceutically acceptable salts, may also include its intramolecular salts, adducts, and solvates thereof. These solvates are compounds in which a solvent molecule is coordinated to compound (I) or its salt, and hydrates are also included. Examples include hydrates, ethanolic dihydrates, or dimethyl sulfoxide dihydrates of compound (I) or its salt.

[0295] Compound (I) of the present invention may also be a prodrug.

[0296] A prodrug of compound (I) of the present invention refers to a compound that is converted to compound (I) in the body by a reaction involving enzymes or gastric acid. A prodrug of compound (I) may be a monoester or diester of a phosphate group, preferably having a structure in which the ester functional group is easily hydrolyzed or metabolized after administration to a patient. Specific examples of such a prodrug ester functional group include, for example, a C group that may be substituted with an acyloxy group. 1-6 Examples include alkyl esters, phenyl esters, and benzyl esters (see Bioorganic Chemistry, 1984; 12: pp. 118-129). Other prodrugs besides the monoesters or diesters of the phosphate group mentioned above include compounds having phosphate-derived groups, as described in Current Opinion in Investigational Drugs, 2006; 7: pp. 109-117, J. Med. Chem. 1994; 37: pp. 1857-1864, and J. Med. Chem. 2000; 43: pp. 4570-4574. Another embodiment of the prodrug of compound (I) is, for example, a compound in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (e.g., a compound in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); or a compound in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., a compound in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, or pivaloylated). Examples include compounds that have been succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated; if compound (I) has a carboxyl group, examples include compounds in which the carboxyl group has been esterified or amidated (for example, compounds in which the carboxyl group of compound (I) has been ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolenn-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, or methylamidated). These compounds can be produced by known methods. Furthermore, the prodrug of compound (I) may be either a hydrate or an unhydrated form. Furthermore, the prodrug of compound (I) may be one that transforms into the compound represented by compound (I) under physiological conditions, as described on pages 163-198 of "Molecular Design," Volume 7 of "Pharmaceutical Development," published by Hirokawa Shoten in 1990.

[0297] (Method for producing compound (I) of the present invention) The following describes a method for producing compound (I) or a pharmaceutically acceptable salt thereof of the present invention. Representative manufacturing methods (A) to (F) of compound (I) are described below as examples, but the manufacturing methods are not limited to these. Furthermore, the following manufacturing methods and processes may be combined with each other. Compound (I) (for example, compounds (I-1) to (I-403) described in the examples below) can be produced by the following production methods (A) to (F), the reference examples, examples described below, or methods similar thereto.

[0298] Each starting compound may form a salt, provided that it does not inhibit the reaction. Examples of such salts include those similar to the salt of compound (I). Unless otherwise specified, the raw material compounds can be readily obtained and used from the market, or they can be manufactured according to known methods or similar methods. Furthermore, the intermediates produced in the following manufacturing methods may be isolated and purified by methods such as column chromatography, recrystallization, and distillation, or they may be used in the next step without isolation.

[0299] All patent, non-patent, or reference materials expressly cited herein may be incorporated herein by reference as part of this specification.

[0300] [Manufacturing method (A)] This manufacturing method involves condensing compound (1-1) and compound (2-1) to obtain compound (3-1), and then adding a protecting group (P 1 This method involves deprotecting compound (Ia) to obtain compound (Ia). Compound (1-1) is obtained by methods known to the present day (see, for example, U.S. Patent No. 10,836,736, etc.). A product synthesized by ) can be suitably used.

[0301] [ka]

[0302] (In the formula, R 1a -P 1 is protected R1 (This represents [the symbol], and other symbols have the same meaning as above.)

[0303] (Process A-1) This process involves condensing compound (1-1) and compound (2-1) in the presence of a coupling agent to produce compound (3-1).

[0304] The amount of compound (2-1) used is 0.8 moles to 5 moles, preferably 0.8 moles to 3 moles, per mole of compound (1-1).

[0305] The bonding 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), hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolidinophosphonium (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-benzotriazol-N,N,N',N'-tetramethyluronium Examples include hexafluoroborate (HBTU) and propylphosphonic anhydride (T3P) solutions, with HATU or WSC hydrochloride being preferred. The amount of condensing agent used is usually 1 to 10 moles per mole of compound (1-1), preferably 1 to 5 moles.

[0306] The reaction may also be carried out in the presence of additives such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-5-carboxylate ethyl ester (HOCt), and 1-hydroxy-7-azabenzotriazole (HOAt). The amount of additive used is typically 0 to 1.5 moles per mole of compound (1-1).

[0307] Examples of bases include organic bases such as triethylamine, pyridine, and N,N-diisopropylethylamine, with triethylamine or N,N-diisopropylethylamine being particularly preferred. The amount of base used is typically 1 to 5 moles, preferably 1.5 moles, per mole of compound (1-1).

[0308] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples include aromatic hydrocarbons such as toluene and xylene; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile, etc., or mixtures thereof.

[0309] The reaction temperature is typically -78°C to room temperature, preferably 0°C to room temperature, and the reaction time is typically 1 to 48 hours.

[0310] (Process A-2) This process involves protecting the amino group (P 1 This is a step to obtain compound (Ia) by deprotecting ).

[0311] The deprotection step in step A-2 involves the protection group (P 1 Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below.

[0312] [Manufacturing method (B)] This manufacturing method involves condensing compound (1-1) and compound (4-1) to obtain compound (5-1), then converting it to compound (7-1) by a coupling reaction with compound (6-1), and then adding a protecting group (P 2 This method involves removing (Ib) to obtain compound (Ib). Compound (1-1) can preferably be synthesized by methods known to the present day (see, for example, U.S. Patent No. 10,836,736).

[0313] [ka]

[0314] (In the formula, X represents a leaving group, and P 2 and P 3 Each of these independently represents a protecting group, and the other symbols have the same meaning as above.

[0315] Protecting group P in compound (6-1) 3 Examples of tri-substituted silyl groups used include trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, and triisopropylsilyl group. Protecting group P 3 This is removed during the reaction process in step B-2.

[0316] (Process B-1) This process involves condensing compound (1-1) and compound (4-1) in the presence of a condensing agent to produce compound (5-1).

[0317] The amount of compound (4-1) used is 0.8 moles to 5 moles, preferably 0.8 moles to 3 moles, per mole of compound (1-1).

[0318] Step B-1 can be carried out under the same conditions as step A-1, except that compound (4-1) is used instead of compound (2-1).

[0319] (Process B-2) This process can be carried out by a cross-coupling reaction (Heck reaction) between compound (5-1) and compound (6-1) in a solvent that does not affect the reaction, in the presence of a metal catalyst (e.g., a palladium catalyst) and, if necessary, a base.

[0320] The amount of compound (6-1) used is 0.8 moles to 5 moles, preferably 0.8 moles to 3 moles, per mole of compound (5-1).

[0321] Examples of metal catalysts include palladium(II) acetate, palladium(II) chloride, dichlorobis(tricyclohexylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(O), bis(dibenzylideneacetone)palladium(O)(Pd2(dba)3), tetrakis(triphenylphosphine)palladium(O), bis(tri-tert-butylphosphine)palladium(O), palladium(II) chloride-diphenylphosphinoferocene (PdCl2(dppf)), PdCl2(dppf)dichloromethane complex, palladium carbon(O), bis(triphenylphosphine)palladium dichloride(II), dichlorobis(tri-o-tolylphosphine)palladium(II), Examples of catalysts include palladium catalysts such as bis(tris(2-tolyl)phosphine)palladium(O); copper catalysts such as copper(I) iodide, copper(I) bromide, copper(I) chloride, and copper(II) chloride; iron catalysts such as iron(III) acetylacetonate; nickel catalysts such as bis(1,5-cyclooctadiene)nickel(O) and bis(acetylacetonate)nickel(II); and ruthenium catalysts such as dichloro(p-cymene)ruthenium(II) dimer and ruthenium alumina. Preferably, the catalyst is a palladium catalyst, and among these, dichlorobis(tricyclohexylphosphine)palladium(II), dichlorobis(tri-o-tolylphosphine)palladium(II), or bis(tri-tert-butylphosphine)palladium(O). Additionally, as needed, 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 3,6-dimethoxy-2-dicyclohexylphosphino-2' Phosphine ligands such as ,4',6'-triisopropylbiphenyl (BrettPhos), tri-t-butylphosphine, tricyclohexylphosphine, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (AmPhos), and (S)-1-[(RP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (JosiPhos); phenanthroline, etc., may also be added. The amount of metal catalyst used is typically 0.01 moles to 1 mole per mole of compound (5-1), preferably 0.05 moles to 0.3 moles. The amount of ligand used is typically 0.05 moles to 1 mole, preferably 0.1 moles to 0.4 moles, per mole of compound (5-1).

[0322] The reaction may also be carried out in the presence of additives such as zinc fluoride (ZnF2), copper fluoride (CuF2), and lithium fluoride (LiF). The amount of additive used is typically 0 to 1.5 moles per mole of compound (5-1).

[0323] Examples of bases include alkali metal amides such as lithium diisopropylamide, sodium amide, and lithium bistrimethylsilylamide; alkali metal carbonate salts such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; alkali metal phosphate salts such as sodium phosphate and potassium phosphate; and amines such as triethylamine, N,N-diisopropylethylamine, pyridine, and N-methylmorpholine. The amount of base used is usually 1 to 5 moles, preferably 1 to 2.5 moles, per mole of compound (5-1).

[0324] The reaction solvent is not particularly limited, but examples include amides such as N,N-dimethylformamide and N-methylpyrrolidone; ethers such as tetrahydrofuran and 1,4-dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene and xylene; nitriles such as acetonitrile; or mixtures thereof.

[0325] The reaction temperature is typically -78°C to 200°C, preferably -78°C to 120°C. The reaction time is typically between 0.5 and 12 hours.

[0326] (Process B-3) This process involves the protecting group (P 2 This is a step to obtain compound (Ib) by deprotecting ).

[0327] The deprotection step in step B-3 involves the protection group (P 2 Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below.

[0328] [Manufacturing method (C)] This manufacturing method involves condensing compound (1-1) and compound (8-1) to obtain compound (9-1), and then adding a protecting group (P 4 By deprotecting ), compound (10-1) is obtained, which is then reacted with compound (11-1) to convert it to compound (12-1), and then the protecting group (P 5 This method involves removing (Ic) to obtain compound (Ic).

[0329] [ka]

[0330] (In the formula, R 1b -P 5 is protected R 1 This represents X 1 represents a leaving group, P 4 and P 5 Each of these independently represents a protecting group, and the other symbols have the same meaning as above.

[0331] (Process C-1) This process involves condensing compound (1-1) and compound (8-1) in the presence of a condensing agent to produce compound (9-1).

[0332] The amount of compound (8-1) used is 0.8 moles to 5 moles, preferably 0.8 moles to 3 moles, per mole of compound (1-1).

[0333] Step C-1 can be carried out under the same conditions as step A-1, except that compound (8-1) is used instead of compound (2-1).

[0334] (Process C-2) This process involves protecting the amino group (P 4 This is a step to obtain compound (10-1) by removing ).

[0335] The deprotection step in step C-2 involves the protection group (P 4Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below. ru.

[0336] (Process C-3) This process involves reacting compound (10-1) and compound (11-1) in the presence of a base to produce compound (12-1).

[0337] The amount of compound (11-1) used is 1 mole to 5 moles, preferably 1 mole to 3 moles, per mole of compound (10-1).

[0338] Examples of bases include organic bases such as triethylamine, pyridine, and N,N-diisopropylethylamine; and inorganic bases such as sodium carbonate, potassium carbonate, and cesium carbonate. Among these, triethylamine or N,N-diisopropylethylamine is preferred. The amount of base used is typically 1 to 5 moles, preferably 1.5 moles, per mole of compound (10-1).

[0339] The reaction may also be carried out in the presence of additives such as tetrabutylammonium iodide (TBAI), sodium iodide, and silver trifluoromethanesulfonate. The amount of additive used is typically 0 to 1.5 moles per mole of compound (10⁻¹).

[0340] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples include aromatic hydrocarbons such as toluene and xylene; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile, or mixtures thereof.

[0341] The reaction temperature is typically 0°C to 100°C, preferably 0°C to 50°C, and the reaction time is typically 1 hour to 48 hours.

[0342] If the product obtained in this reaction contains a halogen, the halo group can be converted to an alkyl group or cycloalkyl group by a subsequent coupling reaction.

[0343] (Process C-4) This process involves protecting the amino group (P 5 This is a step to obtain compound (Ic) by removing ).

[0344] The deprotection step in step C-4 involves the protection group (P 5 Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below. ru.

[0345] If the product obtained in this reaction contains a halogen, the halo group can be converted to an alkyl group or cycloalkyl group by a subsequent coupling reaction.

[0346] [Manufacturing method (D)] This production method involves obtaining compound (14-1) through the reductive alkylation reaction of compound (10-1) and compound (13-1), and then obtaining compound (Id) by removing the protecting group (P 6 ).

[0347] [Chemical formula]

[0348] (In the formula, R 1c -P 6 represents protected R 1 , P 6 represents a protecting group, L a represents a divalent organic group, and the other symbols have the same meanings as described above.)

[0349] (Step D-1) This step involves obtaining compound (14-1) by reacting compound (10-1) with a reducing agent and compound (13-1) in a solvent that does not affect the reaction (reductive alkylation reaction).

[0350] The amount of compound (13-1) used is 1 to 3 moles, preferably 1 to 2 moles, per 1 mole of compound (10-1).

[0351] The reducing agent is not particularly limited, and examples include sodium triacetoxyborohydride, sodium borohydride, etc. The amount of the reducing agent used is 1 to 10 moles, preferably 1 to 3 moles, per 1 mole of compound (10-1).

[0352] As additives, for example, organic acids such as acetic acid; Lewis acids such as titanium(IV) chloride and titanium tetra-isopropyl titanate may be used to carry out the reaction. The amount of the additive used is 1 to 10 moles, preferably 1 to 3 moles, per 1 mole of compound (10-1).

[0353] The reaction solvent is not particularly limited, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran; halogenated hydrocarbons such as chloroform and dichloromethane; or mixtures thereof.

[0354] The reaction temperature is typically -10°C to 100°C, preferably 10°C to 50°C, and the reaction time is typically 1 hour to 48 hours.

[0355] (Process D-2) This process involves protecting the amino group (P 6 This is a step to obtain compound (Id) by removing ).

[0356] The deprotection step in step D-2 involves the protection group (P 6 Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below. ru.

[0357] [Manufacturing method (E)] This manufacturing method involves reacting compound (8-1) and compound (11-1) to obtain compound (15-1), and then adding a protecting group (P 4 By deprotecting ), compound (16-1) is obtained, which is then condensed with compound (1-1) to convert it to compound (12-1), and then the protecting group (P 5 This method involves obtaining compound (Ic) by deprotecting ). Compound (1-1) is obtained by methods known to the present day (see, for example, U.S. Patent No. 10,836,736, etc.). A product synthesized by ) can be suitably used.

[0358] [ka]

[0359] (Each symbol in the formula has the same meaning as described above.)

[0360] (Process E-1) This process involves reacting compound (8-1) and compound (11-1) in the presence of a base to produce compound (15-1). The amount of compound (11-1) used is 1 mole to 5 moles, preferably 1 mole to 3 moles, per mole of compound (8-1).

[0361] Step E-1 can be carried out under the same conditions as step C-3, except that compound (8-1) is used instead of compound (10-1).

[0362] (Process E-2) This process involves protecting the amino group (P 4 This is a step to obtain compound (16-1) by removing ).

[0363] The deprotection step in step E-2 involves the removal of the protecting group (P 4 Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below. ru.

[0364] (Process E-3) This process involves condensing compound (16-1) and compound (1-1) in the presence of a condensing agent to produce compound (12-1).

[0365] The amount of compound (16-1) used is 0.8 moles to 5 moles, preferably 0.8 moles to 3 moles, per mole of compound (1-1).

[0366] Step E-3 can be carried out under the same conditions as step A-1, except that compound (16-1) is used instead of compound (2-1).

[0367] If the product obtained in this reaction contains a halogen, the halo group can be converted to an alkyl group or cycloalkyl group by a subsequent coupling reaction.

[0368] (Process E-4) This process involves protecting the amino group (P 5 This is a step to obtain compound (Ic) by removing ).

[0369] The deprotection step in step E-4 involves the protection group (P 5 Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below. ru.

[0370] If the product obtained in this reaction contains a halogen, the halo group can be converted to an alkyl group or cycloalkyl group by a subsequent coupling reaction.

[0371] [Manufacturing method (F)] This manufacturing method involves reacting compound (8-1) and compound (13-1) to obtain compound (17-1), and then adding a protecting group (P 4 By deprotecting ), compound (18-1) is obtained, which is then reacted with compound (1-1) to convert it to compound (14-1), and then the protecting group (P 6 This method involves obtaining compound (Id) by deprotecting ).

[0372] [ka]

[0373] (Each symbol in the formula has the same meaning as described above.)

[0374] (Process F-1) This step involves reacting compound (8-1) with a reducing agent and compound (13-1) in a solvent that does not affect the reaction (reductive alkylation reaction) to obtain compound (17-1).

[0375] The amount of compound (13-1) used is 1 mole to 3 moles, preferably 1 mole to 2 moles, per mole of compound (8-1).

[0376] Step F-1 can be carried out under the same conditions as step D-1, except that compound (8-1) is used instead of compound (10-1).

[0377] (Process F-2) This process involves protecting the amino group (P 4 This is a step to obtain compound (18-1) by removing ).

[0378] The deprotection step in step F-2 involves the removal of the protective group (P 4Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below.

[0379] (Process F-3) This process involves condensing compound (18-1) and compound (1-1) in the presence of a condensing agent to produce compound (14-1).

[0380] The amount of compound (18-1) used is 0.8 moles to 5 moles, preferably 0.8 moles to 3 moles, per mole of compound (1-1).

[0381] Step F-3 can be carried out under the same conditions as step A-1, except that compound (18-1) is used instead of compound (2-1).

[0382] If the product obtained in this reaction contains a halogen, the halo group can be converted to an alkyl group or cycloalkyl group by a subsequent coupling reaction.

[0383] (Process F-4) This process involves protecting the amino group (P 6 This is a step to obtain compound (Id) by removing ).

[0384] The deprotection step in step F-4 involves the protection group (P 6Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below. ru.

[0385] If the product obtained in this reaction contains a halogen, the halo group can be converted to an alkyl group or cycloalkyl group by a subsequent coupling reaction.

[0386] [Manufacturing method (G)] This manufacturing method involves reacting compound (8-1) and compound (19-1) to obtain compound (20-1), and then adding a protecting group (P 4 By removing ), compound (21-1) is obtained, which is then reacted with compound (11-1) to convert it to compound (22-1), and then the protecting group (P 7 By removing ), compound (23-1) is obtained, which is then reacted with compound (24-1) to convert it to compound (12-1), and the protecting group (P 5 This method involves removing (Ic) to obtain compound (Ic).

[0387] [ka]

[0388] (Each symbol in the formula has the same meaning as described above.)

[0389] (Process G-1) This step involves reacting compound (19-1) with a halogenating agent in a solvent that does not affect the reaction to produce an acid halide, and then reacting it with compound (8-1) to obtain compound (20-1).

[0390] The amount of compound (19-1) used is 1 to 3 moles, preferably 1 to 2 moles, per mole of compound (8-1).

[0391] The halogenating agent is not particularly limited, but examples include thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and oxalyl chloride. The amount of halogenating agent used is 1 mole to 10 moles, preferably 1 mole to 3 moles, per mole of compound (19-1).

[0392] As an additive, the reaction may be carried out in the presence of, for example, DMF. The amount of additive used is 0.05 moles to 1 mole, preferably 10.05 moles to 0.1 moles, per mole of compound (19-1).

[0393] The reaction solvent is not particularly limited, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran; halogenated hydrocarbons such as chloroform and dichloromethane; or mixtures thereof.

[0394] The reaction temperature is typically -10°C to 100°C, preferably 10°C to 50°C, and the reaction time is typically 1 hour to 48 hours.

[0395] (Process G-2) This process involves protecting the amino group (P 4 This is a step to obtain compound (21-1) by removing ).

[0396] The deprotection step in step G-2 involves the protection group (P 4Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below. ru.

[0397] (Process G-3) This process involves reacting compound (21-1) and compound (11-1) in the presence of a base to produce compound (22-1). The amount of compound (11-1) used is 1 mole to 5 moles, preferably 1 mole to 3 moles, per mole of compound (21-1).

[0398] Step G-3 can be carried out under the same conditions as step C-3, except that compound (21-1) is used instead of compound (10-1).

[0399] (Process G-4) This process involves protecting the amino group (P 7 This is a step to obtain compound (23-1) by removing ).

[0400] The deprotection step in step G-4 involves the protection group (P 7 Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below.

[0401] (Process G-5) This process involves condensing compound (23-1) and compound (24-1) in the presence of a condensing agent to produce compound (12-1).

[0402] The amount of compound (23-1) used is 0.8 moles to 5 moles, preferably 0.8 moles to 3 moles, per mole of compound (24-1).

[0403] Step G-5 can be carried out under the same conditions as step A-1, except that compound (23-1) is used instead of compound (2-1).

[0404] (Process G-6) This process involves protecting the amino group (P 5 This is a step to obtain compound (Ic) by removing ).

[0405] The deprotection step in step G-6 involves the removal of the protecting group (P 5 Depending on the type of group, the reaction conditions can be selected. The deprotection reaction conditions are carried out according to known methods, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004; or methods described in the examples below.

[0406] Compound (I) obtained by the above-described manufacturing method, or a pharmaceutically acceptable salt thereof, can be isolated and purified by conventional separation methods such as recrystallization, distillation, and chromatography.

[0407] If compound (I) of the present invention or a pharmaceutically acceptable salt thereof exists as an optical isomer based on an asymmetric carbon, it can be separated into individual optical isomers by conventional optical resolution methods (e.g., fractional crystallization, chiral column resolution). Furthermore, optical isomers can be synthesized using optically pure starting materials. In addition, optical isomers can be synthesized by stereoselectively carrying out each reaction using asymmetric auxiliary groups or asymmetric catalysts.

[0408] (The present invention's pharmaceutical (pharmaceutical composition)) The pharmaceutical product of the present invention is a pharmaceutical product for preventing and / or treating a disease whose symptoms can be alleviated by a B0AT1 inhibitory effect, and which contains compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the pharmaceutical product of the present invention is at least one of the following: a pharmaceutical product for preventing the onset of a disease whose symptoms can be alleviated by a B0AT1 inhibitory effect, and a pharmaceutical product for improving the symptoms of said disease, both containing the active ingredient.

[0409] The pharmaceutical product of the present invention may be either a pharmaceutical product comprising only compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, etc. The pharmaceutical product of the present invention can be administered to a target (for example, a mouse, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey, human, etc.) in a prophylactic or therapeutically effective dose.

[0410] Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethylcellulose, talc, etc.), and solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, etc.). (e.g., cottonseed oil), solubilizers (e.g., polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.), suspending agents (e.g., surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.); polyvinyl alcohol Hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, etc.), isotonic agents (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.), buffering agents (e.g., buffers such as phosphates, acetates, carbonates, citrates, etc.), analgesics (e.g., benzyl alcohol, etc.), preservatives (e.g., parahydroxybenzoic acid esters) Examples of additives include chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc., antioxidants (e.g., sulfites, ascorbic acid, etc.), colorants (e.g., water-soluble edible tar dyes (e.g., food colorants such as Red No. 2 and 3, Yellow No. 4 and 5, Blue No. 1 and 2), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned water-soluble edible tar dyes), natural pigments (e.g., β-carotene, chlorophyll, red iron oxide, etc.)), sweeteners (e.g., sodium saccharin, dipotassium glycyrrhizinate, stevia, etc.).

[0411] The pharmaceutical (pharmaceutical composition) of the present invention can be prepared by mixing the above-mentioned components and then dissolving the mixture according to known means to produce oral preparations such as tablets, granules, capsules, and dry syrups, or parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drip preparations), topical preparations (e.g., transdermal preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, and liposome preparations. Among the pharmaceutical products of the present invention, oral formulations such as tablets are preferred.

[0412] The content of compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the pharmaceutical (pharmaceutical composition) of the present invention varies depending on the form of the formulation, but is usually in the range of about 0.01 to 100% by weight relative to the whole formulation, preferably in the range of about 0.1 to 50% by weight, and more preferably in the range of about 0.5 to 20% by weight.

[0413] The dosage of compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, can be appropriately selected depending on the recipient (age, weight, general health status, sex, severity of the disease, etc.), route of administration, type of disease, type of concomitant medication, etc. For example, in the case of humans, when administered orally to an adult patient (weighing approximately 60 kg), the daily dosage of compound (I), which is the active ingredient, is usually 0.001 mg to 1000 mg, preferably 0.01 mg to 100 mg, and can be administered once to several times a day, regardless of whether it is before, after, or between meals. The duration of administration is not particularly limited.

[0414] Compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, is useful for the prevention of the onset of diseases whose symptoms can be alleviated by its B0AT1 inhibitory effect, or for the treatment of such diseases. In particular, it is especially effective for the prevention or treatment of amino acid metabolic disorders such as phenylketonuria, urea cycle disorders, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia.

[0415] Compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, can be administered in combination with other drugs (concomitant drugs) as long as their efficacy is not impaired. The concomitant drugs are not particularly limited, and for example, one or more known drugs conventionally used to treat the diseases described above as "diseases whose symptoms can be alleviated by B0AT1 inhibitory action" can be suitably used.

[0416] Specifically, when compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, is used as a concomitant agent for the treatment and / or prevention of amino acid metabolic disorders such as phenylketonuria, urea cycle disorders, hypertyrosinemia (types 1-3), hypermethioninemia, maple syrup urine disease, homocystinuria, nonketotic hyperglycinemia, propionic acidemia, methylmalonic acidemia, and isovaleric acidemia, examples of concomitant agents include vitamins (e.g., folic acid (vitamin B9), nicotinamide (vitamin B3), thiamine). Examples include (vitamin B1), pyridoxine (vitamin B6), etc., and drugs to alleviate various symptoms of amino acid metabolism disorders (for example, LNAAs such as L-dopa and 5-hydroxytryptophan, sapropterin hydrochloride, pegvaliase, nicotinic acid, nitisinone, S-adenosylmethionine, betaine, aspirin, dipyridamole, sodium benzoate, sodium phenylbutyrate, dextromethorphan, ketamine, antidepressants, anxiolytics, ADHD medications, etc.).

[0417] When using concomitant drugs, the timing of administration is not limited; they may be administered simultaneously to the target patient, or with a time difference. In the case of time-difference administration, the pharmaceutical agent of the present invention may be administered first, followed by the concomitant drug, or vice versa. The administration methods may be the same or different. Furthermore, the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, may be administered as a single formulation containing the concomitant drug in combination.

[0418] The dosage of concomitant medications can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the compound of the present invention or its pharmaceutically acceptable salts, etc., with the concomitant medication can be appropriately selected according to the target population (age, weight, general health status, sex, severity of illness, etc.), route of administration, type of disease, type of concomitant medication, etc.

[0419] The mass ratio of compound (I) or a pharmaceutically acceptable salt thereof to the concomitant drug is not particularly limited.

[0420] Furthermore, concomitant agents that complement and / or enhance the therapeutic effect of compound (I) or its pharmaceutically acceptable salts include those that have not been discovered to date but may be discovered in the future, based on the mechanisms described above.

[0421] Furthermore, in combination with dietary therapies that avoid the intake of specific amino acids or enzyme supplementation therapy, it is also effective to complement and / or enhance the therapeutic effects of compound (I) or its pharmaceutically acceptable salts.

[0422] The pharmaceutical or pharmaceutical composition of the present invention may be provided in the form of a kit along with instructions on how to administer it. 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 pharmaceutical or pharmaceutical composition for a long period of time, does not adsorb to the inside of the container, and does not alter the components. For example, the sealed glass ampoule may contain a buffer sealed in the presence of a neutral, unreactive gas such as nitrogen gas. Furthermore, the kit may include an instruction manual. This instruction manual may be printed on paper or stored on an electronically readable medium such as a CD-ROM or DVD-ROM and supplied to the user. [Examples]

[0423] 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 without departing from the scope of the present invention. Furthermore, the reagents, apparatus, and materials used in the present invention are commercially available unless otherwise specified.

[0424] The percentages (%) indicate mol / mol% for yield, and weight% for all other values ​​unless otherwise specified. Room temperature refers to a temperature range of 15°C to 30°C unless otherwise specified. In the structural formulas below, * indicates a racemic carbon atom. Other abbreviations used in the text have the following meanings. THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide DMF: N,N-dimethylformamide HATU:O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate WSC: 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide HOBt: 1-hydroxybenzotriazole

[0425] The starting compounds used in the following reference examples and examples are, unless otherwise specified, known compounds, synthesized and identified according to methods known to themselves (e.g., U.S. Patent No. 10,836,736; Bioorganic & Medicinal Chemistry Letters, 2017, 27(21), 4805-4811; J. Med. Chem., 2014, 57, 3687-3706; International Publication No. 2013 / 067274), or equivalent methods.

[0426] Reference example 1: Production of 6-bromo-4-methoxy-1,2,3,4-tetrahydroisoquinoline

[0427] [ka]

[0428] (1) To a solution of 6-bromo-2-(2-nitrophenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-4-ol (300 mg) in toluene (2 ml), tetrabutylammonium bisulfate (25 mg), iodomethane (206 mg), and potassium hydroxide (50% w / v, 2 ml) were added, and the reaction mixture was stirred at 50°C for 1 hour. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~50 / 50) to obtain 6-bromo-4-methoxy-2-(2-nitrophenyl)sulfonyl-3,4-dihydro-1H-isoquinoline (295 mg; yield 95%) as a colorless viscous oil. MS(ESI)m / z:397.1 / 399.1[M-ОMe+H] +

[0429] (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 brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain the crude product of the title compound (167 mg; yield 99%) as a brown viscous oil.

[0430] Reference example 2: Production of methyl 3-(1-methylpiperazin-2-yl)benzoate

[0431] [ka]

[0432] (1) Benzyl 3-(3-bromophenyl)piperazine-1-carboxylate (1.4 g) was dissolved in THF (12 ml), acetic acid (2 ml), aqueous formalin solution (37%, 1.4 ml), and sodium triacetoxyborate (1.58 g) were added, and the reaction mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydroxide solution (1 mol / l) and chloroform were added to the reaction mixture, and after separating the organic layer, the aqueous layer was extracted with chloroform. The organic layer was dried together over anhydrous magnesium sulfate, filtered, and the filtrate was removed under reduced pressure to obtain the crude product of benzyl 3-(3-bromophenyl)-4-methylpiperazine-1-carboxylate (1.47 g) as a yellow oil.

[0433] (2) The crude product of benzyl 3-(3-bromophenyl)-4-methylpiperazine-1-carboxylate obtained in (1) above (350 mg) was dissolved in acetonitrile (6 ml), methanol (3 ml), molybdenum hexacarbonyl (239 mg) and DBU (0.28 ml) were added, and the mixture was purged with nitrogen. Bis(tri-tert-butylphosphine)palladium (0) (46 mg) was added to the reaction mixture and the mixture was stirred at 140 °C for 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 50 / 50~25 / 75) to obtain benzyl 3-(3-methoxycarbonylphenyl)-4-methylpiperazine-1-carboxylate (306 mg; yield 92.4%) as a yellow oil. MS(ESI)m / z:369.2[M+H] +

[0434] (3) The benzyl 3-(3-methoxycarbonylphenyl)-4-methylpiperazine-1-carboxylate (306 mg) obtained in (2) above was dissolved in methanol (2.8 ml), palladium hydroxide (30 mg) was added, and the mixture was hydrogenated. The reaction mixture was stirred at 60°C for 4 hours and 30 minutes, then cooled to room temperature, filtered through Celite, and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound (265 mg; yield 136.2%) as a yellow amorphous material. MS(ESI)m / z:235.2[M+H] +

[0435] Reference example 3: Manufacturing of methyl 2-[2-(1,2,3,6-tetrahydropyridine-5-yl)phenyl]acetate hydrochloride

[0436] [ka]

[0437] (1) Dissolve tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.0 g) in 1,4-dioxane (40 ml), add methyl 2-(2-bromophenyl)acetate (890 mg), tetrakis(triphenylphosphine)palladium (380 mg), cesium carbonate (2.1 g), and water (10 ml), and stir the reaction mixture at 90°C for 1 hour. Cool the reaction mixture to room temperature, add water, and extract with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 80 / 20~50 / 50) to obtain tert-butyl 5-[2-(2-methoxy-2-oxoethyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.0 g; yield 93.3%) as a colorless oil.

[0438] (2) The tert-butyl 5-[2-(2-methoxy-2-oxoethyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (300 mg) obtained in (1) above was dissolved in methanol (3 ml), and hydrogen chloride-1,4-dioxane solution (4 mol / l, 3 ml) was added. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure at 40°C to obtain the crude product of the title compound (242 mg) as a colorless amorphous material.

[0439] Reference example 4: Manufacturing of methyl 2-(3-piperidine-3-ylphenyl)acetate hydrochloride

[0440] [ka]

[0441] (1) Tert-butyl 5-[2-(2-methoxy-2-oxoethyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (700 mg) obtained in step (1) of Reference Example 3 was dissolved in methanol (10 ml), and palladium-carbon (10%, 200 mg) was added. The reaction mixture was hydrogenated and stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 95 / 5~80 / 20) to obtain tert-butyl 3-[3-(2-methoxy-2-oxoethyl)phenyl]piperidine-1-carboxylate (580 mg; yield 82.3%) as a colorless oil. MS(ESI)m / z:334.1[M+H] +

[0442] (2) The tert-butyl 3-[3-(2-methoxy-2-oxoethyl)phenyl]piperidine-1-carboxylate (580 mg) obtained in (1) above was dissolved in methanol (6 ml), and hydrogen chloride-1,4-dioxane solution (4 mol / l, 6 ml) was added. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure at 40°C to obtain the crude product of the title compound (469 mg) as a colorless amorphous material.

[0443] Reference example 5: Preparation of tert-butyl 3-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)propanoate

[0444] [ka]

[0445] (1) A mixture of 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (400 mg), benzyloxycarbonyl chloride (0.48 ml), sodium bicarbonate (326 mg), and 1,4-dioxane (6.4 ml) was mixed with water (1.8 ml) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and the organic layer was extracted with ethyl acetate. The combined organic layers were then washed sequentially with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~30 / 70) to obtain benzyl 2-chloro-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (535 mg; yield 80%) as a colorless viscous oil. MS(ESI)m / z:304.1 / 306.1[M+H] +

[0446] (2) Water (0.8 ml) was added to the mixture of benzyl 2-chloro-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (535 mg), palladium(II) chloride bis[4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (124 mg), tert-butyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (538 mg), cesium carbonate (1.15 g), and 1,4-dioxane (3 ml) obtained in (1) above, and the mixture was stirred at 140°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, the organic layer was extracted with ethyl acetate, and the combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~30 / 70) to obtain benzyl 2-[(E)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (318 mg; yield 46%) as a yellow viscous oil. MS(ESI)m / z:396.2[M+H] +

[0447] (3) To a solution of benzyl 2-[(E)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (52 mg) obtained in (2) above, palladium(II) hydroxide (20 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (35 mg) as a colorless, viscous oil.

[0448] Reference example 6: Preparation of methyl 3-(indolin-4-yl)propanoate trifluoroacetate

[0449] [ka]

[0450] (1) 500 mg of tert-butyl 4-bromoindoline-1-carboxylate was dissolved in 4.5 ml of 1,4-dioxane. Water (1 ml), cesium carbonate (1.1 g), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (570 mg), and bis(4-di-tert-butylphosphanyl-N,N-dimethylaniline)dichloropalladium(II) (100 mg) were added to the reaction mixture. The reaction mixture was stirred at 110°C for 2 hours and 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (560 mg) of tert-butyl 4-[(E)-3-ethoxy-3-oxoprop-1-enyl]indoline-1-carboxylate as a brown solid.

[0451] (2) The crude product of tert-butyl 4-[(E)-3-ethoxy-3-oxopropyl-1-enyl]indoline-1-carboxylate obtained in (1) above (560 mg) was dissolved in methanol (25 ml), magnesium (500 mg) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with hydrochloric acid (1 mol / l), the organic layer was dried over sodium sulfate, and then filtered after adding NH2 silica gel. The filtrate was concentrated under reduced pressure to obtain the crude product of tert-butyl 4-(3-methoxy-3-oxopropyl)indoline-1-carboxylate (550 mg) as a yellow oil.

[0452] (3) The crude product of tert-butyl 4-(3-methoxy-3-oxopropyl)indoline-1-carboxylate obtained in (2) above (247 mg) was dissolved in dichloromethane (1 ml), trifluoroacetic acid (1.3 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the residue was concentrated again under reduced pressure with toluene to obtain the crude product of the title compound (258.2 mg).

[0453] Reference example 7: Manufacturing of tert-butyl 2-(5-cyano-1,2,3,4-tetrahydroisoquinoline-6-yl)acetate

[0454] [ka]

[0455] (1) To a solution of 6-bromoisoquinoline (1 g) in sulfuric acid (10 ml), 1-chloropyrrolidine-2,5-dione (1.3 g) was added and the mixture was stirred at 50°C for 3 hours. Another 1-chloropyrrolidine-2,5-dione (1.3 g) was added and the mixture was stirred at 50°C for a further 15 hours. Water and sodium hydroxide were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~30 / 70) to obtain 6-bromo-5-chloroisoquinoline (824 mg; yield 71%) as a white solid. MS(ESI)m / z:242.0 / 244.0[M+H] +

[0456] (2) To a solution of 6-bromo-5-chloroisoquinoline (824 mg) obtained in (1) above in acetic acid (10 ml), sodium borohydride (141 mg) was added under ice cooling and stirred at room temperature for 1 hour. Under ice cooling, sodium borohydride (71 mg) was added and stirred for a further 2 hours at room temperature. After neutralizing the reaction mixture with an aqueous sodium hydroxide solution, the organic layer was extracted with ethyl acetate. After washing the combined organic layers with saturated brine, they were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product of 6-bromo-5-chloro-1,2,3,4-tetrahydroisoquinoline (837 mg) as a white solid.

[0457] (3) Ethyl acetate (4 ml) and hydrogen chloride (4 mol / l 1,4-dioxane solution) (0.93 ml) were added to the crude product of 6-bromo-5-chloro-1,2,3,4-tetrahydroisoquinoline (837 mg) obtained in (2) above, and the precipitated solid was filtered off to obtain 6-bromo-5-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (766 mg; yield 80%) as a white solid. MS(ESI)m / z:246.0 / 248.0[M+H] +

[0458] (4) To the mixture of 6-bromo-5-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (1 g), pyridine (7 ml), and N,N-dimethylpyridine-4-amine (43 mg) obtained in (3) above, anhydrous trifluoroacetic acid (1.5 g) was added under ice cooling and stirred at room temperature for 2 hours. Water and 1 mol / l hydrochloric acid were added to the reaction mixture and the organic layer was extracted with ethyl acetate. The combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~80 / 20) to obtain 1-(6-bromo-5-chloro-3,4-dihydro-1H-isoquinoline-2-yl)-2,2,2-trifluoroethanone (1.05 g; yield 87%) as a white solid. 1 H-NMR(400MHz, CDCl3)δppm:3.05(2H, t), 3.87(2H, t), 4.76(2H, s), 6.96(1H, d), 7.53(1H, d)( * Rotational isomers were observed with an NMR integration ratio of approximately 2:1.

[0459] (5) The 1-(6-bromo-5-chloro-3,4-dihydro-1H-isoquinoline-2-yl)-2,2,2-trifluoroethanone (1.05 g), 1-tert-butoxyvinyloxy-tert-butyldimethylsilane (285 mg), potassium carbonate (114 mg), and bis(tri-tert-butylphosphine)palladium (0) (63 mg) obtained in (4) above were dissolved in DMF (7 ml) and stirred at 120°C for 1 hour under microwave irradiation. Water was added to the reaction mixture and the organic layer was extracted with ethyl acetate. The combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~30 / 70) to obtain tert-butyl 2-[5-chloro-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-yl]acetate (1.02 g; yield 76%) as a colorless, viscous oil. MS(ESI)m / z:322.1[M-C4H8+H] +

[0460] (6) The tert-butyl 2-[5-chloro-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-yl]acetate (1.02 g), potassium hexacyanoferrate(II) trihydrate (1.65 g), [2-(2-aminophenyl)phenyl]-chloropalladium;2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (212 mg), and potassium acetate (530 mg) obtained in (5) were dissolved in 1,4-dioxane (50 ml), water (15 ml) was added, and the mixture was stirred at 100°C for 2 hours. After filtering the reaction mixture, water was added to the filtrate and the organic layer was extracted with ethyl acetate. The combined organic layers were sequentially washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~80 / 20) to obtain tert-butyl 2-[5-cyano-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-yl]acetate (551 mg; yield 55%) as a brown viscous oil. 1 H-NMR(400MHz, CDCl3)δppm:1.47(9H, s),3.18(2H, t), 3.79(2H, s), 3.91(2H, t),4.81(2H, s), 7.29(1H, d), 7.34(1H, d).( * Rotational isomers were observed with an NMR integration ratio of approximately 2:1.

[0461] (7) The tert-butyl 2-[5-cyano-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-yl]acetate (551 mg) obtained in (6) above was dissolved in ethanol (9 ml), and 1 mol / l aqueous sodium hydroxide solution (5.4 ml) was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the organic layer was extracted with ethyl acetate. The combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~0 / 100) to obtain the title compound (172 mg; yield 42%) as a white solid. MS(ESI)m / z:273.3[M+H] +

[0462] Reference example 8: Manufacturing of tert-butyl 2-(1,2,3,4-tetrahydroisoquinoline-6-yl)acetate

[0463] [ka]

[0464] (1) Benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (2 g), tert-butyl-(1-methoxyvinyloxy)-dimethylsilane (2.5 ml), potassium carbonate (1.6 g), and bis(tri-tert-butylphosphine)palladium (0) (886 mg) were dissolved in DMF (19 ml) and stirred at 120°C for 2 hours under microwave irradiation. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain benzyl 6-(2-methoxy-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (978 mg; yield 48%) as a yellow viscous oil. 1 H-NMR(400MHz, CDCl3)δppm:2.84(2H,br-s), 3.58(2H, s), 3.69(3H, s), 3.72(2H, s), 4.63(2H, s), 5.18(2H, s), 7.01-7.12(3H, m), 7.29-7.42(5H, m).

[0465] (2) The benzyl 6-(2-methoxy-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.41 g) obtained in (1) above was dissolved in methanol (31 ml), and 4 mol / l lithium hydroxide aqueous solution (9.2 ml) was added and the mixture was stirred at room temperature for 3 hours. After neutralizing the reaction mixture, the organic layer was extracted with ethyl acetate. The combined organic layers were washed with saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crude product of 2-(2-phenylmethoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)acetic acid (1.33 g) as a yellow viscous oil.

[0466] (3) The crude product of 2-(2-phenylmethoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)acetic acid obtained in (2) above (1.33 g) was dissolved in toluene (13.6 ml), and 1,1-di-tert-butoxy-N,N-dimethylmethaneamine (4 ml) was added and the mixture was stirred at 120°C for 3 hours. After cooling the reaction mixture, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain benzyl 6-[2-[(2-methylpropane-2-yl)oxy]-2-oxoethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (428 mg; yield 26%) as a colorless viscous oil. MS(ESI)m / z:380.4[MH] -

[0467] (4) To a solution of benzyl 6-[2-[(2-methylpropane-2-yl)oxy]-2-oxoethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (400 mg) obtained in (3) above in ethanol (3.3 ml), palladium(II) hydroxide (40 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (244 mg) as a white solid.

[0468] Reference examples 9~21: By processing the corresponding starting compounds in the same manner as in Reference Example 8, crude products of the compounds listed in Tables 1-1 to 1-2 below were obtained.

[0469] [Table 1-1]

[0470] [Table 1-2]

[0471] Reference example 22: Preparation of tert-butyl (2S)-1-(1,2,3,4-tetrahydroisoquinoline-6-yl)piperidine-2-carboxylate

[0472] [ka]

[0473] (1) A mixture of benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.00 g), tert-butyl (2S)-piperidine-2-carboxylate (800 mg), bis(dibenzylideneacetone)palladium (0) (270 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (135 mg), and toluene (30 ml) was mixed with sodium tert-butoxide (1.10 g) and stirred at 120°C for 1 hour. After the reaction mixture cooled, water was added and the organic layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 90 / 10~60 / 40) to obtain benzyl 6-[(2S)-2-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (113 mg; yield 9%) as a brown viscous oil. MS(ESI)m / z:451.4[M+H] +

[0474] (2) The benzyl 6-[(2S)-2-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (113 mg) obtained in (1) above was dissolved in methanol (5 ml), and 10% palladium-carbon (100 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound as a brown solid.

[0475] Reference example 23: Preparation of tert-butyl 1-(1,2,3,4-tetrahydroisoquinoline-6-yl)pyrrolidine-3-carboxylate

[0476] [ka]

[0477] (1) A mixture of benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.00 g), tert-butylpyrrolidine-3-carboxylate (600 mg), bis(dibenzylideneacetone)palladium (0) (270 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (135 mg), and toluene (30 ml) was mixed with sodium tert-butoxide (1.10 g) and stirred at 120°C for 1 hour. After the reaction mixture cooled, water was added and the organic layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 90 / 10~60 / 40) to obtain benzyl 6-[3-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (517 mg; yield 41%) as a brown viscous oil. MS(ESI)m / z:436.9[M+H] +

[0478] (2) The benzyl 6-[3-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (517 mg) obtained in (1) above was dissolved in methanol (30 ml), and 10% palladium-carbon (200 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (311 mg; yield 87%) as a yellow solid. MS(ESI)m / z:303.3[M+H] +

[0479] Reference example 24: Preparation of tert-butyl 1-(1,2,3,4-tetrahydroisoquinoline-6-yl)piperidine-4-carboxylate

[0480] [ka]

[0481] (1) A mixture of benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.00 g), tert-butyl piperidine-4-carboxylate hydrochloride (770 mg), bis(dibenzylideneacetone)palladium (0) (270 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (135 mg), and toluene (30 ml) was mixed with N,N-diisopropylethylamine (0.6 ml) and sodium tert-butoxide (840 mg) and stirred at 120°C for 1 hour. After the reaction mixture was allowed to cool, water was added and the organic layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 90 / 10~60 / 40) to obtain benzyl 6-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.11 g; yield 85%) as a brown viscous oil. MS(ESI)m / z:450.9[M+H] +

[0482] (2) The benzyl 6-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-1-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.11 g) obtained in (1) above was dissolved in methanol (10 ml), and 10% palladium-carbon (200 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (707 mg; yield 91%) as a brown solid. MS(ESI)m / z:317.3[M+H] +

[0483] Reference example 25: Preparation of tert-butyl 2-methyl-3-(1,2,3,4-tetrahydroisoquinoline-6-yl)propanoate

[0484] [ka]

[0485] (1) Benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1 g), tert-butyl 2-methylprop-2-enoate (821 mg), potassium carbonate (567 mg), and [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II) dichloride (394 mg) were dissolved in DMF (6 ml) and stirred at 120°C for 2 hours under microwave irradiation. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The combined organic layers were sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~30 / 70) to obtain benzyl 6-[2-methyl-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.06 g; yield 32%) as a colorless, viscous oil. MS(ESI)m / z:352.2[M-C4H8+H] +

[0486] (2) To a solution of benzyl 6-[2-methyl-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.06 g) obtained in (1) above in ethanol (4 ml), palladium(II) hydroxide (48 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (1.04 g) as a colorless, viscous oil.

[0487] Reference example 26: Preparation of tert-butyl 3-(1,2,3,4-tetrahydroisoquinoline-6-yl)butanoate

[0488] [ka]

[0489] (1) Benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1 g), tributyl(1-ethoxyvinyl)tin (1.27 ml), and bis(tri-tert-butylphosphine)palladium (0) (74 mg) were dissolved in DMF (9 ml) and stirred at 100°C for 1 hour under microwave irradiation. 1 mol / l hydrochloric acid was added to the reaction mixture and stirred at room temperature for 1 hour. Water was added to the reaction mixture and the organic layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~60 / 40) to obtain benzyl 6-acetyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (67.1 mg; yield 8%) as a colorless viscous oil. 1 H-NMR(400MHz, CDCl3)δppm:2.58(3H, s),2.91(2H, br-s), 3.75(2H, t), 4.70(2H, s),5.19(2H, s), 7.20(1H, br-s), 7.29-7.45(5H, m), 7.74(1H, s), 7.77(1H, d).

[0490] (2) To a solution of tert-butyl 2-diethoxyphosphoryl acetate (109 mg) in THF (1.4 ml), sodium hydride (60%, 17 mg) was added. The THF solution of benzyl 6-acetyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (67.1 mg) obtained in (1) above was added to the reaction mixture and stirred at room temperature for 18 hours. Water was added to the reaction mixture and the organic layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain benzyl 6-[4-[(2-methylpropan-2-yl)oxy]-4-oxobuta-2-en-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (68.5 mg; yield 78%) as a colorless, viscous oil. 1 H-NMR(400MHz, CDCl3)δppm:1.52(9H, s),2.51(3H, d), 2.86(2H, br-s), 3.73(2H, br-s), 4.66(2H, s), 5.18(2H, s), 6.03(1H, d), 6.94-7.16(2H, m), 7.20-7.43(6H, m).( * (A mixture of geometric isomers with an NMR integration ratio of approximately 3:1)

[0491] (3) To a solution of benzyl 6-[4-[(2-methylpropan-2-yl)oxy]-4-oxobuta-2-en-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (68.5 mg) obtained in (2) above, palladium(II) hydroxide (8 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (46.3 mg) as a colorless, viscous oil.

[0492] Reference example 27: Preparation of tert-butyl 1-(1,2,3,4-tetrahydroisoquinoline-6-yl)cyclopropane-1-carboxylate

[0493] [ka]

[0494] (1) A mixture of benzyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (2.2 g), tert-butyl 2-bromoacrylate (1.1 g), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (190 mg), cesium carbonate (3.5 g), 1,4-dioxane (20 ml), and water (4 ml) was stirred in a microwave reactor at 140°C for 1 hour. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain benzyl 6-[3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-en-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (725 mg; yield 31%) as a brown oily substance. MS(ESI)m / z:338.1[M-C4H8+H] +

[0495] (2) Add 60% sodium hydride (148 mg) to a DMSO solution (6 ml) of trimethylsulfoxonium iodide (810 mg) at 0°C and stir for 10 minutes. Add a DMSO solution of benzyl 6-[3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-en-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (725 mg; 89 mass%) obtained in (1) above and stir at room temperature for 18 hours. Add water to the reaction mixture and extract with ethyl acetate. Wash the organic layer with saturated brine, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain benzyl 6-[1-[(2-methylpropan-2-yl)oxycarbonyl]cyclopropyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (454 mg; yield 55%) as a yellow oily substance. 1 H-NMR(400MHz, CDCl3)δppm:1.08-1.10(2H,m),1.38(9H,s),1.47-1.51(2H,m),3.71(2H,br), 2.83(2H,br),4.62(2H,s),5.17(2H,s),7.00-7.15(3H,m),7.30-7.39(5H,m).

[0496] (3) To the benzyl 6-[1-[(2-methylpropan-2-yl)oxycarbonyl]cyclopropyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (454 mg) obtained in (2) above, ethanol (4 ml) and 20% palladium hydroxide (45 mg) were added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (277 mg) as a colorless oil.

[0497] Reference example 28: Preparation of tert-butyl 2-methyl-2-(1,2,3,4-tetrahydroisoquinoline-6-yl)propanoate

[0498] [ka]

[0499] (1) 60% sodium hydride (25.6 mg) was added to DMSO (1.6 ml). To the reaction mixture, methyl iodide (90 mg) and a solution of benzyl 6-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (130 mg) in THF (1.6 ml) were added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~50 / 50) to obtain benzyl 6-[1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (79.7 mg; yield 52%) as a colorless oil. MS(ESI)m / z:340.1[M-C4H8+H] +

[0500] (2) 60% sodium hydride (26 mg) was added to DMSO (1.2 ml). Methyl iodide (91 mg) and a solution of benzyl 6-[1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (79.7 mg) obtained in (1) above in THF (1.2 ml) were added to the reaction mixture at 0°C, and the reaction mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~85 / 15) to obtain benzyl 6-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (22.4 mg; yield 33%) as a colorless oil. MS(ESI)m / z:354.2[M-C4H8+H] +

[0501] (3) Benzyl 6-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (22.4 mg) obtained in (2) above was mixed with ethanol (0.6 ml) and 20% palladium hydroxide (4 mg) and stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the crude product of the title compound (15.1 mg) as a colorless oil.

[0502] Reference example 29: Preparation of tert-butyl 4-(1,2,3,4-tetrahydroisoquinoline-6-yl)butanoate

[0503] [ka]

[0504] (1) To a solution of benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1 g) in 1,4-dioxane (10 ml), [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II) dichloride (197 mg) and 4-ethoxy-4-oxobutylzinc bromide (1 mol / l, 3.5 ml) were added and stirred at room temperature under a nitrogen atmosphere for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~0 / 100) to obtain benzyl 6-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (183 mg; yield 17%) as a yellow oily substance. 1H-NMR(400MHz, CDCl3)δppm:1.25(3H,t),1.89-1.94(2H,m),2.29-2.33(2H,m),2.60-2.61(2H,m),2.82(2H,b r),3.72(2H,br),4.13(2H,q),4.62(2H,s),5.18(2H,s),6.95-7.00(3H,m),7.30-7.40(5H,m).

[0505] (2) To the reaction mixture of benzyl 6-(4-ethoxy-4-oxobutyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (183 mg) and methanol (1.6 ml) obtained in (1), 0.48 ml of 4N lithium hydroxide aqueous solution was added and the mixture was stirred at room temperature for 12 hours. The reaction solution was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crude product of 4-(2-phenylmethoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)butanoic acid (159 mg) as a yellow oil.

[0506] (3) To a mixed solution of the crude product of 4-(2-phenylmethoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-yl)butanoic acid obtained in (2) above (159 mg) and toluene (1.5 ml), N,N-dimethylformamide ditert-butyl acetal (0.3 ml) was added and the mixture was stirred at 120 °C for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain benzyl 6-[4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (57 mg; yield 31%) as a colorless oil. 1H-NMR(400MHz, CDCl3)δppm:1.44(9H,s),1.84-1.92(2H,m),2.21-2.24(2H,m),2.56-1.61(2H,m),2.82 (2H,br),3.71(2H,br),4.62(2H,s),5.18(2H,s),6.95-7.03(3H,m),7.36-7.40(5H,m).

[0507] (4) To the benzyl 6-[4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (57 mg) obtained in (3) above, ethanol (0.9 ml) and 20% palladium hydroxide (4 mg) were added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the crude product of the title compound (39 mg) as a colorless oil.

[0508] Reference example 30: Preparation of tert-butyl 2-(1,2,3,4-tetrahydroisoquinoline-6-yl)propanoate

[0509] [ka]

[0510] Benzyl 6-[1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (85.4 mg) obtained in Reference Example 28 (1) was mixed with ethanol (1.4 ml) and 20% palladium hydroxide (10 mg), and stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (56.4 mg) as a yellow oil.

[0511] Reference example 31: Preparation of tert-butyl rac-(1R,2R)-2-(1,2,3,4-tetrahydroisoquinoline-6-yl)cyclopropane-1-carboxylate

[0512] [ka]

[0513] (1) A mixture of benzyl 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.5 g), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (800 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (155 mg), cesium carbonate (2.8 g), 1,4-dioxane (14 ml), and water (2 ml) was stirred in a microwave reactor at 140°C for 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~80 / 20) to obtain benzyl 6-ethenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (734 mg; yield 55%) as a colorless oil. MS(ESI)m / z:294.1[M+H] +

[0514] (2) The benzyl 6-ethenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (734 mg) obtained in (1) above was dissolved in 1,4-dioxane (8 ml), sodium periodate (1 g), 2,6-lutidine (0.56 ml), and 2.5 wt% osmium tetroxide tert-butanol solution (2.4 ml) were added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain benzyl 6-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (565 mg; yield 74%) as a colorless oil. MS(ESI)m / z:296.2[M+H] +

[0515] (3) The reaction mixture of benzyl 6-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.06 g), tert-butyl diethoxyphosphoryl acetate (1.8 g), 1,1,3,3-tetramethylguanidine (830 mg), and THF (11 ml) obtained in (2) above was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain benzyl 6-[(E)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (698 mg; yield 46%) as a white solid. MS(ESI)m / z:392.4[MH] -

[0516] (4) Add 60% sodium hydride (288 mg) to DMSO solution (12 ml) of trimethylsulfoxonium iodide (1.6 g) at 0°C and stir for 10 minutes. Add DMSO solution of benzyl 6-[(E)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (698 mg) obtained in (3) above to the reaction mixture and stir at room temperature for 18 hours. Add water to the reaction mixture and extract with ethyl acetate. Wash the organic layer with saturated brine, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain benzyl 6-[rac-(1R,2R)-2-[(2-methylpropan-2-yl)oxycarbonyl]cyclopropyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (129 mg; yield 19%) as a colorless oil. 1 H-NMR(400MHz, CDCl3)δppm:1.18-1.21(1H,m),1.46(9H.s),1.47-1.50(1H,m),1.80-1.82(1H ,m),2.38-2.41(1H,m),2.81(br,1H),3.70(1H,br),4.61(2H,s),5.17(2H,s),6.87-7.02(3H,m),7.33-7.39(5H,m).

[0517] (5) Benzyl 6-[rac-(1R,2R)-2-[(2-methylpropan-2-yl)oxycarbonyl]cyclopropyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (129 mg) obtained in (4) above was mixed with ethanol (1 ml) and 20% palladium hydroxide (12 mg) and stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (107 mg; yield 97%) as a gray oil. MS(ESI)m / z:274.3[M+H] +

[0518] Reference example 32: Preparation of tert-butyl 1-(5,6,7,8-tetrahydro-2,7-naphthyrizin-3-yl)piperidine-4-carboxylate

[0519] [ka]

[0520] (1) A mixture of benzyl 6-chloro-3,4-dihydro-1H-2,7-naphthiridine-2-carboxylate (300 mg), DMSO (3 ml), diisopropylethylamine (0.33 ml), and tert-butylpiperidine 4-carboxylate hydrochloride (250 mg) was stirred in a microwave reactor at 180°C for 1 hour. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~40 / 60) to obtain benzyl 6-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-1-yl]-3,4-dihydro-1H-2,7-naphthiridine-2-carboxylate (117 mg; yield 22%) as a yellow oil. MS(ESI)m / z:452.3[M+H] +

[0521] (2) To the benzyl 6-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-1-yl]-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (117 mg) obtained in (1) above, ethanol (1 ml) and 20% palladium hydroxide (12 mg) were added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (65 mg) as a yellow solid.

[0522] Reference example 33: Preparation of tert-butyl 3-(1,2,3,4-tetrahydroisoquinoline-6-yl)propanoate

[0523] [ka]

[0524] (1) 6-bromo-1,2,3,4-tetrahydroisoquinoline (12 g) was dissolved in pyridine (47 ml), and N,N-dimethylpyridine-4-amine (172 mg) and trifluoroacetic anhydride (6 g) were added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, and the residue was washed with ethyl acetate and 1N hydrochloric acid. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain 1-(6-bromo-3,4-dihydro-1H-isoquinoline-2-yl)-2,2,2-trifluoroethanone (11.8 g; yield 68%) as a white solid. MS(ESI)m / z:308.0 / 310.0[M+H] +

[0525] (2) Dissolve 1-(6-bromo-3,4-dihydro-1H-isoquinoline-2-yl)-2,2,2-trifluoroethanone (2.4 g) obtained in (1) above in 1,4-dioxane (16 ml), add water (4 ml), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.16 g), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (178 mg), and cesium carbonate (3.3 g), and stir at 140°C for 1 hour using a microwave reactor. Filter the reaction solution and concentrate the filtrate. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~80 / 20) to obtain 1-(6-ethenyl-3,4-dihydro-1H-isoquinoline-2-yl)-2,2,2-trifluoroethanone (903 mg; 44%) as a white solid. MS(ESI)m / z:256.2[M+H] +

[0526] (3) 1-(6-ethenyl-3,4-dihydro-1H-isoquinoline-2-yl)-2,2,2-trifluoroethanone (903 mg) obtained in (2) above was dissolved in 1,4-dioxane (12 ml), water (3 ml), 2,6-lutidine (0.78 ml), 2.5 wt% osmium tet-butanol tetroxide solution (3.5 ml), and sodium periodate (1.4 g) were added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 80 / 20~50 / 50) to obtain 2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-carbaldehyde (573 mg; 66%) as a white solid. MS(ESI)m / z:258.0[M+H] +

[0527] (4) The 2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-carbaldehyde (573 mg) obtained in (3) above was dissolved in THF (7 ml), and 1,1,3,3-tetramethylguanidine (513 mg) and tert-butyl 2-diethoxyphosphoryl acetate (843 mg) were added and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 100 / 0~70 / 30) to obtain tert-butyl (E)-3-[2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-yl]prop-2-enoate (544 mg; 63%) as a colorless oil. 1 H-NMR(400MHz, CDCl3)δppm:1.56(9H,s),2.99(2H,t),3.88(2H,t),4.82(2H,s),6.38(1H,d),7.19(1H,d),7.32(1H,s),7.41(1H,d),7.56(1H,d).( * (A mixture of rotational isomers with an NMR integration ratio of approximately 2:1)

[0528] (5) The tert-butyl (E)-3-[2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-yl]prop-2-enoate (544 mg) obtained in (4) above was dissolved in ethanol (6 ml), palladium hydroxide-activated carbon (55 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After filtering the reaction solution through a membrane filter, the filtrate was concentrated under reduced pressure to obtain the crude product of tert-butyl 3-[2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-yl]propanoate (527 mg) as a colorless oil. 1 H-NMR(400MHz, CDCl3)δppm:1.35(9H,s),2.45(2H,t),2.80(2H,t),2.85(2H,t),3.76(2H,t),4.69(2H,s),7.01-6.92(3H,m).( * (A mixture of rotational isomers with an NMR integration ratio of approximately 2:1)

[0529] (6) The crude product (527 mg) of tert-butyl 3-[2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-6-yl]propanoate obtained in (5) above was dissolved in ethanol (5 ml), and an aqueous sodium hydroxide solution (4 mol / l, 1.5 ml) was added and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated to obtain the crude product (377 mg) of the title compound as a colorless oil.

[0530] Reference example 34: Manufacturing of tert-butyl 2-[(8-bromo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy]acetate

[0531] [ka]

[0532] (1) A mixture of 8-bromo-6-methoxy-1,2,3,4-tetrahydroisoquinoline (180 mg) and 50% hydrobromic acid (4 ml) was stirred at 130°C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the resulting residue and a mixture of 1,4-dioxane (1 ml) and water (1 ml), 1N sodium hydroxide aqueous solution (2 ml) and benzyl chloroformate (0.15 ml) were added and stirred for 1 hour under an ice bath. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 90 / 10~50 / 50) to obtain benzyl 8-bromo-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (53 mg; yield 23%) as a colorless oil. MS(ESI)m / z:360.1 / 362.1[MH] -

[0533] (2) Add 60% sodium hydride (9 mg) to a mixture of benzyl 8-bromo-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (53 mg) obtained in (1) above, DMF (0.5 ml), and THF (0.1 ml) under an ice bath, stir for 5 minutes, then raise to room temperature, add tert-butyl bromoacetate (47 mg), and stir for 1 hour. Add saturated ammonium chloride aqueous solution to the reaction mixture and extract with chloroform. Wash the organic layer with saturated brine, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 90 / 10~70 / 30) to obtain benzyl 8-bromo-6-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (64 mg; yield 92%) as a colorless oil. MS(ESI)m / z:493.0 / 495.0 [M+NH4] +

[0534] (3) To a mixture of palladium acetate (7 mg) and dichloromethane (1.0 ml), triethylamine (0.02 ml), triethylsilane (0.032 ml), and benzyl 8-bromo-6-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (64 mg) obtained in (2) above were added under a nitrogen atmosphere and the mixture was stirred at room temperature for 30 minutes. After filtering the reaction mixture through Celite, the filtrate was concentrated under reduced pressure to obtain the crude product of tert-butyl 2-[(8-bromo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy]acetate as a brown oily substance. MS(ESI)m / z:342.1 / 344.1 [M+H] +

[0535] Reference example 35: Preparation of tert-butyl 2-[(8-fluoro-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy]-2-methylpropanoate

[0536] [ka]

[0537] (1) Dissolve benzyl 8-fluoro-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (101 mg) in DMF (1 ml), add potassium carbonate (52 mg) and tert-butyl 2-bromo-2-methylpropanoate (0.064 ml), and stir the reaction mixture at room temperature for 5 hours. Add potassium carbonate (49 mg) and tert-butyl 2-bromo-2-methylpropanoate (0.064 ml) to the reaction mixture and stir at room temperature for 15 hours and 30 minutes, then at 50°C for 7 hours, and then at 80°C for 1 hour. Add potassium carbonate (102 mg) and tert-butyl 2-bromo-2-methylpropanoate (0.128 ml) to the reaction mixture and stir at 80°C for 15 hours and 30 minutes. Cool the reaction mixture to room temperature, add water, and extract with ethyl acetate. The organic layer was washed with a 2-fold diluted saturated saline solution, filtered through a Phase-separator (Biotage), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 91 / 9~70 / 30) to obtain benzyl 8-fluoro-6-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (97.2 mg; yield 69.8%) as a colorless oil. MS(ESI)m / z:444.4[M+H] +

[0538] (2) The benzyl 8-fluoro-6-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (97 mg) obtained in (1) above was dissolved in ethanol (1 ml), palladium-carbon (10%, 50 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours and 30 minutes. After purging with nitrogen, the reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure and then vacuum dried to obtain the title compound (65.2 mg; yield 96.2%) as a colorless oil. MS(ESI)m / z:310.3[M+H] +

[0539] Reference example 36: By treating the corresponding starting compounds in the same manner as in Reference Example 35, crude products of the compounds listed in Table 2 below were obtained.

[0540] [Table 2]

[0541] Reference example 37: Preparation of tert-butyl 3-[(8-fluoro-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy]-2,2-dimethylpropanoate

[0542] [ka]

[0543] (1) Benzyl 8-fluoro-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (108 mg) was dissolved in THF (1 ml), and triphenylphosphine (117 mg), tert-butyl 3-hydroxy-2,2-dimethyl-propanoate (115 mg), and diethyl azodicarboxylate (2.2 mol / l toluene solution, 0.31 ml) were added. The reaction mixture was stirred at 70°C for 21 hours. Then, it was stirred for 4 days while allowing it to cool naturally to room temperature. The reaction mixture was concentrated under reduced pressure, the residue was diluted with diisopropyl ether, the precipitate was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 95 / 5 to 75 / 25) to obtain benzyl 6-[2,2-dimethyl-3-[(2-methylpropan-2-yl)oxy]-3-oxopropoxy]-8-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylate (85.8 mg; yield 44.4%) as a colorless oil. MS(ESI)m / z:402.3[M-C4H8+H] +

[0544] (2) The benzyl 6-[2,2-dimethyl-3-[(2-methylpropan-2-yl)oxy]-3-oxopropoxy]-8-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylate (85.8 mg) obtained in (1) above was dissolved in ethanol (2 ml), palladium-carbon (10%, 23 mg) was added, and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. After purging with nitrogen, the reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure and then vacuum dried to obtain the title compound (57.1 mg; yield 104%) as a colorless oil. MS(ESI)m / z:324.3[M+H] +

[0545] Reference example 38: Preparation of tert-butyl 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-yl)propanoate

[0546] [ka]

[0547] (1) A mixture of ethyl 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-yl)propanoate (1.0 g) and dichloromethane (13 ml) was mixed with triethylamine (1.8 ml) and benzyl chloroformate (0.6 ml) and stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain benzyl 2-(3-ethoxy-3-oxopropyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (1.4 g; yield 102%) as a white solid. MS(ESI)m / z:358.2[M+H] +

[0548] (2) A mixture of benzyl 2-(3-ethoxy-3-oxopropyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (1.4 g) and ethanol (13 ml) obtained in (1) above was mixed with 4N sodium hydroxide aqueous solution (1.6 ml) and stirred at 50°C for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3-(5-phenylmethoxycarbonyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl)propanoic acid (940 mg; yield 73%) as a colorless oil. MS(ESI)m / z:328.1[MH] -

[0549] (3) To the mixed solution of 3-(5-phenylmethoxycarbonyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl)propanoic acid (940 mg) and toluene (10 ml) obtained in (2), N,N-dimethylformamide ditert-butylacetal (2.2 ml) was added and the mixture was stirred at 120°C for 30 minutes under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 60 / 40~40 / 60) to obtain benzyl 2-[3-[(2-methylpropan-2-yl)oxy]-3-oxopropyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (611 mg; yield 56%) as a colorless oil. MS(ESI)m / z:386.1[M+H] +

[0550] (4) 20% palladium hydroxide (15 mg) was added to a mixture of benzyl 2-[3-[(2-methylpropan-2-yl)oxy]-3-oxopropyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (95 mg) obtained in (3) above and methanol (1 ml), and the mixture was stirred at 60°C for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (62 mg) as a gray oily substance.

[0551] Reference example 39: Preparation of methyl 2-(4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine-2-yl)acetate trifluoroacetate

[0552] [ka]

[0553] (1) A mixed solution of tert-butyl 4-oxopiperidine-1-carboxylate (15 g) and toluene (70 ml) was mixed with pyrrolidine (6.6 L) and p-toluenesulfonic acid monohydrate (5 mg), and the mixture was heated under reflux for 8 hours using a Dean-Stark apparatus. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. Methanol (30 ml) and sulfur (2.41 g) were added to the residue, and then a solution of cyanamide (3.17 g) in methanol (10 ml) was added dropwise under an ice bath. After the addition was complete, the mixture was stirred under an ice bath for 5 hours. The precipitated solid was filtered, washed with ethyl acetate, and dried under reduced pressure to obtain tert-butyl 2-amino-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate (11.6 g; yield 60%) as a pale yellow solid. MS(APCI)m / z:256.1[M+H] +

[0554] (2) To a mixture of copper(II) bromide (11.9 g) and DMF (40 ml), hexyl nitrite (6.83 g) was added and the mixture was stirred at 50°C for 5 minutes. To the reaction mixture, tert-butyl 2-amino-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate (11.3 g) obtained in (1) above was added and the mixture was stirred at 50°C for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 83 / 17) to obtain tert-butyl 2-bromo-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate (4.1 g; yield 24%) as a pale yellow solid. MS(APCI)m / z:319.0 / 321.0[M+H] +

[0555] (3) The mixture obtained in (2) above, consisting of tert-butyl 2-bromo-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate (150 mg), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (266 mg), potassium carbonate (130 mg), bis(tri-tert-butylphosphine)palladium (0) (72 mg), and DMF (1 ml), was stirred in a microwave reactor at 120°C for 1 hour. After the reaction mixture was cooled to room temperature, saturated ammonium chloride aqueous solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 60 / 40~30 / 70) to obtain tert-butyl 2-(2-methoxy-2-oxoethyl)-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate (36 mg; yield 25%) as a yellow amorphous compound. MS(ESI)m / z:313.2[M+H] +

[0556] (4) Trifluoroacetic acid (0.1 ml) was added to the mixture of tert-butyl 2-(2-methoxy-2-oxoethyl)-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-5-carboxylate (34 mg) and dichloromethane (0.5 ml) obtained in (3) above, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product of the title compound (36 mg) as a colorless amorphous material.

[0557] Reference example 40: Preparation of methyl 2-(8-cyano-1,2,3,4-tetrahydroisoquinoline-6-yl)acetate trifluoroacetate

[0558] [ka]

[0559] (1) A mixture of 6-bromo-8-chloro-1,2,3,4-tetrahydroisoquinoline (58 mg) and dichloromethane (1.5 ml) was mixed with di-tert-butyl dicarbonate (77 mg) and triethylamine (0.05 ml) and stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 30 / 70~0 / 100) to obtain tert-butyl 6-bromo-8-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate (63 mg; yield 77%) as a colorless amorphous material. MS(ESI)m / z:346.0 / 348.0[M+H] +

[0560] (2) The mixture obtained in (1) above, consisting of tert-butyl 6-bromo-8-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate (60 mg), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (98 mg), potassium carbonate (48 mg), bis(tri-tert-butylphosphine)palladium (0) (27 mg), and DMF (0.35 ml), was stirred in a microwave reactor at 120°C for 1 hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (10 mmol / l ammonium carbonate aqueous solution / acetonitrile = 50 / 50 to 20 / 80) to obtain tert-butyl 8-chloro-6-(2-methoxy-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (31 mg; yield 53%) as a pale yellow amorphous substance. MS(ESI)m / z:240.1 / 242.1[M-Boc+H] +

[0561] (3) To a solution of tert-butyl 8-chloro-6-(2-methoxy-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (30 mg) obtained in (2) above in water (1.5 ml) and dioxane (5 ml), potassium hexacyanoferrate(II) trihydrate (24 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (9 mg) and potassium acetate (9 mg) were added and the mixture was stirred at 100°C for 2 hours. After the reaction mixture was allowed to cool, saturated ammonium chloride aqueous solution was added, the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (10 mmol / l aqueous ammonium carbonate solution / acetonitrile = 80 / 20~50 / 50) to obtain 2-[8-cyano-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid (27 mg; yield 97%) as a colorless oil. MS(ESI)m / z:217.2[M-Boc+H] +

[0562] (4) To a solution of 2-[8-cyano-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid (24 mg) obtained in (3) above in methanol (0.3 ml) and toluene (1.2 ml), trimethylsilyldiazomethane (10% hexane solution) (0.3 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. By concentrating the reaction mixture under reduced pressure, tert-butyl 8-cyano-6-(2-methoxy-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (24 mg; yield 96%) was obtained as a colorless amorphous material. MS(ESI)m / z:331.3[M+H] +

[0563] (5) Trifluoroacetic acid (0.1 ml) was added to the mixture of tert-butyl 8-cyano-6-(2-methoxy-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (22 mg) and dichloromethane (1 ml) obtained in (4) above, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain the crude product of the title compound (23 mg) as a colorless amorphous material.

[0564] Reference example 41: Manufacturing of methyl 4-(3-phenylpiperazin-1-yl)butanoate hydrochloride

[0565] [ka]

[0566] (1) Diethyl oxalate (2.3 ml) was added to a solution of 2-phenylpiperazine (1.84 g) in THF (ml), and the reaction mixture was stirred overnight. Di-tert-butyl dicarbonate (3.25 g) was added to the reaction mixture and stirred overnight at room temperature. The solvent was removed from the reaction mixture by distillation, methanol (23 ml) and water (23 ml) were added to the residue, and 10 mol / l sodium hydroxide aqueous solution (11.3 ml) was added, and the mixture was stirred at 80°C for 12 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane / ethyl acetate = 75 / 25~50 / 50), and the fraction containing the target product was concentrated under reduced pressure to obtain tert-butyl 2-phenylpiperazine-1-carboxylate (1.1958 g; yield 40%) as a pale yellow oil. MS(ESI)m / z:263.3[M+H] +

[0567] (2) The tert-butyl 2-phenylpiperazine-1-carboxylate (200 mg) obtained in (1) above was added to DMF (1.9 ml), and methyl 4-bromobutyrate (207 mg), potassium carbonate (316 mg), and potassium iodide (127 mg) were added sequentially, and the mixture was stirred at 80°C for 5 hours and 5 minutes. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain tert-butyl 4-(4-methoxy-4-oxobutyl)-2-phenylpiperazine-1-carboxylate (270 mg; yield 98%) as a pale yellow oil. MS(ESI)m / z:363.3[M+H] +

[0568] (3) Add 270 mg of tert-butyl 4-(4-methoxy-4-oxobutyl)-2-phenylpiperazine-1-carboxylate obtained in (2) above to dioxane (1.86 ml), add 1.86 ml of 4 M hydrogen chloride-dioxane solution, and stir at room temperature for 4 hours and 10 minutes. After removing the reaction mixture under reduced pressure, add dioxane and remove the solvent under reduced pressure to obtain the crude product of the title compound. MS(ESI)m / z:263.3[M+H] +

[0569] Reference examples 42~46: By treating the corresponding raw material compounds in the same manner as in Reference Example 41, the compounds listed in Table 3 below were obtained.

[0570] [Table 3]

[0571] Reference example 47: Preparation of methyl 4-[(2R,5S)-2-methyl-5-phenylpiperazine-1-yl]butanoate

[0572] [ka]

[0573] (1) To a solution of methyl (2S)-2-(benzylamino)-2-phenylacetate (2.3 g) in DMF (20 ml), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (5.0 g), HATU (12.3 g), and N,N-diisopropylethylamine (5.62 ml) were added, and the reaction mixture was stirred at room temperature for 4 days. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20~40 / 60) to obtain methyl (2S)-2-[benzyl-[(2R)-2-(tert-butoxycarbonylamino)propanoyl]amino]-2-phenylacetate (1.74 g; yield 45.3%) as a colorless oil. MS(ESI)m / z:425.3[MH] ―

[0574] (2) The methyl (2S)-2-[benzyl-[(2R)-2-(tert-butoxycarbonylamino)propanoyl]amino]-2-phenylacetate (1.74 g) obtained in (1) above was dissolved in dichloromethane (10 ml), trifluoroacetic acid (10 ml) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure at 40°C, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0~90 / 10) to obtain (3R,6S)-1-benzyl-3-methyl-6-phenylpiperazine-2,5-dione (1.0 g; yield 83.3%) as a colorless amorphous material. MS(ESI)m / z:295.1[M+H] +

[0575] (3) Dissolve the (3R,6S)-1-benzyl-3-methyl-6-phenylpiperazine-2,5-dione (1.0 g) obtained in (2) above in THF (7 ml), add boranedimethyl sulfide (6.59 ml), and stir the reaction mixture at 60°C for 15 hours. Cool the reaction mixture to 0°C, slowly add water, then add hydrochloric acid (1 mol / l, 20 ml), and stir at room temperature for 10 minutes. Add aqueous sodium hydroxide solution (1 mol / l) to the reaction mixture to neutralize it, and extract with chloroform. Wash the organic layer with saturated brine, dry over anhydrous magnesium sulfate, and filter. Concentrate the filtrate under reduced pressure, add methanol (20 ml) and aqueous sodium hydroxide ...

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, R is a C atom substituted with one to three substituents selected from the group consisting of halogen atoms, optionally substituted C1-6 alkyl groups, optionally substituted C3-8 cycloalkyl groups, optionally substituted C1-6 alkoxy groups, optionally substituted C3-8 cycloalkyloxy groups, optionally substituted C1-6 alkylsulfanyl groups, optionally substituted C3-8 cycloalkylsulfanyl groups, and pentafluorosulfanyl groups. ６－１０ Represents an aryl-ethenyl group; R １ This is a carboxyl group, which may be substituted C １－６ An alkoxy-carbonyl group, an optionally substituted carbamoyl group, a cyano group, or the following formula: 【Chemistry 2】 (In the formula, the dashed line represents the bonding site of the group represented by the above chemical formula, and ＊ (This indicates the bonding position with L.) It is a group selected from the group consisting of groups represented by; L is -NR ２ - (wherein R ２ represents a hydrogen atom or a C １－６ alkyl group), -O-, -S-, -C(=O)-, C １－６ alkylene group, C ６－１０ arylene group, C ３－１４ cycloalkylene group, and may have at the terminal one divalent group selected from the group consisting of a 3- to 14-membered divalent non-aromatic heterocyclic group, and may be further substituted by 1 to 3 substituents each selected from the substituent group a, C １－６ alkylene group, C ６－１０ arylene group, C ３－１４ cycloalkylene group, C ２－６ alkynylene group, or a 3- to 14-membered divalent non-aromatic heterocyclic group; and A represents a divalent nitrogen-containing heterocyclic group that may be further substituted. A compound represented by or a pharmaceutically acceptable salt thereof. (Substituent group a): halogen atom; Hydroxyl group; Cyano group; Oxo group; Halogen atom, hydroxyl group, cyano group, C １－６ Alkoxy group, C ６－１４ Aryl group, carboxyl group, C １－６ Alkoxy-carbonyl group, 1 or 2 C １－６ A carbamoyl group which may be substituted with an alkyl group, and C ６－１４ C may be substituted with substituents selected from the group consisting of aryloxy groups. １－６ alkyl group; C may be substituted with halogen atoms. １－６ Alkoxy group; C may be substituted with halogen atoms. １－６ Alkyl sulfonyl group; C １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; Halogen atom, hydroxyl group, diC １－６ Alkylamino group and C １－６ One or two carbon atoms may be substituted with substituents selected from the group consisting of alkoxy groups. １－６ Carbamoyl groups that may be substituted with alkyl groups; C １－６ Alkylamino group; Tri-substituted silyl group; Tri-substituted silyloxy group; C may be substituted with one to three substituents selected from substituent group b. ６－１４ Hydrocarbon ring group; A 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from substituent group b; and A 3- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from substituent group b. (Substituent group b): halogen atom; Hydroxyl group; Cyano group; Oxo group; Carboxy group; Halogen atoms, hydroxyl groups, cyano groups, and C １－６ C may be substituted with substituents selected from the group consisting of alkoxy groups. １－６ alkyl group; Halogen atoms, hydroxyl groups, cyano groups, and C １－６ C may be substituted with substituents selected from the group consisting of alkoxy groups. ３－８ Cycloalkyl groups; Halogen atom, hydroxyl group, cyano group, C １－６ Alkyl and C １－６ C may be substituted with substituents selected from the group consisting of alkoxy groups. ６－１０ Aryl group; Halogen atom, hydroxyl group, cyano group, C １－６ Alkyl and C １－６ A 5- to 14-membered aromatic heterocyclic group which may be substituted with substituents selected from the group consisting of alkoxy groups; Halogen atom, hydroxyl group, cyano group, C １－６ Alkyl and C １－６ A 3- to 14-membered non-aromatic heterocyclic group which may be substituted with substituents selected from the group consisting of alkoxy groups; Halogen atoms, hydroxyl groups, cyano groups, and C １－６ C may be substituted with substituents selected from the group consisting of alkoxy groups. １－６ Alkoxy group; Halogen atoms, hydroxyl groups, cyano groups, and C １－６ C may be substituted with substituents selected from the group consisting of alkoxy groups. １－６ Alkyl sulfanyl group; Halogen atoms, hydroxyl groups, cyano groups, and C １－６ C may be substituted with substituents selected from the group consisting of alkoxy groups. ３－８ Cycloalkyloxy group; C may be substituted with halogen atoms. １－６ Alkyl sulfonyl group; C may be substituted with halogen atoms. １－６ Alkyl-carbonyl group; C １－６ Alkoxy-carbonyl group; Halogen atom, hydroxyl group, diC １－６ Alkylamino group and C １－６ One or two carbon atoms may be substituted with substituents selected from the group consisting of alkoxy groups. １－６ Carbamoyl groups that may be substituted with alkyl groups; Halogen atoms, hydroxyl groups, cyano groups, and C １－６ C may be substituted with one to three substituents selected from the group consisting of alkoxy groups. １－６ alkyl group, C ３－８ A sulfamoyl group substituted with one substituent selected from the group consisting of cycloalkyl groups and non-aromatic heterocyclic groups; and Pentafluorosulfanyl group.

2. In equation (I), R may be a halogen atom, or C may be substituted. １－６ Alkyl alkyl groups, optionally substituted C ３－８ Cycloalkyl groups, may be substituted C １－６ A carbon atom may be substituted with an alkoxy group. ３－８ Cycloalkyloxy group, may be substituted C １－６ Alkylsulfanyl group, optionally substituted C ３－８ A 2-phenylethenyl group substituted with one to three substituents selected from the group consisting of cycloalkylsulfanyl groups and pentafluorosulfanyl groups; and A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula: 【Transformation 3】 (In the formula, ＊＊ This represents the bonding site with the carbonyl group. ＊＊＊ This represents the bonding site with group L, and ring A １ This represents a monoring of 3 to 10 members, a fused ring of 8 to 14 members, a spiroring of 6 to 16 members, or a bridging ring of 6 to 14 members, and may include, in addition to nitrogen and carbon atoms, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. In equation (I), R may be a halogen atom, or C may be substituted with a halogen atom. １－６ A 2-(E)-phenylethenyl group substituted with one to three substituents selected from the group consisting of alkyl groups and pentafluorosulfanyl groups; L, -NR ２ - (Here, R ２ is a hydrogen atom or C １－６ Represents an alkyl group. ), -O-, -S-, -C(=O)-, C ６－１０ Arylene group, C ３－１０ C may have a terminal divalent group selected from the group consisting of a cycloalkylene group and a 3- to 8-membered divalent non-aromatic heterocyclic group, and may be further substituted with 1 to 3 substituents selected from the substituent group a. １－６ The alkylene group may be further substituted with one to three substituents selected from the substituent group a. ６－１０ Arylene group, C may be further substituted with one to three substituents selected from the substituent group a. ３－１０ Cycloalkylene group, C may be further substituted with one to three substituents selected from the substituent group a. ２－４ Alkynylene group, or A 3 to 8-membered divalent non-aromatic heterocyclic group which may be further substituted with 1 to 3 substituents selected from the substituent group a above. and A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula: 【Chemistry 4】 (In the formula, the wavy line represents the bonding site of the group represented by the above chemical formula.) 【Transformation 5】 The bond represented by is a single bond or a double bond, and Y is, independently of each other, a nitrogen atom or CR ３ where R ３ represents a hydrogen atom or C １－６ alkyl group. ), Z is an oxygen atom, a sulfur atom, NR ４ or CR ５ R ６ where R ４ , R ５ and R ６ each independently represents a hydrogen atom or C １－６ alkyl group. ), n represents an integer from 0 to 2, m represents an integer from 0 to 2, n １ and n ２ each independently represents an integer from 0 to 2, m １ and m ２ each independently represents an integer from 0 to 2, ＊＊ represents the bonding site with the carbonyl group, and and ＊＊＊ represents the bonding site with the group L. ) It is a divalent nitrogen-containing non-aromatic heterocyclic group represented by The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. In equation (I), L, -NR ２ - (Here, R ２ is a hydrogen atom or C １－６ Represents an alkyl group. ), -O-, -S-, C ３－１０ C may have a terminal divalent group selected from the group consisting of a cycloalkylene group and a 3- to 8-membered divalent non-aromatic heterocyclic group, and may be further substituted with 1 to 3 substituents selected from the substituent group a. １－６ Alkylene group, C may be further substituted with one to three substituents selected from the substituent group a. ３－１０ Cycloalkylene group, or A 3 to 8-membered divalent non-aromatic heterocyclic group which may be further substituted with 1 to 3 substituents selected from the substituent group a above. The compound according to claim 3 or a pharmaceutically acceptable salt thereof.

5. In equation (I), L is a C alkylene group which may be further substituted with 1 to 3 substituents selected from the group of substituents a １－６ The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein L is an alkylene group.

6. In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula: 【Transformation 6】 (The definitions of each symbol in the formula are the same as those given above.) The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is a divalent nitrogen-containing non-aromatic heterocyclic group represented by .

7. In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula: 【Transformation 7】 (The definitions of each symbol in the formula are the same as above. However, Z is CR ５ R ６ If this is the case, the substituents that may be further substituted may be substituted with one to three substituents selected from substituent group b among the substituents of substituent group a. ６－１４ (Selected from the group consisting of hydrocarbon ring groups; 5- to 14-membered aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b; and 3- to 14-membered non-aromatic heterocyclic groups which may be substituted with 1 to 3 substituents selected from substituent group b.) The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is a divalent nitrogen-containing non-aromatic heterocyclic group represented by .

8. In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula: 【Transformation 8】 (The definitions of each symbol in the formula are the same as those given above.) The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is a divalent nitrogen-containing non-aromatic heterocyclic group represented by .

9. In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula: 【Chemistry 9】 (The definitions of each symbol in the formula are the same as those given above.) The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is a divalent nitrogen-containing non-aromatic heterocyclic group represented by .

10. In equation (I), A may be further substituted with one to three substituents selected from the substituent group a, as shown in the following formula: 【Chemistry 10】 (The definitions of each symbol in the formula are the same as those given above.) The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is a divalent nitrogen-containing non-aromatic heterocyclic group represented by .

11. In equation (I), R １ However, the carboxyl group may be substituted. １－６ A compound according to any one of claims 1 to 10, wherein the compound is an alkoxy-carbonyl group or an optionally substituted carbamoyl group, or a pharmaceutically acceptable salt thereof.

12. 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 3-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; N,N-dimethyl-3-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl]propanamide; 1-[7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,8-dihydro-5H-2,7-naphthyridine-3-yl]piperidine-4-carboxylic acid; 3-[3-bromo-5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl]propanoic acid; 2-[[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]oxy]acetic acid; 2-[2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; (1R*,2R*)-2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]cyclopropane-1-carboxylic acid and both enantiomers; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[7-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[7-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,8-dihydro-5H-2,7-naphthyridine-3-yl]acetic acid; 3-[3-bromo-5-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl]propanoic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]aminoacetic acid; 2-[2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-cyano-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-(2-fluoro-4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-yl]sulfanyl]acetic acid; 2-[7-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-cyano-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; (E)-N-[2-[6-(2-amino-2-oxoethyl)-3,4-dihydro-1H-isoquinoline-2-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide; 2-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-[1,3]thiazolo[4,5-c]pyridine-2-yl]acetic acid; (E)-N-[2-[6-[2-(methylamino)-2-oxoethyl]-3,4-dihydro-1H-isoquinoline-2-yl]-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide; 4-[4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3-phenylpiperazine-1-yl]butanoic acid and both enantiomers; 2-[[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2,3-dihydroindole-4-yl]oxy]acetic acid; 1-[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperidine-3-yl]bicyclo[2.1.1]hexane-5-carboxylic acid; 2-[[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]oxy]-2-methylpropanoic acid; 3-[[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]oxy]-2,2-dimethylpropanoic acid; 4-[4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(3-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 3-[[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]methyl]cyclobutan-1-carboxylic acid and both enantiomers; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]-2,2-dimethylbutanoic acid; 4-[3-(3-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid and both enantiomers; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chloro-3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-2-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]-2,2-dimethylbutanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

13. 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 3-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; N,N-dimethyl-3-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl]propanamide; 2-[2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; (1R*,2R*)-2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]cyclopropane-1-carboxylic acid and both enantiomers; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[7-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-cyano-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-(2-fluoro-4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[7-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-6,7-dihydro-4H-[1,3]thiazolo[4,5-c]pyridine-2-yl]acetic acid; 4-[(3S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3-phenylpiperazine-1-yl]butanoic acid; 1-[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperidine-3-yl]bicyclo[2.1.1]hexane-5-carboxylic acid; 4-[(3S)-3-(4-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(3-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 3-[[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]methyl]cyclobutan-1-carboxylic acid and both enantiomers; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid and both enantiomers; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chloro-3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-2-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]-2,2-dimethylbutanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

14. 2-[7-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[2-[2-[[(E)-3-(4-iodophenyl)prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-fluoro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[7-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[5-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 4-[(3S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3-phenylpiperazine-1-yl]butanoic acid; 1-[1-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperidine-3-yl]bicyclo[2.1.1]hexane-5-carboxylic acid; 4-[(3S)-3-(4-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(3-bromophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(3,4-difluorophenyl)-2-methyl-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-5-(4-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]-2,2-dimethylbutanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

15. 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 3-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; N,N-dimethyl-3-[5-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl]propanamide; 2-[2-[2-[[(E)-3-[4-(pentafluoro-λ6-sulfanyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]propanoic acid; 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-3,4-dihydro-1H-isoquinoline-6-yl]acetic acid; 4-[(3R)-3-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid; 4-[(2R,5S)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methyl-5-phenylpiperazine-1-yl]butanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 3-[(2R,5S)-5-(4-chlorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]propanoic acid; 4-[(2R,5S)-5-(3-fluorophenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-2-methylpiperazine-1-yl]butanoic acid; 4-[(2R,5S)-2-ethyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]-5-phenylpiperazine-1-yl]butanoic acid; and 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

16. 2-[8-chloro-2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid or a pharmaceutically acceptable salt thereof.

17. 2-[2-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid or a pharmaceutically acceptable salt thereof.

18. 2-[8-fluoro-2-[2-[[(E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]aminoacetyl]3,4-dihydro-1H-isoquinoline-6-yl]acetic acid or a pharmaceutically acceptable salt thereof.

19. 4-[(3S)-3-(4-cyclopropylphenyl)-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid or a pharmaceutically acceptable salt thereof.

20. 4-[(3S,6R)-3-phenyl-6-methyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid or a pharmaceutically acceptable salt thereof.

21. 4-[(3S,6R)-3-(3-fluorophenyl)-6-methyl-4-[2-[[(E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]acetyl]piperazine-1-yl]butanoic acid or a pharmaceutically acceptable salt thereof.

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