benzotriazole compounds, pharmaceutical compositions containing them, and their uses

Abstract

[式中，各符號如說明書中所記載]所表示之化合物或其藥學上所容許之鹽。又，本發明亦關於一種含有上述化合物之醫藥，該醫藥用以預防及 / 或治療選自由慢性腎病、非酒精性脂肪性肝炎、慢性阻塞性肺病、放射線皮膚損傷、放射線黏膜損傷、心衰竭、肺動脈高壓、帕金森氏症、弗里德賴希隱性遺傳運動失調症、多發性硬化症、老年性黃斑變性、視網膜色素變性及青光眼所組成之群中之與氧化壓力相關之疾病。;

Description

Technical Field

[0001] This invention relates to a benzotriazole compound or a pharmaceutically permissible salt thereof, which, by inhibiting Kelch-like ECH-associated protein 1 (Keap1) and activating NF-E2-associated factor 2 (Nrf2), is used to treat and / or prevent diseases related to oxidative stress, particularly those selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma. Prior Technology

[0002] If reactive oxygen species generated during energy metabolism are detected, biological defense systems such as antioxidant enzyme groups or detoxification enzyme groups are activated. Nrf2 controls the activation of these biological defense systems.

[0003] It is known that activation of Nrf2 induces the production of NAD(P)H quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), and the γ-glutamylcysteine ​​ligase catalytic subunit (GCLC), which are its target genes (Non-Patent Literature 1). NQO1 is a phase 2 enzyme in the xenobiotic biotin metabolism system and plays an important role in detoxification. HO-1 and GCLC are known as typical antioxidant enzymes. If the amount of these enzymes increases or they are activated, cells become resistant to toxins, oxidative stress, inflammation, etc., therefore compounds that activate Nrf2 are considered to be therapeutics for various diseases (Non-Patent Literature 2).

[0004] Since Nrf2 is ubiquitinated by Keap1 in a stable state and degraded in protease systems, Keap1 inhibitory compounds can activate Nrf2. To date, compounds that activate Nrf2 by modifying cysteine ​​residues of Keap1 are known, but their activation mechanisms raise concerns about low specificity. On the other hand, compounds that inhibit the protein-protein interaction (PPI) between Keap1 and Nrf2 show promise as a more specific mechanism for activating Nrf2, and have recently attracted increasing attention as preventative and / or therapeutic agents for various diseases caused by oxidative stress (Non-Patent Literature 3).

[0005] To date, compounds that inhibit Keap1 and activate Nrf2 have been reported, for example, as compounds described in Patent Documents 1 to 11, but their structures are different from those of the compounds of the present invention. [Previous Technical Documents] [Patent Literature]

[0006] [Patent Document 1] International Publication No. 2015 / 092713 [Patent Document 2] International Publication No. 2016 / 202253 [Patent Document 3] International Publication No. 2016 / 203400 [Patent Document 4] International Publication No. 2016 / 203401 [Patent Document 5] International Publication No. 2018 / 109643 [Patent Document 6] International Publication No. 2018 / 109647 [Patent Document 7] International Publication No. 2018 / 109648 [Patent Document 8] International Publication No. 2019 / 224667 [Patent Document 9] International Publication No. 2020 / 165776 [Patent Document 10] International Publication No. 2018 / 181345 [Patent Document 11] International Publication No. 2020 / 241853 [Non-patent literature]

[0007] [Non-Patent Literature 1] Int. J. Biochem. Cell. Biol., 2012, 44, 1315-1320 [Non-Patent Literature 2] Nat. Rev. Drug. Discov., 2019, 18, 295-317 [Non-Patent Literature 3] Eur. J. Med. Chem., 2020, 202, 112532 Summary of the Invention

[0008] [The problem the invention aims to solve] The present invention provides a medicine that, by inhibiting the protein-protein interaction between Keap1 and Nrf2 and activating Nrf2, can treat and / or prevent diseases related to oxidative stress, particularly those selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma. [Technical means to solve the problem]

[0009] The inventors have conducted diligent research to solve the aforementioned problems and have discovered that the compound represented by the following general formula (1) (hereinafter, sometimes simply referred to as "compound (1)") or its pharmaceutically permissible salt has excellent Nrf2 activation activity by inhibiting Keap1, thereby completing the present invention:

[0010] [Chemistry 1]

[0011] [In the formula, R1a and R1b independently represent a hydrogen atom or a C1-6 alkyl group, respectively. R2 represents a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from substituent group a. R3 represents a hydrogen atom, a halogen atom, or a C1-6 alkyl group. Y represents -CH-, -CR4-, or a nitrogen atom. R4 represents a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group. -V- denotes the basis represented by any of the following expressions:

[0012] [Chemistry 2]

[0013] (In the formula, * and ** indicate the bonding positions with the benzene ring.) Each of the n R7 groups independently represents a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group. n represents an integer from 0 to 2, and Z represents the basis expressed by the following formulas (A1), (A2), or (A3):

[0014] [Chemistry 3]

[0015] (in the formula, *** indicates the bond position of the carbon atom with the Z bond. R8 indicates a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from substituent group a. R5a and R5b independently represent a hydrogen atom, a C1-6 alkyl group or a C3-6 cycloalkyl group that can be substituted with 1 to 3 substituents selected from substituent group a, respectively. Alternatively, R5a and R5b may bond together and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from substituent group b. Each of the m R6 groups independently represents a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m represents an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 represents a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X represents -CH-, -CR10-, or a nitrogen atom. R10 represents a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U represents -CH-, -CR11-, or a nitrogen atom, and R11 represents a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. Replacement of base group a: hydroxyl, Halogen atoms, cyano, C1-6 alkyl groups that can be substituted with 1 to 3 substituents selected from substituent group b C1-6 alkoxy groups can be substituted with 1 to 3 substituents selected from substituent group b. C1-6 alkylsulfonyl groups can be substituted with 1 to 3 substituents selected from substituent group b. Amino groups that can be substituted with one or two C1-6 alkyl groups Replacement of base group b: Halogen atoms, cyano, C1-6 alkyl, C1-6 alkoxy group.

[0016] That is, the present invention is as follows. [1] A compound or a pharmaceutically permissible salt thereof, wherein the compound is represented by the following general formula (1):

[0017] [Chemistry 4]

[0018] [In the formula, R1a and R1b independently represent a hydrogen atom or a C1-6 alkyl group, respectively. R2 represents a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from substituent group a. R3 represents a hydrogen atom, a halogen atom, or a C1-6 alkyl group. Y represents -CH-, -CR4-, or a nitrogen atom. R4 represents a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group. -V- denotes the basis represented by any of the following expressions:

[0019] [Chemistry 5]

[0020] (In the formula, * and ** indicate the bonding positions with the benzene ring.) Each of the n R7 groups independently represents a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group. n represents an integer from 0 to 2, and Z represents the basis expressed by the following formulas (A1), (A2), or (A3):

[0021] [Chemistry 6]

[0022] (in the formula, *** indicates the bond position of the carbon atom with the Z bond. R8 indicates a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from substituent group a. R5a and R5b independently represent a hydrogen atom, a C1-6 alkyl group or a C3-6 cycloalkyl group that can be substituted with 1 to 3 substituents selected from substituent group a, respectively. Alternatively, R5a and R5b may bond together and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from substituent group b. Each of the m R6 groups independently represents a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m represents an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 represents a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X represents -CH-, -CR10-, or a nitrogen atom. R10 represents a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U represents -CH-, -CR11-, or a nitrogen atom, and R11 represents a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. Replacement of base group a: hydroxyl, Halogen atoms, cyano, C1-6 alkyl groups that can be substituted with 1 to 3 substituents selected from substituent group b C1-6 alkoxy groups can be substituted with 1 to 3 substituents selected from substituent group b. C1-6 alkylsulfonyl groups can be substituted with 1 to 3 substituents selected from substituent group b. Amino groups that can be substituted with one or two C1-6 alkyl groups Replacement of base group b: Halogen atoms, cyano, C1-6 alkyl, C1-6 alkoxy group. [2] The compound described above [1] or its pharmaceutically permissible salt, wherein R1a and R1b are independently hydrogen atoms or methyl groups. [3] The compound described above in [1] or [2] or its pharmaceutically permissible salt, wherein R2 is a C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonylurea)propyl. [4] The compound described in any of [1] to [3] above, or its pharmaceutically permissible salt, wherein R3 is a halogen atom or a C1-6 alkyl group. [5] The compound or its pharmaceutically permissible salt described in any of [1] to [4] above, wherein R4 is a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group or a trifluoromethoxy group. [6] The compound or its pharmaceutically permissible salt described in any of [1] to [5] above, wherein -V- represents a base represented by any of the following formulas:

[0023] [Chemistry 7]

[0024] (In the formula, * and ** represent the same meaning as above). [7] The compound described in any of [1] to [6] above, or its pharmaceutically permissible salt, wherein n is 1 and R7 is a C1-6 alkyl group. [8] The compound or its pharmaceutically permissible salt described in any of [1] to [6] above, where n is 0. [9] The compound or its pharmaceutically permissible salt described in any of [1] to [8] above, wherein Z is a base represented by the following formula (A1) or (A2):

[0025] [Chemistry 8]

[0026] (The symbols in the formula have the same meaning as described above).

[10] The compound described above [9] or its pharmaceutically permissible salt, wherein R8 is methyl or ethyl.

[11] The compounds described above in [9] or

[10] , or their pharmaceutically permissible salts, wherein R5a and R5b are independently hydrogen atoms, methyl, ethyl or cyclopropyl groups, respectively. Alternatively, R5a and R5b may bond together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran.

[12] The compound or its pharmaceutically permissible salt described in any of [9] to

[11] above, wherein each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom, and m is an integer from 0 to 2.

[13] The compound or its pharmaceutically permissible salt described in any of [9] to

[12] above, wherein W is -CH2- or an oxygen atom.

[14] A compound (hereinafter, sometimes simply referred to as "compound (1')") or a pharmaceutically permissible salt thereof, the compound being represented by the following general formula (1'):

[0027] [Chemistry 9]

[0028] [In the formula, R1a' and R1b' independently represent a hydrogen atom or a methyl group, respectively. R2' represents methyl, R3' represents a chlorine atom or a methyl group. Y' represents -CH-, -CR4'-, or a nitrogen atom. R4' represents a chlorine atom, methyl, cyclopropyl, difluoromethoxy, or trifluoromethoxy. -V'- denotes the basis represented by any of the following expressions:

[0029] [Chemistry 10]

[0030] (In the formula, *' and **' indicate the bonding positions with the benzene ring.) R5a' and R5b' can each independently represent a hydrogen atom or an ethyl group, or R5a' and R5b' can be bonded together to form cyclopropane. Each of the m' R6' atoms independently represents either a fluorine atom or a chlorine atom. m' represents an integer from 0 to 2, and W' represents an oxygen atom.

[15] A compound or a pharmaceutically permissible salt thereof, wherein the compound is selected from any of the following groups: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid, and (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid.

[16] A compound or a pharmaceutically permissible salt thereof, wherein the compound is selected from any of the following groups: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, and (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid.

[17] A (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid or a pharmaceutically permissible salt thereof.

[18] A (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid or a pharmaceutically permissible salt thereof.

[19] A (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid or a pharmaceutically permissible salt thereof.

[20] A (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid or a pharmaceutically permissible salt thereof.

[21] A compound (hereinafter, sometimes simply referred to as "compound (1'')") or a pharmaceutically permissible salt thereof, the compound being represented by the following general formula (1''):

[0031] [Chemistry 11]

[0032] [In the formula, R1a'' and R1b'' independently represent a hydrogen atom or a methyl group, respectively. R2'' represents methyl, R3'' represents a chlorine atom or a methyl group. Y'' represents -CH-, -CR4''-, or a nitrogen atom. R4'' represents a chlorine atom, methyl, cyclopropyl, difluoromethoxy, or trifluoromethoxy group. -V''- denotes the basis represented by any of the following expressions:

[0033] [Chemistry 12]

[0034] (In the formula, *'' and **'' represent the bonding positions with the benzene ring.) R5a'' and R5b'' independently represent a hydrogen atom or an ethyl atom, or R5a'' and R5b'' bonds together to form cyclopropane. R8'' indicates methyl or ethyl. Each of the m'' R6''' independently represents a chlorine atom or a hydroxyl group. m'' represents 0 or 1, U'' represents a nitrogen atom, and W'' represents an oxygen atom.

[22] A compound or a pharmaceutically permissible salt thereof, selected from any of the following groups: (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopon-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopon-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopon-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopon-4(5H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid, (3R)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid, (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid, (3S)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3R)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, and (3S)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazop-4(5H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid.

[23] A medicine (hereinafter, sometimes referred to as "the medicine of the present invention") containing as an active ingredient a compound described in any of [1] to

[22] above or a pharmaceutically permissible salt thereof.

[24] The medicine described above

[23] is used to activate Nrf2.

[25] The medicine described above

[23] is used to inhibit the protein-protein interaction between Keap1 and Nrf2.

[26] The medicine described above in

[23] is used to prevent and / or treat oxidative stress-related diseases.

[27] As described in

[26] above, the oxidative stress-related diseases are selected from the group consisting of kidney disease, liver disease, respiratory disease, skin disease, cardiovascular disease, central nervous system disease, autoimmune disease and eye disease.

[28] Medicines as described above in

[23] are used to prevent and / or treat diseases selected from the group consisting of the following diseases: Choose from the following groups of kidney diseases: chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; choose from the following groups of liver diseases: alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis, and cirrhosis; choose from the following groups of respiratory diseases: bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia, and asthma; choose from the following groups of skin diseases: ultraviolet and radiation-induced skin damage, radiation-induced mucosal damage, bullous epidermolysis, psoriasis, atopic dermatitis, and scleroderma; choose from the following groups of cardiovascular diseases: heart failure, myocardial infarction, arteriosclerosis, and pulmonary hypertension; choose from the following groups of Alzheimer's disease. Central nervous system diseases in the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, glutamic acidosis, and autism; mitochondrial diseases in the group consisting of Friedreich recessive motor disorder and mitochondrial myopathy; autoimmune diseases in the group consisting of multiple sclerosis, chronic rheumatoid arthritis, systemic lupus erythematosus, Hughes syndrome, type 1 diabetes, ulcerative colitis, and Crohn's disease; and eye diseases in the group consisting of allergic conjunctival diseases, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal disorders, uveitis, Bessie's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma, and cataracts.

[29] The medicine described above

[23] is used to prevent and / or treat diseases selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

[30] The medicine described above in

[23] is used to prevent and / or treat diseases selected from the group consisting of glaucoma, age-related macular degeneration and retinitis pigmentosa.

[31] The medicine described above in

[23] is used to prevent and / or treat radiation-induced skin or mucosal damage.

[32] The medicine described above in

[23] is used to prevent and / or treat chronic obstructive pulmonary disease.

[33] The use of a compound or a pharmaceutically permissible salt thereof as described in any one of [1] to

[22] above, for the manufacture of a preventive and / or therapeutic agent for diseases selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

[34] A method for preventing and / or treating diseases in mammals selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma, comprising: administering a pharmaceutically effective amount of a compound described in any one of [1] to

[22] above or a pharmaceutically permissible salt thereof to the mammal.

[35] A method for activating Nrf2 in a mammal, comprising: administering to the mammal a pharmaceutically effective amount of a compound as described in any one of [1] to

[22] above, or a pharmaceutically permissible salt thereof.

[36] A method for inhibiting the protein-protein interaction between Keap1 and Nrf2 in a mammal, comprising: administering to the mammal a pharmaceutically effective amount of a compound as described in any one of [1] to

[22] above, or a pharmaceutically permissible salt thereof.

[37] An Nrf2 activator containing, as an active ingredient, a compound or a pharmaceutically permissible salt thereof as described in any of [1] to

[22] above.

[38] An inhibitor of the interaction between Keap1 and Nrf2 proteins, comprising as an active ingredient a compound described in any of [1] to

[22] above or a pharmaceutically permissible salt thereof.

[39] The compound or salt thereof described in any of [1] to

[22] above, for the prevention and / or treatment of diseases selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

[40] The medicine described above

[23] is used for the prevention and / or treatment of diseases selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

[41] Any of the medicines described in any of

[23] to

[32] and

[40] above are administered in combination with other medicines.

[42] The medicines mentioned above

[41] include other agents selected from the group of diseases including chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

[43] The medicine described in

[41] or

[42] above, wherein the medicine described in any of

[23] to

[32] and

[40] above, and other pharmaceutical preparations are contained as active ingredients in different preparations and are administered at the same time or at different times.

[44] The medicine described above in

[41] or

[42] , wherein the compound described in any of [1] to

[22] above, or its pharmaceutically permissible salt, or other pharmaceutical agents are contained in a single preparation.

[45] A pharmaceutical composition (hereinafter, sometimes referred to as "the pharmaceutical composition of the present invention"), comprising a compound as described in any one of [1] to

[22] above, or a pharmaceutically permissible salt thereof, and a pharmaceutically permissible carrier.

[46] A method for manufacturing a compound or a salt thereof, wherein the method is as described in any of [1] to

[22] above.

[47] A pre-precursor of a compound or a salt thereof, which is a pre-precursor of a compound or a salt thereof as described in any of [1] to

[22] above. [Effects of the Invention]

[0035] The compound (1) of the present invention, or its pharmaceutically permissible salt, exhibits an effective activation of Nrf2 by inhibiting the protein-protein interaction between Keap1 and Nrf2. That is, it can be used to prevent and / or treat diseases whose symptoms are improved by activating Nrf2 by administering a medicine containing the compound (1) of the present invention, or its pharmaceutically permissible salt, as an active ingredient to mammals. Examples of diseases whose symptoms are improved by activating Nrf2 include oxidative stress-related diseases, specifically, diseases selected from the following groups of diseases: Choose from the following groups of kidney diseases: chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; choose from the following groups of liver diseases: alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis, and cirrhosis; choose from the following groups of respiratory diseases: bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia, and asthma; choose from the following groups of skin diseases: ultraviolet and radiation-induced skin damage, radiation-induced mucosal damage, bullous epidermolysis, psoriasis, atopic dermatitis, and scleroderma; choose from the following groups of cardiovascular diseases: heart failure, myocardial infarction, arteriosclerosis, and pulmonary hypertension; choose from the following groups of Alzheimer's disease. Central nervous system diseases in the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, glutamic acidosis, and autism; mitochondrial diseases in the group consisting of Friedreich recessive motor disorder and mitochondrial myopathy; autoimmune diseases in the group consisting of multiple sclerosis, chronic rheumatoid arthritis, systemic lupus erythematosus, Hughes syndrome, type 1 diabetes, ulcerative colitis, and Crohn's disease; and eye diseases in the group consisting of allergic conjunctival diseases, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal disorders, uveitis, Bessie's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma, and cataracts. Suitable candidates may be selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma. Implementation

[0036] The terms and symbols used in this specification are defined below. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0037] In this specification, "halogen atom" means fluorine atom, chlorine atom, bromine atom or iodine atom.

[0038] In this specification, "C1-6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples of C1-6 alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, tributyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, etc.

[0039] In this specification, "C1-6 haloalkyl" means that one or more hydrogen atoms in the aforementioned "C1-6 alkyl" are replaced by a halogen group. Examples of C1-6 haloalkyl groups include: fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, etc.

[0040] In this specification, "C1-6 alkoxy" refers to a group formed by the bonding of a "C1-6 alkyl" to an oxygen atom. Examples of C1-6 alkoxy groups include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, dibutoxy, terbutoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, n-hexyloxy, etc.

[0041] In this specification, "C1-6 haloalkoxy" means that one or more hydrogen atoms in the aforementioned "C1-6 alkoxy" are replaced by a halogen group. Examples of C1-6 haloalkoxy groups include: fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentoxy, 6,6,6-trifluorohexyloxy, etc.

[0042] In this specification, "C3-6 cycloalkyl" refers to a 3- to 6-membered monocyclic saturated hydrocarbon cycloalloy, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0043] In this specification, "C1-6 alkylsulfonyl" refers to a group formed by the bonding of the aforementioned "C1-6 alkyl" group with the sulfur atom of the sulfonyl group. Examples of C1-6 alkylsulfonyl groups include: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, dibutylsulfonyl, tributylsulfonyl, n-pentylsulfonyl, etc.

[0044] In this specification, "amino group that can be substituted with one or two C1-6 alkyl groups" means an unsubstituted amino group, or an amino group in which one or two hydrogen atoms are independently substituted with the aforementioned "C1-6 alkyl" group. Examples of amino groups that can be substituted with one or two C1-6 alkyl groups include: amino, methylamino, dimethylamino, ethylamino, diethylamino, ethyl(methyl)amino, n-propylamino, di(n-propyl)amino, isopropylamino, n-butylamino, di(n-butyl)amino, dibutylamino, dibutylamino, dibutylamino, n-pentylamino, n-hexylamino, etc.

[0045] In this specification, "C3-8 cycloalkanes" refers to saturated hydrocarbon rings with 3 to 8 members, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or cyclooctane. Cyclopropane or cyclobutane are suitable examples of "C3-8 cycloalkanes".

[0046] In this specification, "3 to 8-membered saturated oxygen-containing heterocycles" refers to 3 to 8-membered monocyclic saturated oxygen-containing heterocycles, such as ethylene oxide, oxetane, tetrahydrofuran, tetrahydropyran, oxetane, and oxetane. "3 to 8-membered saturated oxygen-containing heterocycles" are preferably oxetane or tetrahydropyran.

[0047] In this specification, "substitutable" means unsubstituted or substituted at any position where substitution is possible by a specific number of specific substituents (any hydrogen atom is substituted as a substituent). Examples of such "substituents" include substituents selected from the groups "substituent group a" and "substituent group b" described below. In the case of multiple substituents, the substituents may be the same or different.

[0048] Replacement of base group a: hydroxyl, Halogen atoms, cyano, C1-6 alkyl groups that can be substituted with 1 to 3 substituents selected from substituent group b C1-6 alkoxy groups can be substituted with 1 to 3 substituents selected from substituent group b. C1-6 alkylsulfonyl groups can be substituted with 1 to 3 substituents selected from substituent group b. Amino groups that can be substituted with one or two C1-6 alkyl groups

[0049] Replacement of base group b: Halogen atoms, cyano, C1-6 alkyl, C1-6 alkoxy Wherein, when any substituent of "substitutable C1-6 alkyl" or "substitutable C1-6 alkoxy" is selected from the above-mentioned substituent group a or substituent group b, "C1-6 alkyl" is not included in the list of the above-mentioned substituent group a or substituent group b.

[0050] In this instruction manual, "pharmaceutically permissible salts" means salts that can be used in medicine, including both pharmaceutically permissible acid addition salts and pharmaceutically permissible base addition salts.

[0051] In this specification, "pharmaceutically permissible carrier" means any pharmaceutically permissible material (e.g., excipients, diluents, additives, solvents, etc.) relating to the delivery of the compound (1) of the present invention (or compound (1') or compound (1'')) or a composition comprising it from one organ to another.

[0052] In this instruction manual, "treatment" and its derivatives mean the relief, mitigation, or delay of the deterioration of clinical symptoms of a disease, symptom, disorder, etc. (hereinafter referred to as "disease, etc.") in patients who have developed the disease.

[0053] In this manual, "prevention" and its derivatives mean the suppression, control, mitigation, or cessation of the onset of clinical symptoms of a disease or other disease that may occur but has not yet occurred, or the prevention of recurrence of a disease or other disease after treatment in mammals.

[0054] In this specification, "oxidative stress" refers to a state in which excessive reactive oxygen species are produced due to external factors (such as ultraviolet radiation, radiation, air pollution, tobacco, pharmaceuticals, and the intake of oxidizing substances), leading to an imbalance in the antioxidant defense mechanism. Furthermore, "oxidative stress-related diseases" refers to diseases in which the aforementioned oxidative stress is associated with the onset of disease or the worsening of symptoms. Examples of "oxidative stress-related diseases" include diseases selected from the following groups: Choose from the following groups of kidney diseases: chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; choose from the following groups of liver diseases: alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis, and cirrhosis; choose from the following groups of respiratory diseases: bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia, and asthma; choose from the following groups of skin diseases: ultraviolet and radiation-induced skin damage, radiation-induced mucosal damage, bullous epidermolysis, psoriasis, atopic dermatitis, and scleroderma; choose from the following groups of cardiovascular diseases: heart failure, myocardial infarction, arteriosclerosis, and pulmonary hypertension; choose from the following groups of Alzheimer's disease. Central nervous system diseases in the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, glutamic acidosis, and autism; mitochondrial diseases in the group consisting of Friedreich recessive motor disorder and mitochondrial myopathy; autoimmune diseases in the group consisting of multiple sclerosis, chronic rheumatoid arthritis, systemic lupus erythematosus, Hughes syndrome, type 1 diabetes, ulcerative colitis, and Crohn's disease; and eye diseases in the group consisting of allergic conjunctival diseases, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal disorders, uveitis, Bessie's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma, and cataracts. The "oxidative stress-related diseases" in this invention are specifically selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[0055] In this specification, "inhibitor of the protein-protein interaction between Keap1 and Nrf2" means a substance that exhibits the following effect: under normal circumstances, Keap1 and Nrf2 form a complex, inhibiting the action of Nrf2 by ubiquitination based on E3 ubiquitin ligase, but inhibiting the formation of this complex will release Nrf2.

[0056] In this specification, "activating Nrf2" or "Nrf2 activator" means the following substance: by inhibiting the protein-protein interaction between Keap1 and Nrf2, without forming a Keap1-Nrf2 complex, free Nrf2 is transferred to the nucleus, thereby increasing the expression of the antioxidant genome or making the antioxidant genome highly expressive.

[0057] In this specification, "pharmaceuticalally effective amount" means the amount of the compound (1) of this invention (or compound (1') or compound (1'') or its pharmaceutically permissible salt thereof administered orally or non-orally (locally, rectarily, intravenously, intramuscularly, subcutaneously, etc.) to a mammal.

[0058] In this instruction manual, the term "mammal" is not specifically limited and can be exemplified as: humans, or other mammals (such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.).

[0059] (The compound of this invention (compound (1))) The following will explain each group in formula (1) of compound (1).

[0060] R1a and R1b represent hydrogen atoms or C1-6 alkyl groups, respectively.

[0061] R1a and R1b are preferably either hydrogen atoms or methyl groups, respectively.

[0062] R2 represents a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from the above substituent group a.

[0063] R2 is preferably C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonylurea)propyl, and more preferably methyl.

[0064] R3 represents a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

[0065] R3 is preferably a halogen atom or a C1-6 alkyl group, and more preferably a chlorine atom or a methyl group.

[0066] Y represents -CH-, -CR4- (where R4 represents a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group) or a nitrogen atom.

[0067] Y is preferably -CH-, -CR4- (where R4 is a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group) or a nitrogen atom, and more preferably -CH-, -CR4- (where R4 is a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group) or a nitrogen atom.

[0068] -V- denotes the basis represented by any of the following expressions:

[0069] [Chemistry 13]

[0070] (In the formula, * and ** indicate the bonding positions with the benzene ring).

[0071] -V- is preferably represented by any of the following bases:

[0072] [Chemistry 14]

[0073] (In the formula, * and ** represent the same meaning as above), It is preferable to use any of the following formulas as the basis:

[0074] [Chemistry 15]

[0075] (In the formula, * and ** represent the same meaning as above).

[0076] Each of the n R7 groups independently represents a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group.

[0077] The n R7s are preferably C1-6 alkyl groups.

[0078] n represents an integer from 0 to 2.

[0079] n is preferably 0 or 1, and even better is 0.

[0080] Z represents the basis expressed by the following formulas (A1), (A2), or (A3):

[0081] [Chemistry 16]

[0082] (in the formula, *** indicates the bond position of the carbon atom with the Z bond. R8 indicates a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from substituent group a. R5a and R5b independently represent a hydrogen atom, a C1-6 alkyl group or a C3-6 cycloalkyl group that can be substituted with 1 to 3 substituents selected from substituent group a, or R5a and R5b are bonded to each other and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from substituent group b. Each of the m R6 groups independently represents a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m represents an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 represents a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X represents -CH-, -CR10-, or a nitrogen atom. R10 represents a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U represents -CH-, -CR11-, or a nitrogen atom, and R11 represents a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0083] Z is preferably represented by the basis expressed by the following formula (A1) or (A2):

[0084] [Chemistry 17]

[0085] (The symbols in the formula have the same meaning as described above.) It is better to use the basis expressed by the following formula:

[0086] [Chemistry 18]

[0087] (In the formula, R8 is methyl or ethyl) R5a and R5b are independently hydrogen atoms, methyl, ethyl, or cyclopropyl groups, or R5a and R5b bond together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom. m is an integer from 0 to 2, and W represents -CH2- or an oxygen atom. Or the basis represented by the following formula:

[0088] [Chemistry 19]

[0089] (In the formula, R5a and R5b are independently hydrogen atoms, methyl, ethyl or cyclopropyl, or R5a and R5b bond together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom. m is an integer from 0 to 2, and W represents -CH2- or an oxygen atom. Therefore, the basis is better represented by the following formula:

[0090] [Chemistry 20]

[0091] (In the formula, R8 is methyl or ethyl) R5a and R5b are independently hydrogen atoms or ethyl groups, respectively. Alternatively, R5a and R5b may bond together to form cyclopropane. Each of the m R6 atoms is independently a chlorine atom or a hydroxyl group. m is 0 or 1, and W represents oxygen atoms. Or the basis represented by the following formula:

[0092] [Chemistry 21]

[0093] (In the formula, R5a and R5b are independently hydrogen atoms, methyl, ethyl or cyclopropyl, or R5a and R5b bond together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom. m is an integer from 0 to 2, and W represents an oxygen atom.

[0094] As compound (1), the following compounds are suitable. [Compound (1A)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are either hydrogen atoms or methyl groups, respectively. R2 is a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from the above substituent group a; R3 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; Y is -CH-, -CR4-, or a nitrogen atom; R4 is a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group; -V- denotes the basis represented by any of the following expressions:

[0095] [Chemistry 22]

[0096] (The symbols in the formula have the same meaning as described above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group; n is an integer from 0 to 2; and Z is a basis represented by the following formulas (A1), (A2), or (A3):

[0097] [Chemistry 23]

[0098] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from the above substituent group a. R5a and R5b are each independently hydrogen atoms, and can be substituted with 1 to 3 substituents selected from the above substituent group a, either C1-6 alkyl or C3-6 cycloalkyl, or... R5a and R5b are bonded to each other and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from the above substituent group b. Each of the m R6 groups is independently a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m is an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0099] [Compound (1B)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are each independently a hydrogen atom or a C1-6 alkyl group (preferably each independently a hydrogen atom or a methyl group); R2 is a C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl; R3 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; Y is -CH-, -CR4-, or a nitrogen atom; R4 is a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group; -V- denotes the basis represented by any of the following expressions:

[0100] [Chemistry 24]

[0101] (The symbols in the formula have the same meaning as described above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group; n is an integer from 0 to 2; and Z is a basis represented by the following formulas (A1), (A2), or (A3):

[0102] [Chemistry 25]

[0103] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from the above substituent group a. R5a and R5b are hydrogen atoms, which may be substituted with C1-6 alkyl groups or C3-6 cycloalkyl groups selected from substituent group a above. Alternatively, R5a and R5b may bond together and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from the above substituent group b. Each of the m R6 groups is independently a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m is an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0104] [Compound (1C)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are each independently a hydrogen atom or a C1-6 alkyl group (preferably each independently a hydrogen atom or a methyl group); R2 is a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from the above substituent group a (preferably C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl). R3 is a halogen atom or a C1-6 alkyl group; Y is -CH-, -CR4-, or a nitrogen atom; R4 is a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group; -V- denotes the basis represented by any of the following expressions:

[0105] [Chemistry 26]

[0106] (The symbols in the formula have the same meaning as described above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group; n is an integer from 0 to 2; and Z is a basis represented by the following formulas (A1), (A2), or (A3):

[0107] [Chemistry 27]

[0108] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from the above substituent group a. R5a and R5b are hydrogen atoms, which may be substituted with 1 to 3 substituents selected from the above substituent group a, and are C1-6 alkyl or C3-6 cycloalkyl groups, or Alternatively, R5a and R5b may bond together and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from the above substituent group b. Each of the m R6 groups is independently a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m is an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0109] [Compound (1D)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are each independently a hydrogen atom or a C1-6 alkyl group (preferably each independently a hydrogen atom or a methyl group); R2 is a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from the above substituent group a (preferably C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl). R3 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group (preferably a halogen atom or a C1-6 alkyl group); Y is -CH-, -CR4-, or a nitrogen atom; R4 can be a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group; -V- denotes the basis represented by any of the following expressions:

[0110] [Chemistry 28]

[0111] (The symbols in the formula have the same meaning as described above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group; n is an integer from 0 to 2; and Z is a basis represented by the following formulas (A1), (A2), or (A3):

[0112] [Chemistry 29]

[0113] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from the above substituent group a. R5a and R5b are hydrogen atoms, which may be substituted with C1-6 alkyl groups or C3-6 cycloalkyl groups selected from substituent group a above. Alternatively, R5a and R5b may bond together and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from the above substituent group b. Each of the m R6 groups is independently a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m is an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0114] [Compound (1E)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are each independently a hydrogen atom or a C1-6 alkyl group (preferably each independently a hydrogen atom or a methyl group); R2 is a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from the above substituent group a (preferably C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl). R3 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group (preferably a halogen atom or a C1-6 alkyl group); Y is -CH-, -CR4-, or a nitrogen atom; R4 is a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group (preferably hydroxyl, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group); -V- denotes the basis represented by any of the following expressions:

[0115] [Chemistry 30]

[0116] (In the formula, * and ** represent the same meaning as above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group (preferably independently a C1-6 alkyl group). n is an integer from 0 to 2 (preferably 0 or 1); and Z is a basis represented by the following formulas (A1), (A2), or (A3):

[0117] [Chemistry 31]

[0118] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from the above substituent group a. R5a and R5b are hydrogen atoms, and can be C1-6 alkyl or C3-6 cycloalkyl atoms that can be substituted with 1 to 3 substituents selected from substituent group a above. Alternatively, R5a and R5b can be bonded to each other and together with the carbon atoms bonded to R5a and R5b can form C3-8 cycloalkanes or 3 to 8-membered saturated oxygen-containing heterocycles that can be substituted with 1 to 3 substituents selected from substituent group b above. Each of the m R6 groups is independently a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m is an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0119] [Compound (1F)] Compound (1) or its pharmaceutically permissible salt: R1a and R1b are each independently a hydrogen atom or a C1-6 alkyl group (preferably each independently a hydrogen atom or a methyl group); R2 is a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from the above substituent group a (preferably C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl). R3 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group (preferably a halogen atom or a C1-6 alkyl group); Y is -CH-, -CR4-, or a nitrogen atom; R4 is a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group (preferably hydroxyl, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group); -V- denotes the basis represented by any of the following expressions:

[0120] [Chemistry 32]

[0121] (In the formula, * and ** represent the same meaning as above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group (preferably independently a C1-6 alkyl group). n is an integer from 0 to 2 (preferably 0 or 1); and Z is the basis represented by the following formula (A1) or (A2):

[0122] [Chemistry 33]

[0123] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from the above substituent group a. R5a and R5b are hydrogen atoms, which may be substituted with C1-6 alkyl groups or C3-6 cycloalkyl groups selected from substituent group a above. Alternatively, R5a and R5b may bond together and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from the above substituent group b. Each of the m R6 groups is independently a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m is an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0124] [Compound (1G)] Compound (1) or its pharmaceutically permissible salt: R1a and R1b are each independently a hydrogen atom or a C1-6 alkyl group (preferably each independently a hydrogen atom or a methyl group); R2 is a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from the above substituent group a (preferably C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl). R3 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group (preferably a halogen atom or a C1-6 alkyl group); Y is -CH-, -CR4-, or a nitrogen atom; R4 is a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group (preferably hydroxyl, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group); -V- denotes the basis represented by any of the following expressions:

[0125] [Chemistry 34]

[0126] (In the formula, * and ** represent the same meaning as above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group (preferably independently a C1-6 alkyl group). n is an integer from 0 to 2 (preferably 0 or 1); and Z is the basis represented by the following formula (A1) or (A2):

[0127] [Chemistry 35]

[0128] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is methyl or ethyl. R5a and R5b are hydrogen atoms, which may be substituted with C1-6 alkyl groups or C3-6 cycloalkyl groups selected from substituent group a above. Alternatively, R5a and R5b may bond together and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from the above substituent group b. Each of the m R6 groups is independently a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m is an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0129] [Compound (1H)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are each independently a hydrogen atom or a C1-6 alkyl group (preferably each independently a hydrogen atom or a methyl group); R2 is a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from the above substituent group a (preferably C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl). R3 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group (preferably a halogen atom or a C1-6 alkyl group); Y is -CH-, -CR4-, or a nitrogen atom; R4 is a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group (preferably hydroxyl, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group); -V- denotes the basis represented by any of the following expressions:

[0130] [Chemistry 36]

[0131] (In the formula, * and ** represent the same meaning as above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group (preferably independently a C1-6 alkyl group). n is an integer from 0 to 2 (preferably 0 or 1); and Z is the basis represented by the following formula (A1) or (A2):

[0132] [Chemistry 37]

[0133] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is methyl or ethyl. R5a and R5b can be independently hydrogen atoms, methyl, ethyl, or cyclopropyl groups, or R5a and R5b can be bonded together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 groups is independently a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m is an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0134] [Compound(1J)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are each independently a hydrogen atom or a C1-6 alkyl group (preferably each independently a hydrogen atom or a methyl group); R2 is a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from the above substituent group a (preferably C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl). R3 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group (preferably a halogen atom or a C1-6 alkyl group); Y is -CH-, -CR4-, or a nitrogen atom; R4 is a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group (preferably hydroxyl, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group); -V- denotes the basis represented by any of the following expressions:

[0135] [Chemistry 38]

[0136] (In the formula, * and ** represent the same meaning as above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group (preferably independently a C1-6 alkyl group). n is an integer from 0 to 2 (preferably 0 or 1); and Z is the basis represented by the following formula (A1) or (A2):

[0137] [Chemistry 39]

[0138] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is methyl or ethyl. R5a and R5b can be independently hydrogen atoms, methyl, ethyl, or cyclopropyl groups, or R5a and R5b can be bonded together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom, and m is an integer from 0 to 2. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0139] [Compound (1K)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are each independently a hydrogen atom or a C1-6 alkyl group (preferably each independently a hydrogen atom or a methyl group); R2 is a C1-6 alkyl group that can be substituted with 1 to 3 substituents selected from the above substituent group a (preferably C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl). R3 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group (preferably a halogen atom or a C1-6 alkyl group); Y is -CH-, -CR4-, or a nitrogen atom; R4 is a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group (preferably hydroxyl, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group); -V- denotes the basis represented by any of the following expressions:

[0140] [Chemistry 40]

[0141] (In the formula, * and ** represent the same meaning as above); Each of the n R7 atoms is independently a halogen atom, a cyano group, a C1-6 alkyl group, or a C1-6 alkoxy group (preferably independently a C1-6 alkyl group). n is an integer from 0 to 2 (preferably 0 or 1); and Z is the basis represented by the following formula (A1) or (A2):

[0142] [Chemistry 41]

[0143] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is methyl or ethyl. R5a and R5b can be independently hydrogen atoms, methyl, ethyl, or cyclopropyl groups, or R5a and R5b can be bonded together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom, and m is an integer from 0 to 2. W represents -CH2- or an oxygen atom. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0144] [Compound (1L)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are either hydrogen atoms or methyl groups, respectively. R2 is a C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl; R3 is a halogen atom or a C1-6 alkyl group; Y is -CH-, -CR4-, or a nitrogen atom; R4 can be a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group; -V- denotes the basis represented by any of the following expressions:

[0145] [Chemistry 42]

[0146] (In the formula, * and ** represent the same meaning as above); Each of the n R7s is independently a C1-6 alkyl group; n is 0 or 1; and Z is the basis represented by the following formula (A1) or (A2):

[0147] [Chemistry 43]

[0148] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from the above substituent group a. R5a and R5b are hydrogen atoms, which may be substituted with C1-6 alkyl groups or C3-6 cycloalkyl groups selected from substituent group a above. Alternatively, R5a and R5b may bond together and together with the carbon atoms bonded to R5a and R5b, form a C3-8 cycloalkanes or 3- to 8-membered saturated oxygen-containing heterocycles that can be substituted by 1 to 3 substituents selected from the above substituent group b. Each of the m R6 groups is independently a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by one or two C1-6 alkyl groups. m is an integer from 0 to 3. W represents -CH2-, -CHR9-, or an oxygen atom. R9 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0149] [Compound (1M)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are either hydrogen atoms or methyl groups, respectively. R2 is a C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl, or 3-(methylsulfonylurea)propyl; R3 is a halogen atom or a C1-6 alkyl group; Y is -CH-, -CR4-, or a nitrogen atom; R4 can be a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group; -V- denotes the basis represented by any of the following expressions:

[0150] [Chemistry 44]

[0151] (In the formula, * and ** represent the same meaning as above); Each of the n R7s is independently a C1-6 alkyl group; n is 0 or 1; and Z is the basis represented by the following formula (A1) or (A2):

[0152] [Chemistry 45]

[0153] (in the formula, *** indicates the bonding position of the carbon atom with the Z bond. R8 is methyl or ethyl. R5a and R5b are independently hydrogen atoms, methyl, ethyl, or cyclopropyl groups, or R5a and R5b are bonded together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom, and m is an integer from 0 to 2. W represents -CH2- or an oxygen atom. X is -CH-, -CR10-, or a nitrogen atom. R10 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group. U is -CH-, -CR11-, or a nitrogen atom, and R11 is a halogen atom, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C1-6 haloalkyl group, or C1-6 haloalkoxy group.

[0154] [Compound (1N)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are either hydrogen atoms or methyl groups, respectively. R2 is a methyl group; R3 is a chlorine atom or a methyl group; Y is -CH-, -CR4-, or a nitrogen atom; R4 is a chlorine atom, methyl, cyclopropyl, difluoromethoxy, or trifluoromethoxy. -V- denotes the basis represented by any of the following expressions:

[0155] [Chemistry 46]

[0156] (In the formula, * and ** represent the same meaning as above); n is 0; and Z is the basis represented by the following formula:

[0157] [Chemistry 47]

[0158] (In the formula, *** represents the bonding position of the carbon atom bonded to the Z bond, R8 is methyl or ethyl. R5a and R5b are independently hydrogen atoms, methyl, ethyl, or cyclopropyl groups, respectively. Alternatively, R5a and R5b may bond together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom. m is an integer from 0 to 2, and W represents -CH2- or an oxygen atom. Or the basis represented by the following formula:

[0159] [Chemistry 48]

[0160] (In the formula, *** represents the bonding position of the carbon atom bonded to the Z bond, R5a and R5b are independently hydrogen atoms, methyl, ethyl, or cyclopropyl groups, respectively. Alternatively, R5a and R5b may bond together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom. m is an integer from 0 to 2, and W represents -CH2- or an oxygen atom.

[0161] [Compound (1P)] The following compounds (1) or their pharmaceutically permissible salts: R1a and R1b are either hydrogen atoms or methyl groups, respectively. R2 is a methyl group; R3 is a chlorine atom or a methyl group; Y is -CH-, -CR4-, or a nitrogen atom; R4 is a chlorine atom, methyl, cyclopropyl, difluoromethoxy, or trifluoromethoxy. -V- denotes the basis represented by any of the following expressions:

[0162] [Chemistry 49]

[0163] (In the formula, * and ** represent the same meaning as above); n is 0; and Z is the basis represented by the following formula:

[0164] [Transformation 50]

[0165] (In the formula, *** represents the bonding position of the carbon atom bonded to the Z bond, R8 is methyl or ethyl. R5a and R5b are independently hydrogen atoms or ethyl groups, respectively. Alternatively, R5a and R5b may bond together to form cyclopropane. Each of the m R6 atoms is independently a chlorine atom or a hydroxyl group. m is 0 or 1, and W represents oxygen atoms. Or the basis represented by the following formula:

[0166] [Chemistry 51]

[0167] (In the formula, *** represents the bonding position of the carbon atom bonded to the Z bond, R5a and R5b are independently hydrogen atoms, methyl, ethyl, or cyclopropyl groups, respectively. Alternatively, R5a and R5b may bond together to form cyclopropane, cyclobutane, oxacyclobutane, or tetrahydropyran. Each of the m R6 atoms is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl atom. m is an integer from 0 to 2, and W represents an oxygen atom.

[0168] Another preferred embodiment of the compound (1) of the present invention or a pharmaceutically permissible salt thereof is the compound (1) or a pharmaceutically permissible salt thereof represented by the following formula (1'):

[0169] [Chemistry 52]

[0170] [In the formula, R1a' and R1b' independently represent a hydrogen atom or a methyl group, respectively. R2' represents methyl, R3' represents a chlorine atom or a methyl group. Y' represents -CH-, -CR4'-, or a nitrogen atom. R4' represents a chlorine atom, methyl, cyclopropyl, difluoromethoxy, or trifluoromethoxy. -V'- indicates that a base is selected from any of the following:

[0171] [Chemistry 53]

[0172] (In the formula, *' and **' indicate the bonding positions with the benzene ring.) R5a' and R5b' can each independently represent a hydrogen atom or an ethyl group, or R5a' and R5b' can be bonded together to form cyclopropane. Each of the m' R6' atoms independently represents either a fluorine atom or a chlorine atom. m' represents an integer from 0 to 2, and W' represents an oxygen atom. Or the compound (1) represented by the following formula (1'') or its pharmaceutically permissible salt:

[0173] [Chemistry 54]

[0174] [In the formula, R1a'' and R1b'' independently represent a hydrogen atom or a methyl group, respectively. R2'' represents methyl, R3'' represents a chlorine atom or a methyl group. Y'' represents -CH-, -CR4''-, or a nitrogen atom. R4'' represents a chlorine atom, methyl, cyclopropyl, difluoromethoxy, or trifluoromethoxy group. -V''- denotes the basis represented by any of the following expressions:

[0175] [Chemistry 55]

[0176] (In the formula, *'' and **'' represent the bonding positions with the benzene ring.) R5a'' and R5b'' independently represent a hydrogen atom or an ethyl atom, or R5a'' and R5b'' bonds together to form cyclopropane. R8'' indicates methyl or ethyl. m'' of R6'' represents a chlorine atom or a hydroxyl group, m'' represents 0 or 1, U'' represents a nitrogen atom, and W'' represents an oxygen atom.

[0177] Specific examples of suitable compound (1) are the compounds of Examples 1 to 112 described below, or pharmaceutically permissible salts thereof, preferably... Compounds selected from any of the following groups (1) or their pharmaceutically permissible salts: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid, and (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid or Selected from any compound (1) of the following group or a pharmaceutically permissible salt thereof: (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid, (3R)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid, (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid, (3S)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3R)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, and (3S)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazop-4(5H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid.

[0178] Yu Jiawei (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, and, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid.

[0179] The compound (1) of the present invention generally forms pharmaceutically permissible acid addition salts because it contains basic groups such as nitrogen-containing heterocyclic groups within the molecule. Examples of such acid addition salts include: hydrohalates such as hydrofluoric acid salts, hydrochloride salts, hydrobromide salts, and hydroiodide salts; inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates; lower alkyl sulfonates such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; aryl sulfonates such as benzenesulfonates and p-toluenesulfonates; organic acid salts such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleic acid, mucoic acid, and adipates; and amino acid salts such as ornithine salts, glutamine salts, and aspartate salts, among which hydrohalates, aryl sulfonates, and organic acid salts are preferred.

[0180] The acid addition salt in the compound (1) of the present invention includes an acid addition salt that can be formed by combining the acid to which the compound of the present invention is added with the compound (1) of the present invention in any proportion. For example, hydrochloride salts include salts that can be formed by 1 hydrochloride, 2 hydrochloride, 3 hydrochloride, etc., fumarate salts include salts that can be formed by 1 fumarate, 1 / 2 fumarate, etc., and succinate salts include salts that can be formed by 1 succinate, 2 / 3 succinate, 1 / 3 succinate, etc.

[0181] The compound (1) of this invention generally forms pharmaceutically permissible base addition salts because it has a carboxyl group in its molecule. Examples of such base addition salts include: alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as dibenzylamine salts, α-phosphorylamine salts, alkyl phenylglycine salts, ethylenediamine salts, N-methylglucosamine salts, diethylamine salts, triethylamine salts, cyclohexylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, diethanolamine salts, N-benzyl-N-(2-phenylethoxy)amine salts, piperazine salts, tetramethylammonium salts, and tri(hydroxymethyl)aminomethane salts.

[0182] When the compound (1) of the present invention has asymmetric carbon atoms within the molecule, it may exist in the form of a plurality of stereoisomers (i.e., non-mirror image isomers, optical isomers) based on the asymmetric carbon atoms. Any one of these stereoisomers, and mixtures containing the plurality of stereoisomers in any ratio, are included in the present invention. Furthermore, although isomers based on configuration or tautomerism are sometimes generated, such isomers or mixtures thereof are also included in the compound (1) of the present invention. Furthermore, regarding the names of the compounds of this invention, when the structure of the compound contains a carbon atom that serves as an asymmetric center, its absolute configuration is represented by R and S (which simultaneously indicate position numbers). Furthermore, even when optical isomers are separated, if the stereo configuration of the carbon atom that serves as the asymmetry center in the structure of the compound is not determined, it is represented by R* or S*. Furthermore, by using R* and S* simultaneously, a relative configuration can sometimes be represented even when the absolute configuration is not determined.

[0183] The compound (1) of this invention may also be a compound labeled or substituted with isotopes (e.g., 2H, 3H, 13C, 14C, 15N, 18F, 32P, 35S, 125I, etc.). The isotopically labeled or substituted compound (1) can be used as a therapeutic or preventive agent, a research reagent (e.g., an analytical reagent), and a diagnostic agent (e.g., a live imaging diagnostic agent). All compounds of this invention containing radioactive or non-radioactive isotopes in all proportions are included within the scope of this invention.

[0184] The compound (1) of the present invention or its pharmaceutically permissible salt may be crystalline, and may be a single crystal form or a mixture of multiple crystal forms.

[0185] The compound (1) of the present invention is sometimes present in the form of a solvent-free compound or a solvent compound. As a solvent compound, there are no particular limitations as long as it is pharmaceutically permissible; specifically, hydrates, ethanol compounds, etc., are preferred.

[0186] The compound (1) of this invention can also be a prodrug.

[0187] The pre-expellant of compound (1) of the present invention refers to a compound that is converted into compound (1) in the body by reaction with enzymes or gastric acid. As a pre-expellant of compound (1), it is conceivable that it has a structure that is easily hydrolyzed or metabolized after administration to a patient.

[0188] As a precursor to compound (1), for example, when compound (1) has an amino group, examples can be given of compounds formed by acetylation, alkylation, or phosphorylation of the amino group (e.g., compounds formed by eicosylation, propylaminoation, pentylaminocarbonylation, (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation, tert-pentyloxymethylation, acetyloxymethylation, tert-butylation, etc.); when compound (1) has a hydroxyl group, examples can be given of compounds formed by acetylation, alkylation, phosphorylation, or borate formation of the hydroxyl group (e.g., compounds formed by acetylation, alkylation, phosphorylation, or borate formation of the hydroxyl group in compound (1)). Compounds formed by acetylation, palmitylation, propylation, pentacyclopentylation, succinylation, fumarylation, propylaminopyrylation, dimethylaminomethyl carbonylation, etc.; and compounds formed by esterification or amination of the carboxyl group of compound (1) (e.g., compounds formed by ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pentacyclopentyloxymethyl esterification, 1-{(ethoxycarbonyl)oxy}ethyl esterification, phthaloyl esterification, (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methyl esterification, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterification, methyl amination, etc.).

[0189] The precursor of compound (1) of the present invention can be manufactured from compound (1) by known methods. Furthermore, the precursor of compound (1) also includes the physiological condition changes described in the molecular design section of Volume 7 of "Pharmaceutical Development" published by Hirokawa Shoten in 1990, pages 163-198, which are compounds (1). Moreover, the precursor of compound (1) can be either a hydrated or a non-hydrated form.

[0190] (Method for manufacturing compound (1) of the present invention) Hereinafter, a representative method for manufacturing compound (1) of the present invention or its pharmaceutically permissible salt will be described. Since compound (1) also includes compound (1') and compound (1'') of the present invention, the following, including the manufacturing method of compound (1') and compound (1''), will be referred to as the manufacturing method of compound (1). The compound (1) of the present invention can be manufactured by various manufacturing methods. The manufacturing methods shown below, as well as the reference examples and embodiments described below, are examples, and the present invention should not be interpreted as limited to them.

[0191] Each raw material compound can also form a salt as long as it does not inhibit the reaction. Examples of such salts are those that are pharmaceutically permissible salts of the above-mentioned compound (1). When the specific preparation method is not described, the raw material compound can be readily obtained from commercial sources or manufactured according to its own well-known methods or methods thereof. Furthermore, the manufacturing intermediates generated in the following manufacturing methods can also be purified by column chromatography (including normal and reversed phase chromatography) using silicone or alumina, recrystallization, reprecipitation, distillation, etc., or can be used directly in the subsequent reactions without purification.

[0192] All patent documents, non-patent documents, or references expressly cited in this specification may be incorporated into this document as part of this specification.

[0193] Compound (1), its pharmaceutically permissible salts, and their manufacturing intermediates can be manufactured using various known manufacturing methods based on the characteristics of their basic skeletons or the types of substituents. Known methods include, for example, those described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS," 2nd edition, ACADEMIC PRESS, INC., 1989; and "Comprehensive Organic Transformations," 2nd edition, VCH Publishers Inc., 1999.

[0194] At this point, the effective manufacturing technique is to protect the functional group in advance with an appropriate protecting group at the raw material or intermediate stage, depending on the type of functional group present in the compound, or to replace it with a group that can be easily converted into the functional group.

[0195] Such functional groups include, for example, amino, hydroxyl, methyl, carbonyl, and carboxyl groups. Protecting groups for these groups include, for example, those described in PG Wuts, "Protective Groups in Organic Synthesis", 5th edition, Wiley, 2014.

[0196] Protecting groups, or groups that can be easily converted into the functional group, can be appropriately selected and used according to the respective reaction conditions of the manufacturing method used to produce the compound.

[0197] According to this method, after the above-mentioned group is introduced and reacted, the protecting group can be removed or converted into the desired group as needed, thereby obtaining the desired compound.

[0198] Furthermore, precursor compounds can be manufactured by introducing specific groups at the raw material or intermediate stage, similar to the aforementioned protecting groups, or by reacting the obtained compounds. Reactions used to manufacture precursor compounds can be carried out using commonly known methods such as esterification, amination, dehydration, and hydrogenation.

[0199] The compound (1) of the present invention can be manufactured, for example, by methods A to C described below. The manufacturing intermediates used in methods A to C can be manufactured, for example, by methods D to J described below.

[0200] In each step of the reactions described in methods A through J, the reaction temperature varies depending on the solvent, starting materials, reagents, etc., and the reaction time also varies depending on the solvent, starting materials, reagents, reaction temperature, etc. Furthermore, the amounts of solvent, starting materials, reagents, etc., used can be appropriately determined according to the progress of the reaction.

[0201] Furthermore, the functional group transformation on the heterocycle in the manufacturing intermediates used in each step of methods A through J below can be achieved by methods known in themselves (specifically, reaction conditions for converting halogen atoms into C1-6 alkyl or C3-6 cycloalkyl groups are described in, for example, Zou, G.; Reddy, YK; Falck, JR Tetrahedron Lett. 2001, 42, 7213; Molander, GA; Yun, C.-S. Tetrahedron 2002, 58, 1465; Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons, Inc.: England, 2004; Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.; Diederich, F.; Wiley-VCH: Weinheim, The method may be performed in accordance with or based on the method described in the following embodiments.

[0202] (Method A) The manufacturing method is as follows: after condensing compound (IIA) and compound (III) to obtain compound (IV), the protecting group of compound (IV) is removed, thereby manufacturing compound (1).

[0203] [Chemistry 56]

[0204] (In the formula, L1 represents the deactivating group, Pro1 represents the protecting group (suitably C1-6 alkyl such as methyl, ethyl, tributyl, or 2-(trimethylsilyl)ethyl), and other symbols have the same meaning as above).

[0205] (Step A-1) This step involves condensing compound (IIA) and compound (III) in a solvent in the presence or absence of a base, thereby producing compound (IV).

[0206] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0207] The base used is not particularly limited as long as it is used as a base in ordinary reactions. Suitable bases include: organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylphosphonoline, dimethylpyridine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; and alkali metal phosphates such as tripotassium phosphate.

[0208] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -10℃ and 150℃, and is suitable between 0℃ and 100℃.

[0209] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0210] (Step A-2) This step is the process of manufacturing compound (1) by removing the protecting group (Pro1) of compound (IV).

[0211] This procedure is performed according to the type of Pro1, for example, by appropriately selecting a known method described in PG Wuts, "Protective Groups in Organic Synthesis", 5th edition, Wiley, 2014, etc. Here, the method of converting Pro1 to hydrogen atoms using a base in a solvent (step A-2-1); the method of converting Pro1 to hydrogen atoms using an acid in a solvent (step A-2-2); or the method of converting Pro1 to hydrogen atoms using a fluoride salt in a solvent (step A-2-3) is described, but this procedure is not limited to these methods.

[0212] (Step A-2-1) As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; esters such as ethyl acetate and propyl acetate; nitrile solvents such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0213] There are no particular limitations on the base used, as long as it is used as a base in a common reaction. Examples include: organic bases such as triethylamine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; and alkali metal phosphates such as tripotassium phosphate.

[0214] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -10℃ and 150℃, with an optimal range of 10℃ to 90℃.

[0215] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 1 minute to 24 hours, and is suitable from 10 minutes to 6 hours.

[0216] (Step A-2-2) As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; esters such as ethyl acetate and propyl acetate; nitrile solvents such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0217] The acid used is not particularly limited as long as it is used as an acid in a normal reaction. Examples include inorganic acids such as hydrochloric acid and sulfuric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilane iodide; and organic acids such as trifluoroacetic acid.

[0218] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between -78℃ and 100℃.

[0219] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0220] (Steps A-2-3) As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; esters such as ethyl acetate and propyl acetate; nitrile solvents such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0221] There are no particular limitations on the fluoride salts used; examples include tetrabutylammonium fluoride and pyridine hydrogen fluoride.

[0222] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 100℃, and is suitable between -20℃ and 60℃.

[0223] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0224] (Method B) The manufacturing method is as follows: after obtaining compound (IV) by reductive amination reaction of compound (IIB) and compound (III), the protecting group of compound (IV) is removed, thereby manufacturing compound (1).

[0225] [Chemistry 57]

[0226] (In the formula, Pro1 represents a protecting group (suitably C1-6 alkyl such as methyl, ethyl, tributyl, or 2-(trimethylsilyl)ethyl), and other symbols have the same meaning as above.)

[0227] (Step B-1) This step is as follows: in a solvent, in the presence or absence of an acid and in the presence or absence of an additive, using a reducing agent, a reducing amination reaction of compound (IIB) and compound (III) is carried out, thereby producing compound (IV).

[0228] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0229] There are no particular limitations on the reducing agents used. Examples include sodium cyanoborohydride, sodium triethoxyborohydride, sodium borohydride, methylpyridineborane, and pyridineborane.

[0230] As long as an acid can be used, there are no particular limitations, such as Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilane iodide; and organic acids such as acetic acid and trifluoroacetic acid.

[0231] There are no particular limitations on the additives that can be used; for example, inorganic salts such as sodium sulfate and magnesium sulfate can be cited.

[0232] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between 0℃ and 50℃.

[0233] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 168 hours, and is suitable from 10 minutes to 120 hours.

[0234] (Step B-2) This step is the process of manufacturing compound (1) by removing the protecting group (Pro1) of compound (IV).

[0235] This step can be carried out under the same conditions as step A-2 above.

[0236] (Method C) The manufacturing method is as follows: after obtaining compound (IV) by photo-tracing reaction of compound (IIC) and compound (III), the protecting group of compound (IV) is removed, thereby manufacturing compound (1).

[0237] [Chem.58]

[0238] (In the formula, Pro1 is a protecting group (suitably C1-6 alkyl such as methyl, ethyl, tributyl, or 2-(trimethylsilyl)ethyl), and other symbols have the same meaning as above.)

[0239] (Step C-1) This step involves the production of compound (IV) by photo-extending the reaction of compound (IIC) and compound (III) in a solvent.

[0240] Examples of solvents used include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethyl ether, dimethoxyethane, and diethylene glycol dimethyl ether. Among these, halogenated hydrocarbons or ethers are suitable, with dichloromethane or tetrahydrofuran being more suitable.

[0241] The reagents used in the photoelongation reaction are not particularly limited as long as they are known reagents that can be used in the usual photoelongation reaction. Suitable examples include: dialkyl esters of azodicarboxylate such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-tert-butyl azodicarboxylate; azo compounds such as 1,1'-azobis(N,N-dimethylformamide) and 1,1'-(azodicarbonyl)dipiperidine, and triarylphosphine such as triphenylphosphine; and tri-lower alkylphosphine such as tri-n-butylphosphine. More suitable combinations are di-tert-butyl azodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine and tri-n-butylphosphine.

[0242] The reaction temperature varies depending on the raw material compound or reagent, and is usually carried out at -50℃ to 100℃, with -10℃ to 60℃ being suitable.

[0243] The reaction time varies depending on the reaction temperature, the type of raw material compound, the reaction reagent, or the type of solvent used, and is usually from 10 minutes to 48 hours, with an optimal range of 30 minutes to 24 hours.

[0244] (Step C-2) This step is the process of manufacturing compound (1) by removing the protecting group (Pro1) of compound (IV).

[0245] This step can be carried out under the same conditions as step A-2 above.

[0246] (Method D) This manufacturing method is a method for manufacturing the intermediate compounds used in methods A to C above, namely compounds (IIA-1), (IIB-1) and (IIC-1) (where R1a and R1b in formulas (IIA), (IIB) and (IIC) are compounds containing hydrogen atoms).

[0247] [Chemistry 1]

[0248] (In the formula, R12 represents a hydrogen atom, alkyl or haloalkyl, L1 represents a detached group, Pro1 represents a protecting group (suitably C1-6 alkyl such as methyl, ethyl, tributyl, or 2-(trimethylsilyl)ethyl), and other symbols have the same meaning as above.)

[0249] (Step D-1) This step involves converting compound (V) into compound (VI) in a solvent. The method of bromination is described here, but is not limited to this.

[0250] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; sulfoxides such as dimethyl sulfoxide; carboxylic acids such as acetic acid and trifluoroacetic acid; sulfonic acids such as methanesulfonic acid; mineral acids such as sulfuric acid; and mixed solvents that contain multiple of the above organic solvents in any proportion.

[0251] There are no particular limitations on the brominating agent used; examples include N-bromobutadieneimide and bromine.

[0252] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between -20℃ and 50℃.

[0253] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0254] (Step D-2) This step is as follows: after converting compound (VI) into a amide compound in a solvent (step D-2-1), a nitro group is introduced (step D-2-2) (or after introducing a nitro group, it is converted into an amide compound), thereby converting it into compound (VII).

[0255] (Step D-2-1) (Conversion steps to amide compounds) Here, the method of using formic acid (equivalent to R12 being a hydrogen atom) on compound (VI) in a solvent with or without a suitable acid anhydride (step D-2-1a); and the method of amination of compound (VI) with an alkyl carboxylic acid (equivalent to R12CO2H being alkyl or haloalkyl) by using a suitable condensing agent in or without a base (step D-2-1b) are described, but are not limited to these methods.

[0256] (Step D-2-1a) As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0257] As for the acid anhydrides that can be used, there are no particular limitations as long as they are used as acid anhydrides in ordinary reactions. Examples include carboxylic anhydrides such as acetic anhydride.

[0258] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between 0℃ and 50℃.

[0259] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0260] (Step D-2-1b) As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0261] The base used is not particularly limited as long as it is used as a base in ordinary reactions. Suitable bases include: organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylphosphonoline, dimethylpyridine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; and alkali metal phosphates such as tripotassium phosphate.

[0262] As for the condensing agent used, there are no particular limitations as long as it is a condensing agent used to form amide bonds (e.g., the methods described in Kusumoto et al., Experimental Science Lecture IV; Chemical Society of Japan; Maruzen, 1990, or Izumiya Nobuo et al., Fundamentals and Experiments of Peptide Synthesis; Maruzen, 1985, etc.). Suitable examples include: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), O-benzotriazol-N,N,N',N'-tetramethylureon hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon tetrafluoroborate (TBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiamide hydrochloride (ED). CI), 4-(2-{[(cyclohexylimino)methylene]amino}ethyl-4-methylmorpholinium p-toluenesulfonate (CMC), dicyclohexylcarbodiimide (DCC), 1,1'-carbonylbis(1H-imidazolium) (CDI), (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP), bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBrOP), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), 2-chloro-4,6-dimethoxy-1,3,5-triazine (DMT), etc. Additionally, 1-hydroxybenzotriazole (HOBT), N,N-dimethylaminopyridine, etc., may be added as additives as needed.

[0263] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -10℃ and 150℃, and is suitable between 0℃ and 100℃.

[0264] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0265] (Step D-2-2) (Nitro Introduction Step) This step involves introducing a nitro group using a nitrating agent. Here, the method of using a suitable nitrating agent on compound (VI) in a solvent, in the presence or absence of a suitable acid, is described, but is not limited to this.

[0266] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. It is preferable to use an acid that also serves as a solvent, such as mineral acids like sulfuric acid; or a mixed solvent that contains multiple solvents in any ratio.

[0267] The nitrifying agent used is not particularly limited as long as it is used as a nitrifying agent in a normal reaction, such as mineral acids such as nitric acid.

[0268] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between -20℃ and 50℃.

[0269] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0270] (Step D-3) This step involves reducing compound (VII) in a solvent using a suitable reducing agent to convert it into compound (VIII).

[0271] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any ratio.

[0272] The reducing agent used is not particularly limited as long as it is used as a reducing agent in a normal reaction. Examples include: lithium aluminum hydride, diisobutyl aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride and other metal hydrides; boron hydrides such as borane; silicon hydrides such as triethylsilane, etc.

[0273] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between 0℃ and 80℃.

[0274] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0275] (Step D-4) This step involves converting the fluorine atom of compound (IX) into an NHR2 group (step D-4-1), then introducing a bromine atom (step D-4-2) (or introducing a bromine atom and then converting the fluorine atom into an NHR2 group), thereby converting it into compound (VIII). In step D-4, steps D-4-1 and D-4-2 can be performed either first; the manufacturer can choose the appropriate order.

[0276] (Step D-4-1) This step involves reacting a primary amine (R2NH2 (where R2 represents the same meaning as above)) in a solvent, in the presence or absence of a base, thereby converting fluorine atoms into NHR2 groups.

[0277] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; alcohols such as methanol and ethanol; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0278] There are no particular limitations on the bases that can be used, as long as they are used as bases in common reactions. Suitable bases include: organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylphosphonoline, dimethylpyridine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate; and metal alkoxides such as sodium terbutoxide and potassium terbutoxide.

[0279] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -10℃ and 150℃, and is suitable between 0℃ and 100℃.

[0280] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 12 hours.

[0281] (Step D-4-2) This step involves introducing bromine atoms into the solvent. This step can be carried out under the same conditions as step D-1 described above.

[0282] (Step D-5) This step involves converting the nitro group of compound (VIII) into an amino group in a solvent to produce compound (X).

[0283] As methods for converting the nitro group of compound (VIII) into an amino group, the following methods are described: using a suitable metal and a suitable acid (step D-5-1); using hydrogen in the presence of a suitable metal catalyst (step D-5-2); and using a metal hydride (step D-5-3), but are not limited to these methods.

[0284] (Step D-5-1) This step involves using a metal in a solvent in the presence of an acid to convert the nitro group of compound (VIII) into an amino group.

[0285] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0286] The acid used is not particularly limited as long as it is used as an acid in a normal reaction. Suitable examples include: inorganic acids such as hydrochloric acid, sulfuric acid, and ammonium chloride; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilane iodide; and organic acids such as acetic acid and trifluoroacetic acid.

[0287] There are no particular restrictions on the metals used; for example, iron, zinc, and tin can be cited.

[0288] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -10℃ and 150℃, and is suitable between 0℃ and 100℃.

[0289] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0290] (Step D-5-2) This step involves using hydrogen in a solvent, in the presence of a suitable metal catalyst, to convert the nitro group of compound (VIII) into an amino group.

[0291] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0292] There are no particular limitations on the metal catalysts used; suitable examples include palladium-activated carbon, platinum-activated carbon, nickel, and osmium-activated carbon.

[0293] Examples of hydrogen sources used include hydrogen gas, ammonium formate, and hydrazine.

[0294] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -10℃ and 150℃, and is suitable between 0℃ and 100℃.

[0295] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 12 hours.

[0296] (Step D-5-3) This step involves converting the nitro group of compound (VIII) into an amino group in a solvent using a suitable metal hydride.

[0297] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethyl ether, and 1,2-dimethoxyethane; and mixed solvents that contain multiple of the above organic solvents in any proportion.

[0298] There are no particular limitations on the metal hydride used; suitable examples include lithium aluminum hydride.

[0299] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -10℃ and 150℃, and is suitable between 0℃ and 100℃.

[0300] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 12 hours.

[0301] (Step D-6) This step involves constructing a triazole ring from compound (X) to produce compound (XI). The following description describes a method using nitrites or nitrite esters in the presence of an acid in a solvent, but is not limited to this method.

[0302] That is, this step is a step of constructing a triazole ring by reacting compound (X) with nitrites or nitrite esters in the presence of acid in a solvent.

[0303] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0304] The acid used is not particularly limited as long as it is used as an acid in a normal reaction. Suitable examples include: inorganic acids such as hydrochloric acid, sulfuric acid, and tetrafluoroboric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilane iodide; and organic acids such as acetic acid and trifluoroacetic acid.

[0305] There are no particular limitations on the types of nitrites used; for example, alkali metal salts such as sodium nitrite can be cited.

[0306] There are no particular limitations on the types of nitrites used; for example, isobutyl nitrite and tributyl nitrite can be cited.

[0307] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -20℃ and 100℃, with an optimal range of -10℃ to 60℃.

[0308] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0309] (Step D-7) This step is as follows: in a solvent, in the presence or absence of a base and in the presence or absence of an additive, in the presence of a metal catalyst, the acrylate compound is reacted to convert the bromine group of compound (XI) into an acrylate group (-CH=CH-CO2Pro1), thereby producing compound (XII).

[0310] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0311] As for usable bases, there are no particular limitations as long as they are used as bases in ordinary reactions. Suitable examples include: organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylphosphonoline, dimethylpyridine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate; and metal alkoxides such as sodium terbutoxide and potassium terbutoxide.

[0312] As for additives that can be used, there are no particular limitations as long as they are used in known methods. Suitable examples include: metal oxides such as silver oxide and aluminum oxide; phosphines such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, diphenylphosphine ferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), and 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP); phosphine oxides such as triphenylphosphine oxide; metal salts such as lithium chloride, potassium fluoride, and cesium fluoride; and ammonium salts such as tetrabutylammonium bromide. These can also be used in any combination in any ratio.

[0313] The metal catalyst used is not particularly limited as long as it is used in a known method. Suitable examples include: tetra(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, palladium dichloride-diphenylphosphine-ferrocene complex, palladium dichloride-benzonitrile complex, palladium dichloride-acetonitrile complex, bis(dibenzylideneacetone)palladium, tri(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphine)ethane]palladium, 3-chloropyridine[1,3-bis(2,6-diisopropylphenyl)imidazo-2-ylidene]palladium, palladium-activated carbon, and other palladium catalysts.

[0314] There are no particular limitations on the acrylate compounds used; for example, methyl acrylate, ethyl acrylate, and tributyl acrylate can be cited.

[0315] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between 0℃ and 150℃, with an optimal range of 20℃ to 120℃.

[0316] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 12 hours.

[0317] (Step D-8) This step is as follows: in a solvent, in the presence or absence of a base and in the presence or absence of an additive, using a metal catalyst, compound (XII) reacts with compound (XIII) obtained by method E described later, thereby producing compound (IIC-1).

[0318] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0319] As for usable bases, there are no particular limitations as long as they are used as bases in ordinary reactions. Suitable examples include: organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylphosphonoline, dimethylpyridine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate; and metal alkoxides such as sodium terbutoxide and potassium terbutoxide.

[0320] As for additives that can be used, there are no particular limitations as long as they are used in a known manner. Suitable examples include phosphines such as 2,3-bis(diphenylphosphine)butane, and different types of phosphines can be combined in any ratio.

[0321] As for the metal catalyst used, there are no particular limitations as long as it is used in a known method. Suitable examples include rhodium catalysts such as bis(nordediene) rhodium tetrafluoroborate (I) and (1,5-cyclooctadiene) rhodium chloride (I) dimer.

[0322] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between 0℃ and 150℃, with an optimal range of 20℃ to 100℃.

[0323] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 12 hours.

[0324] (Step D-9) This step is as follows: by reacting a acetic acid chloride or anhydride in a solvent, in the presence or absence of a base, the hydroxyl group of compound (IIC-1) is converted into a detached group (L1), thereby producing compound (IIA-1).

[0325] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0326] There are no particular limitations on the acetyl chlorides or anhydrides used, but suitable examples include: acetyl chlorides of sulfurous acids such as thionyl chloride; substituted or unsubstituted alkyl sulfonic anhydrides or aryl sulfonic anhydrides such as trifluoromethanesulfonic anhydride; substituted or unsubstituted alkyl sulfonic chlorides or aryl sulfonic chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride; and substituted or unsubstituted alkylphosphochlorides or arylphosphochlorides.

[0327] As for usable bases, there are no particular limitations as long as they are used as bases in ordinary reactions. Suitable examples include: organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylphosphonoline, dimethylpyridine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; and alkali metal phosphates such as tripotassium phosphate.

[0328] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between -80℃ and 40℃.

[0329] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0330] (Step D-10) This step involves using a suitable oxidizing agent in a solvent to convert the hydroxyl group of compound (IIC-1) into a formaldehyde group, thereby producing compound (IIB-1).

[0331] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0332] There are no particular limitations on the oxidizing agent used. For example, one can appropriately choose a well-known method as described in the fourth edition of the Lectures on Experimental Chemistry (21. Organic Synthesis III: Aldehydes, Ketones, and Quinones), the methods described by Kazuhiro Maruyama et al., the Chemical Society of Japan, Maruzen Co., Ltd., etc., and this step can be performed accordingly. Representative examples of oxidation reactions include: oxidation reactions using chromic anhydride, chromium(VI) oxide-pyridine complex (Collins' reagent), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), etc.; oxidation reactions using activated manganese dioxide; oxidation reactions using dicyclohexylcarbodiimide (DCC), acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, or a combination of oxalic acid chloride and dimethyl sulfoxide (DMSO); and oxidation reactions using superatomic iodine compounds (Dess-Martin's reagent), etc.

[0333] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between 0℃ and 50℃.

[0334] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0335] (E method) This manufacturing method is a method for manufacturing the intermediate compounds used in methods A to C above, namely compounds (IIA-2), (IIB-2) and (IIC-2) (where R1a and R1b in formulas (IIA), (IIB) and (IIC) are each independently C1-6 alkyl compounds).

[0336] [Chemistry 2]

[0337] (In the formula, Pro1 represents a protecting group (suitably C1-6 alkyl such as methyl or ethyl, or 2-(trimethylsilyl)ethyl), Pro2 represents a protecting group (suitably p-methoxybenzyl), and other symbols have the same meaning as above).

[0338] (Step E-1) This step involves protecting the hydroxyl group of compound (IIC-1) with a protecting group (Pro2). Here, a method using a p-methoxybenzyl protecting group and a suitable protecting agent in the presence of an acid is described, but it is not limited to this method.

[0339] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0340] The acid used is not particularly limited as long as it is used as an acid in a normal reaction. Examples include: inorganic acids such as hydrochloric acid, sulfuric acid, and tetrafluoroboric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilane iodide; organic acids such as acetic acid and trifluoroacetic acid; and sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, and (S)-(+)-camphor-10-sulfonic acid.

[0341] Examples of protective agents used include 4-methoxybenzyl-2,2,2-trichloroethyleneimine ester and 2,4,6-tris(p-methoxybenzyloxy)-1,3,5-triazine.

[0342] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -50℃ and 150℃, and is suitable between -20℃ and 100℃.

[0343] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0344] (Step E-2) This step is as follows: by using a suitable base and a C1-6 alkyl halide or a C1-6 alkyl pseudohalide in a solvent or without a solvent, C1-6 alkyl R1a and R1b are sequentially introduced into the α-position of the ester group of compound (XIV) to produce compound (XV).

[0345] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide; amides such as dimethyl sulfoxide; and mixed solvents that contain multiple of the above organic solvents in any proportion.

[0346] There are no particular limitations on the bases used, but suitable examples include: organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; metal alkoxides such as sodium terbutoxide and potassium terbutoxide; metal amides such as lithium diisopropylamide and sodium bis(trimethylsilane)amino; organometallic compounds such as lithium terbutyrate; and hydrides such as potassium hydride and sodium hydride.

[0347] A pseudohalide is a substituent known to undergo a substitution reaction in alkylation, similar to that of a halide. There are no particular limitations on the substituent that is known to undergo this substitution reaction; examples include sulfonyl groups such as trifluoromethanesulfonyloxy, methanesulfonyloxy, and p-toluenesulfonyloxy; and acetoxy groups such as acetoxy. There are no particular restrictions on the alkyl halide or alkyl pseudohalide used, as long as it is a known compound or synthesized by a known method.

[0348] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -80℃ and 150℃, with an optimal range of -20℃ to 60℃.

[0349] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0350] (Step E-3) This step is for removing the protecting group (Pro2). Here, the method of removing Pro2 in a solvent using a suitable oxidizing agent (step E-3a) when Pro2 is p-methoxybenzyl, and the method of removing it in the presence or absence of anisole using a suitable acid (step E-3b) will be described, but are not limited to these methods.

[0351] (Step E-3a) (Deprotection step using an oxidant) As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0352] Examples of oxidizing agents used include 2,3-dichloro-5,6-dicyano-p-benzoquinone.

[0353] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -20℃ and 150℃, and is suitable between 0℃ and 100℃.

[0354] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 12 hours.

[0355] (Step E-3b) (Using acid to remove protection) As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0356] The acid used is not particularly limited as long as it is used as an acid in a normal reaction. Examples include inorganic acids such as hydrochloric acid and sulfuric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilane iodide; and organic acids such as trifluoroacetic acid.

[0357] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between -78℃ and 100℃.

[0358] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0359] (Step E-4) This step is to convert compound (IIC-2) into compound (IIA-2), and can be performed according to step D-9 above.

[0360] (Step E-5) This step is to convert compound (IIC-2) into compound (IIB-2), and can be performed according to step D-10 above.

[0361] (F method) This manufacturing method is a method for producing the intermediate compound (XIII) used in the above-mentioned method D from compound (XVI).

[0362] [Chemistry 61]

[0363] (In the formula, L2 represents the releasing group, Pro3 represents the protecting group (preferably acetylated), and other symbols have the same meaning as above.)

[0364] (Step F-1) This step describes the process of producing compound (XVII) by introducing a bromine group into compound (XVI). Here, the method of using a brominating agent in a solvent in the presence of a suitable catalyst is described, but it is not limited to this.

[0365] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0366] Examples of catalysts used include free radical initiators such as azobisisobutyronitrile (AIBN) and benzoyl peroxide.

[0367] Examples of brominating agents used include N-bromobutadieneimide and N-bromoacetamide.

[0368] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between 0℃ and 200℃, with an optimal range of 20℃ to 150℃.

[0369] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 12 hours.

[0370] (Step F-2) This step involves converting the bromine group of compound (XVII) into a hydroxyl group protected by a protecting group (Pro3) to produce compound (XVIII). Here, the method of using a metal salt of carboxylic acid in a solvent is described, but it is not a limitation.

[0371] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0372] Examples of carboxylic acid metal salts used include potassium acetate, sodium acetate, potassium benzoate, and sodium benzoate.

[0373] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between 0℃ and 150℃, with an optimal range of 20℃ to 100℃.

[0374] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0375] (Step F-3) This step is the process of manufacturing compound (XIX) by removing the protecting group (Pro3) of compound (XVIII), and can be carried out according to step A-2-1 above.

[0376] (Step F-4) This step is as follows: under an inert gas (nitrogen or argon) atmosphere, in a solvent, in the presence or absence of a base and in the presence or absence of an additive, using a suitable metal catalyst and a boron compound, the decomposition group (L2) of compound (XIX) is converted into a boron ester, thereby producing compound (XIII).

[0377] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0378] There are no particular limitations on the boron compound used, as long as it is commonly used in the synthesis of boron esters. Suitable examples include bis(pinacol)diboron and pinacolborane.

[0379] As for usable bases, there are no particular limitations as long as they are used as bases in ordinary reactions. Suitable examples include: organic bases such as triethylamine and N,N-diisopropylethylamine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as sodium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide and cesium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal acetates such as sodium acetate and potassium acetate; alkali metal phosphates such as tripotassium phosphate; and metal alkoxides such as sodium terbutoxide and potassium terbutoxide.

[0380] As for additives that can be used, there are no particular limitations as long as they are used in known methods. Suitable examples include: metal oxides such as silver oxide and aluminum oxide; phosphines such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, diphenylphosphine ferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), and 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP); phosphine oxides such as triphenylphosphine oxide; metal salts such as lithium chloride, potassium fluoride, and cesium fluoride; and ammonium salts such as tetrabutylammonium bromide. These can also be used in any combination in any proportion.

[0381] The metal catalyst used is not particularly limited as long as it is used in a known method. Suitable examples include: tetra(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, palladium dichloride-diphenylphosphine-ferrocene complex, palladium dichloride-benzonitrile complex, palladium dichloride-acetonitrile complex, bis(dibenzylideneacetone)palladium, tri(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphine)ethane]palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane adduct, 3-chloropyridine[1,3-bis(2,6-diisopropylphenyl)imidazo-2-yl]palladium, palladium-activated carbon, and other palladium catalysts.

[0382] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -10℃ and 200℃, and is suitable between 0℃ and 150℃.

[0383] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 12 hours.

[0384] (G method) This manufacturing method is a method for producing the intermediate compound (XIII) used in the above-mentioned method D from compound (XX).

[0385] [Chemistry 62]

[0386] (In the formula, L3 represents the release group, Pro4 represents the protecting group (suitably C1-6 alkyl such as methyl or ethyl), and other symbols have the same meaning as above.)

[0387] (Step G-1) This step involves the following steps: in a solvent, in the presence or absence of a base and in the presence or absence of an additive, in the presence of an alcohol, using a metal catalyst, carbon monoxide is introduced, thereby converting compound (XX) into compound (XXI).

[0388] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0389] As for usable bases, there are no particular limitations as long as they are used as bases in ordinary reactions. Suitable examples include: organic bases such as triethylamine and N,N-diisopropylethylamine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate; and metal alkoxides such as sodium terbutoxide and potassium terbutoxide.

[0390] There are no particular limitations on the additives that can be used, as long as they are used in known methods. Suitable additives include, for example, metal oxides such as silver oxide and aluminum oxide; triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tris(o-tolyl)phosphine, diphenylphosphine ferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), and 4,5-bis(diphenylphosphine)-9,9-dimethylphosphine. Phosphine derivatives such as Xantphos; phosphine oxides such as triphenylphosphine oxide; metal salts such as lithium chloride, potassium fluoride, and cesium fluoride; ammonium salts such as tetrabutylammonium bromide; acid anhydrides such as acetic anhydride, etc., which can also be used in any combination in any proportion.

[0391] The metal catalyst used is not particularly limited as long as it is used in a known method. Suitable examples include: tetra(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, palladium dichloride-diphenylphosphine-ferrocene complex, palladium dichloride-benzonitrile complex, palladium dichloride-acetonitrile complex, bis(dibenzylideneacetone)palladium, tri(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphine)ethane]palladium, 3-chloropyridine[1,3-bis(2,6-diisopropylphenyl)imidazo-2-ylidene]palladium, palladium-activated carbon, and other palladium catalysts.

[0392] There are no particular limitations on the alcohol (Pro4OH) used; for example, methanol and ethanol can be cited.

[0393] There are no particular limitations on the carbon monoxide source used; examples include carbon monoxide gas, lithium formate, and 2,4,6-trichlorophenyl formate.

[0394] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between 0℃ and 150℃, with an optimal range of 20℃ to 120℃.

[0395] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 12 hours.

[0396] (Step G-2) This step is a process of producing compound (XXII) by introducing a detached group L2 (suitably a halogen atom or pseudohalogen group) into compound (XXI). For example, when L2 is a bromine group, it can be carried out according to step D-1 above, but it is not limited to this.

[0397] (Step G-3) This step involves reducing compound (XXII) in a solvent to produce compound (XIX).

[0398] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide; amides such as dimethyl sulfoxide; and mixed solvents that contain multiple of the above organic solvents in any proportion.

[0399] The reducing agent used is not particularly limited as long as it is used as a reducing agent in a normal reaction. Examples include lithium aluminum hydride, diisobutyl aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and lithium boron hydride.

[0400] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between -78℃ and 80℃.

[0401] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0402] (Step G-4) This step involves converting the carboxyl group of compound (XXIII) into a C1-6 alkyl ester group in a solvent to produce compound (XXI). Here, the method of condensation with the corresponding alcohol in the presence of an acid is described, but it is not limited to this.

[0403] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents and reactants include alcohols such as methanol, ethanol, and n-butanol, or mixed solvents containing such alcohols and organic solvents in any ratio.

[0404] There are no particular limitations on the acids used; for example, inorganic acids such as sulfuric acid, hydrochloric acid, and nitric acid, and organic acids such as p-toluenesulfonic acid can be included.

[0405] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between 0℃ and 200℃, with an optimal range of 20℃ to 130℃.

[0406] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0407] (Step G-5) This step involves introducing a detached radical L2 (suitably a halogen atom or pseudohalogen group) into compound (XXIII) in a solvent to produce compound (XXIV). For example, if L2 is a bromine group, it can be carried out according to step D-1 above, but it is not limited to this step.

[0408] (Step G-6) This step involves reducing compound (XXIV) in a solvent using a suitable reducing agent to produce compound (XIX).

[0409] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include ethers such as diethyl ether and tetrahydrofuran.

[0410] The reducing agent used is not particularly limited as long as it is used as a reducing agent in a normal reaction. Examples include lithium aluminum hydride and borane-tetrahydrofuran complex.

[0411] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 100℃, and is suitable between -78℃ and 50℃.

[0412] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0413] (Step G-7) This step is the process of producing compound (XIII) by converting the detached group (L2) of compound (XIX) into a borate ester, and can be carried out according to step F-4 above.

[0414] (H method) This manufacturing method is a method for manufacturing the intermediate compound used in methods A and B above, namely compound (III) whose Z is the base represented by formula A1 above. Hereinafter, the method for manufacturing compound (IIIA1-1) whose base W in formula A1 above is an oxygen atom will be described, but it is not limited thereto.

[0415] [Chemistry 63]

[0416] (In the formula, L4 represents the dissociation group (preferably a halogen atom or pseudohalogen group), Pro5 represents the protecting group (preferably p-methoxybenzyl, allyl, or benzyl), and other symbols have the same meaning as above.)

[0417] (Step H-1) This step involves the following steps: In a solvent, a suitable organometallic compound is used to perform a nucleophilic addition reaction on the methyl group of compound (XXV), thereby introducing the substituent R8 to produce compound (XXVI).

[0418] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents that contain multiple of the above organic solvents in any proportion.

[0419] Examples of organometallic reagents used include: organolithium compounds such as methyllithium and n-butyllithium; Grignard reagents such as methylmagnesium bromide and ethylmagnesium bromide; and organozinc compounds such as diethylzinc.

[0420] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 100℃, and is suitable between -80℃ and 50℃.

[0421] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 12 hours, and is suitable from 10 minutes to 6 hours.

[0422] (Step H-2) This step involves oxidizing the hydroxyl group of compound (XXVI) to a carbonyl group, and can be performed according to step D-10 above.

[0423] (Step H-3) This step is the process of preparing compound (XXX) from compound (XXVI) and compound (XXVIII). The following describes the method of converting the hydroxyl group of compound (XXVI) into a release group (step H-3-1) and then condensing it with compound (XXVIII) (step H-3-2), but it is not limited to this method.

[0424] (Step H-3-1) This step can be performed according to step D-9 above.

[0425] (Step H-3-2) This step can be performed based on step A-1 above.

[0426] (Step H-4) This step is the process of producing compound (XXX) by a reducing amination reaction of compound (XXVII) and compound (XXVIII). The following describes the method using a hydrogenation reducing agent in a solvent (step H-4a) and the method using formic acid in the presence of an iridium catalyst (step H-4b), but is not limited to these methods.

[0427] (Step H-4a) This step is performed in accordance with step B-1 above.

[0428] (Step H-4b) This step can be performed using formic acid in the presence of an iridium catalyst in a solvent.

[0429] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0430] As for the iridium catalyst used, there are no particular limitations as long as it is used by a known method. Suitable examples include: chloro(pentamethylcyclopentadienyl)(8-hydroxyquinoline)iridium(III) and chloro(pentamethylcyclopentadienyl)(4-dimethylamino-8-hydroxyquinoline)iridium(III).

[0431] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -20℃ and 150℃, and is suitable between 0℃ and 100℃.

[0432] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0433] (Step H-5) This step is the process of producing compound (XXXI) from compound (XXVI) and compound (XXIX), and can be carried out according to step H-3 above.

[0434] (Step H-6) This step is the process of producing compound (XXXI) by reductive amination of compounds (XXVII) and (XXIX), and is carried out according to step H-4 above.

[0435] (Step H-7) This step involves preparing compound (IIIA1-1) from compound (XXX) by using a suitable base in a solvent.

[0436] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0437] The base used is not particularly limited as long as it is used as a base in a normal reaction. Examples include: organic bases such as triethylamine; alkali metal alkoxides such as potassium terbutoxide and sodium terbutoxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; and alkali metal phosphates such as tripotassium phosphate.

[0438] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 150℃, and is suitable between 0℃ and 80℃.

[0439] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0440] (Step H-8) This step involves protecting the secondary amino group of compound (XXX) with a protecting group (Pro5) to produce compound (XXXI). Depending on the type of Pro5, a known method, such as that described in PG Wuts, "Protective Groups in Organic Synthesis," 5th edition, Wiley, 2014, is appropriately selected and performed accordingly. The following descriptions will cover the case where Pro5 is p-methoxybenzyl, using a reductive amination method (step H-8a) and a method using p-methoxybenzyl halides (step H-8b), but are not limited to these methods.

[0441] (Step H-8a) This step involves the reductive amination of compound (XXX) and p-methoxybenzaldehyde, and can be performed according to step B-1 above.

[0442] (Step H-8b) This step involves protecting the secondary amine group of compound (XXX) in a solvent by using p-methoxybenzyl chloride or p-methoxybenzyl bromide in the presence of a suitable base.

[0443] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; and mixed solvents containing multiple of the above organic solvents in any proportion.

[0444] The base used is not particularly limited as long as it is used as a base in a normal reaction, including organic bases such as triethylamine; alkali metal alkoxides such as potassium terbutoxide and sodium terbutoxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; metal hydrides such as sodium hydride; and alkali metal phosphates such as tripotassium phosphate.

[0445] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -100℃ and 200℃, and is suitable between 0℃ and 150℃.

[0446] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 48 hours, and is suitable from 10 minutes to 24 hours.

[0447] (Step H-9) This step is the process of converting compound (XXXI) into compound (IIIA1-1) by using a suitable base in a solvent to form a 7-membered ring from compound (XXXI) (step H-9-1), and then removing the protecting group (Pro5) (step H-9-2), thereby converting it into compound (IIIA1-1).

[0448] (Step H-9-1) This step can be performed according to step H-7 above.

[0449] (Step H-9-2) This step is to remove the protective base (Pro5), and can be performed according to step E-3.

[0450] (I method) This manufacturing method is a method for manufacturing the intermediate compound used in methods A and C above, namely compound (III) whose Z is the base represented by formula A2 above. Hereinafter, the method for manufacturing compound (IIIA2-1) whose base W in formula A2 above is an oxygen atom will be described, but it is not limited thereto.

[0451] [Chemistry 64]

[0452] (In the formula, L5 and L6 are independent detachment groups (preferably halogen atoms or pseudohalogen groups), and other symbols have the same meaning as above.)

[0453] (Step I-1) This step involves the condensation of compound (XXXII) and compound (XXVIII) in a solvent, in the presence or absence of a base, to produce compound (XXXIII).

[0454] As for the solvent used, there are no particular limitations as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable solvents include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dimethylethane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as methylamine and N,N-dimethylmethylamine; amides such as dimethyl sulfoxide; mixed solvents containing multiple of the above organic solvents in any proportion; and mixed solvents containing the above organic solvents and water in any proportion.

[0455] The base used is not particularly limited as long as it is used as a base in a normal reaction. Suitable bases include: organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylphosphonoline, dimethylpyridine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; and alkali metal phosphates such as tripotassium phosphate.

[0456] The reaction temperature varies depending on the raw material compounds, reagents, etc., but it is usually between -80℃ and 100℃, and is suitable between -20℃ and 50℃.

[0457] The reaction time varies depending on the raw material compounds, reagents, etc., but it is usually from 5 minutes to 24 hours, and is suitable from 10 minutes to 6 hours.

[0458] (Step I-2) This step is the process of producing compound (IIIA2-1) from compound (XXXIII), and can be carried out according to step H-7 above.

[0459] (J method) This manufacturing method is a method for manufacturing the intermediate compound used in methods A and C above, namely compound (III) whose Z is the base represented by formula A3 above. Hereinafter, the method for manufacturing compound (IIIA3-1) whose base W in formula A3 above is an oxygen atom will be described, but it is not limited thereto.

[0460] [Chemistry 65]

[0461] (In the formula, L7 and L8 are independent detachment groups (suitably halogen atoms or pseudohalogen groups), and other symbols have the same meaning as above.)

[0462] (Step J-1) This step involves condensing compound (XXXIV) with compound (XXVIII) to produce compound (XXXV), and can be performed according to step I-1 above.

[0463] (Step J-2) This step is the process of producing compound (IIIA3-1) from compound (XXXV), and can be carried out according to step H-7 above.

[0464] The compound (1) obtained by the manufacturing method described above, or its pharmaceutically permissible salt, can be isolated and purified by conventional separation methods such as recrystallization, distillation, and chromatography.

[0465] When the compound (1) of the present invention or its pharmaceutically permissible salt exists as an optical isomer based on asymmetric carbon, it can be separated into individual optical isomers by conventional optical resolution methods (e.g., fractional crystallization, resolution using chiral columns). Alternatively, optical isomers can be synthesized using optically pure starting materials. Furthermore, optical isomers can be synthesized by stereoselectively carrying out each reaction using asymmetric auxiliary groups or asymmetric catalysts.

[0466] (The pharmaceutical (or pharmaceutical composition) of this invention) The medicine of the present invention contains a compound (1) or a pharmaceutically permissible salt thereof as an active ingredient and is used to prevent and / or treat oxidative stress-related diseases.

[0467] The medicine of the present invention may be a medicine containing only compound (1) or a pharmaceutically permissible salt thereof, or a pharmaceutical composition containing either compound (1) or a pharmaceutically permissible salt thereof and a pharmaceutically permissible carrier. The medicine of the present invention may be administered in a pharmaceutically effective amount to a subject (e.g., a human, mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, monkey, or other mammal).

[0468] Examples of pharmaceutically permissible carriers include: excipients (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethyl cellulose, talc, etc.), and solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohols, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.). ), excipients (e.g., polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.), suspending agents (e.g., stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzyl ammonium chloride, benzyl chloride, glyceryl monostearate, etc. surfactants; polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyl... Hydrophilic polymers such as ethyl cellulose and hydroxypropyl cellulose; polysorbates, polyoxyethylene hydrogenated castor oil, etc.; isotensin agents (e.g., sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose, etc.); buffers (e.g., phosphate, acetate, carbonate, citrate, etc.); analgesics (e.g., benzyl alcohol, etc.); preservatives (e.g., parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.); antioxidants (e.g., sulfites, anti-oxidants, etc.). Ascorbic acid salts, etc.), colorants (e.g., water-soluble edible tar pigments (e.g., edible red No. 2 and No. 3, edible yellow No. 4 and No. 5, edible blue No. 1 and No. 2, etc.), water-insoluble lake pigments (e.g., the above-mentioned water-soluble edible tar pigments aluminum salts), natural pigments (e.g., β-carotene, chlorophyll, iron oxide, etc.), sweeteners (e.g., sodium saccharin, dipotassium glycyrrhizate, stevia, etc.), flavoring agents (e.g., anise oil, cinnamon oil, ethoxylan, orange oil, etc.), flavoring agents, etc.

[0469] Regarding the pharmaceutical (pharmaceutical composition) of the present invention, after mixing the various components described above, the mixture can be formulated into oral preparations such as tablets, pills, granules, pellets, capsules, dry syrups, and elixirs, according to methods known herein; or non-oral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drops), topical preparations (e.g., transdermal absorption preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, inhaled preparations, eye drops, implants, microcapsules, and liposome preparations. Tablets or pills may also be coated with sugar coating or gastric-soluble or enteric coating agents as needed. Non-oral preparations may be sterilized, for example, by filtering using a bacterial retention filter, preparing bactericides, or irradiating with radiation. Alternatively, a composition obtained by dissolving or suspending a sterile solid composition in sterile water or an injectable solvent before use may be used as a non-oral formulation.

[0470] The content of the compound (1) of the present invention or its pharmaceutically permissible salt in the pharmaceutical (pharmaceutical composition) of the present invention varies depending on the form of the preparation, and is generally in the range of about 0.001 to 100% by weight relative to the whole preparation, preferably in the range of about 0.01 to 50% by weight, and even more preferably in the range of about 0.01 to 20% by weight.

[0471] The dosage and frequency of administration of the compound (1) of the present invention or its pharmaceutically permissible salt are determined appropriately according to various circumstances, taking into account symptoms, the age or sex of the recipient, etc. Regarding the dosage, in the case of oral administration, the usual adult dose is 0.001 mg / kg to 100 mg / kg per dose, and in the case of intravenous administration, the usual adult dose is 0.0001 mg / kg to 10 mg / kg per dose. Regarding the frequency of administration, it is usually from once a day to 6 times or once a day to once every 7 days.

[0472] The compound (1) of the present invention, or its pharmaceutically permissible salt, is effective for the prevention and / or treatment of oxidative stress-related diseases, specifically, for the prevention and / or treatment of diseases selected from, for example, a group consisting of chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; and for diseases selected from alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis, and cirrhosis. The following are selected categories of diseases: liver diseases (including bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia, and asthma); respiratory diseases (including ultraviolet and radiation-induced skin damage, radiation-induced mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis, and scleroderma); cardiovascular diseases (including heart failure, myocardial infarction, arteriosclerosis, and pulmonary hypertension); and Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and cerebral infarction. Central nervous system diseases in the group consisting of glutamine disorders and autism; mitochondrial diseases in the group consisting of Friedreich recessive motor disorders and mitochondrial myopathy; autoimmune diseases in the group consisting of multiple sclerosis, chronic rheumatoid arthritis, systemic lupus erythematosus, Shoegrange syndrome, type 1 diabetes, ulcerative colitis, and Crohn's disease; and allergic conjunctivitis, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal disorders, uveitis, Bessie's disease, diabetic retinopathy, retinal detachment, and retinal detachment. It is particularly effective for the prevention and / or treatment of oxidative stress-related diseases in the group consisting of arterial occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma, and cataracts.

[0473] The compound (1) of the present invention or its pharmaceutically permissible salt may be used in combination with other pharmaceutical agents (concomitant drugs) as long as it does not impair its efficacy. There are no particular limitations on the concomitant drugs, for example, one or more known pharmaceutical agents previously used in the treatment of oxidative stress-related diseases selected from the above-described group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma may be used.

[0474] Other pharmaceutical agents (combined drugs) suitable for use with the compound (1) of the present invention or its pharmaceutically permissible salts are not limited to these, but include, for example: ACE inhibitors (e.g., enalapril, etc.), angiotensin II receptor antagonists (e.g., olmesartan, etc.), β-blockers (e.g., carvedilol, etc.), aldosterone antagonists (e.g., spironolactone, etc.), bronchodilators (e.g., anticholinergics, theophylline, etc.), steroids (e.g., prednisolone, etc.), prostacyclin preparations (e.g., (e.g., belasacilin, etc.), endothelin receptor antagonists (e.g., bosentan, etc.), phosphodiesterase-5 inhibitors (e.g., sildenafil, etc.), soluble guanine nucleotide cyclase (sGC) stimulants (e.g., velicipiparine, etc.), L-DOPA and dopamine agonists (e.g., pramipexole, etc.), catechol-O-methyltransferase (COMT) inhibitors (e.g., entacapone, etc.), monoamine oxidase B (MAO-B) inhibitors (e.g., citrinin, etc.), interferon β, clopasone, etc.

[0475] When using concurrent medications, there is no limitation on the timing of administration; they can be administered simultaneously to the target or administered with a time interval. Administration with a time interval may involve administering the medicine of this invention first, followed by the concurrent medication, or vice versa. The administration methods can be the same or different. Furthermore, a single formulation (preparation agent) containing the compound (1) of this invention or its pharmaceutically permissible salt in combination with the concurrent medication can also be administered. Examples of pharmaceutically permissible carriers that can be used to manufacture this preparation agent include carriers used in the pharmaceutical compositions of this invention described above.

[0476] Furthermore, the dosage of the concurrent medication can be appropriately selected based on clinically commonly used dosages. Also, the mixing ratio of the compound of the present invention or its pharmaceutically permissible salts with the concurrent medication can be appropriately selected according to the recipient (age, weight, general health status, gender, severity of illness, etc.), route of administration, type of disease, and type of concurrent medication.

[0477] There is no particular limitation on the mass ratio of compound (1) or its pharmaceutically permissible salt to the adjuvant drug.

[0478] Furthermore, adjunctive medications that supplement and / or enhance the therapeutic effects of compound (1) or its pharmaceutically permissible salts also include those based on the mechanisms described above (i.e., the mechanism of activating Nrf2 by inhibiting the protein-protein interaction between Keap1 and Nrf2) that will be discovered in the future but have not yet been discovered.

[0479] The pharmaceutical or pharmaceutical composition of the present invention may also be provided in kit form along with instructions for administration methods, etc. The agent contained in the kit effectively maintains the activity of the constituent components of the pharmaceutical or pharmaceutical composition for a long period of time, and does not adhere to the inside of the container. Furthermore, it is supplied using a container made of a material that will not degrade the constituent components. For example, a sealed glass ampoule may also contain a buffer solution sealed in the presence of a neutral and non-reactive gas such as nitrogen. Furthermore, an instruction manual may also be included with the set. The instruction manual for this set may be printed on paper or stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM for user use.

[0480] Experimental Example 1: FP Analysis (In Vitro) The inhibitory activity of the test compounds on the binding between Nrf2 and Keap1 was determined using polarized fluorescence spectrometry. A buffer solution containing 50 mM tris(hydroxymethyl)aminomethane hydrochloride pH 8.0 (NACALAI, REF: 06938-15) and 5 mM DTT (SIGMA-ALDRICH, REF: 646563-10X.5 mL) was used. 8 µL of buffer containing 40 nM GST fused to human Keap1 (amino acid residues: 325-642) protein (Protein Tech, REF: Ag0779) was added to black 384-well plates (final concentration 20 nM), and 4 µL of the test compound solution prepared using the buffer was added. Wells containing a portion of buffer without Keap1 served as negative controls. Wells without added compounds served as positive controls. Here, 40 nM of FITC-labeled Nrf2 peptide (FITC-X-LQLDEETGEFLPIQ (X=ε-Acp), Peptide Research Institute Co., Ltd.) was added (final concentration 10 nM). The mixture was incubated at room temperature for 2 hours, and fluorescence polarization at an excitation wavelength of 485 nm and a fluorescence wavelength of 535 nm was measured using a SPECTRAMAX Paradigm (Molecular devices). The fluorescence polarization of the negative control was taken as 100% inhibition, and the fluorescence polarization of the positive control was taken as 0% inhibition. The inhibition rate upon addition of the test compound was calculated using the following formula.

[0481] [Number 1] Inhibition rate (%) = ((fluorescence polarization of negative control - fluorescence polarization with test compound added) / (fluorescence polarization of positive control - fluorescence polarization of negative control)) × 100

[0482] The results for each compound tested in this experiment are shown in Table 1 below within the range of two concentrations (μM) with an inhibition rate of 50% (A: 50% inhibition rate concentration (IC50) ≦ 0.01, B: 0.01 < 50% inhibition rate concentration (IC50) ≦ 0.03, C: 0.03 < 50% inhibition rate concentration (IC50) ≦ 0.1).

[0483] [Table 1] Example number IC50 Example number IC50 Example number IC50 1 C 38 A 75 A 2 B 39 B 76 A 3 A 40 B 77 A 4 A 41 A 78 B 5 B 42 A 79 C 6 A 43 A 80 B 7 A 44 A 81 B 8 A 45 A 82 B 9 B 46 B 83 C 10 B 47 A 84 C 11 B 48 A 85 B 12 A 49 C 86 C 13 A 50 B 87 A 14 B 51 B 88 B 15 C 52 B 89 A 16 A 53 B 90 B 17 A 54 B 91 B 18 C 55 B 92 B 19 B 56 B 93 A 20 B 57 B 94 A 21 A 58 C 95 A 22 A 59 B 96 A 23 A 60 B 97 A 24 B 61 B 98 A 25 B 62 B 99 A 26 C 63 B 100 A 27 A 64 A 101 A 28 A 65 B 102 A 29 A 66 B 103 A 30 A 67 A 104 B 31 A 68 A 105 B 32 A 69 A 106 A 33 C 70 C 107 B 34 B 71 A 108 C 35 B 72 A 109 C 36 B 73 C 110 C 37 A 74 A 111 A 112 A

[0484] Experimental Example 2: NAD(P)H:quinone oxidoreductase-1 (NQO1) enzyme induction assay (in vitro) The NQO1 analysis was performed based on an existing report (Methods in Enzymology 2004; 382: 243-258). Hepa1c1c7 cells (mouse hepatocyte line, ATCC, cat. No. CRL-2026) were cultured in D-MEM medium containing 10% FBS and 1% penicillin / streptomycin (5% CO2, 37°C) and seeded into 96-well plates (Corning REF. 353072) at a rate of 1×10⁴ cells / well. Wells containing only culture medium and no cells were prepared for partial background assays. The next day, the test compound was added to a final concentration of 400 nM DMSO (DMSO final concentration 0.004%), and the mixture was stirred for approximately 48 hours. Wells without the added compound were prepared for partial base activity assays.

[0485] Prepare cell lysate (a solution containing 0.8% digitonin and 2 mM EDTA), reaction solution (a solution containing 25 mM tris(hydroxymethyl)aminomethane hydrochloride, 0.07% albumin, 0.01% Tween-20, 2 U / mL glucose-6-phosphate dehydrogenase, 5 μM flavin adenine dinucleotide, 1 μM glucose-6-phosphate, 30 μM nicotinamide adenine dinucleotide phosphate, 0.03% 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT), and 50 μM menadione), and reaction termination solution (a solution containing 0.3 mM dicoumarol and 5 mM potassium dihydrogen phosphate, pH 7.4). After removing the culture medium, add 50 μL of cell lysate, incubate at 37°C for 10 minutes, and then shake at room temperature for 10 minutes. Add 200 μL of reaction solution and let it stand at room temperature for 5 minutes. Add 50 μL of reaction termination solution and measure the absorbance at 610 nm using SpectraMax PLUS384 (Molecular devices) or POWERSCAN HT (DS Pharma Biomedical). Analyze the test results using Excel and calculate the NQO1 activity when adding 400 nM of the test compound in the form of the ratio of the bases when no compound is added.

[0486] [Number 2] NQO1 activity ratio when adding the test compound = (Absorbance when adding the test compound - Absorbance of only the culture medium) / (Absorbance when no compound is added - Absorbance of only the culture medium)

[0487] Show the results of each test compound in this test in Table 2 below (A: 5 < NQO1 activity ratio, B: 3 < NQO1 activity ratio ≤ 5).

[0488] [Table 2] Example number Activity ratio Example number Activity ratio Example number Activity ratio 1 A 38 A 75 A 2 A 39 B 76 A 3 A 40 B 77 A 4 A 41 A 78 A 5 A 42 A 79 A 6 A 43 A 80 A 7 A 44 B 81 B 8 A 45 A 82 A 9 A 46 B 83 A 10 A 47 B 84 A 11 A 48 A 85 A 12 A 49 A 86 A 13 A 50 A 87 A 14 A 51 B 88 A 15 A 52 A 89 A 16 A 53 A 90 A 17 B 54 A 91 A 18 B 55 A 92 A 19 A 56 A 93 A 20 A 57 A 94 A 21 A 58 A 95 A 22 A 59 A 96 A 23 A 60 A 97 A 24 A 61 A 98 A 25 A 62 A 99 A 26 A 63 A 100 A 27 A 64 B 101 A 28 A 65 A 102 A 29 A 66 A 103 A 30 B 67 A 104 A 31 A 68 A 105 A 32 A 69 B 106 A 33 A 70 B 107 A 34 A 71 A 108 A 35 A 72 A 109 A 36 A 73 A 110 A 37 B 74 A 111 B 112 B

[0489] Based on the above results, it is confirmed that the compound (1) of the present invention or its pharmaceutically permissible salt has the effect of activating Nrf2 by inhibiting the protein-protein interaction between Keap1 and Nrf2.

[0490] Experimental Example 3: Determination of plasma drug concentration in rats after oral administration Male SD rats (7 weeks old, Japan SLC) were orally administered 10 mg / 2 mL / kg of the test compound suspended in 0.5% methylcellulose solution. Blood was collected from the jugular vein at 0.5, 1, 2, 4, 6, and 24 hours after administration using a heparin-filled syringe. An equal volume of acetonitrile was added to 20 µL of the plasma obtained after centrifugation, followed by 200 µL of internal standard (IS) solution. After stirring, the mixture was centrifuged, and the supernatant was filtered. The recovered filtrate was used as the assay sample. An equal volume of the test compound solution prepared from acetonitrile was added to blank plasma, and the resulting sample, processed in the same manner as above, was used as the calibration curve sample. The prepared samples were analyzed using LC / MS / MS, and the area under the plasma concentration-time curve (AUC) was calculated based on the compound concentration in the plasma. The experimental results are shown in Table 3 below.

[0491] [Table 3] Example Maximum plasma concentration (μM) AUCO-24 (μM * time) Example 4 0.029 0.050 Example 5 0.006 0.035 Example 7 0.009 0.030 Example 8 0.005 0.023

[0492] It was confirmed that among the compounds in the examples, the four compounds described in Table 3 above have excellent pharmacokinetic properties, especially in the absence of systemic exposure, and exhibit excellent pharmacokinetic properties as agents for local administration. [Example]

[0493] The present invention is described in detail by way of the following embodiments, but these embodiments are merely implementation methods and are not intended to limit the present invention. Furthermore, variations may be made without departing from the scope of the present invention. In the following examples, "room temperature" generally means about 10°C to about 35°C. % refers to mol / mol% for yield, volume% for solvent obtained by chromatography, and weight for other parameters. Nuclear magnetic resonance spectroscopy (hereinafter 1H-NMR, resonance frequency 400 MHz or 500 MHz) uses tetramethylsilane as a standard substance, or the chemical shift value of the deuterated solvent used as a reference value, and records the chemical shift value as δ value (ppm). Other abbreviations used in this article have the following meanings. s: singlet d: doublet dd: doublet of doublets t: triplet q: quartet m: multiplet (multiplet) br: broad J: Coupling constant Hz: Hertz CDCl3: Deuterated chloroform DMSO-D6: Deuterated dimethyl sulfoxide CD3OD: Deuterated methanol XPhos:2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl 1H-NMR: Proton Nuclear Magnetic Resonance HPLC: High Performance Liquid Chromatography APCI: Atmospheric Pressure Chemical Liquefaction Method ESI: Electro-spraying ionization method

[0494] Unless otherwise stated, the reagents, solvents, apparatus, etc. used in the following examples and test cases are commercially available. Furthermore, unless otherwise stated, the starting compound is a known compound, commercially available, or synthesized and identified using methods known in themselves or by methods thereof.

[0495] (Example 1) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0496] (1a) (2R)-1-aminobutane-2-ol

[0497] A solution of 28% ammonia (100 mL) in ethanol (25 mL) was added to a solution of (2R)-2-ethylethylene oxide (100 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was removed by distillation under reduced pressure, and toluene was added for azeotropic reaction. 21.6 g of a mixture containing the title compound was obtained as an oil.

[0498] (1b) 2,5-Dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide

[0499] Water (13 mL) was added to a mixture of (2R)-1-aminobutane-2-ol (5.10 g), sodium bicarbonate (2.00 g), and tetrahydrofuran (71 mL) from Example 1(1a), and the mixture was stirred at room temperature for 5 minutes. Then, 2,5-dichloropyridine-3-sulfonyl chloride (3.5 g) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 100 / 0-75 / 25 (V / V)] to obtain 4.38 g (yield: 100%) of the title compound as an oil.

[0500] (1c) (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyr-1,1-dioxide

[0501] 4.38 g of 2,5-dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide and 4.93 g of potassium tert-butoxide from Example 1(1b) were dissolved in 100 mL of N,N-dimethylformamide and stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, added to 100 mL of water, and 1 M hydrochloric acid (1.35 mL) was added and stirred. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 70 / 30-40 / 60 (V / V)] to obtain 3.18 g of the title compound as a solid (yield: 83%).

[0502] (1d) 5-Bromo-7-methyl-1-benzothiophene-2-carboxylic acid

[0503] Diisopropylamine (86.7 g) was dissolved in tetrahydrofuran (800 mL), and n-butyllithium (1.6 M n-hexane solution) (500 mL) was added dropwise over 25 minutes at -78 °C, followed by stirring for 30 minutes. Then, 4-bromo-1-fluoro-2-methylbenzene (108 g) in tetrahydrofuran (300 mL) was added dropwise over 35 minutes, and the mixture was stirred at -78 °C for 30 minutes. N,N-dimethylformamide (53.3 mL) was added to the reaction mixture at -78 °C, and the mixture was stirred for 10 minutes, then heated to room temperature while stirring for 1 hour. 2 M hydrochloric acid (800 mL) was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (830 mL), potassium carbonate (86.5 g) and ethyl thioglycolate (54.7 mL) were added, and the mixture was stirred at 90 °C for 1 hour. The reaction mixture was brought to room temperature, water was added, and extraction was performed using ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was dissolved in ethanol (820 mL), 5 M sodium hydroxide aqueous solution (209 mL) was added, and the mixture was stirred at room temperature for 1 hour. 6 M hydrochloric acid (228 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. The solid was filtered off and washed with water. The obtained solid was dissolved in a mixed solvent of ethyl acetate (1 L) and tetrahydrofuran (1 L), washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the residue. Furthermore, the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The previously obtained residues were combined, n-hexane was added, and the solid was filtered off to obtain 120.0 g of the title compound as a solid (yield: 78%).

[0504] (1e) 5-Bromo-7-methyl-1-benzothiophene

[0505] 105 g of 5-bromo-7-methyl-1-benzothiophene-2-carboxylic acid from Example 1 (1d) was dissolved in 390 mL of 1-methyl-2-pyrrolidone, and 289 mL of 1,8-diazabicyclo[5.4.0]-7-undecene was added. The mixture was stirred at 190 °C for 20.5 h. At 0 °C, 720 mL of 3 M hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 100 / 0-95 / 5 (V / V)] to obtain 49.8 g of the title compound as an oil (yield: 57%).

[0506] (1f) (5-bromo-1-benzothiophene-7-yl)methyl acetate

[0507] 114.2 g of 5-bromo-7-methyl-1-benzothiophene from Example 1(1e) was dissolved in carbon tetrachloride (1.0 L), and N-bromobutyldiamide (98.5 g) and 2,2'-azobisisobutyronitrile (8.26 g) were added. The mixture was heated under reflux for 12 hours. The reaction mixture was brought to room temperature, and the insoluble matter was filtered off. The filtrate was washed with water, and the organic layer was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in N,N-dimethylformamide (535 mL), and potassium acetate (247 g) was added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography [dissolution solvent: n-hexane / ethyl acetate = 100 / 0-90 / 10 (V / V)] to obtain 94.4 g of the title compound as a solid (yield: 66%).

[0508] (1g) (5-bromo-1-benzothiophene-7-yl)methanol

[0509] 50.2 g of methyl 5-bromo-1-benzothiophene-7-yl acetate from Example 1 (1f) was dissolved in a mixed solvent of methanol (290 mL) and tetrahydrofuran (290 mL), and 2 M aqueous sodium hydroxide solution (264 mL) was added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was subjected to ultrasonic treatment with n-hexane. The solid was filtered off to obtain 39.6 g of the title compound as a solid (yield: 92%).

[0510] (1h) [5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-benzothiophene-7-yl]methanol

[0511] (5-bromo-1-benzothiophene-7-yl)methanol (2.00 g) of Example 1 (1 g) was dissolved in 1,4-dimethylalkanes (25 mL), and bis(pinacolyl)diboron (2.51 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane adduct (672 mg) and potassium acetate (2.42 g) were added. The mixture was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature, water was added, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 100 / 0-70 / 30 (V / V)] to obtain 2.75 g of the title compound as an oil (yield: quantitative).

[0512] (1i) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate

[0513] [5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-benzothiophene-7-yl]methanol (500 mg) from Example 1 (1 h) was dissolved in a mixed solvent of 1,4-dimethylethane (11.2 mL) and water (5.6 mL). Triethylamine (0.48 mL) and ethyl (2E)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoate (International Publication No. 2015 / 092713) (423 mg) were added, and the mixture was stirred at 90 °C for 5 minutes. Subsequently, (1,5-cyclooctadiene)rhodium chloride (I) dimer (42 mg) was added, and the mixture was stirred at 90 °C for 15 minutes. The reaction mixture was allowed to return to room temperature, water was added, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography [dissolving solvent: n-hexane / ethyl acetate = 80 / 20-30 / 70 (V / V)] to obtain 276 mg of the title compound as a solid (yield: 39%).

[0514] (1j) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0515] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophene-5-yl]propionate (127 mg) from Example 1(1i) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran 1,1-dioxide (98 mg) from Example 1(1c) were dissolved in tetrahydrofuran (1 mL), and tri-n-butylphosphine (0.12 mL) and 1,1'-(azodicarbonyl)piperidine (117 mg) were added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silicone column chromatography [dissolution solvent: n-hexane / ethyl acetate = 90 / 10-40 / 60 (V / V)]. The residue was purified by NH silicone column chromatography [dissolution solvent: n-hexane / ethyl acetate = 90 / 10-50 / 50 (V / V)] to obtain 155 mg of the title compound as a solid (yield: 76%).

[0516] (1k) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0517] Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (155 mg) from Example 1(1j) was dissolved in a mixed solvent of tetrahydrofuran (2.1 mL) and methanol (0.71 mL), and 0.71 mL of 1 M lithium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silicone column chromatography [dissolution solvent: chloroform / methanol = 100 / 0-90 / 10 (V / V)]. Ethyl acetate and n-hexane were added to the residue, and the mixture was ultrasonically treated. The solid was filtered off, yielding 75.3 mg of the title compound as a solid (yield: 51%).

[0518] (Example 2) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propionic acid

[0519] (2a) Ethyl 3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate

[0520] Using the [5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-benzothiophene-7-yl]methanol (300 mg) and (2E)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)prop-2-enoate ethyl ester (International Publication No. 2015 / 092713) (275 mg) from Example 1 (1h), 167 mg of the title compound as a solid (yield: 39%) was obtained by the same method as in Example 1 (1i).

[0521] (2b) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)ethyl propionate

[0522] Using ethyl 3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate (100 mg) from Example 2 (2a) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran 1,1-dioxide (76 mg) from Example 1 (1c), 141 mg of the title compound as a solid was obtained by the same method as in Example 1 (1j) (yield: 87%).

[0523] (2c) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propionic acid

[0524] Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propionate (141 mg) from Example 2(2b) was dissolved in a mixed solvent of tetrahydrofuran (1.8 mL) and methanol (0.63 mL). A 1 M aqueous solution of lithium hydroxide (0.63 mL) was added, and the mixture was stirred at 40 °C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silicone column chromatography [dissolution solvent: chloroform / methanol = 100 / 0-90 / 10 (V / V)]. Ethyl acetate and n-hexane were added to the residue, and the mixture was ultrasonically treated. The solid was filtered off, yielding 91.3 mg of the title compound as a solid (yield: 68%).

[0525] (Example 3) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0526] (3a) methyl 1-sideoxy-2,3-dihydro-1H-indene-4-carboxylate

[0527] Dissolve 31.7 g of 4-bromo-2,3-dihydro-1H-indone in N,N-dimethylformamide (750 mL), then add 52.5 g of lithium formate monohydrate and 4,5-bis(diphenylphosphine)-9,9-dimethylformamide. (4.34 g), tris(dibenzylacetone)dipalladium(0) (6.87 g), lithium chloride (38.2 g), N,N-diisopropylethylamine (103 mL), and acetic anhydride (56.7 mL) were added and stirred at 80 °C for 17 hours under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature, and 1 M hydrochloric acid and ethyl acetate were added. The mixture was filtered through diatomaceous earth to remove insoluble matter, and the filtrate was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue (40.4 g) was dissolved in N,N-dimethylformamide (450 mL), and potassium carbonate (31.1 g) and methyl iodoform (11.2 mL) were added. The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 90 / 10-65 / 35 (V / V), chloroform] to obtain 24.9 g of the title compound as a solid (yield: 87%).

[0528] (3b) 2,3-Dihydro-1H-inden-4-carboxylic acid methyl ester

[0529] Methyl 1-sideoxy-2,3-dihydro-1H-indene-4-carboxylic acid (21.4 g) from Example 3 (3a) was dissolved in methanol (330 mL), and sodium borohydride (8.51 g) was added in portions at 0 °C, with stirring at room temperature for 20 minutes. Water was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in trifluoroacetic acid (200 mL), and triethylsilane (30 mL) was added. After stirring at room temperature for 10 minutes, triethylsilane (30 mL) was added, and stirring was performed at room temperature for 70 minutes. The reaction mixture was added to a suspension of sodium bicarbonate (200 g) in water (1 L), and then saturated sodium bicarbonate water was added to make it alkaline. Extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silicone column chromatography [dissolution solvent: n-hexane / ethyl acetate = 100 / 0-90 / 10 (V / V)] to obtain 10.0 g of the title compound as an oil (yield: 53%).

[0530] (3c) (6-Bromo-2,3-dihydro-1H-inden-4-yl)methanol

[0531] Methyl 2,3-dihydro-1H-indene-4-carboxylic acid (10.0 g) from Example 3 (3b) was dissolved in methanesulfonic acid (100 mL), and N-bromobutyldiimidimide (10.6 g) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a suspension of sodium bicarbonate (200 g) in water (1 L) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in tetrahydrofuran (210 mL), and lithium aluminum hydride (2.15 g) was added in portions over 7 minutes at 0 °C, while stirring at 0 °C for 30 minutes. Water (2.2 mL), 5 M sodium hydroxide aqueous solution (2.2 mL), and water (6.6 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 25 minutes. The precipitate was then separated by filtration. The filtrate was dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 90 / 10-60 / 40 (V / V)] to obtain 8.13 g of the title compound as an oil (yield: 63%).

[0532] (3d) [6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydro-1H-inden-4-yl]methanol

[0533] Using 8.13 g of (6-bromo-2,3-dihydro-1H-indene-4-yl)methanol from Example 3 (3c), 7.85 g of the title compound as a solid (yield: 80%) was obtained by the same method as in Example 1 (1h).

[0534] (3e) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propionate

[0535] Ethyl (2E)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoate (International Publication No. 2015 / 092713) (3.979 g), [6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydro-1H-indene-4-yl]methanol (17.7 g), triethylamine (11.4 mL), and (1,5-cyclooctadiene)rhodium chloride (I) dimer (1.58 g) from Example 3 (3d) were suspended in a mixed solvent of 1,4-dimethylalkanes (52 mL) and water (13.6 mL), purged with nitrogen, and heated and stirred at 80°C for 3 hours. The reaction mixture was allowed to return to room temperature, and the residue obtained by concentration under reduced pressure was added to ethyl acetate and saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 80 / 20-0 / 100 (V / V)] to obtain 4.651 g of the title compound as a solid (yield: 73%).

[0536] (3f) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0537] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (2.50 g) from Example 3 (3e) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazepine 1,1-dioxide (1.70 g) from Example 1 (1c) were dissolved in toluene (32 mL). Under a nitrogen atmosphere, di-tert-butyl azodicarbonate (4.40 g) was added, followed by triphenylphosphine (5.00 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was injected into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 70 / 30-50 / 50 (V / V)] to obtain 4.16 g of the title compound as an oil (yield: quantitative).

[0538] (3g) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0539] Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyran-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (4.16 g), ethanol (30 mL), and tetrahydrofuran (30 mL) from Example 3(3f) were added to a 1 M aqueous solution of sodium hydroxide (32.6 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was then extracted with ethyl acetate after adding 1 M hydrochloric acid (32.6 mL) and stirring. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was then purified by silicone column chromatography [dissolution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 95 / 5 (V / V / V)]. Ethyl acetate and n-hexane were added to the dissolved compound, and the mixture was ultrasonically treated. The solid was filtered off and dried under vacuum to obtain 2.00 g of the title compound as a solid (yield: 50%).

[0540] (Example 4) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0541] (4a) Ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propionate (4b) Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propionate

[0542] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (59 g) from Example 3(3e) was subjected to chiral HPLC [column: CHIRALPAK IG (50 mm ID × 250 mm), mobile phase: acetonitrile, temperature: 40 °C], thereby obtaining 27.5 g of (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (yield: 47%) with the first peak. Similarly, 27.3 g of ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (yield: 46%) was obtained as the second peak. HPLC conditions for analysis: [Column: CHIRALPAK IG (4.6 mm ID×250 mm), mobile phase: acetonitrile, flow rate: 1.0 mL / min, temperature: 40℃, wavelength: 260 nm]; holding times: 4.187 min (first peak), 5.087 min (second peak).

[0543] (4c) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0544] Ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (61.7 mg) from Example 4 (4a) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (49.4 mg) from Example 1 (1c) were added sequentially under a nitrogen atmosphere to a mixture of di-tert-butyl azodicarbonate (50.5 mg), tetrahydrofuran (2.24 mL), and tri-n-butylphosphine (0.0664 mL), and stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was then purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 70 / 30-50 / 50 (V / V)] to obtain 96.5 mg of the title compound as an oil (yield: 96%).

[0545] (4d) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0546] Ethyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyran-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (720 mg) from Example 4(4c) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL). 1 M sodium hydroxide aqueous solution (2.2 mL) was added, and the mixture was stirred at room temperature for 24 hours. 1 M hydrochloric acid was added to adjust the pH to 5-6, and the reaction solvent was removed by distillation under reduced pressure. Ethanol was added and azeotropically reacted. The resulting residue was suspended in chloroform, and anhydrous magnesium sulfate was added and stirred for 10 minutes. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was then purified by silicone column chromatography [dissolving solvent: chloroform / methanol = 90 / 1-20 / 1 (V / V)]. Ethyl acetate and n-hexane were added and the mixture was solidified to obtain 446 mg of the title compound as a solid (yield: 64%).

[0547] (Example 5) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0548] (5a) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0549] Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (3.15 g) from Example 4(4b) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazepine 1,1-dioxide (2.31 g) from Example 1(1c) were dissolved in toluene (50 mL). 1,1'-(azodicarbonyl)piperidine (3.03 g) was added under a nitrogen atmosphere, followed by tri-n-butylphosphine (2.99 mL), and the mixture was stirred at room temperature for 3 hours. Tetrahydrofuran (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with dichloromethane, and the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure to obtain a residue, which was then purified by silicone column chromatography [dissolution solvent: n-hexane / ethyl acetate = 2 / 1-4 / 6 (V / V)]. Components containing impurities were further purified by silicone column chromatography [dissolution solvent: n-hexane / ethyl acetate = 6 / 4-4 / 6 (V / V)]. This purification was repeated twice using NH silicone column chromatography [dissolution solvent: n-hexane / ethyl acetate = 2 / 1-1 / 1 (V / V)], thereby obtaining 3.78 g of the title compound as a solid (yield: 74%).

[0550] (5b) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0551] Ethyl (3.75 g) of (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyran-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate, ethanol (30 mL), and tetrahydrofuran (60 mL) were added to a 1 M sodium hydroxide aqueous solution (30 mL), and the mixture was stirred at 40 °C for 3 hours. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid (33 mL) was added and stirred. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the solid obtained by concentrating the filtrate under reduced pressure was dissolved in ethanol (100 mL) and recrystallized. The precipitated solid was filtered off, washed with a small amount of ethanol, and dried under reduced pressure at 50°C to obtain 2.20 g of the title compound as a solid (yield: 61%).

[0552] (Example 6) 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazolo-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0553] (6a) 4-Bromo-3-fluoro-N1-methylphenyl-1,2-diamine

[0554] 5.27 g of 3-fluoro-N-methyl-2-nitroaniline (International Publication No. 2011 / 021676) was dissolved in 60 mL of N,N-dimethylformamide. A solution of 4.88 g of N-bromobutyldiamide in 30 mL of N,N-dimethylformamide was added at 0 °C, and the mixture was stirred at 0 °C for 2 hours. Water was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Hexane was added to the residue, and the solid was filtered off. The solid was suspended in 50 mL of ethanol, and 10.6 g of stannous(II) chloride dihydrate was added. The mixture was heated under reflux for 1 hour. The reaction mixture, restored to room temperature, was added to a suspension obtained by adding sodium bicarbonate (15 g) to water (100 mL) and ethyl acetate (100 mL), and stirred at room temperature for 0.5 hours. The mixture was filtered through diatomaceous earth to remove insoluble matter, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography [dissolving solvent: n-hexane / ethyl acetate = 90 / 10-80 / 20 (V / V)] to obtain 2.95 g of the title compound as a solid (yield: 89%).

[0555] (6b) 5-Bromo-4-fluoro-1-methyl-1H-benzotriazole

[0556] 2.95 g of 4-bromo-3-fluoro-N1-methylphenyl-1,2-diamine from Example 6 (6a) was dissolved in acetonitrile (27 mL), and 2.4 mL of tert-butyl nitrite and 4.3 mL of 42% tetrafluoroboric acid were added dropwise at 0 °C, while stirring at room temperature for 30 minutes. Saturated sodium bicarbonate solution was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue obtained was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 85 / 15-60 / 40 (V / V)] to obtain 620 mg of the title compound as a solid (yield: 17%).

[0557] (6c) Ethyl (2E)-3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)prop-2-enoate

[0558] 5-Bromo-4-fluoro-1-methyl-1H-benzotriazole (620 mg) from Example 6 (6b) was dissolved in N,N-dimethylformamide (8.0 mL), and ethyl acrylate (2.46 mL), N,N-diisopropylethylamine (2.0 mL), tris(dibenzylacetone)dipalladium (0) (207 mg), and tris(o-tolyl)phosphine (275 mg) were added. The mixture was stirred at 100 °C for 13.5 hours under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature, water was added, and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 85 / 15-60 / 40 (V / V)] to obtain 370 mg of the title compound as a solid (yield: 43%).

[0559] (6d) Ethyl 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propionate

[0560] Using [6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydro-1H-indene-4-yl]methanol (481 mg) from Example 3 (3d) and (2E)-3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)prop-2-enoate ethyl ester (370 mg) from Example 6 (6c), the title compound as a solid was obtained in 390 mg (yield: 84%) by the same method as in Example 95 (95a).

[0561] (6e) Ethyl 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazolo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionate

[0562] Using ethyl 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (190 mg) and (4R)-4-methyl-3,4-dihydro-2H-5,1,2-benzoxazine 1,1-dioxide (International Publication No. 2015 / 092713) (122 mg) from Example 6 (6d), 260 mg of the title compound as a solid (yield: 92%) was obtained by the same method as in Example 2 (2b).

[0563] (6f) 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazolo-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0564] Using ethyl 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazothiazol-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate (260 mg) from Example 6 (6e), 186 mg of the title compound as a solid was obtained by the same method as in Example 2 (2c) (yield: 68%).

[0565] (Example 7) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0566] (7a) Ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate (7b) Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate

[0567] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate (120 g) from Example 1 (1i) was fed into a chiral SFC [column: CHIRALPAK AD (50 mm ID × 250 mm), mobile phase: carbon dioxide / ethanol = 60 / 40 (V / V)], thereby obtaining 51.0 g of (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate (yield: 43%) as the first peak. Similarly, 52.5 g of ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate (yield: 44%) was obtained as the second peak. SFC conditions were analyzed [column: CHIRALPAK AD-3 (4.6 mm ID × 50 mm), mobile phase: carbon dioxide / ethanol (0.05% diethylamine) = 95 / 5-60 / 40 (V / V), flow rate: 3.0 mL / min, temperature: 35℃, wavelength: 220 nm]; hold times: 2.078 min (first peak), 2.455 min (second peak).

[0568] (7c) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0569] Using ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate (0.20 g) from Example 7 (7a) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran 1,1-dioxide (0.141 g) from Example 1 (1c), 0.34 g of the title compound as an oil was obtained by the same method as in Example 3 (3f) (yield: quantitative).

[0570] (7d) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0571] Using ethyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (0.35 g) from Example 7 (7c), the title compound was obtained in 0.24 g (yield: 72%) by the same method as in Example 3 (3 g).

[0572] (Example 8) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0573] (8a) Ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate

[0574] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate (0.20 g) from Example 7 (7b) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran 1,1-dioxide (0.141 g) from Example 1 (1c), 0.32 g of the title compound as an oil was obtained by the same method as in Example 3 (3f) (yield: quantitative).

[0575] (8b) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0576] Using ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (0.34 g) from Example 8 (8a), the title compound was obtained in 0.15 g (yield: 46%) by the same method as in Example 3 (3 g).

[0577] (Example 9) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0578] (9a) 2,6-Dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide

[0579] Using (2R)-1-aminobutane-2-ol (2.0 g) and 2,6-dichloropyridine-3-sulfonyl chloride (1.4 g) from Example 1 (1a), 1.4 g of the title compound as an oil (yield: 82%) was obtained by the same method as in Example 1 (1b).

[0580] (9b) (4R)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyr-1,1-dioxide

[0581] Using 1.25 g of 2,6-dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide from Example 9 (9a), 1.04 g of the title compound as a solid was obtained by the same method as in Example 1 (1c) (yield: 95%).

[0582] (9c) 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0583] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (200 mg) from Example 3 (3e) and (4R)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazepine 1,1-dioxide (133 mg) from Example 9 (9b), 172 mg of the title compound as a solid (yield: 53%) was obtained by the same method as in Example 3 (3f).

[0584] (9d) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0585] Using ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyridin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (80 mg) from Example 9 (9c), 14 mg of the title compound (yield: 18%) was obtained by the same method as in Example 3 (3 g).

[0586] (Example 10) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0587] (10a) 2-Chloro-N-[(2R)-2-hydroxybutyl]-5-methylpyridine-3-sulfonamide

[0588] Using (2R)-1-aminobutane-2-ol (1.41 g) and 2-chloro-5-methylpyridine-3-sulfonyl chloride (0.90 g) from Example 1 (1a), 1.1 g of the title compound as a solid was obtained by the same method as in Example 1 (1b) (yield: quantitative).

[0589] (10b) (4R)-4-ethyl-8-methyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyr-1,1-dioxide

[0590] Using 1.2 g of 2-chloro-N-[(2R)-2-hydroxybutyl]-5-methylpyridine-3-sulfonamide from Example 10 (10a), 0.68 g of the title compound as a solid (yield: 65%) was obtained by the same method as in Example 1 (1c).

[0591] (10c) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate

[0592] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (100 mg) from Example 3 (3e) and (4R)-4-ethyl-8-methyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazepine 1,1-dioxide (120 mg) from Example 10 (10b), 165 mg of the title compound as a solid (yield: 53%) was obtained by the same method as in Example 3 (3f).

[0593] (10d) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0594] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyran-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate (165 mg) from Example 10 (10c), 90 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 57%).

[0595] (Example 11) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0596] (11a) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate

[0597] Ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyran-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (79 mg), 50% tetrahydrofuran solution of trimethylborooxane (0.087 mL), palladium acetate (2.8 mg), cesium carbonate (120 mg), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (5.1 mg) from Example 9(9c) were dissolved in toluene (3.0 mL). The mixture was heated and stirred at 100°C for 4 hours under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature, water was added, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by NH4 silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 80 / 20-0 / 100 (V / V)] to obtain 60 mg of the title compound as an oil (yield: 78%).

[0598] (11b) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0599] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyran-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate (60 mg) from Example 11 (11a), 35 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 62%).

[0600] (Example 12) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazolo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid

[0601] (12a) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazolo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionate

[0602] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (140 mg) and (4R)-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxazine 1,1-dioxide (International Publication No. 2015 / 092713) (80 mg) from Example 3(3f), 140 mg of the title compound as a solid was obtained (yield: 65%).

[0603] (12b) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazolo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid

[0604] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazothiazol-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate (140 mg) from Example 12 (12a), 120 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 90%).

[0605] (Example 13) 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0606] (13a) 5-Chloro-2,4-difluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0607] Using (2R)-1-aminobutane-2-ol (0.72 g) and 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.50 g) from Example 1 (1a), 0.70 g of the title compound as an oil was obtained by the same method as in Example 1 (1b) (yield: quantitative).

[0608] (13b) (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxazine-1,1-dioxide

[0609] Using 0.35 g of 5-chloro-2,4-difluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide from Example 13 (13a), 0.22 g of the title compound as a solid (yield: 67%) was obtained by the same method as in Example 1 (1c).

[0610] (13c) 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0611] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (100 mg) from Example 3 (3e) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxazine 1,1-dioxide (80 mg) from Example 13 (13b), 140 mg of the title compound as a solid (yield: 84%) was obtained by the same method as in Example 3 (3f).

[0612] (13d) 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0613] Using ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (140 mg) from Example 13 (13c), 90 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 67%).

[0614] (Example 14) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0615] (14a) 5-Chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0616] Using (2R)-1-aminobutane-2-ol (1.0 g) and 5-chloro-2-fluorobenzenesulfonyl chloride (1.56 g) from Example 1 (1a), 1.3 g of the title compound as an oil was obtained by the same method as in Example 1 (1b) (yield: quantitative).

[0617] (14b) (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxazine-1,1-dioxide

[0618] Using 1.3 g of 5-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide from Example 14 (14a), 1.0 g of the title compound as a solid was obtained by the same method as in Example 1 (1c) (yield: 83%).

[0619] (14c) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0620] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (140 mg) from Example 3 (3e) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxazothiazate 1,1-dioxide (95 mg) from Example 14 (14b), 160 mg of the title compound as a solid (yield: 71%) was obtained by the same method as in Example 3 (3f).

[0621] (14d) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0622] Using ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (160 mg) from Example 14 (14c), 140 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 92%).

[0623] (Example 15) 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0624] (15a) 4-Chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0625] Using (2R)-1-aminobutane-2-ol (1.55 g) and 4-chloro-2-fluorobenzenesulfonyl chloride (1.0 g) from Example 1 (1a), 1.2 g of the title compound as an oil (yield: 98%) was obtained by the same method as in Example 1 (1b).

[0626] (15b) (4R)-7-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxazine-1,1-dioxide

[0627] Using 1.2 g of 4-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide from Example 15 (15a), 0.92 g of the title compound as a solid (yield: 83%) was obtained by the same method as in Example 1 (1c).

[0628] (15c) 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0629] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (100 mg) from Example 3 (3e) and (4R)-7-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxazothiazate 1,1-dioxide (75 mg) from Example 15 (15b), 160 mg of the title compound as a solid (yield: 99%) was obtained by the same method as in Example 3 (3f).

[0630] (15d) 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0631] Using ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (160 mg) from Example 15 (15c), 110 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 72%).

[0632] (Example 16) 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0633] (16a) 3-Chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0634] Using (2R)-1-aminobutane-2-ol (1.55 g) and 5-chloro-2-fluorobenzenesulfonyl chloride (1.0 g) from Example 1 (1a), 1.2 g of the title compound as an oil (yield: 98%) was obtained by the same method as in Example 1 (1b).

[0635] (16b) (4R)-6-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxazine-1,1-dioxide

[0636] Using 1.2 g of 3-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide from Example 16 (16a), 0.90 g of the title compound as a solid (yield: 81%) was obtained by the same method as in Example 1 (1c).

[0637] (16c) 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0638] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (160 mg) from Example 3 (3e) and (4R)-6-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxazothiazate 1,1-dioxide (117 mg) from Example 16 (16b), 250 mg of the title compound as a solid (yield: 96%) was obtained by the same method as in Example 3 (3f).

[0639] (16d) 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0640] Using ethyl 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (250 mg) from Example 16 (16c), 160 mg of the title compound as a solid (yield: 67%) was obtained by the same method as in Example 3 (3 g).

[0641] (Example 17) 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0642] (17a) 2-Chloro-6-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0643] Using (2R)-1-aminobutane-2-ol (1.1 g) and 2-chloro-6-fluorobenzenesulfonyl chloride (0.70 g) from Example 1 (1a), 0.90 g of the title compound as an oil was obtained by the same method as in Example 1 (1b) (yield: quantitative).

[0644] (17b) (4R)-9-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxazine-1,1-dioxide

[0645] Using 0.90 g of 2-chloro-6-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide from Example 17 (17a), 598 mg of the title compound as a solid (yield: 72%) was obtained by the same method as in Example 1 (1c).

[0646] (17c) 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0647] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (150 mg) from Example 3 (3e) and (4R)-9-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxazothiazate 1,1-dioxide (110 mg) from Example 17 (17b), 100 mg of the title compound as a solid (yield: 41%) was obtained by the same method as in Example 3 (3f).

[0648] (17d) 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0649] Using ethyl 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (100 mg) from Example 17 (17c), 65 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 68%).

[0650] (Example 18) 3-(7-{[(4R)-8-chloro-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0651] 400 mg of 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid from Example 13 (13d) was dissolved in 25 mL of ethanol, and 3.2 mL of 1 M sodium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 48 hours. 1 M hydrochloric acid (3.2 mL) was added to the reaction mixture and stirred. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 60 / 40-40 / 60 (V / V)] to obtain 250 mg of the title compound as a solid (yield: 60%).

[0652] (Example 19) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)propionic acid

[0653] (19a) 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0654] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate (130 mg) from Example 1 (1i) and (4R)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran 1,1-dioxide (65 mg) from Example 9 (9b), 150 mg of the title compound as a solid was obtained by the same method as in Example 3 (3f) (yield: 93%).

[0655] (19b) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)propionic acid

[0656] Using ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (150 mg) from Example 19 (19a), 85 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 58%).

[0657] (Example 20) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0658] (20a) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tris(propane-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]propionate

[0659] Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propionate (520 mg) from Example 4(4b) was dissolved in N,N-dimethylformamide (5 mL), and imidazole (110 mg) and triisopropylchlorosilane (380 mg) were added. The mixture was stirred at room temperature for 3 hours. Water (2.5 mL) was added to the reaction mixture and stirred. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 90 / 10-50 / 50 (V / V)] to obtain 720 mg of the title compound as an oil (yield: 99%).

[0660] (20b) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tris(propane-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]tert-butyl propionate

[0661] Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tris(propane-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-indene-5-yl]propionate (720 mg) from Example 20 (20a) was dissolved in tetrahydrofuran (3 mL), ethanol (3 mL) and 1 M sodium hydroxide aqueous solution (0.30 mL) were added, and the mixture was stirred at room temperature for 12 hours. 1 M hydrochloric acid (0.30 mL) was added to the reaction mixture, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure was dissolved in tributyl alcohol (5 mL), dibutyl dicarbonate (600 mg) and 4-dimethylaminopyridine (48 mg) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was injected into water, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 90 / 10-60 / 40 (V / V)] to obtain 540 mg of the title compound as an oil (yield: 71%).

[0662] (20c) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]tert-butyl propionate

[0663] The (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tris(propane-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]propionate (540 mg) from Example 20 (20b) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (2.8 mL) was added. The mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction mixture and stirred. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 70 / 30-20 / 80 (V / V)] to obtain 283 mg of the title compound as a solid (yield: 72%).

[0664] (20d) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)tert-butyl propionate

[0665] Using (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate tert-butyl ester (283 mg) from Example 20 (20c) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxazothiazate 1,1-dioxide (73 mg) from Example 13 (13b), 140 mg of the title compound as a solid (yield: 79%) was obtained by the same method as in Example 3 (3f).

[0666] (20e) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0667] Tertiary butyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (140 mg) from Example 20 (20d) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours. Sodium bicarbonate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 50 / 50-20 / 80 (V / V)] to obtain 73 mg of the title compound as a solid (yield: 57%).

[0668] (Example 21) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0669] (21a) (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tris(propane-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]tert-butyl propionate

[0670] Using ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (520 mg) from Example 4 (4a), the title compound as an oil was obtained in 754 mg (yield: 98%) by the same method as in Examples 20 (20a) and 20 (20b).

[0671] (21b) (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]tert-butyl propionate

[0672] Using the (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tris(propane-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-indene-5-yl]propionate (754 mg) from Example 21 (21a), 484 mg of the title compound as a solid (yield: 88%) was obtained by the same method as in Example 20 (20c).

[0673] (21c) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)tert-butyl propionate

[0674] Using (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate tert-butyl ester (110 mg) from Example 21 (21b) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxazothiazate 1,1-dioxide (73 mg) from Example 13 (13b), the title compound was obtained as a solid in 145 mg (yield: 81%) by the same method as in Example 3 (3f).

[0675] (21d) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0676] Using the (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate tertiary butyl ester (145 mg) from Example 21 (21c), 77 mg of the title compound as a solid (yield: 58%) was obtained by the same method as in Example 20 (20e).

[0677] (Example 22) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0678] (22a) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0679] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophene-5-yl]propionate (200 mg) of Example 7 (7b) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxazine 1,1-dioxide (136 mg) of Example 13 (13b), 350 mg of the title compound as a solid was obtained by the same method as in Example 3 (3f) (yield: quantification).

[0680] (22b) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0681] Ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (350 mg), tributanol (3.0 mL), and tetrahydrofuran (2.0 mL) of Example 22(22a) were added to a 1 M sodium hydroxide aqueous solution (1.5 mL), and the mixture was stirred at room temperature for 12 hours. 1 M hydrochloric acid (1.5 mL) was added to the reaction mixture, and after stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was then purified by silicone column chromatography [dissolution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 95 / 5 (V / V / V)]. Ethyl acetate and n-hexane were added to the dissolved compound, followed by ultrasonic treatment. The solid was filtered off and dried under vacuum to obtain 148 mg of the title compound as a solid (yield: 44%).

[0682] (Example 23) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0683] (23a) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)ethyl propionate

[0684] Using ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionate (200 mg) from Example 7 (7a) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxazothiazate 1,1-dioxide (136 mg) from Example 13 (13b), the title compound was obtained as a solid in 330 mg (yield: quantification) by the same method as in Example 3 (3f).

[0685] (23b) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid

[0686] Using ethyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxazin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate (350 mg) from Example 23 (23a), 70 mg of the title compound as a solid (yield: 21%) was obtained by the same method as in Example 22 (22b).

[0687] (Example 24) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0688] (24a) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate

[0689] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (90 mg) and (4R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran 1,1-dioxide (International Publication No. 2015 / 092713) (60 mg) from Example 3(3f), 130 mg of the title compound as a solid was obtained (yield: 94%).

[0690] (24b) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0691] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyran-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate (130 mg) from Example 24 (24a), 70 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 56%).

[0692] (Example 25) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0693] (25a) 2-Chloro-N-[(2R)-2-hydroxybutyl]-5-(trifluoromethyl)pyridine-3-sulfonamide

[0694] Using (2R)-1-aminobutane-2-ol (1.27 g) and 2-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (1.0 g) from Example 1 (1a), 417 mg of the title compound as an oil (yield: 35%) was obtained by the same method as in Example 1 (1b).

[0695] (25b) (4R)-4-ethyl-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyr-1,1-dioxide

[0696] Using 2-chloro-N-[(2R)-2-hydroxybutyl]-5-(trifluoromethyl)pyridine-3-sulfonamide (417 mg) from Example 25 (25a), 370 mg of the title compound as a solid was obtained by the same method as in Example 1 (1c) (yield: quantification).

[0697] (25c) [(6-bromo-2,3-dihydro-1H-inden-4-yl)methoxy](tert-butyl)dimethylsilane

[0698] To the mixture of (6-bromo-2,3-dihydro-1H-inden-4-yl)methanol (70 g), imidazole (42 g), and dichloromethane (800 mL) of Example 3 (3c), 70 g of tert-butyldimethylchlorosilane was added, and the mixture was stirred at 15°C for 1 hour. The reaction mixture was diluted with dichloromethane, and the organic layer was washed twice with water, once with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography [dissolving solvent: petroleum ether] to obtain 98 g of the title compound as a solid (yield: 93%).

[0699] (25d) Tertiary butyl(dimethyl){[6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydro-1H-inden-4-yl]methoxy}silane

[0700] Using [(6-bromo-2,3-dihydro-1H-indene-4-yl)methoxy](tert-butyl)dimethylsilane (49 g) from Example 25 (25c), 51 g of the title compound as a solid (yield: 91%) was obtained by the same method as in Example 1 (1h).

[0701] (25e) 3-[7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate tert-butyl ester

[0702] Rhodium bis(nordiene)tetrafluoroborate (I) (152 mg), (2S,3S)-bisdiphenylphosphine butane (87 mg), and (2R,3R)-bisdiphenylphosphine butane (87 mg) were dissolved in a mixed solvent of 1,4-diphenylacetic acid (27 mL) and water (7.2 mL) and stirred at room temperature for 15 minutes. Subsequently, 2.22 g of (2E)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoic acid tributyl ester (International Publication No. 2018 / 109646), 4.73 g of tributyl(dimethyl){[6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydro-1H-inden-4-yl]methoxy}silane from Example 25 (25d), and 8.12 mL of 1 M potassium hydroxide aqueous solution were added, and the mixture was heated and stirred at 50°C for 4 hours. The reaction mixture was allowed to return to room temperature, and a saturated ammonium chloride aqueous solution was added. Extraction was performed using ethyl acetate. The organic layer was washed with saturated brine and dried using anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography [dissolving solvent: n-hexane / ethyl acetate = 90 / 10-60 / 40 (V / V)] to obtain 4.0 g of the title compound as an oil (yield: 92%).

[0703] (25f) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]tert-butyl propionate

[0704] Using 4.0 g of 3-[7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-indene-5-yl]-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionate tributyl ester from Example 25 (25e), 3.0 g of the title compound as a solid was obtained by the same method as in Example 20 (20c) (yield: 95%).

[0705] (25g) 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)tert-butyl propionate

[0706] Using 100 mg of 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate from Example 25 (25f) and 70 mg of (4R)-4-ethyl-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran 1,1-dioxide from Example 25 (25b), 116 mg of the title compound as a solid was obtained by the same method as in Example 3 (3f) (yield: 70%).

[0707] (25h) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0708] Using 116 mg of 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate tributyl ester from Example 25 (25 g), 75 mg of the title compound as a solid was obtained by the same method as in Example 20 (20e) (yield: 70%).

[0709] (Example 26) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxo-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazazo-4-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0710] (26a) 1-Fluoro-N-[(2R)-2-hydroxybutyl]naphthalene-2-sulfonamide

[0711] Using (2R)-1-aminobutane-2-ol (1.10 g) and 1-fluoronaphthalene-2-sulfonyl chloride (0.75 g) from Example 1 (1a), 0.90 mg of the title compound as a solid (yield: 99%) was obtained by the same method as in Example 1 (1b).

[0712] (26b) (2R)-2-ethyl-3,4-dihydro-2H-naphtho[1,2-b][1,4,5]oxathiazopyran 5,5-dioxide

[0713] Using 1-fluoro-N-[(2R)-2-hydroxybutyl]naphthalene-2-sulfonamide (900 mg) from Example 26 (26a), 700 mg of the title compound as a solid (yield: 83%) was obtained by the same method as in Example 1 (1c).

[0714] (26c) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxo-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazazo-4-yl]methyl}-2,3-dihydro-1H-indene-5-yl)tert-butyl propionate

[0715] Using tert-butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (110 mg) from Example 25 (25f) and (2R)-2-ethyl-3,4-dihydro-2H-naphtho[1,2-b][1,4,5]oxathiazopyran 5,5-dioxide (72 mg) from Example 26 (26b), 170 mg of the title compound as a solid (yield: 96%) was obtained by the same method as in Example 3 (3f).

[0716] (26d) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxo-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazazo-4-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid

[0717] Using 180 mg of 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxo-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazazo-4-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate from Example 26 (26c), 100 mg of the title compound as a solid was obtained by the same method as in Example 20 (20e) (yield: 61%).

[0718] (Example 27) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S*)-4-ethyl-1,1-dioxo-4,5-dihydropyrido[2,3-f][1,2]thiazopyr-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid

[0719] (27a) (4S*)-4-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazopyridine-1,1-dioxide

[0720] At room temperature, 10 g of 2,2'-azobis(isobutyronitrile) was added to a 500 mL solution of 30 g of 2-chloro-N-(2-methylenebutyl)pyridine-3-sulfonamide (International Publication No. 2018 / 109643), and the reaction mixture was heated to 65 °C. 70 g of tributyltin hydrogenation was added, and the reaction mixture was stirred at 85 °C for 16 hours. A 500 mL solution of 50 g of potassium fluoride was added to the reaction mixture, and the mixture was stirred at 15 °C for 10 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography [dissolution solvent: petroleum ether / ethyl acetate = 20 / 1-5 / 1 (V / V)], and then purified by preparative HPLC [column: Phenomenex Luna C18 (100 mm ID × 250 mm), mobile phase: 0.225% formic acid aqueous solution / acetonitrile = 75 / 25-55 / 45 (V / V)] to obtain the racemic derivative of the title compound. It was fed into a chiral SFC [column: CHIRALPAK IC (30 mm ID × 250 mm), mobile phase: carbon dioxide / 2-propanol (0.1% ammonia) = 60 / 40 (V / V)], thereby obtaining 7.09 g of (4S*)-4-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazopyridine 1,1-dioxide as the first peak (yield: 26%). SFC conditions were analyzed [column: CHIRALPAK AS-3 (4.6 mm ID×50 mm), mobile phase: carbon dioxide / ethanol (0.05% diethylamine) = 95 / 5-60 / 40 (V / V), flow rate: 3 mL / min, temperature: 35℃, wavelength: 220 nm]; hold time: 1.081 min (first peak).

[0721] (27b) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S*)-4-ethyl-1,1-dioxo-4,5-dihydropyrido[2,3-f][1,2]thiazopyr-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)ethyl propionate

[0722] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (158 mg) from Example 4 (4b) and (4S*)-4-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiamethoxam 1,1-dioxide (90 mg) from Example 27 (27a), 230 mg of the title compound as a solid (yield: 95%) was obtained by the same method as in Example 3 (3f).

[0723] (27c) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S*)-4-ethyl-1,1-dioxo-4,5-dihydropyrido[2,3-f][1,2]thiazopyr-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid

[0724] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S*)-4-ethyl-1,1-dioxo-4,5-dihydropyrido[2,3-f][1,2]thiazopyrido-2(3H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate (120 mg) from Example 27 (27b), 50 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 44%).

[0725] (Example 28) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S*)-4-ethyl-1,1-dioxo-4,5-dihydro-1,2-benzothiazopyran-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid

[0726] (28a) (4S*)-4-ethyl-2,3,4,5-tetrahydro-1,2-benzothiazopyran-1,1-dioxide

[0727] 16 g of 4-ethyl-2,3,4,5-tetrahydro-1,2-benzothiazopyran 1,1-dioxide (International Publication No. 2017 / 060854) was supplied to a chiral SFC [column: CHIRALPAK AD (30 mm ID × 250 mm), mobile phase: carbon dioxide / methanol (0.1% ammonia) = 70 / 30 (V / V)] to obtain 4.8 g of (4S*)-4-ethyl-2,3,4,5-tetrahydro-1,2-benzothiazopyran 1,1-dioxide as the first peak. SFC conditions were analyzed [column: CHIRALPAK AY-3 (4.6 mm ID×50 mm), mobile phase: carbon dioxide / ethanol (0.05% diethylamine) = 95 / 5-60 / 40 (V / V), flow rate: 3 mL / min, temperature: 35℃, wavelength: 220 nm]; hold time: 1.513 min (first peak).

[0728] (28b) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S*)-4-ethyl-1,1-dioxo-4,5-dihydro-1,2-benzothiazopyran-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)ethyl propionate

[0729] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (158 mg) from Example 4 (4b) and (4S*)-4-ethyl-2,3,4,5-tetrahydro-1,2-benzothiazopyran 1,1-dioxide (90 mg) from Example 28 (28a), 100 mg of the title compound as a solid (yield: 41%) was obtained by the same method as in Example 3 (3f).

[0730] (28c) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S*)-4-ethyl-1,1-dioxo-4,5-dihydro-1,2-benzothiazopyran-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propionic acid

[0731] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S*)-4-ethyl-1,1-dioxo-4,5-dihydro-1,2-benzothiazopyran-2(3H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionate (100 mg) from Example 28 (28b), 85 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 89%).

[0732] (Example 29) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propionic acid

[0733] (29a) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)ethyl propionate

[0734] Ethyl 3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propionate (181 mg) from Example 95 (95a) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazepine 1,1-dioxide (115 mg) from Example 1 (1c) were dissolved in toluene (5 mL). Under a nitrogen atmosphere, 1,1'-(azodicarbonyl)piperidine (221 mg) was added, followed by tri-n-butylphosphine (0.218 mL), and the mixture was stirred at room temperature for 25 hours. The reaction mixture was diluted with dichloromethane, and the residue was purified by silicone column chromatography [dissolution solvent: n-hexane / ethyl acetate = 2 / 1-1 / 2 (V / V)] to obtain 270 mg of the title compound as a solid (yield: 94%).

[0735] (29b) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propionic acid

[0736] Using ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyran-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propionate (270 mg) from Example 29 (29a), 218 mg of the title compound as a solid was obtained by the same method as in Example 3 (3 g) (yield: 84%).

[0737] (Example 30) (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)propionic acid

[0738] (30a) 4-Bromo-6-chloro-N,3-dimethyl-2-nitroaniline

[0739] 5.04 g of 4-bromo-N,3-dimethyl-2-nitroaniline (International Publication No. 2020 / 165776) was dissolved in N,N-dimethylformamide, and 2.88 g of N-chlorobutylideneimide was added. The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed three times with water, once with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 5.72 g of the unpurified title compound as a solid (yield: quantitative).

[0740] (30b) 4-Bromo-6-chloro-N,3-dimethylphenyl-1,2-diamine

[0741] Using 5.84 g of 4-bromo-6-chloro-N,3-dimethyl-2-nitroaniline from Example 30 (30a), 2.69 g of the title compound as an oil (yield: 52%) was obtained by the same method as in Example 54 (54d).

[0742] (30c) 5-Bromo-7-chloro-1,4-dimethyl-1H-benzotriazole

[0743] 2.69 g of 4-bromo-6-chloro-N,3-dimethylphenyl-1,2-diamine from Example 30 (30b) was suspended in 5 M hydrochloric acid (50 mL). A solution of sodium nitrite (1.49 g) in water (6 mL) was added dropwise over 20 minutes at 0°C under a nitrogen atmosphere. After stirring at room temperature for 1.5 hours, the reaction mixture was cooled to 0°C and neutralized by adding 5 M so...

Claims

1. A compound or a pharmaceutically permissible salt thereof, the compound being represented by the following general formula (1): [wherein, R1a and R1b independently represent a hydrogen atom or a C1-6 alkyl group, R2 represents a C1-6 alkyl group that may be substituted by 1 to 3 substituents selected from substituent group a, R3 represents a halogen atom or a C1-6 alkyl group, Y represents -CH-, -CR4- or a nitrogen atom, R4 represents a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group or a C1-6 haloalkoxy group, -V- represents a group represented by any of the following formulas: (wherein, * and ** represent the bonding positions with the benzene ring), n R7s independently represent a halogen atom, a cyano group, a C1-6 alkyl group or a C1-6 alkoxy group, n represents an integer from 0 to 2, and Z represents a group represented by the following formula (A1), (A2) or (A3): (wherein, *** indicates the bonding position of the carbon atom bonded to Z; R8 indicates a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from substituent group a; R5a and R5b independently represent a hydrogen atom, a C1-6 alkyl group that can be substituted by 1 to 3 substituents selected from substituent group a, or a C3-6 cycloalkyl group; or, R5a and R5b are bonded to each other and together with the carbon atoms bonded to R5a and R5b form a C3-8 cycloalkane that can be substituted by 1 to 3 substituents selected from substituent group b, or a 3 to 8-member saturated oxygen-containing heterocycle; m R6s independently represent a hydroxyl group, a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or an amino group that can be substituted by 1 or 2 C1-6 alkyl groups; m represents an integer from 0 to 3; W represents -CH2-, -CHR9-, or an oxygen atom. R9 represents a halogen atom, cyano, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, or C1-6 haloalkoxy; X represents -CH-, -CR10-, or a nitrogen atom; R10 represents a halogen atom, cyano, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, or C1-6 haloalkoxy; U represents -CH-, -CR11-, or a nitrogen atom; and R11 represents a halogen atom, cyano, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, or C1-6 haloalkoxy, except for compounds in which R5a and R5b are both hydrogen atoms, and compounds in which W is -CH2- or -CHR9- and U is -CH- or -CR11- when Z is a group represented by formula (A1).Substituent group a: hydroxyl, halogen atom, cyano, C1-6 alkyl group substituted with 1 to 3 substituents selected from substituent group b, C1-6 alkoxy group substituted with 1 to 3 substituents selected from substituent group b, C1-6 alkylsulfonyl group substituted with 1 to 3 substituents selected from substituent group b, amino group substituted with 1 or 2 C1-6 alkyl groups. Substituent group b: halogen atom, cyano, C1-6 alkyl, C1-6 alkoxy group.

2. The compound of claim 1 or its pharmaceutically permissible salt, wherein R1a and R1b are independently hydrogen atoms or methyl groups, respectively.

3. The compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein R2 is a C1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonylurea)propyl.

4. The compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein R3 is a halogen atom or a C1-6 alkyl group.

5. The compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein R4 is a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group.

6. A compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein -V- denotes a base represented by any of the following formulas: (where * and ** have the same meaning as in claim 1).

7. The compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein n is 1 and R7 is a C1-6 alkyl group.

8. The compound of claim 1 or 2 or its pharmaceutically permissible salt, wherein n is 0.

9. A compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein Z is a base represented by the following formula (A1) or (A2): (the symbols in the formula have the same meaning as in claim 1).

10. The compound of claim 9 or a pharmaceutically permissible salt thereof, wherein R8 is methyl or ethyl.

11. The compound of claim 9 or its pharmaceutically permissible salt, wherein R5a and R5b are independently hydrogen atoms, methyl, ethyl or cyclopropyl, or R5a and R5b are bonded together to form cyclopropane, cyclobutane, oxetane or tetrahydropyran.

12. The compound of claim 9 or a pharmaceutically permissible salt thereof, wherein each of the m R6s is independently a hydroxyl, fluorine, chlorine, methyl, ethoxy, or trifluoromethyl group, and m is an integer from 0 to 2.

13. The compound of claim 9 or its pharmaceutically permissible salt, wherein W is -CH2- or an oxygen atom.

14. A compound or a pharmaceutically permissible salt thereof, the compound being represented by the following general formula (1'): [wherein, R1a' and R1b' independently represent a hydrogen atom or a methyl group, R2' represents a methyl group, R3' represents a chlorine atom or a methyl group, Y' represents -CH-, -CR4'- or a nitrogen atom, R4' represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group, -V'- represents a group represented by any of the following formulas: (wherein, *' and **' represent the bonding positions with the benzene ring), R5a' and R5b' independently represent a hydrogen atom or an ethyl group, or R5a' and R5b' are bonded together to form cyclopropane, m' R6's independently represent a fluorine atom or a chlorine atom, m' represents an integer from 0 to 2, and W' represents an oxygen atom].

15. A compound or a pharmaceutically permissible salt thereof, wherein the compound is selected from any of the following group: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophen-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-Dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazapyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazazo-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid, and (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-2,3-Dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propionic acid.

16. A compound or a pharmaceutically permissible salt thereof, wherein the compound is selected from any of the following group: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid, and, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid.

17. A (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid or a pharmaceutically permissible salt thereof.

18. A (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyran-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid or a pharmaceutically permissible salt thereof.

19. A (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid or a pharmaceutically permissible salt thereof.

20. A (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazopyrido-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid or a pharmaceutically permissible salt thereof.

21. A compound or a pharmaceutically permissible salt thereof, the compound being represented by the following general formula (1''): [wherein, R1a'' and R1b'' independently represent a hydrogen atom or a methyl group, R2'' represents a methyl group, R3'' represents a chlorine atom or a methyl group, Y'' represents -CH-, -CR4''- or a nitrogen atom, R4'' represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group, -V''- represents a group represented by any of the following formulas: (wherein, *'' and **'' represent the bonding positions with the benzene ring), R5a'' and R5b'' independently represent a hydrogen atom or an ethyl group, or R5a'' and R5b'' are bonded together to form cyclopropane, R8'' represents a methyl group or an ethyl group, m'' each R6'' independently represent a chlorine atom or a hydroxyl group, m'' represents 0 or 1, U'' represents a nitrogen atom, and W'' represents an oxygen atom].

22. A compound or a pharmaceutically permissible salt thereof, wherein the compound is selected from any of the following group: (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazol-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propionic acid, (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazol-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propionic acid, (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazol-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazol-4(5H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazol-4(5H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid, (3R)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazol-4(5H)-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopon-4(5H)-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propionic acid, (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazopon-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propionic acid, (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]Oxyazopyran-4(5H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid, (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxyazopyran-4(5H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid, (3S)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazopyr-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, (3R)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazol-4(5H)-yl]methyl}-1-benzothiophene-5-yl)propionic acid, and (3S)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyridino[2,3-f][1,4]oxazol-4(5H)-yl]methyl}-2,3-dihydro-1H-indene-5-yl)propionic acid.

23. A pharmaceutical composition comprising, as an active ingredient, any one of claims 1 to 22, a compound or a pharmaceutically permissible salt thereof.

24. The pharmaceutical composition of claim 23, used to activate Nrf2.

25. The pharmaceutical composition of claim 23, used to inhibit the protein-protein interaction between Keap1 and Nrf2.

26. The pharmaceutical composition of claim 23, used to treat oxidative stress-related diseases.

27. The pharmaceutical composition of claim 26, wherein the oxidative stress-related diseases are selected from the group consisting of kidney disease, liver disease, respiratory diseases, skin diseases, cardiovascular diseases, central nervous system diseases, autoimmune diseases and eye diseases.

28. The pharmaceutical composition of claim 23, used to treat diseases selected from the group consisting of: Choose from the following groups of kidney diseases: chronic kidney disease, acute nephritis, acute renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; choose from the following groups of liver diseases: alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis, and cirrhosis; choose from the following groups of respiratory diseases: bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia, and asthma; choose from the following groups of skin diseases: ultraviolet and radiation-induced skin damage, radiation-induced mucosal damage, bullous epidermolysis bullosa, psoriasis, atopic dermatitis, and scleroderma; choose from the following groups of cardiovascular diseases: heart failure, myocardial infarction, arteriosclerosis, and pulmonary hypertension; choose from the following groups of Alzheimer's disease and Parkinson's disease. Central nervous system diseases in the group consisting of Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, glutamic acidosis, and autism; mitochondrial diseases in the group consisting of Friedreich recessive motor disorder and mitochondrial myopathy; autoimmune diseases in the group consisting of multiple sclerosis, chronic rheumatoid arthritis, systemic lupus erythematosus, Shoegrange syndrome, type 1 diabetes, ulcerative colitis, and Crohn's disease; and eye diseases in the group consisting of allergic conjunctival diseases, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal disorders, uveitis, Bessie's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma, and cataracts.

29. The pharmaceutical composition of claim 23, used to treat diseases selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

30. The pharmaceutical composition of claim 23, used to treat diseases selected from the group consisting of glaucoma, age-related macular degeneration, and retinitis pigmentosa.

31. The pharmaceutical composition of claim 23, used to treat radiation-induced skin damage or radiation-induced mucosal damage.

32. The pharmaceutical composition of claim 23, used to treat chronic obstructive pulmonary disease.

33. Use of any compound of claims 1 to 22 or a pharmaceutically permissible salt thereof for the manufacture of a therapeutic agent for diseases selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich recessive motor disorder, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

34. An Nrf2 activator comprising, as an active ingredient, a compound of any one of claims 1 to 22 or a pharmaceutically permissible salt thereof.

35. An inhibitor of the protein-protein interaction between Keap1 and Nrf2, comprising a compound of any one of claims 1 to 22 or a pharmaceutically permissible salt thereof as an active ingredient.

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