Indoleacetic acid derivative

Abstract

Provided is: a compound represented by formula (I), an enantiomer or diastereomer of the compound; a pharmaceutically acceptable salt of the compound or the enantiomer or diastereomer; or a prodrug of the compound, the enantiomer or diastereomer, or the pharmaceutically acceptable salt.

Description

Indoleacetic acid derivatives

[0001] This invention relates to indoleacetic acid derivatives, or pharmaceutically acceptable salts thereof, or prodrugs thereof.

[0002] Mitochondria are the primary energy-supplying organelles in cells and are abundant in human body tissues that are highly active and have high energy requirements (e.g., brain, skeletal muscle, cardiac muscle, kidneys, etc.). Therefore, a decline in mitochondrial function due to genetic background or aging can affect many major organs.

[0003] Japanese Patent Publication No. 2019-116453

[0004] One of the objectives of the present invention is to provide indoleacetic acid derivatives, or pharmaceutically acceptable salts thereof, or prodrugs thereof.

[0005] That is, an indoleacetic acid derivative according to one embodiment, or a pharmaceutically acceptable salt thereof, or a prodrug thereof is as follows: [1] Formula (I) below: [In equation (I), R1 is (a) the following equation (II) (In formula (II), R41, R42, R43, R44, and R45 are each independently a hydrogen atom, a C1-C10 alkyl group (the hydrogen atoms of the alkyl group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C2-C6 alkoxyalkyl group (the hydrogen atoms of the alkoxyalkyl group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C1-C6 alkoxy group (the hydrogen atoms of the alkoxy group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C3-C6 cycloalkyl group, a phenyl group, a halogen atom, OH, COOH, NHCOR5, NR6R7, or CONR8R9, and R5 is a C1-C4 alkyl group. R6 and R7 are each independently a hydrogen atom, a C1-C6 alkyl group, or a C2-C6 cyclic amino group formed by R6 and R7 working together (the cyclic amino group may contain an oxygen atom, a nitrogen atom, and a sulfur atom in its ring structure, and the nitrogen atom may be bonded to a C1-C6 alkyl group, and the sulfur atom may be oxidized by 1-2 oxygen atoms), and R8 and R9 are each independently a hydrogen atom, a C1-C6 alkyl group, or a C2-C6 cyclic amino group formed by R8 and R9 working together); or (b) an unsubstituted or R10 substituted naphthyl group or heteroaryl group (the heteroaryl group has a 5-membered to 10-membered monocyclic or bicyclic structure, and contains a total of 1-5 nitrogen atoms, oxygen atoms, and sulfur atoms in its ring structure), R10 is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, NHCOR11, or NR12R13; R11 is an alkyl group having 1 to 4 carbon atoms; R12 and R13 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cyclic amino group having 2 to 6 carbon atoms formed by the integration of R12 and R13; A is -(CH ２ ) １～３ -, -CH(CH ３ )-, or -C(O)CH ２a group represented by -; R2 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group having 2 to 4 carbon atoms, or a halogen atom; R3 is COOH, COOR14, CONH ２ , CONHCN, carboxylic acid bioisostere, or a tetrazole group, R14 is an alkyl group having 1 to 6 carbon atoms; Y1, which is a substituent at the 2-position of the indole ring, is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a phenyl group; Y2, which is a substituent on N of the indole ring, is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms (1 to 5 hydrogen atoms of said alkyl group may be substituted with fluorine atoms), an alkoxyalkyl group having 2 to 6 carbon atoms (a hydrogen atom of said alkoxyalkyl group may be substituted with an alkoxy group having 1 to 6 carbon atoms), -(CH ２ ) １～２ -O-(CH ２ ) １～３ -SiY3Y4Y5 (Y3, Y4 and Y5 are each independently an alkyl group having 1 to 4 carbon atoms), or the following formula (III) (in formula (III), Y6 is an unsubstituted or Y7-substituted phenyl group, pyridyl group, furyl group, thienyl group, naphthyl group, or a cycloalkyl group having 3 to 6 carbon atoms, Y7 is an alkyl group having 1 to 6 carbon atoms, a phenyl group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, CONY8Y9, NHCOY10, or NHY11Y12, Y8 and Y9 are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a cyclic amino group having 2 to 6 carbon atoms formed by Y8 and Y9 together, Y10 is an alkyl group having 1 to 4 carbon atoms, Y11 and Y12 are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a cyclic amino group having 2 to 6 carbon atoms formed by Y11 and Y12 together (said cyclic amino group may contain an oxygen atom, a nitrogen atom, and a sulfur atom in its ring structure, an alkyl group having 1 to 6 carbon atoms may be bonded to said nitrogen atom, and said sulfur atom may be oxidized with 1 or 2 oxygen atoms)); a group represented by ); B is -(CH ２ ) １～３ -, -CH(CH ３)-, -C(O)-, or -C(O)CH ２ - is a group represented by; Z1, Z2, Z3, and Z4 are each independently a hydrogen atom, a C1-C4 alkyl group, a halogen atom, a C1-C8 alkoxy group (the hydrogen atoms of the alkoxy group may be substituted with C1-C6 alkoxy groups), -O-(CH ２ ) １～２ - Ph, CN, or CF ３ [2] A is a compound represented by [ ], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. ２ - The compound described in [1], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. [3] R1 is the group represented by formula (II), R2 is a hydrogen atom or a C1 or C2 alkyl group, and R3 is COOH, COOR14, or CONH ２[1] The compound, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. [4] At least one of R41, R42, R43, R44, and R45 is a C1-C10 alkyl group (the hydrogen atoms of the alkyl group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C2-C6 alkoxyalkyl group (the hydrogen atoms of the alkoxyalkyl group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C1-C6 alkoxy group (the hydrogen atoms of the alkoxy group may be substituted with a C1-C6 alkoxy group), a C3-C6 cycloalkyl group, a phenyl group, a halogen atom, OH, COOH, NHCOR5, NR6R7, or CONR8R9, the compound, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. [5] R1 is an unsubstituted, C1-C6 alkyl group, or pyridyl, naphthyl, or quinolyl group substituted with a C1-C6 alkoxy group, as described in [1], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. [6] R1 is an unsubstituted, or R10-substituted indolyl, furyl, or thienyl group, as described in [1], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. [7] Y1 is a hydrogen atom or a C1 or C2 alkyl group, and Y2 is a hydrogen atom, a C3-C8 alkyl group (the hydrogen atoms of the alkyl group may be substituted with 1-5 fluorine atoms), a C2-C4 alkoxyalkyl group (the hydrogen atoms of the alkoxyalkyl group may be substituted with a C1-C3 alkoxy group), -CH ２ -O-(CH ２ ) ２-SiY3Y4Y5 (where Y3, Y4, and Y5 are each methyl groups), or a group represented by formula (III), where Y6 is an unsubstituted carbon 5 or carbon 6 cycloalkyl group, or an unsubstituted or Y7 phenyl group, pyridyl group, furyl group, or naphthyl group, and Y7 is a carbon 1 to carbon 4 alkyl group, a phenyl group, a halogen atom, a carbon 1 or carbon 2 alkoxy group, CONY8Y9, NHCOY10, or NY11Y12, the compound described in [1], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. [8] Z1, Z2, Z3, and Z4 are each independently a hydrogen atom, a halogen atom, a carbon 1 to carbon 8 alkoxy group (the hydrogen atom of the alkoxy group may be substituted with a carbon 2 to carbon 4 alkoxy group), -O-CH ２ - Ph, CN, or CF ３ The compound described in [1], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. [9] The compound described in [1], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is selected from the compounds represented by formulas (1) to (58), (71) and (72).

[10] A prodrug of any compound described in [1] to [9], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof.

[11] A NAMPT activator containing as an active ingredient any compound described in any of [1] to [9], its enantiomer, its diastereomer, a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a compound represented by the following formulas (59) to (70), its enantiomer, its diastereomer, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0006] The following describes each embodiment in detail.

[0007] [First Embodiment] The first embodiment is a compound represented by the following formula (I), its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0008]

[0009] In this specification, the number of substituents on a group defined as "may be substituted" or "substituted" is not particularly limited, as long as they are substituted, and may be one or more.

[0010] In this specification, the term "group" means a monovalent group. For example, "alkyl group" means a monovalent saturated hydrocarbon group. In addition, the term "group" may be omitted in the description of substituents in this specification.

[0011] In formula (I) above, R1 is (a) a group represented by the following formula (II), or (b) an unsubstituted or R10-substituted naphthyl or heteroaryl group. It is preferable that R1 is a group represented by the following formula (II).

[0012]

[0013] In the above formula (II), R41, R42, R43, R44, and R45 are each independently a hydrogen atom, a C1-C10 alkyl group, a C2-C6 alkoxyalkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a phenyl group, a halogen atom, OH, COOH, NHCOR5, NR6R7, or CONR8R9.

[0014] Preferably, at least one of R41, R42, R43, R44, and R45 is a C1-C10 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkoxyalkyl group, a C3-C6 cycloalkyl group, a phenyl group, a halogen atom, OH, or CF. ３ These are COOH, NHCOR5, NR6R7, or CONR8R9.

[0015] In this specification, "C1-C10 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms. Examples of these include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, sec-pentyl group, isoamyl group, n-hexyl group, n-heptyl group, n-octyl group, isooctyl group, 2-ethylhexyl group, decyl group, etc. In R41, R42, R43, R44, and R45, "C1-C10 alkyl group" is preferably a C3-C8 alkyl group, and more preferably n-propyl, isopropyl group, n-butyl group, tert-butyl group, n-pentyl group, sec-pentyl group, n-hexyl group, or n-octyl group.

[0016] In R41, R42, R43, R44, and R45, the hydrogen atoms of the "C1-C10 alkyl group" may be substituted with a C1-C6 alkoxy group. In such cases, the alkyl group is preferably a C3-C6 alkyl group, and the alkoxy group is preferably a C1-C3 alkoxy group.

[0017] In R41, R42, R43, R44, and R45, the hydrogen atoms of the "C1-C10 alkyl group" may be substituted with 1-5 fluorine atoms. In such cases, the alkyl group is preferably a C3-C6 alkyl group. Furthermore, it is preferable that multiple hydrogen atoms bonded to the terminal carbon atoms of the alkyl group are substituted with fluorine atoms. Moreover, it is even more preferable that multiple hydrogen atoms bonded to the terminal carbon atoms are also substituted with fluorine atoms.

[0018] In this specification, "C1-C6 alkoxy group" is synonymous with "C1-C6 alkyloxy group." Furthermore, the "C1-C6 alkyl group" portion refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of these include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, etc. In R41, R42, R43, R44, and R45, the "C1-C6 alkoxy group" is preferably a C3-C5 alkoxy group, and more preferably a C4 alkoxy group.

[0019] In R41, R42, R43, R44, and R45, the hydrogen atoms of the "alkoxy group having 1 to 6 carbon atoms" may be substituted with an alkoxy group having 1 to 6 carbon atoms. Examples of such groups include methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, isopropoxymethoxy, and isobutoxymethoxy. It is preferable that the hydrogen atoms of the alkoxy group having 1 to 3 carbon atoms are substituted with an alkoxy group having 1 to 3 carbon atoms. It is even more preferable that the group be an ethoxyethoxy group.

[0020] In R41, R42, R43, R44, and R45, the hydrogen atoms of the "alkoxy group having 1 to 6 carbon atoms" may be substituted with 1 to 5 fluorine atoms. In such cases, the alkoxy group is preferably an alkoxy group having 3 to 6 carbon atoms. Furthermore, it is preferable that multiple hydrogen atoms bonded to the terminal carbon atoms of the alkoxy group are substituted with fluorine atoms. Moreover, it is even more preferable that multiple hydrogen atoms bonded to the carbon atoms bonded to the terminal carbon atoms are also substituted with fluorine atoms.

[0021] In this specification, "2-6 carbon alkoxyalkyl groups" means saturated hydrocarbon groups containing a linear or branched ether linkage (-O-) having 2-6 carbon atoms. Examples of these include methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxymethyl group, butoxymethyl group, isobutoxymethyl group, sec-butoxymethyl group, tert-butoxymethyl group, methoxyethyl group, ethoxyethyl group, and the like.

[0022] In R41, R42, R43, R44, and R45, the hydrogen atoms of the "alkoxyalkyl group having 2 to 6 carbon atoms" may be substituted with an alkoxy group having 1 to 6 carbon atoms. Examples of these include methoxyethoxymethyl group, ethoxypropoxyethyl group, isopropoxybutoxymethyl group, butoxypentyloxyethyl group, methoxymethoxymethyl group, ethoxyethoxyethyl group, propoxypropoxypropyl group, butoxybutoxybutyl group, pentyloxypentyloxymethyl group, and hexyloxyhexyloxyethyl group.

[0023] In R41, R42, R43, R44, and R45, the hydrogen atoms of the "alkoxyalkyl group having 2 to 6 carbon atoms" may be substituted with 1 to 5 fluorine atoms. In this case, it is preferable that multiple hydrogen atoms bonded to the terminal carbon atoms of the alkoxyalkyl group are substituted with fluorine atoms. Furthermore, it is even more preferable that multiple hydrogen atoms bonded to the carbon atoms bonded to the terminal carbon atoms are also substituted with fluorine atoms.

[0024] In this specification, "C3-C6 cycloalkyl group" means a 3- to 6-membered monocyclic saturated or partially unsaturated hydrocarbon group. Examples of these include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. In R41, R42, R43, R44, and R45, "C3-C6 cycloalkyl group" is preferably a C5 or C6 cycloalkyl group, and more preferably a cyclopentyl group or a cyclohexyl group.

[0025] In this specification, "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. In R41, R42, R43, R44, and R45, it is preferable that the "halogen atom" is a fluorine atom or a chlorine atom.

[0026] R5 is an alkyl group having 1 to 4 carbon atoms. R6 and R7 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cyclic amino group having 2 to 6 carbon atoms formed by the integration of R6 and R7. R8 and R9 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cyclic amino group having 2 to 6 carbon atoms formed by the integration of R8 and R9.

[0027] In this specification, "C1-C4 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. Examples of these include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like. In R5, "C1-C4 alkyl group" is preferably a C2-C4 alkyl group, and more preferably a C3 alkyl group.

[0028] In this specification, "C1-C6 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of these include, in addition to the aforementioned "C1-C4 alkyl group," n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like. In R6 and R7, "C1-C6 alkyl group" is preferably a C3-C5 alkyl group, and more preferably a C4 alkyl group. In R8 and R9, "C1-C6 alkyl group" is preferably a C3-C5 alkyl group.

[0029] "A cyclic amino group having 2 to 6 carbon atoms formed by the integration of R6 and R7" refers to a residue obtained by removing one hydrogen atom from a saturated heterocyclic compound having 2 to 6 carbon atoms that contains a nitrogen atom in the ring, with R6 and R7 each bonded to the nitrogen atom. Examples of such groups include cyclic secondary amino groups such as ethyleneimino, trimethyleneimino, pyrrolidino, piperidino, and hexamethyleneimino groups. When NR6R7 forms a cyclic amino group, a piperidino or hexamethyleneimino group is preferred.

[0030] Furthermore, if NR6R7 forms a cyclic amino group, the cyclic amino group may contain an oxygen atom, a nitrogen atom, and a sulfur atom in its ring structure. The nitrogen atom may have an alkyl group having 1 to 6 carbon atoms bonded to it. The sulfur atom may be oxidized by 1 to 2 oxygen atoms.

[0031] The "cyclic amino group having 2 to 6 carbon atoms formed by the integration of R8 and R9" is synonymous with the "cyclic amino group having 2 to 6 carbon atoms formed by the integration of R6 and R7" described above. When NR8R9 forms a cyclic amino group, a piperidino group or a hexamethyleneimino group is preferred.

[0032] In this specification, "heteroaryl group" refers to, for example, monocyclic or polycyclic aromatic groups with 5 to 10 members. A heteroaryl group contains one or more (e.g., 1 to 5) heteroatoms selected from nitrogen, sulfur, or oxygen atoms, either the same or different. Polycyclic heteroaryl groups also include those formed by fusion of the monocyclic heteroaryl group with an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, piperidine, etc.). Specific examples of "heteroaryl groups" include, for example, the group represented by the following formula.

[0033]

[0034] In the above formula, a bond that crosses the ring means that the "base" is bonded at a substitutable position in the ring. For example, in the following formula

[0035] In the case of a heteroaryl group, this means it is either a 2-furyl group or a 3-furyl group.

[0036] Furthermore, when the "heteroaryl group" is a polycyclic group, for example, the following formula

[0037] When expressed as such, it may be 4-, 5-, 6-, or 7-benzofuryl in addition to 2- or 3-benzofuryl.

[0038] However, in the case of polycyclic heteroaryl groups in which an aromatic ring and a non-aromatic ring (such as a cyclohexane ring or a piperidine ring) are fused, only the aromatic ring has the "group" bond. For example, the following formula

[0039] In the case of a "polycyclic heteroaryl group" represented by , it means that the "group" is bonded at the 2-, 3-, or 4-position. The "heteroaryl group" is preferably a monocyclic or polycyclic aromatic group with 5 to 10 members, and more preferably a monocyclic aromatic group with 5 or 6 members.

[0040] In R1, the "heteroaryl group" is preferably a bicyclic or monocyclic group, and more preferably a five-membered or six-membered monocyclic aromatic group. Preferred examples include a pyridyl group, a quinolyl group, an indolyl group, a furyl group, or a thienyl group.

[0041] R10 is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, NHCOR11, or NR12R13. When R1 is a pyridyl group, naphthyl group, or quinolyl group, R10 is preferably an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms.

[0042] R11 is an alkyl group having 1 to 4 carbon atoms. R12 and R13 are, independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cyclic amino group having 2 to 6 carbon atoms formed by the integration of R12 and R13.

[0043] The phrase "a cyclic amino group having 2 to 6 carbon atoms formed by the integration of R12 and R13" is synonymous with the aforementioned "a cyclic amino group having 2 to 6 carbon atoms formed by the integration of R6 and R7". When NR12R13 forms a cyclic amino group, a piperidino group or a hexamethyleneimino group is preferred.

[0044] In the above formula (I), A is -(CH ２ ) １～３ -, -CH(CH ３ )-, or -C(O)CH ２ It is a group represented by -. In A, "- (CH ２ ) １～３ The "-" symbol represents an alkylene group with 1 to 3 carbon atoms. In other words, "-(CH ２ ) １～３ -" is -CH ２ -, - (CH ２ ) ２ - and - (CH ２ ) ３ -. A is -CH ２ - or -CH(CH ３ ) - Preferably -CH ２ - is preferable.

[0045] In the above formula (I), R2 is a hydrogen atom, a C1-C4 alkyl group, a C2-C4 alkoxyalkyl group, or a halogen atom. Preferably, R2 is a hydrogen atom or a C1 or C2 alkyl group. More preferably, R2 is a hydrogen atom or a methyl group.

[0046] In the above formula (I), R3 is COOH, COOR14, CONH ２ , CONHCN, carboxylic acid bioisostea, or tetrazole group. Preferably, R3 is COOH, COOR14, CONH ２ That is the case.

[0047] R14 is an alkyl group having 1 to 6 carbon atoms. R14 is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or a tert-butyl group.

[0048] In this specification, "carboxylic acid bioisostea" means a group having chemical and physical similarities that produce biological properties very similar to those of a carboxylic acid. Examples of "carboxylic acid bioisostea" include, for example, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobuten-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl, or heterocyclic phenols, such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

[0049] In the above formula (I), Y1 corresponds to the substituent at position 2 of the indole ring. Y1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a phenyl group. Preferably, Y1 is a hydrogen atom or an alkyl group having 1 or 2 carbon atoms.

[0050] In the above formula (I), Y2 corresponds to a substituent on the indole ring N. Y2 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, -(CH ２ ) １～２ -O-(CH ２ ) １～３ - The group is represented by SiY3Y4Y5, or by the following formula (III).

[0051]

[0052] In this specification, "C1-C8 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms. Examples of "C1-C8 alkyl groups" include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, n-pentyl group, isoamyl group, n-hexyl group, n-heptyl group, n-octyl group, etc. In Y2, "C1-C8 alkyl group" is preferably a C3-C8 alkyl group, and more preferably an n-butyl group, isobutyl group, n-pentyl group, or n-heptyl group.

[0053] In Y2, the hydrogen atoms of the "C1-C8 alkyl group" may be substituted with 1-5 fluorine atoms. In such cases, the alkyl group is preferably a C3-C6 alkyl group. Furthermore, it is preferable that multiple hydrogen atoms bonded to the terminal carbon atoms of the alkyl group are substituted with fluorine atoms. Moreover, it is even more preferable that multiple hydrogen atoms bonded to the carbon atoms bonded to the terminal carbon atoms are also substituted with fluorine atoms.

[0054] In Y2, the hydrogen atoms of the "alkoxyalkyl group having 2 to 6 carbon atoms" may be substituted with alkoxy groups having 1 to 6 carbon atoms. Examples of these include methoxyethoxymethyl group, ethoxypropoxyethyl group, isopropoxybutoxymethyl group, butoxypentyloxyethyl group, methoxymethoxymethyl group, ethoxyethoxyethyl group, propoxypropoxypropyl group, butoxybutoxybutyl group, pentyloxypentyloxymethyl group, and hexyloxyhexyloxyethyl group.

[0055] In Y2, the "alkoxyalkyl group having 2 to 6 carbon atoms" is preferably a "alkoxyalkyl group having 2 to 4 carbon atoms." Furthermore, in Y2, if the hydrogen atoms of the alkoxyalkyl group are substituted with an alkoxy group, it is preferable that the hydrogen atoms of the "alkoxyalkyl group having 2 to 4 carbon atoms" are substituted with an "alkoxy group having 1 to 3 carbon atoms."

[0056] "-(CH)" in Y2 ２ ) １～２ -O-(CH ２ ) １～３ -SiY3Y4Y5" - (CH ２ ) １～２ -" is -CH ２ - or - (CH ２ ) ２ - is. "- (CH ２ ) １～３ -" is the same as the aforementioned "-(CH)" in A. ２ ) １～３ This is synonymous with "-". Preferably, "-(CH ２ ) １～２ -O-(CH ２ ) １～３-SiY3Y4Y5" is "-CH ２ -O-(CH ２ ) ２ -SiY3Y4Y5.

[0057] Y3, Y4, and Y5 are each independently alkyl groups having 1 to 4 carbon atoms. Preferably, Y3, Y4, and Y5 are each independently alkyl groups having 1 or 2 carbon atoms, and more preferably, each of Y3, Y4, and Y5 is a methyl group.

[0058] In the above formula (III), Y6 is an unsubstituted or substituted phenyl group, pyridyl group, furyl group, thienyl group, naphthyl group, or a cycloalkyl group having 3 to 6 carbon atoms. It is preferable that Y6 is an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or an unsubstituted or substituted phenyl group, pyridyl group, furyl group, or naphthyl group having 3 to 6 carbon atoms. When Y6 is a "cycloalkyl group having 3 to 6 carbon atoms," a "pyridyl group," a "furyl group," or a "naphthyl group," it is preferable that they are unsubstituted. Furthermore, in Y6, the "cycloalkyl group having 3 to 6 carbon atoms" is preferably a "cycloalkyl group having 5 or 6 carbon atoms," and more preferably a cyclopentyl group or a cyclohexyl group.

[0059] Y7 is an alkyl group having 1 to 6 carbon atoms, a phenyl group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, CONY8Y9, NHCOY10, or NHY11Y12. Preferably, Y7 is an alkyl group having 1 to 4 carbon atoms, a phenyl group, a halogen atom, an alkoxy group having 1 or 2 carbon atoms, CONY8Y9, NHCOY10, or NY11Y12.

[0060] Y8 and Y9 are, independently, a hydrogen atom, a C1-C4 alkyl group, or a C2-C6 cyclic amino group formed by Y8 and Y9 working together.

[0061] The term "cyclic amino group having 2 to 6 carbon atoms formed by the integration of Y8 and Y9" is synonymous with the term "cyclic amino group having 2 to 6 carbon atoms formed by the integration of R6 and R7" as described above. When CONY8Y9 forms a cyclic amino group, a piperidino group or a hexamethyleneimino group is preferred.

[0062] Y10 is an alkyl group having 1 to 4 carbon atoms. Y11 and Y12 are, independently, a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a cyclic amino group having 2 to 6 carbon atoms formed by the integration of Y11 and Y12.

[0063] The term "cyclic amino group having 2 to 6 carbon atoms formed by the integration of Y11 and Y12" is synonymous with the term "cyclic amino group having 2 to 6 carbon atoms formed by the integration of R6 and R7" as described above. When NY11 and Y12 form a cyclic amino group, a piperidino group or a hexamethyleneimino group is preferred.

[0064] Furthermore, in Y11 and Y12, the cyclic amino group may contain an oxygen atom, a nitrogen atom, and a sulfur atom in its ring structure. The nitrogen atom may have an alkyl group having 1 to 6 carbon atoms bonded to it. The sulfur atom may be oxidized by 1 to 2 oxygen atoms.

[0065] In equation (I), B is -(CH ２ ) １～３ -, -CH(CH ３ )-, -C(O)-, or -C(O)CH ２ It is a group represented by -. B is -CH ２ - or -CH(CH ３ ) - is preferable.

[0066] In formula (I), Z1, Z2, Z3, and Z4 are each independently a hydrogen atom, a C1-C4 alkyl group, a C1-C8 alkoxy group, and -O-(CH ２ ) １～２ - Ph, halogen atom, CN, or CF ３ Z1, Z2, Z3, and Z4 are each independently a hydrogen atom, a halogen atom, an alkoxy group having 1 to 8 carbon atoms, and -O-CH ２ - Ph, CN, or CF３ It is preferable that this be the case.

[0067] In Z1, Z2, Z3, and Z4, the hydrogen atoms of the "alkoxy group having 1 to 8 carbon atoms" may be substituted with an alkoxy group having 1 to 6 carbon atoms. Examples of these include methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, isopropoxymethoxy, and isobutoxymethoxy. It is preferable that the hydrogen atoms of the "alkoxy group having 1 to 3 carbon atoms" be substituted with an alkoxy group having 2 to 4 carbon atoms. It is even more preferable that the group be an ethoxyethoxy group.

[0068] "-O-(CH ２ ) １～２ -Ph" of which "-(CH ２ ) １～２ -" is the aforementioned "-(CH ２ ) １～２ This is synonymous with "-". In Z1, Z2, Z3, and Z4, "-O-(CH ２ ) １～２ -Ph" is "-O-CH ２ It is preferable that it be "-Ph".

[0069] In this embodiment, the compound represented by formula (I) is, for example, the compound represented by the following formulas (1) to (58), (71) and (72).

[0070]

[0071] Compounds represented by formula (I) may have one or more chiral carbon atoms and may exhibit geometric isomerism or axial chirality. Therefore, compounds represented by formula (I) may exist as multiple stereoisomers. In this embodiment, these stereoisomers, mixtures thereof, and racemates are also included.

[0072] Furthermore, the present embodiment also includes an isotope-labeled compound that is identical to the compound represented by formula (I) (except for the fact that one or more atoms in the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature), and a pharmaceutically acceptable salt thereof. Examples of isotopes contained in the compound according to the present embodiment are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, bromine, and chlorine. Examples thereof include ２ H, ３ H, １１ C, １３ C, １４ C, １３ N, １５ N, １５ O, １７ O, １８ O, １８ F, ７５ Br, ７６ Br, ７７ Br, ８２ Br, and ３６ isotopes such as Cl. Compounds of the present embodiment that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts thereof are also included in the present embodiment.

[0073] Furthermore, substitution with deuterium, that is, ２ substitution with heavy isotopes such as H can be expected to provide certain therapeutic advantages resulting from increased metabolic stability. For example, it may result in prolonged in vivo half-life or reduced dosage requirements, which may be preferred in some circumstances.

[0074] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Acid addition salts include inorganic salts and organic salts. Inorganic salts include, for example, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, hydroiodide, nitrate, and phosphate. Organic salts include, for example, citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, fumarate, maleate, malonate, succinate, tartrate, hydrogen tartrate, lactate, malate, pyruvate, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate [1,1'-methylene-bis-(2-hydroxy-3-naphthoate)].

[0075] Examples of base addition salts include inorganic base salts and organic base salts. Inorganic base salts include, for example, sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts. Organic base salts include, for example, triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt.

[0076] Furthermore, basic amino acid salts or acidic amino acid salts such as arginine salts, aspartate salts, and glutamate salts can also be mentioned. Preferred base addition salts are sodium salts, potassium salts, calcium salts, and magnesium salts.

[0077] Compounds represented by formula (I) or their pharmaceutically acceptable salts may exist in the form of hydrates and / or pharmaceutically acceptable solvates. For example, these hydrates or solvates such as ethanolates are also included in the compounds of this embodiment. Furthermore, the compounds of this embodiment also include crystalline forms of all embodiments.

[0078] "Prodrug" means a derivative of a compound that can be reacted in vitro or in vivo by hydrolysis, oxidation, or other means to give an active compound, particularly the compound according to this embodiment. For example, if a hydroxyl group or carboxyl group is present in the compound, it is an ester of such a group. For example, if a hydroxyl group is present in the compound, it is an acetal or ketal of such a group. For example, if an amine group is present in the compound, it is an N-Mannich base or imine of such a group. For example, if a carbonyl group is present in the compound, it is a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidinedion of such a group.

[0079] [Second Embodiment] The second embodiment is a Nampt activator containing as an active ingredient the compound of formula (I) above, its enantiomer, its diastereomer, a pharmaceutically acceptable salt thereof, or a prodrug thereof, or the compound represented by the following formulas (59) to (70), its enantiomer, its diastereomer, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0080]

[0081] In the following description, the compound represented by formula (I) above, its enantiomer, its diastereomer, their pharmaceutically acceptable salts, or their prodrugs may be referred to as the first component. The compounds represented by formulas (59) to (70), their enantiomers, their diastereomers, their pharmaceutically acceptable salts, or their prodrugs may be referred to as the second component.

[0082] As shown below, the present inventors have shown that the compound according to the example binds to nicotinamide phosphoribosyltransferase (Nampt) and NAD ＋ It was discovered that it increases . Nampt is an enzyme that synthesizes nicotinamide mononucleotide (NMN) from nicotinamide (NAM), and oxidized nicotinamide adenine dinucleotide (NAD ＋It is the rate-limiting enzyme in the biosynthetic pathway of ).

[0083] In other words, the binding of the first and second components to Nampt enhances the activity of Nampt and promotes the synthesis of NMN. The synthesized NMN undergoes several further enzymatic reactions to form NAD. ＋ It is converted to NAD. ＋ The production of increases.

[0084] NAD ＋ NAD is an important coenzyme involved in redox reactions within cells. ＋ It accepts electrons in the electron transport chain and is reduced to NADH. NADH supplies electrons to the electron transport chain and drives ATP synthesis. Furthermore, NAD ＋ It is also involved in various intracellular processes such as DNA repair and signal transduction. Therefore, in improving mitochondrial function, NAD ＋ Increasing the production of [the substance] is effective.

[0085] Based on the above, the first and second components can be used as active ingredients in a Nampt activator. Furthermore, as mentioned above, the activity of Nampt is NAD ＋ It is closely related to the production of NAD. Therefore, the first and second components are NAD ＋ It can also be used as an active ingredient in a production promoter.

[0086] Nampt activator and NAD according to this embodiment ＋ The target of administration of the production promoter is any test animal or any cell or tissue that needs to have Nampt activity enhanced. ＋ This may be a test animal or any cell or tissue that needs to have its production promoted.

[0087] Such test animals include, for example, subjects that need to have their lifespan extended (subjects that need longevity); patients with neurological diseases (Parkinson's disease, depression, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), etc.); patients with cardiovascular diseases (heart failure, arrhythmia, etc.); patients with muscular diseases (sarcopenia, inclusion body myositis, muscular dystrophy, etc.); patients with renal diseases (chronic kidney disease, renal failure, diabetic nephropathy, nephritis, etc.); patients with respiratory diseases (COPD, pulmonary fibrosis, etc.); patients with metabolic diseases (diabetes, hepatic dysfunction, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD)); and non-alcoholic steatohepatitis [NASH]. Patients with thyroid or adrenal gland diseases (such as steatohepatitis); patients with digestive system diseases (such as inflammatory bowel disease); cancer patients; patients with age-related symptoms or diseases (such as thinning hair or hair loss, hearing loss, visual impairment, anemia, muscle weakness, and shortened lifespan); patients with radiation damage; and others.

[0088] In this specification, the animals used as test subjects include mammals (human or non-human mammals), birds, reptiles, amphibians, fish, invertebrates, etc. Other forms of test subjects include humans and livestock. Here, "livestock" means animals that are raised and bred by humans. Examples of such livestock include non-human mammals (e.g., rodents such as mice, rats, hamsters, and guinea pigs; lagomorphs such as rabbits; ungulates such as pigs, cattle, goats, horses, and sheep; carnivores such as dogs and cats), birds (e.g., chickens, quail, turkeys, pigeons, ducks, geese, etc.), fish (e.g., carp, goldfish, etc.), and invertebrates (e.g., silkworms, honeybees, etc.). Preferably, the animal used as a test subject is a mammal.

[0089] "Animal cells or tissues thereof" refers, for example, to cells or tissues derived from the animal being tested, and preferably to cells or tissues derived from mammals. Cells derived from the animal being tested include, for example, cells isolated from the animal being tested, pluripotent stem cells prepared using cells isolated from the animal being tested, and cells differentiated from said stem cells.

[0090] As explained above, by administering the Nampt activator according to this embodiment to a target, the binding of the first or second component to Nampt is activated in the cell, thereby promoting NAD production. ＋ Production of these substances is promoted. As a result, life expectancy can be extended, and the aforementioned diseases and disorders can be prevented or treated.

[0091] [Third Embodiment] The third embodiment is a mitochondrial inner membrane protein (IMMT) activator containing as an active ingredient the compound of formula (I) above, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or the compound represented by formulas (59) to (70) above, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0092] As shown below, the inventors have discovered that the compound according to the embodiment binds to mitochondrial inner membrane proteins (IMMTs). IMMTs are proteins located in the mitochondrial inner membrane that are responsible for the energy production of mitochondria by various substances.

[0093] Within the mitochondria, oxidative phosphorylation occurs via the electron transport chain, synthesizing adenosine triphosphate (ATP). The binding of the first and second components to the IMMT causes structural changes in the mitochondrial inner membrane, leading to an increase in ATP production.

[0094] ATP is a high-energy compound used in all energy-intensive reactions within cells and is essential for maintaining life activities. Therefore, increasing ATP production is effective in improving mitochondrial function.

[0095] Based on the above, the first and second components bind to IMMT and promote ATP production. Therefore, in this embodiment, the first and second components can be used as active ingredients in an ATP production promoter.

[0096] The target of administration of the IMMT binder according to this embodiment may be a test animal or any cells or tissues that require promotion of ATP production.

[0097] Such test animals include, for example, subjects that need life extension (subjects requiring longevity); patients with neurological diseases (Parkinson's disease, depression, Alzheimer's disease, amyotrophic lateral sclerosis [ALS], etc.); patients with cardiovascular diseases (heart failure, arrhythmia, etc.); patients with muscle diseases (sarcopenia, inclusion body myositis, muscular dystrophy, etc.); patients with kidney diseases (chronic kidney disease, renal failure, diabetic nephropathy, nephritis, etc.); patients with respiratory diseases (COPD, pulmonary fibrosis, etc.); patients with metabolic diseases (diabetes, hepatic dysfunction, alcoholic liver disease, non-alcoholic fatty liver disease [NAFLD]); and non-alcoholic steatohepatitis [NASH]. Patients with thyroid or adrenal gland diseases (such as steatohepatitis); patients with digestive system diseases (such as inflammatory bowel disease); cancer patients; patients with age-related symptoms or diseases (such as thinning hair or hair loss, hearing loss, visual impairment, anemia, muscle weakness, and shortened lifespan); patients with radiation damage; and others.

[0098] In this specification, the animals used as test subjects include mammals (human or non-human mammals), birds, reptiles, amphibians, fish, invertebrates, etc. Other forms of test subjects include humans and livestock. Here, "livestock" means animals that are raised and bred by humans. Examples of such livestock include non-human mammals (e.g., rodents such as mice, rats, hamsters, and guinea pigs; lagomorphs such as rabbits; ungulates such as pigs, cattle, goats, horses, and sheep; carnivores such as dogs and cats), birds (e.g., chickens, quail, turkeys, pigeons, ducks, geese, etc.), fish (e.g., carp, goldfish, etc.), and invertebrates (e.g., silkworms, honeybees, etc.). Mammals are preferred.

[0099] "Animal cells or tissues thereof" refers, for example, to cells or tissues derived from the animal being tested, and preferably to cells or tissues derived from mammals. Cells derived from the animal being tested include, for example, cells isolated from the animal being tested, pluripotent stem cells prepared using cells isolated from the animal being tested, and cells differentiated from said stem cells.

[0100] As described above, administering the IMMT binder according to this embodiment to a target promotes ATP production in cells through the binding of the first or second component to IMMT. As a result, lifespan can be extended, or the above-mentioned diseases and disorders can be prevented or treated.

[0101] [Manufacturing Method] The manufacturing method of the compound according to this embodiment will be described with specific examples. Note that the compound according to this embodiment is not limited to the following examples.

[0102] In the examples, the following abbreviations may be used: Me: methyl Et: ethyl ｔ But: tert-butyl aq. NaOH: sodium hydroxide aqueous solution DCC: N,N'-dicyclohexylcarbodiimide DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DMSO-D ６ : Deuterated dimethyl sulfoxide HATU: Azabenzotriazole tetramethyluronium hexafluorophosphate HMPA: Hexamethyltriamide LAH: Lithium aluminum hydride LDA: Lithium diisopropylamide TBAI: Tetra-n-butylammonium iodide TFA: Trifluoroacetic acid THF: Tetrahydrofuran TMSCl: Chlorotrimethylsilane

[0103] In NMR, the symbols used are as follows: s for single line, d for double line, t for triple line, q for quadruple line, dd for double double line, brs for broad single line, m for multi-line, and J for coupling constant.

[0104] Proton nuclear magnetic resonance spectrum ( １H-NMR was measured using a JEOL FT-NMR measuring device (400 MHz or 600 MHz). Chemical shift values ​​are recorded as delta values ​​(ppm).

[0105] Mass spectrometry spectra (ESI / MS) were measured using a triple quadrupole mass spectrometer equipped with an electrospray ion source from Thermo Fisher Scientific. The observed main mass spectrometry spectra [ESI / MS (m / z)], the positive / negative mode of observation, and the adducted ions [M+H] are shown. ＋ [M+Na] ＋ [M+NH ４ ] ＋ or [M-H] － It was written as follows.

[0106] The compounds according to this embodiment can be produced, for example, by the method described below. For this production, commercially available compounds, known compounds, or compounds that can be produced by combining commercially available compounds or known compounds using known synthesis methods can be used as raw materials.

[0107] [Example 1] Preparation of 3-(4-butylphenyl)-2-(1H-indole-3-yl)propanoic acid (compound 1D)

[0108]

[0109] Step 1: A 300 mL round-bottom flask was purged with argon gas, and compound 1A (4.95 g, 20.0 mmol) and a THF solution of HMPA (20 mL) (100 mL) were added. The reaction mixture was cooled to -78°C, and LDA / THF solution (2 mol / L, 15 mL, 30.0 mmol) was added and stirred for 30 minutes. Then, a THF solution of compound 1B (3.75 mL, 20.1 mmol) (20 mL) was added to the reaction mixture and stirred at -78°C for 1 hour. The round-bottom flask was transferred to an ice bath, dilute hydrochloric acid (1 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed 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 (elution solvent: hexane / dichloromethane / ethyl acetate) to obtain the title compound 1C (3.97 g, 1.01 mmol, 50.1%). ESI / MS[M+Na]＋ = 416.2 Step 2: A 300 mL round-bottom flask was purged with argon gas, and a methanol solution (120 mL) of compound 1C (3.95 g, 10.0 mmol) and an aqueous sodium hydroxide solution (2 mol / L, 30 mL) were added in sequence. The mixture was stirred at 70°C for 2 hours. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate) to obtain the title compound 1D (2.55 g, 79.3 mmol, 78.9%). １ H-NMR (600MHz, DMSO-D ６ ) δ12.11 (brs, 1H), 10.94 (d, J = 1.7Hz, 1H), 7.63 (d, J = 8.1Hz, 1H), 7.34 (d, J = 8.1H z, 1H), 7.24 (d, J = 2.4Hz, 1H), 7.13 (d, J = 7.9Hz, 2H), 7.08-7.04 (m, 3H), 6.99-6.97 (m, 1H), 4.03 (dd, J=9.0, 6.5Hz, 1H), 3.33-3.30 (m, 1H), 3.04 (dd, J=13.9, 6.5Hz, 1 H), 2.51-2.49 (m, 2H), 1.53-1.48 (m, 2H), 1.30-1.24 (m, 2H), 0.88 (t, J = 7.4Hz, 3H)

[0110] [Reference Examples IM1 to IM18] Using the corresponding starting compounds, the compounds of Reference Examples IM1 to IM18 were obtained in the same manner as the synthesis of compound 1C.

[0111]

[0112] [Examples 2-19] Using the raw material compounds of the corresponding Reference Examples IM1-IM18, the compounds of Examples 2-19 were obtained in the same manner as in Example 1.

[0113]

[0114] [Example 20] Preparation of 2-(1H-indole-3-yl)-3-(4-(pentan-2-yl)phenyl)propanoic acid (compound 2F)

[0115]

[0116] Step 1: In a 20 mL round-bottom flask under ice cooling, 3 mL of a dichloromethane solution of compound 2A (520 μL, 3.02 mmol), 600 mg of aluminum chloride (4.50 mmol), and 770 μL of oxalyl chloride (8.98 mmol) were added in sequence. The flask was then purged with argon gas and stirred at room temperature for 18 hours. The flask was transferred to an ice bath, methanol was added to the reaction mixture and stirred for 1 hour, then water was added, and the mixture was liquid-liquid extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. 5 mL of THF and 5 mL of aqueous sodium hydroxide solution (2 mol / L) were added to the concentrated residue and stirred at 50°C for 2 hours. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and the mixture was liquid-liquid extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 2B (480 mg, 2.50 mmol, 82.8%). ESI / MS [M-H] －= 190.9 Step 2: A 30 mL round-necked flask was purged with argon gas under ice cooling, and 10 mL of THF solution of compound 2B (450 mg, 2.34 mmol) and LAH / THF solution (1 mol / L, 5.85 mL, 5.85 mmol) were added, and the mixture was heated under reflux for 1 hour. The flask was transferred to an ice bath, and water (150 μL), sodium hydroxide aqueous solution (3 mol / L, 150 μL), and water (450 μL) were carefully added to the reaction mixture in that order. The precipitate was filtered through Celite, liquid-liquid extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude alcohol. In another 50 mL two-necked round-necked flask, triphenylphosphine (920 mg, 3.51 mmol), imidazole (240 mg, 3.53 mmol), and dichloromethane (8 mL) were added, the mixture was purged with argon gas, and stirred at room temperature for 5 minutes. Iodine (890 mg, 3.51 mmol) was added to the reaction mixture and stirred for 10 minutes. Then, a dichloromethane solution of the crude alcohol (1 mL) was added and the mixture was stirred at room temperature for 2 hours. Diethyl ether (20 mL) was added to the reaction mixture and stirred for 30 minutes. The precipitate was filtered, and the filtrate was separated by liquid-liquid extraction with saturated sodium thiosulfate aqueous solution. 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 (elution solvent: hexane / dichloromethane) to obtain the title compound 2C (385 mg, 1.34 mmol, 57.1%). １ H-NMR (600MHz, CDCl ３)δ 7.29 (d, J=8.1 Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 4.45 (s, 2H), 2.70–2.64 (m, 1H), 1.55–1.49 (m, 2H), 1.31–1.20 (m, 5H), 0.86 (t, J=7.4 Hz, 3H) Step 3: A 20 mL round-bottom flask was purged with argon gas, and compound 2D (200 mg, 0.809 mmol) and HMPA (700 μL) in THF solution (4 mL) were added. The reaction mixture was cooled to -78 °C, LDA / THF solution (2 mol / L, 600 μL, 1.20 mmol) was added, and the mixture was stirred for 30 minutes. Subsequently, 0.5 mL of a THF solution of compound 2C (200 mg, 0.694 mmol) was added to the reaction mixture, and the mixture was stirred at -78°C for 1 hour. The round-bottom flask was transferred to an ice bath, dilute hydrochloric acid (1 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 2E (215 mg, 0.528 mmol, 75.9%). ESI / MS [M+Na] ＋ = 430.2 Step 4: A 20 mL round-bottom flask was purged with argon gas, and methanol solution (4 mL) of compound 2E (100 mg, 0.245 mmol) and aqueous sodium hydroxide solution (2 mol / L, 1 mL) were added in sequence, and the mixture was stirred at 70°C for 2 hours. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate) to obtain the title compound 2F (40.2 mg, 0.120 mmol, 48.8%). １ H-NMR (600MHz, DMSO-D ６) δ12.12 (brs, 1H), 10.95 (s, 1H), 7.62 (d, J = 7.9Hz, 1H), 7.34 (d, J = 8.1Hz, 1H) , 7.25 (d, J=2.4Hz, 1H), 7.15 (d, J=8.1Hz, 2H), 7.08-7.05 (m, 3H), 6.98 (t, J=7. 4Hz, 1H), 4.05-4.03 (m, 1H), 3.33-3.30 (m, 1H), 3.03 (dd, J=13.8, 6.2Hz, 1H), 2.65-2.59 (m, 1H), 1.48-1.44 (m, 2H), 1.18-1.08 (m, 5H), 0.82 (t, J=7.4Hz, 3H)

[0117] [Example 21] Preparation of 3-(4-butylphenyl)-2-(5-cyano-1H-indole-3-yl)propanoic acid (compound 3E)

[0118]

[0119] Step 1: Compound 3A (300 mg, 1.47 mmol), TBAI (8.0 mg, 0.022 mmol), and dichloromethane (2 mL) were added to a 20 mL round-bottom flask under ice cooling. The flask was then purged with argon gas, and sodium hydroxide aqueous solution (10 mol / L, 2 mL) and ethyl chloroformate (280 μL, 2.94 mmol) were added in that order, followed by stirring for 2 hours. Hydrochloric acid (6 mol / L) was added to the reaction mixture, and the mixture was separated by liquid-liquid extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 3B (319 mg, 1.11 mmol, 75.9%). ESI / MS [M+Na] ＋=309.1 Step 2: A 20 mL round-bottom flask was purged with argon gas, and a THF solution (4 mL) of compound 3B (200 mg, 0.699 mmol) and HMPA (700 μL) was added. The reaction mixture was cooled to -78°C, and LDA / THF solution (2 mol / L, 600 μL, 1.20 mmol) was added and stirred for 30 minutes. Then, a THF solution (0.5 mL) of compound 3C (150 μL, 0.806 mmol) was added to the reaction mixture and stirred at -78°C for 1 hour. The round-bottom flask was transferred to an ice bath, dilute hydrochloric acid (1 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 3D (165 mg, 0.381 mmol, 54.5%). ESI / MS [M+Na] ＋ =455.2 Step 3: A 20 mL round-bottom flask was purged with argon gas, and a methanol solution (2 mL) of compound 3D (80.0 mg, 0.185 mmol) and an aqueous sodium hydroxide solution (2 mol / L, 0.5 mL) were added in sequence. The mixture was stirred at 70°C for 2 hours. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate) to obtain the title compound 3E (52.7 mg, 0.152 mmol, 82.2%). １ H-NMR (600MHz, DMSO-D ６ ) δ12.30 (brs, 1H), 11.55 (s, 1H), 8.09 (t, J=0.7Hz, 1H), 7.50 (dd, J=8.4, 0.5Hz, 1H ), 7.47 (d, J = 2.4Hz, 1H), 7.41 (dd, J = 8.3, 1.6Hz, 1H), 7.12 (d, J = 7.9Hz, 2H), 7.03 ( d, J = 8.1Hz, 2H), 4.13 (dd, J = 8.5, 7.1Hz, 1H), 3.31-3.29 (m, 1H), 3.03 (q, J = 6.9Hz, 1H), 2.50-2.48 (m, 2H), 1.52-1.47 (m, 2H), 1.29-1.23 (m, 2H), 0.87 (t, J = 7.4Hz, 3H)

[0120] [Reference Examples IM19-IM20] Using the corresponding starting compounds, the compounds of Reference Examples IM19-IM20 were obtained in the same manner as the synthesis of compound 3B.

[0121]

[0122] [Reference Examples IM21-IM22] Using the starting compounds of the corresponding Reference Examples IM19-IM20, the compounds of Reference Examples IM21-IM22 were obtained in the same manner as the synthesis of compound 3D.

[0123]

[0124] [Examples 22-23] Using the raw material compounds of the corresponding Reference Examples IM21-IM22, the compounds of Examples 22-23 were obtained in the same manner as in Example 21.

[0125]

[0126] [Example 24] Preparation of 3-(4-butylphenyl)-2-(5-(heptyloxy)-1H-indole-3-yl)propanoic acid (compound 4E)

[0127]

[0128] Step 1: Palladium-activated carbon (10%, 30 mg, 0.028 mmol) was added to a 20 mL round-bottom flask and purged with argon gas. Methanol (2 mL) and a dichloromethane solution of compound 4A (290 mg, 0.565 mmol) (1 mL) were added. A balloon filled with hydrogen gas was connected to the round-bottom flask, and the flask was purged with hydrogen gas. The reaction mixture was then stirred at room temperature for 24 hours. Palladium-activated carbon was filtered from the reaction mixture through a 0.22 μm membrane filter, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane / ethyl acetate) to obtain the title compound 4B (181 mg, 0.427 mmol, 75.7%). ESI / MS [M+H] ＋=424.1 Step 2: Add cesium carbonate (100 mg, 0.307 mmol) to a 10 mL screw-cap test tube in an ice bath, purge with argon gas, and then add a DMF solution (1 mL) of compound 4B (85 mg, 0.20 mmol) and stir for 30 minutes. Add compound 4C (50 μL, 0.31 mmol) to the reaction mixture and stir at room temperature for 2 hours. Add saturated ammonium chloride aqueous solution to the reaction mixture and separate with ethyl acetate. Wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 4D (65.0 mg, 0.125 mmol, 62.3%). ESI / MS [M+H] ＋ = 522.3 Step 3: A 20 mL round-bottom flask was purged with argon gas, and a methanol solution (2 mL) of compound 4D (60 mg, 0.12 mmol) and an aqueous sodium hydroxide solution (2 mol / L, 0.5 mL) were added in sequence. The mixture was stirred at 70°C for 2 hours. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate) to obtain the title compound 4E (28 mg, 0.064 mmol, 55%). １ H-NMR (600MHz, DMSO-D ６ ) δ12.13 (brs, 1H), 10.76 (d, J=2.1Hz, 1H), 7.21 (d, J=8.8Hz, 1H), 7.18 (d, J=2.4Hz, 1H), 7.13 (d, J=7. 9Hz, 2H), 7.07 (d, J = 2.4Hz, 1H), 7.04 (d, J = 8.1Hz, 2H), 6.70 (dd, J = 8.6, 2.4Hz, 1H), 3.98 (dd, J = 9.0, 6. 5Hz, 1H), 3.92 (t, J=6.5Hz, 2H), 3.28 (dd, J=13.9, 9.0Hz, 1H), 3.00 (dd, J=13.7, 6.5Hz, 1H), 2.51-2.49 (m, 2H), 1.74-1.69 (m, 2H), 1.53-1.48 (m, 2H), 1.45-1.40 (m, 2H), 1.36-1.25 (m, 8H), 0.89-0.86 (m, 6H)

[0129] [Reference Example IM23] Using the corresponding starting compound, the compound of Reference Example IM23 was obtained in the same manner as the synthesis of compound 4D.

[0130]

[0131] [Example 25] Using Reference Example IM23 as the starting compound, the compound of Example 25 was obtained in the same manner as in Example 24.

[0132]

[0133] [Example 26] Preparation of 3-(4-(butylamino)phenyl)-2-(1H-indole-3-yl)propanoic acid (compound 5G)

[0134]

[0135] Step 1: A 30 mL round-bottom flask was purged with argon gas, and compound 5A (450 mg, 1.56 mmol) and HMPA (1.4 mL) in a THF solution (8 mL) were added. The reaction mixture was cooled to -78°C, and LDA / THF solution (2 mol / L, 1.20 mL, 2.40 mmol) was added and stirred for 30 minutes. Then, compound 5B (350 mg, 1.62 mmol) in a THF solution (1 mL) was added to the reaction mixture and stirred at -78°C for 1 hour. The round-bottom flask was transferred to an ice bath, dilute hydrochloric acid (1 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed 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 (elution solvent: hexane / dichloromethane) to obtain the title compound 5C (466 mg, 1.10 mmol, 70.6%). ESI / MS [M+Na] ＋=447.2 Step 2: Palladium-activated carbon (10%, 50 mg, 0.047 mmol) was added to a 20 mL round-bottom flask and purged with argon gas. Methanol (3 mL) and a dichloromethane solution of compound 5C (450 mg, 1.06 mmol) (1.5 mL) were added. A balloon filled with hydrogen gas was connected to the round-bottom flask, and the flask was purged with hydrogen gas. The reaction mixture was then stirred at room temperature for 4 hours. The palladium-activated carbon in the reaction mixture was filtered through a 0.22 μm membrane filter, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate) to obtain the title compound 5D (303 mg, 0.768 mmol, 72.5%). ESI / MS [M+H] ＋ =395.2 Step 3: Add cesium carbonate (55 mg, 0.17 mmol) to a 10 mL screw-cap test tube in an ice bath, purge with argon gas, and then add a DMF solution (0.5 mL) of compound 5D (50 mg, 0.13 mmol) and stir for 30 minutes. Add compound 5E (15 μL, 0.13 mmol) to the reaction mixture and stir at 60°C for 3 hours. After cooling, add saturated sodium bicarbonate aqueous solution to the reaction mixture and separate with ethyl acetate. Wash the organic layer with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane / ethyl acetate) to obtain the title compound 5F (14.8 mg, 0.0328 mmol, 25.9%). ESI / MS [M+H] ＋=451.3 Step 4: Add a 0.5 mL solution of compound 5F (14.0 mg, 0.031 mmol) in dichloromethane to a 10 mL screw-cap test tube, purge with argon gas, then add triethylsilane (45 mg, 0.39 mmol) and trifluoroacetic acid (0.5 mL) in sequence, and stir at room temperature for 30 minutes. Add saturated sodium bicarbonate aqueous solution to the reaction mixture, and separate extract with ethyl acetate. Wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Add methanol (2 mL) and sodium hydroxide aqueous solution (2 mol / L, 0.5 mL) in sequence to the resulting residue, and stir at 70°C for 30 minutes. After cooling, add pure water to the reaction mixture, separate extract with ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol) to obtain the title compound 5G (1.9 mg, 0.0056 mmol, 18%). １ H-NMR (600MHz, DMSO-D ６ ) δ12.05 (brs, 1H), 10.91 (s, 1H), 7.62 (d, J = 7.7Hz, 1H), 7.33 (d, J = 8.1Hz, 1H), 7.21 (d, J = 2.4Hz, 1H), 7.07-7.05 (m, 1H), 6.99-6.96 (m, 1H), 6.92 (d, J = 8.4Hz, 2H), 6.42 ( d, J=8.4Hz, 2H), 5.29 (brs, 1H), 3.93 (dd, J=9.2, 6.1Hz, 1H), 3.18 (dd, J=13.6, 9.3Hz , 1H), 2.94-2.88 (m, 3H), 1.52-1.47 (m, 2H), 1.39-1.33 (m, 2H), 0.90 (t, J = 7.4Hz, 3H)

[0136] [Reference Examples IM24-IM25] Using the corresponding starting compounds, the compounds of Reference Examples IM24-IM25 were obtained in the same manner as the synthesis of compound 5F.

[0137]

[0138] [Examples 27-28] Using the raw material compounds of the corresponding Reference Examples IM24-IM25, the compounds of Examples 27-28 were obtained in the same manner as in Example 26.

[0139]

[0140] [Example 29] Preparation of 3-(4-butylphenyl)-2-(1H-indole-3-yl)-2-methylpropanoic acid (compound 6E)

[0141]

[0142] Step 1: A 100 mL round-bottom flask was purged with argon gas, and compound 6A (990 mg, 4.00 mmol) and HMPA (3.5 mL) in a THF solution (20 mL) were added. The reaction mixture was cooled to -78°C, and LDA / THF solution (2 mol / L, 1.45 mL, 10.0 mmol) was added and stirred for 30 minutes. Then, methyl iodide (250 μL, 4.01 mmol) was added to the reaction mixture and stirred at -78°C for 1 hour. The round-bottom flask was transferred to an ice bath, dilute hydrochloric acid (1 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed 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 (elution solvent: hexane / dichloromethane) to obtain the title compound 6B (793 mg, 3.04 mmol, 75.8%). １ H-NMR (600MHz, DMSO-D ６Step 2: A 30 mL round-bottom flask was purged with argon gas, and compound 6B (300 mg, 1.15 mmol) and HMPA (1 mL) in THF solution (6 mL) were added. The reaction mixture was cooled to -78 °C, and LDA / THF solution (2 mol / L, 860 μL, 1.72 mmol) was added and the mixture was stirred for 30 minutes. Subsequently, 1 mL of THF solution of compound 6C (320 μL, 1.72 mmol) was added to the reaction mixture, and the mixture was stirred at -78°C for 1 hour. The round-bottom flask was transferred to an ice bath, dilute hydrochloric acid (1 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 6D (256 mg, 0.628 mmol, 54.7%). ESI / MS [M+H] ＋ =408.2 Step 3: A 30 mL round-bottom flask was purged with argon gas, and a methanol solution (12 mL) of compound 6D (256 mg, 0.628 mmol) and an aqueous sodium hydroxide solution (2 mol / L, 3 mL) were added in sequence. The mixture was stirred at 70°C for 2 hours. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate) to obtain the title compound 6E (81.6 mg, 0.243 mmol, 38.7%). １ H-NMR (600MHz, DMSO-D ６) δ12.23 (brs, 1H), 10.90 (d, J = 1.8Hz, 1H), 7.63 (d, J = 8.1Hz, 1H), 7.37 ( d, J = 8.1Hz, 1H), 7.09-7.06 (m, 2H), 6.99-6.97 (m, 3H), 6.83 (d, J = 7.9Hz, 2H), 3.38 (d, J = 13.1Hz, 1H), 3.25 (d, J = 13.1Hz, 1H), 2.51-2.48 (m, 2H), 1.52-1.47 (m, 2H), 1.36 (s, 3H), 1.30-1.24 (m, 2H), 0.87 (t, J=7.3Hz, 3H)

[0143] [Example 30] Preparation of methyl 3-(4-butylphenyl)-2-(1H-indole-3-yl)propanoate (Compound 7B)

[0144]

[0145] A 30 mL round-bottom flask was purged with argon gas, and a THF solution (5 mL) of compound 7A (2.00 g, 5.08 mmol), methanol (5 mL), and an aqueous sodium hydroxide solution (2 mol / L, 5 mL) were added in sequence. The mixture was stirred at 50°C for 1 hour. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 7B (1.38 g, 4.11 mmol, 80.8%). １ H-NMR (600MHz, DMSO-D ６ ) δ10.99 (s, 1H), 7.59 (d, J = 7.9Hz, 1H), 7.34 (d, J = 8.1Hz, 1H), 7.26 (d, J = 2.4Hz, 1H ), 7.10 (d, J = 7.9 Hz, 2H), 7.08-7.06 (m, 1H), 7.04 (d, J = 8.1Hz, 2H), 7.00-6.97 (m, 1 H), 4.14 (dd, J = 9.0, 6.7Hz, 1H), 3.49 (s, 3H), 3.35-3.31 (m, 1H), 3.09 (q, J = 6.8Hz, 1H), 2.51-2.49 (m, 2H), 1.53-1.48 (m, 2H), 1.30-1.24 (m, 2H), 0.87 (t, J = 7.4Hz, 3H)

[0146] [Example 31] Preparation of tert-butyl 3-(4-butylphenyl)-2-(1H-indole-3-yl)propanoate (Compound 8B)

[0147]

[0148] In a 50 mL round-bottom flask cooled on ice, compound 8A (970 mg, 3.02 mmol) in dichloromethane solution (15 mL), tert-butanol (430 μL, 4.53 mmol), N,N'-dicyclohexylcarbodiimide (1.25 g, 6.06 mmol), and 4-dimethylaminopyridine (370 mg, 3.03 mmol) were added in that order. The flask was then purged with argon gas and stirred at room temperature for 24 hours. Dilute hydrochloric acid (1 mol / L) and ethyl acetate were added to the reaction mixture and stirred for 30 minutes. The precipitate was filtered, and the filtrate was separated by liquid-liquid extraction. 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 (elution solvent: hexane / dichloromethane) to obtain the title compound 8B (371 g, 0.983 mmol, 32.5%). １ H-NMR (600MHz, DMSO-D ６ ) δ10.95 (s, 1H), 7.64 (d, J = 7.9Hz, 1H), 7.35 (d, J = 8.1Hz, 1H), 7.25 (d, J = 2.4Hz , 1H), 7.15 (d, J = 7.9Hz, 2H), 7.09-7.06 (m, 3H), 7.01-6.98 (m, 1H), 4.00 (dd, J = 1 0.1, 5.8Hz, 1H), 3.24 (dd, J=13.6, 10.2Hz, 1H), 3.06-3.03 (m, 1H), 2.53-2.51 ( m, 2H), 1.53-1.48 (m, 2H), 1.28-1.22 (m, 2H), 1.22 (s, 9H), 0.87 (t, J = 7.3Hz, 3H)

[0149] [Example 32] Preparation of 2-(1-benzyl-1H-indole-3-yl)-3-(4-butylphenyl)propanoic acid (compound 9D)

[0150]

[0151] Step 1: Sodium hydride (60%, 15 mg, 0.38 mmol) was added to a 10 mL screw-cap test tube under ice cooling, purged with argon gas, and then 0.5 mL of a DMF solution of compound 9A (100 mg, 0.298 mmol) was added and stirred for 30 minutes. 0.5 mL of a DMF solution of compound 9B (50 μL, 0.42 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. The reaction mixture was poured into dilute hydrochloric acid (1 mol / L), separated by liquid-liquid extraction with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 9C (121 mg, 0.284 mmol, 95.0%). １ H-NMR (600MHz, DMSO-D ６ ) δ7.61 (d, J = 7.6Hz, 1H), 7.43 (s, 1H), 7.38 (d, J = 8.3Hz, 1H), 7.29-7.26 (m, 2H ), 7.24-7.22 (m, 1H), 7.11-7.07 (m, 5H), 7.03-7.00 (m, 3H), 5.36 (s, 2H), 4.16 ( Step 2: A 20 mL round-bottom flask was purged with argon gas, and methanol solution (4 mL) of compound 9C (116 mg, 0.273 mmol) and aqueous sodium hydroxide solution (2 mol / L, 1 mL) were added in sequence, and the mixture was stirred at 70°C for 2 hours. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed 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 (elution solvent: hexane / dichloromethane / ethyl acetate) to obtain the title compound 9D (55.9 mg, 0.136 mmol, 49.8%). １ H-NMR (600MHz, DMSO-D ６) δ12.26 (brs, 1H), 7.64 (d, J=7.9Hz, 1H), 7.39-7.37 (m, 2H), 7.29-7 .22 (m, 3H), 7.12-7.06 (m, 5H), 7.03-6.99 (m, 3H), 5.36 (s, 2H), 4.03 ( t, J = 7.8Hz, 1H), 3.30-3.28 (m, 1H), 3.06 (q, J = 6.9Hz, 1H), 2.51-2.4 9 (m, 2H), 1.52-1.47 (m, 2H), 1.30-1.24 (m, 2H), 0.87 (t, J = 7.3Hz, 3H)

[0152] [Reference Examples IM26-IM44] Using the corresponding starting compounds, the compounds of Reference Examples IM26-IM44 were obtained in the same manner as the synthesis of compound 9C.

[0153]

[0154] [Examples 33-51] Using the raw material compounds of the corresponding Reference Examples IM26-IM44, the compounds of Examples 33-51 were obtained in the same manner as in Example 32.

[0155]

[0156] [Example 52] Preparation of 3-(4-butylphenyl)-2-(1-(3-(ethylamino)benzyl)-1H-indole-3-yl)propanoic acid (compound 10G)

[0157]

[0158] Step 1: Sodium hydride (60%, 55 mg, 1.38 mmol) was added to a 10 mL screw-cap test tube under ice cooling, purged with argon gas, and then 2 mL of a DMF solution of compound 10A (418 mg, 1.24 mmol) was added and stirred for 30 minutes. Compound 10B (268 mg, 1.24 mmol) was added to the reaction mixture and stirred at room temperature for 12 hours. The reaction mixture was poured into dilute hydrochloric acid (1 mol / L), separated by liquid-liquid extraction with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 10C (514 mg, 1.09 mmol, 87.9%). ESI / MS [M+H] ＋ =471.2 Step 2: Palladium-activated carbon (10%, 5 mg, 0.0047 mmol) was added to a 20 mL round-bottom flask and purged with argon gas. Methanol (1 mL) and a dichloromethane solution of compound 10C (306 mg, 0.650 mmol) (1 mL) were added. A balloon filled with hydrogen gas was connected to the round-bottom flask, and the flask was purged with hydrogen gas. The reaction mixture was then stirred at room temperature for 12 hours. The palladium-activated carbon in the reaction mixture was filtered through a 0.22 μm membrane filter, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain the title compound 10D (182 mg, 0.414 mmol, 63.7%). ESI / MS [M+H] ＋ =441.2 Step 3: A methanol solution (1 mL) of compound 10D (100 mg, 0.21 mmol) was added to a 10 mL screw-cap test tube and purged with argon gas. Triethylamine (43 μL, 0.3 mmol) and compound 10E (33 mg, 0.21 mmol) were then added, and the mixture was stirred at 75°C for 18 hours. After cooling, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane / ethyl acetate) to obtain the title compound 10F (20 mg, 0.043 mmol, 20%). ESI / MS [M+H] ＋= 469.2 Step 4: A 10 mL screw-cap test tube was purged with argon gas, and a methanol solution (0.1 mL) of compound 10F (20 mg, 0.043 mmol) and an aqueous sodium hydroxide solution (2 mol / L, 0.1 mL) were added in sequence, and the mixture was stirred at 70°C for 30 minutes. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol) to obtain the title compound 10G (5.7 mg, 0.013 mmol, 29%). １ H-NMR (600MHz, DMSO-D ６ ) δ12.20 (brs, 1H), 7.63 (d, J = 7.9Hz, 1H), 7.38 (d, J = 8.1Hz, 1H), 7.35 (s, 1H), 7.12 (d, J = 8.1Hz, 2H), 7.09-7.06 (m, 1 H), 7.04 (d, J = 7.9Hz, 2H), 7.01-6.98 (m, 1H), 6.97-6.94 (m, 1H), 6.41 (s, 1H), 6.41 (d, J = 6.2Hz, 1H), 6.26 (d, J = 7.4Hz) , 1H), 5.51 (brs, 1H), 5.21 (s, 2H), 4.01 (dd, J = 9.0, 6.5Hz, 1H), 3.32-3.27 (m, 1H), 3.03 (dd, J = 13.9, 6.5Hz, 1H), 2.9 7-2.93 (m, 2H), 2.51-2.49 (m, 2H), 1.53-1.48 (m, 2H), 1.30-1.24 (m, 2H), 1.10 (t, J = 7.1Hz, 3H), 0.88 (t, J = 7.4Hz, 3H)

[0159] [Reference Example IM45] Using the corresponding starting compound, the compound of Reference Example IM45 was obtained in the same manner as the synthesis of compound 10F.

[0160]

[0161] [Example 53] Using Reference Example IM45 as the starting compound, the compound of Example 53 was obtained in the same manner as in Example 52.

[0162]

[0163] [Example 54] Preparation of 3-(4-butylphenyl)-2-(1-(3-carbamoylbenzyl)-1H-indole-3-yl)propanoic acid (compound 11F)

[0164]

[0165] Step 1: Sodium hydride (60%, 40 mg, 1.0 mmol) was added to a 10 mL screw-cap test tube under ice cooling, purged with argon gas, and then 0.5 mL of a DMF solution of compound 11A (150 mg, 0.398 mmol) was added and stirred for 30 minutes. A DMF solution of compound 11B (92 mg, 0.40 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. The reaction mixture was poured into dilute hydrochloric acid (1 mol / L), separated by liquid-liquid extraction with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / dichloromethane) to obtain the title compound 11C (40 mg, 0.076 mmol, 19%). ESI / MS [M+H] ＋ = 526.3 Step 2: A 20 mL round-bottom flask was purged with argon gas, and methanol solution (0.2 mL) of compound 11C (40 mg, 0.076 mmol) and aqueous sodium hydroxide solution (2 mol / L, 0.2 mL) were added in sequence. The mixture was stirred at 70°C for 2 hours. After cooling, dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain the title compound 11D (31 mg, 0.060 mmol, 79%). ESI / MS [M-H] －= 510.2 Step 3: In a 10 mL screw-cap test tube cooled on ice, a DMF solution (0.5 mL) of compound 11D (30.9 mg, 0.0604 mmol), HATU (40 mg, 0.11 mmol), and ammonium chloride (5 mg, 0.09 mmol) were sequentially added, and the mixture was purged with argon gas. Then, N,N-diisopropylethylamine (100 μL) was added, and the mixture was stirred at room temperature for 24 hours. After cooling, saturated aqueous ammonium chloride solution was added to the reaction mixture, and liquid-liquid extraction was performed 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 (elution solvent: hexane / dichloromethane / ethyl acetate) to obtain the title compound 11E (25.3 mg, 0.0496 mmol, 82.1%). ESI / MS [M+Na] ＋ = 533.2 Step 4: Add a 1 mL solution of compound 11E (25.3 mg, 0.0496 mmol) in dichloromethane to a 10 mL screw-cap test tube, purge with argon gas, then sequentially add triethylsilane (45 mg, 0.39 mmol) and trifluoroacetic acid (1 mL), and stir at room temperature for 30 minutes. Add pure water to the reaction mixture, separate extraction with ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol) to obtain the title compound 11F (14.4 mg, 0.0317 mmol, 63.9%). １ H-NMR (600MHz, DMSO-D ６) δ12.12 (brs, 1H), 7.96 (brs, 1H), 7.85 (s, 1H), 7.74 (d, J = 7.9Hz, 1H), 7.64 (d, J = 7.9Hz, 1H), 7.43 (s, 1H), 7.40 (d, J = 8.3Hz, 1H), 7.37 (brs, 1H), 7.34 (t, J = 7.7Hz, 1H), 7.16 (d, J = 7.6Hz, 1H), 7.11-7.07 (m, 3H), 7.04-7.00 (m, 3H), 5.40 (s, 2H), 4.03 (dd, J = 8.8, 6.7Hz, 1H), 3.30 (dd, J = 13.7, 8.7Hz, 1H), 3.05 ( dd, J = 13.6, 6.7Hz, 1H), 2.51-2.49 (m, 2H), 1.52-1.47 (m, 2H), 1.30-1.24 (m, 2H), 0.87 (t, J = 7.4Hz, 3H)

[0166] [Example 55] Preparation of 4-(4-butylphenyl)-2-(1H-indole-3-yl)-4-oxobutanoic acid (compound 12C)

[0167]

[0168] Compound 12A (2.78 g, 12.0 mmol) and compound 12B (1.41 g, 12.0 mmol) were added to a 100 mL round-bottom flask. A condenser was attached, the flask was purged with argon gas, and then toluene (25 mL) was added. The mixture was heated under reflux for 6 hours. After cooling, the precipitated solid was filtered off and washed with cold toluene. The resulting crude product was recrystallized from acetone / hexane to obtain the title compound 12C (1.70 g, 4.87 mmol, 40.6%). １ H-NMR (600MHz, DMSO-D ６ ) δ12.15 (brs, 1H), 11.00 (s, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.67 (d, J = 7.9Hz, 1H), 7.36-7.33 (m, 4H), 7.10-7.07 (m, 1H), 7.01-6.99 (m, 1H), 4.32 (dd, J=1 0.6, 3.9Hz, 1H), 4.00 (dd, J=18.1, 10.7Hz, 1H), 3.32-3.28 (m, 1H), 2.65 (t , J=7.7Hz, 2H), 1.60-1.55 (m, 2H), 1.33-1.27 (m, 2H), 0.89 (t, J=7.4Hz, 3H)

[0169] [Example 56] Using the corresponding raw material compound, the compound of Example 56 was obtained in the same manner as in Example 55.

[0170]

[0171] [Example 57] Preparation of 4-(4-butylphenyl)-2-(1H-indole-3-yl)butanoic acid (compound 13B)

[0172]

[0173] In a 10 mL screw-cap test tube cooled on ice, a THF solution (1.5 mL) of compound 13A (105 mg, 0.300 mmol), pure water (15 μL), and zinc (392 mg, 6.00 mmol) were added in sequence. The mixture was then purged with argon gas, and chlorotrimethylsilane (380 μL, 3.00 mmol) was added, followed by stirring for 4 hours. Dilute hydrochloric acid (2 mol / L) was added to the reaction mixture, and the mixture was separated by liquid-liquid extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate) to obtain the title compound 13B (45.5 mg, 0.136 mmol, 45.1%). １ H-NMR (600MHz, DMSO-D ６ ) δ12.22 (brs, 1H), 10.96 (s, 1H), 7.53 (d, J = 7.9Hz, 1H), 7.35 (d, J = 8.1Hz, 1 H), 7.23 (d, J = 2.4Hz, 1H), 7.09-7.05 (m, 5H), 6.98-6.95 (m, 1H), 3.71 (t, J = 7.5Hz, 1H), 2.68-2.61 (m, 2H), 2.53 (t, J=7.7Hz, 2H), 2.33-2.27 (m, 1H), 2. 08-2.02 (m, 1H), 1.55-1.50 (m, 2H), 1.32-1.26 (m, 2H), 0.88 (t, J=7.4Hz, 3H)

[0174] [Example 58] Preparation of 3-(4-butylphenyl)-2-(1H-indole-3-yl)propanamide (compound 14B)

[0175]

[0176] In a 10 mL screw-cap test tube cooled on ice, a 1 mL solution of compound 14A (100 mg, 0.311 mmol) in DMF, 178 mg of HATU (0.468 mmol), and ammonium chloride (20 mg, 0.37 mmol) were added in sequence, and the mixture was purged with argon gas. Then, 271 μL of N,N-diisopropylethylamine (1.56 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After cooling, saturated aqueous ammonium chloride solution was added to the reaction mixture, and liquid-liquid extraction was performed 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 (elution solvent: hexane / dichloromethane / methanol) to obtain the title compound 14B (58.4 mg, 0.182 mmol, 58.6%). １ H-NMR (600MHz, DMSO-D ６ ) δ10.84 (s, 1H), 7.69 (d, J = 7.9Hz, 1H), 7.32-7.30 (m, 2H), 7.19 (d, J = 2.4Hz, 1 H), 7.13 (d, J = 7.9Hz, 2H), 7.06-7.03 (m, 3H), 6.97-6.94 (m, 1H), 6.70 (s, 1H), 3.95 (dd, J=9.3, 6.0Hz, 1H), 3.31-3.27 (m, 1H), 2.94 (dd, J=13.6, 5.9Hz, 1H), 2.51-2.49 (m, 2H), 1.53-1.48 (m, 2H), 1.31-1.25 (m, 2H), 0.88 (t, J = 7.3Hz, 3H)

[0177] [Example 71] Preparation of 3-(4-butylphenyl)-2-(5-fluoro-1H-indole-3-yl)propanoic acid (compound 15H)

[0178]

[0179] Step 1: A 10 mL screw-cap test tube was purged with argon gas, and 3 mL of THF solution of compound 15A (33.9 mg, 0.394 mmol) was added. The reaction mixture was cooled to -78°C, and LDA / THF solution (2 mol / L, 0.4 mL, 0.8 mmol) was added and stirred for 30 minutes. Then, compound 15B (0.10 g, 0.37 mmol) was added to the reaction mixture and stirred at -78°C for 2.5 hours. The round-bottom flask was transferred to an ice bath, pure water was added to the reaction mixture, and liquid-liquid extraction was performed 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 (elution solvent: hexane / ethyl acetate) to obtain the title compound 15C (38.4 mg, 0.165 mmol, 45%). １ H-NMR (600MHz, CDCl ３ ) δ7.13-7.10 (m, 4H), 4.21 (td, J=8.7, 3.2Hz, 1H), 4.14 (td, J=9.2, 6. 8Hz, 1H), 3.21 (dd, J = 13.9, 4.3Hz, 1H), 2.85-2.80 (m, 1H), 2.72 (dd, J =13.9, 9.5Hz, 1H), 2.58 (t, J=7.7Hz, 2H), 2.27-2.22 (m, 1H), 2.03-1. 96 (m, 1H), 1.61-1.55 (m, 2H), 1.38-1.32 (m, 2H), 0.92 (t, J = 7.4Hz, 3H) Step 2: A 50 mL screw-cap test tube was purged with argon gas under ice cooling, and a methanol solution (5 mL) of compound 15C (450 mg, 1.94 mmol) and concentrated hydrochloric acid (35 wt%, 17 μL, 0.20 mmol) were added in sequence. The mixture was heated under reflux overnight. After cooling, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain the title compound 15D (91.9 mg, 0.348 mmol, 17.9%). １ H-NMR (600MHz, CDCl ３) δ7.09 (d, J=8.1Hz, 2H), 7.06 (d, J=7.9Hz, 2H), 3.66-3.64 (m, 2H), 3. 63 (s, 3H), 2.97 (dd, J = 13.5, 7.7Hz, 1H), 2.86-2.81 (m, 1H), 2.73 (dd, J = 13.4, 7.2Hz, 1H), 2.57 (t, J = 7.7Hz, 2H), 1.91-1.86 (m, 1H), 1.80-1. 75 (m, 1H), 1.60-1.55 (m, 2H), 1.37-1.31 (m, 2H), 0.92 (t, J = 7.4Hz, 3H) Step 3: A 10 mL screw-cap test tube was purged with argon gas, and a 3 mL solution of DMSO (100 μL, 1.41 mmol) in dichloromethane was added. The reaction mixture was cooled to -78°C, oxalyl chloride (100 μL, 1.17 mmol) was added, and the mixture was stirred for 5 minutes. Then, compound 15D (160 mg, 0.605 mmol) was added to the reaction mixture and the mixture was stirred at -78°C for 15 minutes, and then triethylamine (420 μL, 3.01 mmol) was added and the mixture was stirred for 10 minutes. The round-bottom flask was transferred to an ice bath, saturated ammonium chloride aqueous solution was added to the reaction mixture, and liquid-liquid extraction was performed with dichloromethane. The organic layer was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain the title compound 15E (119 mg, 0.454 mmol, 75.0%). １ H-NMR (600MHz, CDCl ３) δ9.69 (s, 1H), 7.10 (d, J = 7.2Hz, 2H), 7.04 (d, J = 7.2Hz, 2H), 3.68 (s, 3H) , 3.18-3.15 (m, 1H), 3.05 (dd, J=13.6, 6.0Hz, 1H), 2.82 (dd, J=18.2, 9.1Hz , 1H), 2.71 (dd, J = 13.6, 8.6Hz, 1H), 2.57 (t, J = 7.7Hz, 2H), 2.51 (dd, J = 18. 3, 4.0Hz, 1H), 1.60-1.55 (m, 2H), 1.37-1.31 (m, 2H), 0.92 (t, J = 6.7Hz, 3H) Step 4: Compound 15E (80.0 mg, 0.305 mmol) was added to a 10 mL screw-cap test tube on an ice bath and purged with argon gas. Then, a toluene solution (1.5 mL) of p-toluenesulfonic acid monohydrate (143 mg, 0.752 mmol) and compound 15F (109 mg, 0.672 mmol) were added in that order, and the mixture was stirred at 80°C for 3 hours. After cooling, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain the title compound 15G (60.1 mg, 0.170 mmol, 55.7%). １ H-NMR (600MHz, DMSO-D ６) δ11.10 (s, 1H), 7.35-7.30 (m, 3H), 7.10 (d, J=8.1Hz, 2H), 7.04 (d, J=7.9Hz, 2H), 6.93-6.89(m, 1H), 4.13(dd, J=8.8, 6.9Hz, 1H), 3.52( s, 3H), 3.33-3.29 (m, 1H), 3.06 (dd, J=13.7, 7.0Hz, 1H), 2.53-2.49 (m, 2H), 1.52-1.47 (m, 2H), 1.29-1.23 (m, 2H), 0.87 (t, J=7.4Hz, 3H) Step 5: A 10 mL screw-cap test tube was purged with argon gas, and a methanol solution (2 mL) of compound 15 G (60.0 mg, 0.170 mmol) and an aqueous sodium hydroxide solution (2 mol / L, 0.5 mL) were added in sequence. The mixture was stirred at 70°C for 1 hour. After cooling, dilute hydrochloric acid (1 mol / L) was added to the reaction mixture, and liquid-liquid extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol) to obtain the title compound 15H (46.6 mg, 0.137 mmol, 80.6%). １ H-NMR (600MHz, DMSO-D ６ ) δ12.16 (brs, 1H), 11.01 (s, 1H), 7.33-7.28 (m, 3H), 7.09 (d, J = 8.1Hz, 2H), 7.00 (d, J = 8.1Hz, 2H), 6.91-6.85 (m, 1H), 4.01-3 95 (m, 1H), 3.27-3.22 (m, 1H), 3.02-2.95 (m, 1H), 2.51-2.46 (m, 2H), 1.49-1.44 (m, 2H), 1.27-1.19 (m, 2H), 0.85-0.81 (m, 3H)

[0180] [Reference Example IM46] Using the corresponding starting compound, the compound of Reference Example IM46 was obtained in the same manner as the synthesis of compound 15G.

[0181]

[0182] [Example 71] Using Reference Example IM46 as the starting compound, the compound of Example 72 was obtained in the same manner as in Example 71.

[0183]

[0184] [Test Examples] The following shows the pharmacological effects of the compounds according to this embodiment, but the present invention is not limited to these test examples. The compounds according to Examples 59 to 70 shown in the test examples can be manufactured by the methods described in Japanese Patent No. 6284159 and Japanese Patent No. 7125719.

[0185] [Test Example 1: Binding Affinity to Biotin Nampt Protein] Regarding the compound according to this embodiment, mammalian NAD ＋ To evaluate the binding affinity to nicotinamide phosphoribosyltransferase (Nampt), the main enzyme involved in biotin production, we measured the binding affinity to biotin Nampt using the Octet K2 intermolecular interaction analysis system from Forte Biosciences.

[0186] [Methods] A 0.01% DDM PBS solution was prepared as the measurement buffer. 1 μL of biotin Nampt was added to 1000 μL of the measurement buffer. This was diluted 2-fold to obtain a 0.4 ng / μL ligand solution. DMSO solutions (100 mM) of each test compound were diluted from 31.3 μM to 1000 μM to obtain analyte solutions. 200 μL each of the measurement buffer, 1 μM biotin solution, ligand solution, 100 μM biocitin solution, and analyte solution were added to a 96-well plate, and the plate was set in an Octet K2 for measurement. The data were analyzed using the accompanying software. Kd values ​​were plotted using Prism9 with the concentrations of the analyte solutions and the Req (nm) values ​​calculated in the analysis.

[0187] [Results] Table 17 shows the results of the measurement of the binding affinity of each compound to biotin Nampt. The binding measurements at concentrations of 250 μM and 31.3 μM for each compound are referred to as [Constant Concentration Evaluation]. If binding to biotin Nampt protein was observed at 31.3 μM, it is indicated as ++, and if it was observed only at 250 μM, it is indicated as +. The equilibrium dissociation constant of biotinylated Nampt binding for representative compounds is expressed as [Kd (μM)], and blank spaces indicate compounds that were not tested.

[0188]

[0189] Based on the above, the compounds listed in Table 17 are intracellular NAD ＋ It has been shown that it binds to Nampt, the main enzyme in production, and the compound according to this embodiment has the effect of activating Nampt in living organisms and NAD ＋ This supports the idea that it has the effect of increasing quantity.

[0190] [Test Example 2: Binding Affinity to Biotin IMMT Protein] To evaluate the binding affinity of the compound according to this embodiment to mitochondrial inner membrane proteins (IMMTs), which are important for improving mitochondrial function, such as intracellular ATP production, the binding affinity to biotin IMMTs was measured using the Octet intermolecular interaction analysis system manufactured by Forte Biosciences.

[0191] [Methods] A 0.01% DDM PBS solution was prepared as the measurement buffer. 1 μL of biotin IMMT was added to 1000 μL of the measurement buffer. This was diluted 2-fold to obtain a 0.4 ng / μL ligand solution. DMSO solutions (100 mM) of each test compound were diluted from 31.3 μM to 1000 μM to obtain analyte solutions. 200 μL each of the measurement buffer, 1 μM biotin solution, ligand solution, 100 μM biocitin solution, and analyte solution were added to a 96-well plate, and the plate was set in an Octet K2 for measurement.

[0192] [Results] Table 18 shows the results of measuring the binding affinity of each compound to biotin IMMT. If binding to the biotin IMMT protein was observed at 31.3 μM, it is indicated as ++, and if it was observed only at 250 μM, it is indicated as +.

[0193]

[0194] Based on the above, it is shown that the compounds listed in Table 18 bind to IMMT, which is a target for improving mitochondrial function, and this supports the idea that the compounds according to this embodiment have the effect of promoting ATP production and improving mitochondrial function.

[0195] [Test Example 3: NAD in animal cells]＋ [Quantitative Evaluation] Regarding the compound according to this embodiment, intracellular NAD ＋ To evaluate the effect of increasing the amount, animal cells were cultured in the presence of the compound, and NAD ＋ Quantity and NAD ＋ The NADH ratio was measured.

[0196] [Method] A 96-well plate was used, with 6 x 10⁶ of cells per well. ３ Each HEI-OC1 cell line was seeded and cultured for 24 hours in the presence of DMEM low-glucose culture medium. After removing the culture medium, 100 μL each of DMEM low-glucose culture medium containing 0.1% DMSO (the solvent for the compound) or DMEM low-glucose culture medium containing the test compound at various concentrations (3 nM, 10 nM, 30 nM, or 100 nM) was added, and the cells were cultured for 6 hours. Subsequently, intracellular NAD was measured using NAD / NADH-Glo Assay (G9071, Promega). ＋ Quantity, and NAD ＋ The NADH ratio was measured.

[0197] [Results] NAD levels in HEI-OC1 cells for each compound ＋ The effect of increasing the dosage is shown in Table 19. Statistically significant NAD ＋ Increase in quantity or NAD ＋ When the concentration showing an increase in the / NADH ratio is 3 pM, it is represented as +++; at 10 pM, as ++; and at 30 pM, as +.

[0198]

[0199] Based on the above, the compounds listed in Table 19 are found to be effective in animal cells in intracellular NAD ＋ The effect of increasing the amount (i.e., NAD in animal cells) ＋ This demonstrates that the compound according to this embodiment has the effect of promoting the production of NAD in living organisms, and that the compound according to this embodiment has the effect of promoting the production of NAD in living organisms. ＋ This indicates that it has the effect of increasing the quantity.

[0200] This result shows that the compound according to this embodiment is effective in animal cells in NAD ＋ This supports the idea that it has a dose-increasing effect.

[0201] [Test Example 4: Evaluation of Intracellular ATP Production Ability] To evaluate the effect of the compound according to this embodiment on enhancing intracellular ATP production ability, cell lines derived from patients with Leber's hereditary optic neuropathy were cultured in the presence of the compound, and the amount of ATP was measured.

[0202] [Method] A 96-well plate was used, with 1.5 × 10⁶ of material per well. ３ Cell lines derived from Leber's hereditary optic neuropathy patients were seeded and cultured for 24 hours in the presence of a low-glucose DMEM culture medium. Then, 0.1% DMSO, the solvent for the compound, or the test compound at various concentrations (0.1 μM, 1 μM, or 10 μM) was added, and the cells were cultured for 6 hours. The concentration of ATP produced in the culture medium was measured using a GloMa96 Microplate Luminometer (Promega) with a 'Cellular' ATP Measurement Reagent (Toyo B-Net Co., Ltd.).

[0203] [Results] Table 20 shows the effect of each compound on enhancing ATP production in cell lines derived from patients with Leber's hereditary optic neuropathy. A concentration that showed a statistically significant increase in ATP levels is indicated as +++ for 0.1 μM, ++ for 1 μM, and + for 10 μM.

[0204]

[0205] Based on the above, it is shown that the compounds listed in Table 20 have the effect of enhancing intracellular ATP production capacity in human-derived cell lines, and that the compounds according to this embodiment have the effect of promoting ATP production and improving mitochondrial function.

[0206] These results support the claim that the compound according to this embodiment has an effect of enhancing ATP production capacity in cells.

[0207] [Test Example 5: Measurement of Minimum Binding Concentration] For the compound according to this embodiment, in order to evaluate the minimum binding concentration to biotin Nampt protein and biotin IMMT protein, the binding concentration was measured using the Octet K2 intermolecular interaction analysis system manufactured by Forte Biosciences.

[0208] [Methods] A 0.01% DDM PBS solution was prepared as the measurement buffer. 1 μL of biotin Nampt or 1 μL of biotin IMMT was added to 500 μL of the measurement buffer to prepare a 1.6 ng / μL ligand solution. DMSO solution (100 mM) of each test compound was diluted from 15.6 μM to 1000 μM to prepare the analyte solution. 200 μL each of the measurement buffer, 1 μM biotin solution, ligand solution, 100 μM biocitin solution, and analyte solution were added to a 96-well plate, and the plate was set in an Octet K2 for measurement. The data were analyzed using the accompanying software.

[0209] [Results] The results of the measurement of the binding affinity of each compound to biotin IMMT are shown in Table 21.

[0210]

[0211] The above demonstrates that the compounds of Examples 71 and 72 bind to the target protein at concentrations equivalent to or lower than those of the compound of Example 1, supporting the idea that these compounds have a high binding ability to the target protein.

[0212] As shown in Test Examples 1, 3, and 5, the compound according to this embodiment binds to NAMPT, the major enzyme in the salvage pathway, and to intracellular NAD ＋ It has the effect of increasing the amount. The compound according to this embodiment also has the effect of binding to mitochondrial inner membrane proteins (IMMTs) and increasing the amount of intracellular ATP, as shown in Test Examples 2, 4, and 5. Thus, the compound according to this embodiment is a compound that has a unique effect of activating mitochondrial function in living organisms through two different pathways.

Claims

The following equation (I): [In equation (I), R1 is, (a) The following equation (II) (In formula (II), R41, R42, R43, R44, and R45 are each independently a hydrogen atom, a C1-C10 alkyl group (the hydrogen atoms of the alkyl group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C2-C6 alkoxyalkyl group (the hydrogen atoms of the alkoxyalkyl group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C1-C6 alkoxy group (the hydrogen atoms of the alkoxy group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C3-C6 cycloalkyl group, a phenyl group, a halogen atom, OH, COOH, NHCOR5, NR6R7, or CONR8R9) R5 is an alkyl group having 1 to 4 carbon atoms. R6 and R7 are each independently a hydrogen atom, a C1-C6 alkyl group, or a C2-C6 cyclic amino group formed by R6 and R7 working together (the cyclic amino group may contain an oxygen atom, a nitrogen atom, and a sulfur atom in its ring structure, the nitrogen atom may be bonded to a C1-C6 alkyl group, and the sulfur atom may be oxidized by 1-2 oxygen atoms). R8 and R9 are each independently represented by a hydrogen atom, a C1-C6 alkyl group, or a C2-C6 cyclic amino group formed by R8 and R9 working together; or, (b) an unsubstituted or R10-substituted naphthyl group or heteroaryl group (the heteroaryl group has a monocyclic or bicyclic structure with 5 to 10 members, and contains a total of 1 to 5 nitrogen atoms, oxygen atoms, and sulfur atoms in its ring structure), R10 is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, NHCOR11, or NR12R13. R11 is an alkyl group having 1 to 4 carbon atoms. R12 and R13 are, independently, a hydrogen atom, a C1-C6 alkyl group, or a C2-C6 cyclic amino group formed by the integration of R12 and R13; A is - (CH ２ ) １～３ -, -CH(CH ３ )-, or -C(O)CH ２ It is a base represented by -; R2 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group having 2 to 4 carbon atoms, or a halogen atom; R3 is COOH, COOR14, CONH ２ CONHCN, carboxylic acid bioisostea, or tetrazole group, R14 is an alkyl group having 1 to 6 carbon atoms; The substituent Y1 at position 2 of the indole ring is a hydrogen atom, a C1-C4 alkyl group, or a phenyl group; Y<sbnd>2< / sbnd>, which is a substituent on the nitrogen of the indole ring, is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms (the hydrogen atoms of the alkyl group may be substituted with 1 to 5 fluorine atoms), an alkoxyalkyl group having 2 to 6 carbon atoms (the hydrogen atoms of the alkoxyalkyl group may be substituted with an alkoxy group having 1 to 6 carbon atoms), -(CH ２ ) １～２ -O-(CH ２ ) １～３ -SiY<sbnd>3< / sbnd>Y<sbnd>4< / sbnd>Y<sbnd>5< / sbnd> (Y<sbnd>3< / sbnd>, Y<sbnd>4< / sbnd> and Y<sbnd>5< / sbnd> are each independently an alkyl group having 1 to 4 carbon atoms), or the following formula (III) (In formula (III), Y6 is an unsubstituted or substituted phenyl group, pyridyl group, furyl group, thienyl group, naphthyl group, or a cycloalkyl group having 3 to 6 carbon atoms, Y7 is an alkyl group having 1 to 6 carbon atoms, a phenyl group, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, CONY8Y9, NHCOY10, or NHY11Y12. Y8 and Y9 are, independently, a hydrogen atom, a C1-C4 alkyl group, or a C2-C6 cyclic amino group formed by Y8 and Y9 working together. Y10 is an alkyl group having 1 to 4 carbon atoms. Y11 and Y12 are each independently represented by a hydrogen atom, a C1-C4 alkyl group, or a C2-C6 cyclic amino group formed by Y11 and Y12 working together (the cyclic amino group may contain an oxygen atom, a nitrogen atom, and a sulfur atom in its ring structure, the nitrogen atom may be bonded to a C1-C6 alkyl group, and the sulfur atom may be oxidized by one or two oxygen atoms); B is - (CH ２ ) １～３ -, -CH(CH ３ )-, -C(O)-, or -C(O)CH ２ - is a base represented by; Z1, Z2, Z3, and Z4 are each independently a hydrogen atom, a C1-C4 alkyl group, a halogen atom, a C1-C8 alkoxy group (the hydrogen atoms of the alkoxy group may be substituted with C1-C6 alkoxy groups), and -O-(CH ２ ) １～２ - Ph, CN, or CF ３ Compounds represented by [ ], their enantiomers, their diastereomers, or pharmaceutically acceptable salts thereof. A is -CH ２ - is, The compound described in claim 1, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. 　 R1 is a group represented by formula (II) above, R2 is a hydrogen atom or an alkyl group having one or two carbon atoms. R3 is COOH, COOR14, or CONH ２ , The compound described in claim 1, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. At least one of R41, R42, R43, R44, and R45 is a C1-C10 alkyl group (the hydrogen atoms of the alkyl group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C2-C6 alkoxyalkyl group (the hydrogen atoms of the alkoxyalkyl group may be substituted with a C1-C6 alkoxy group or 1-5 fluorine atoms), a C1-C6 alkoxy group (the hydrogen atoms of the alkoxy group may be substituted with a C1-C6 alkoxy group), a C3-C6 cycloalkyl group, a phenyl group, a halogen atom, OH, COOH, NHCOR5, NR6R7, or CONR8R9. The compound according to claim 3, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. 　 R1 is an unsubstituted pyridyl group, a C1-C6 alkyl group, or a pyridyl, naphthyl, or quinolyl group substituted with a C1-C6 alkoxy group. The compound described in claim 1, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. 　 R1 is an unsubstituted or R10-substituted indolyl, furyl, or thienyl group. The compound described in claim 1, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. 　 Y1 is a hydrogen atom or an alkyl group having 1 or 2 carbon atoms. Y2 is a hydrogen atom, a C3-C8 alkyl group (the hydrogen atoms of the alkyl group may be substituted with 1-5 fluorine atoms), a C2-C4 alkoxyalkyl group (the hydrogen atoms of the alkoxyalkyl group may be substituted with a C1-C3 alkoxy group), -CH ２ -O-(CH ２ ) ２ -SiY3Y4Y5 (where Y3, Y4, and Y5 are each methyl groups), or a group represented by the above formula (III), Y6 is an unsubstituted cycloalkyl group having 5 or 6 carbon atoms, or an unsubstituted phenyl, pyridyl, furyl, or naphthyl group substituted with Y7. Y7 is an alkyl group having 1 to 4 carbon atoms, a phenyl group, a halogen atom, an alkoxy group having 1 or 2 carbon atoms, CONY8Y9, NHCOY10, or NY11Y12. The compound described in claim 1, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. Z1, Z2, Z3, and Z4 each independently consist of a hydrogen atom, a halogen atom, a carbon-1 to carbon-8 alkoxy group (the hydrogen atoms of the alkoxy group may be substituted with carbon-2 to carbon-4 alkoxy groups), and -O-CH ２ -Ph, alkoxy group having 1 to 3 carbon atoms, CN, or CF ３ That is, The compound described in claim 1, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. The compound represented by formula (I) is selected from the compounds represented by formulas (1) to (58), (71), and (72). The compound described in claim 1, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. 　 A prodrug of any compound according to claim 1 to 9, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof. 　 A compound according to any one of claims 1 to 9, its enantiomer, its diastereomer, a pharmaceutically acceptable salt thereof, or a prodrug thereof, NAMPT activators containing as active ingredients compounds represented by the following formulas (59) to (70), their enantiomers, their diastereomers, pharmaceutically acceptable salts thereof, or their prodrugs.

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