Nrf2 Activating Compounds

Abstract

The present invention addresses the problem of providing a compound having Nrf2-activation action. Provided are: compounds represented by general formula (I), or compounds of the lower-polarity group among two groups of diastereomers in which the carbon atom indicated by * in general formula (II) is an asymmetric carbon atom; salts of these; and solvates of these.

Description

[Technical field]

[0001] The present invention relates to an Nrf2 activating compound and the like. [Background technology]

[0002] Nrf2 (NF-E2-related factor 2) is a transcription factor that promotes the expression of oxidative stress defense genes. Nrf2 is ubiquitinated through interaction with Keap1 (Kelch-like ECH-associated protein 1) and degraded by the proteasome. Therefore, inhibition of the interaction between Nrf2 and Keap1 promotes the translocation of Nrf2 into the nucleus, activating the expression of oxidative stress defense genes. For example, Nrf2 activators are expected to be used as therapeutic agents for various diseases in the systemic field, such as multiple sclerosis, psoriasis, and diabetic nephropathy, and in the ophthalmological field, such as dry eye, diabetic retinopathy, retinitis pigmentosa, and glaucoma.

[0003] Patent Document 1 discloses an Nrf2 activator intended primarily for the treatment of COPD (chronic obstructive pulmonary disease). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2015 / 092713 Summary of the Invention [Problem to be solved by the invention]

[0005] An objective of the present invention is to provide a compound that has Nrf2 activation activity. [Means for solving the problem]

[0006] In view of the above problems, the present inventors have conducted intensive research and found that compounds represented by the general formula (I) described below, or compounds in the group with the lower polarity of two groups of diastereomers in which the carbon atom represented by * in the general formula (II) described below is an asymmetric carbon atom, their salts, and their solvates have Nrf2 activation activity. Based on this finding, further research was conducted and the present invention was completed.

[0007] That is, the present invention includes the following aspects.

[0008] Section 1. General formula (I):

[0009] [ka]

[0010] [In the formula: R 1 R represents an alkyl group. 2 R represents an optionally substituted thienyl group. 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group, or R 4 and R 5 are bonded together to form -NH-CH=N-. R 6 R represents an optionally substituted alkyl group. 7 is a hydroxy group, a hydrolyzable group, or -NR 71 R 72 (R 71 and R 72 are the same or different and each represents a hydrogen atom or -[C(=O)] 0-1 - represents a hydrocarbon group. 1 , A 2 , A 3 and A 4 are the same or different and represent CH or N (however, the number of N is one or less). Z represents a hydrogen atom or a halogen atom. A compound represented by the formula:

[0011] Section 2. General formula (II):

[0012] [ka]

[0013] [In the formula: R 1a and R 1b R represents an alkyl group. 2 R represents an optionally substituted thienyl group. 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group, or R 4 and R 5 are bonded together to form -NH-CH=N-. R 6 R represents an optionally substituted alkyl group. 7 is a hydroxy group, a hydrolyzable group, or -NR 71 R 72 (R 71 and R 72 are the same or different and each represents a hydrogen atom or -[C(=O)] 0-1 - represents a hydrocarbon group. 1 , A 2 , A 3 and A 4 are the same or different and represent CH or N (however, the number of N is one or less). Z represents a hydrogen atom or a halogen atom. Of the two diastereomers in which the carbon atom marked with * in the formula is an asymmetric carbon atom, the compound with the lower polarity, its salt, or a solvate thereof.

[0014] Item 3. The compound of the present invention is a compound of the above-mentioned R 6 Item 3. The compound according to Item 2, a salt thereof, or a solvate thereof, which is the first compound to be eluted when an isomeric mixture containing two diastereomers when the configuration of the compound is fixed is subjected to column separation (column type: CHIRAL ART Cellulose-SC, elution solvent: a 40 / 60 / 0.1 mixed solvent of n-hexane / ethanol / trifluoroacetic acid).

[0015] Item 4. The compound, salt, or solvate thereof according to any one of Items 1 to 3, wherein the substituent which may be present on the thienyl group includes an electron-withdrawing group.

[0016] Item 5. The compound, salt, or solvate thereof according to any one of Items 1 to 4, wherein the substituent which the thienyl group may have includes an acetyl group, a sulfamoyl group, a cyano group, or a cycloalkanecarbonyl group.

[0017] Section 6. Said R 2 is of the general formula (R2Aa) or (R2Ab):

[0018] [ka]

[0019] [In the formula: R 3 represents an acetyl group, a sulfamoyl group, a cyano group, or a cycloalkanecarbonyl group; and Y represents a hydrogen atom, an alkyl group, a halogen atom, or an alkoxy group. The compound, salt thereof, or solvate thereof according to any one of items 1 to 5, wherein R is a group represented by the following formula:

[0020] Section 7. Said R 3 Item 7. The compound, salt thereof, or solvate thereof according to item 6, wherein is an acetyl group.

[0021] Section 8. Said R 4 and the above R 5 and are the same or different and are a hydrogen atom or an alkyl group, or a salt thereof, or a solvate thereof according to item 6 or 7.

[0022] Section 9. Said R 2 is of the general formula (R2Aa):

[0023] [ka]

[0024] [In the formula: R 3represents an acetyl group; Y represents a hydrogen atom, an alkyl group, a halogen atom or an alkoxy group. and R 4 is a hydrogen atom, R 5 is an alkyl group, R 6 is an optionally substituted ethyl group, R 7 is a hydroxy group, The above A 1 , the above A 2 , and the A 4 are all CH, and the A 3 is CH or N, and wherein Z is a hydrogen atom; Item 9. The compound according to any one of items 1 to 8, a salt thereof, or a solvate thereof.

[0025] Item 9a. A compound, a salt thereof, or a solvate thereof according to any one of the following: (2R,3S)-3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methylpropanoic acid (compound A1), (2R,3S)-3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methylpropanoic acid (compound B1), (2R,3S)-3-(5-acetyl-4-methoxythiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methylpropanoic acid (compound C1). Item 9b. The compound (Compound D1), its salt, or a solvate thereof that is eluted first when 3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoic acid is separated on a column (column type: CHIRAL ART Cellulose-SC, elution solvent: a 40 / 60 / 0.1 mixed solvent of n-hexane / ethanol / trifluoroacetic acid).

[0026] Item 10. A medicine comprising at least one selected from the group consisting of the compound according to any one of items 1 to 9, 9a, and 9b, a salt thereof, and a solvate thereof.

[0027] Item 11. The pharmaceutical according to Item 10, which is an Nrf2 (NF-E2-related factor 2) activator.

[0028] Item 12. The pharmaceutical agent according to Item 10 or 11, which is a topical administration formulation.

[0029] Item 13. The pharmaceutical composition according to any one of Items 10 to 12, which is an ophthalmic preparation.

[0030] Item 14. The pharmaceutical composition according to Item 10 or 11, which is a parenteral administration formulation.

[0031] Item 15. The pharmaceutical agent according to Item 10, 11, or 14, which is an intravenous formulation.

[0032] Item 16. The medicine according to any one of Items 10 to 15, which is a medicine for preventing or treating a brain disease, a lung disease, a skin disease, an otorhinolaryngological disease, a kidney disease, or an ophthalmological disease.

[0033] Item 17. A method for preventing or treating a disease in which Nrf2 is involved, comprising administering to a patient at least one selected from the group consisting of the compound according to any one of items 1 to 9, 9a, and 9b, a salt thereof, and a solvate thereof.

[0034] Item 17a. The preventive or therapeutic method according to Item 17, wherein the patient has a disease in which Nrf2 is involved.

[0035] Item 17b. The method for preventing or treating the disease according to Item 17 or 17a, wherein the disease is a brain disease, a lung disease, a skin disease, an otorhinolaryngological disease, a kidney disease, or an ophthalmological disease.

[0036] Item 18: At least one substance selected from the group consisting of the compound according to any one of items 1 to 9, 9a, and 9b, a salt thereof, and a solvate thereof, for use as a medicine.

[0037] Item 19: At least one substance selected from the group consisting of the compound according to any one of items 1 to 9, 9a, and 9b, a salt thereof, and a solvate thereof, for use in the prevention or treatment of a disease in which Nrf2 is involved.

[0038] Item 19a. The substance for use according to Item 19, wherein the disease is a brain disease, a lung disease, a skin disease, an otolaryngological disease, a renal disease, or an ophthalmological disease.

[0039] Item 20: Use of at least one substance selected from the group consisting of the compound according to any one of items 1 to 9, 9a, and 9b, a salt thereof, and a solvate thereof, for the manufacture of a medicament.

[0040] Item 20a. The use according to Item 20, wherein the medicament is an Nrf2 (NF-E2-related factor 2) activator.

[0041] Item 20b. The use according to Item 20 or 20a, wherein the medicine is a medicine for preventing or treating a brain disease, a lung disease, a skin disease, an otorhinolaryngological disease, a kidney disease, or an ophthalmological disease. Effect of the Invention

[0042] According to the present invention, it is possible to provide a compound having an Nrf2 activating effect, a salt thereof, and a solvate thereof. Furthermore, according to the present invention, it is possible to provide a medicine containing at least one of these, more specifically, for example, an Nrf2 activator, a topical administration preparation, a medicine for preventing or treating brain diseases, lung diseases, skin diseases, otorhinolaryngological diseases, kidney diseases, ophthalmological diseases, and the like. [Brief description of the drawings]

[0043] [Figure 1] 1 shows an ORTEP diagram of the crystal structure of compound A1. [Diagram 2] 1 shows one of the most stable conformations of the anti type of the compounds of Example 1 and Reference Example 219. [Diagram 3] 1 shows one of the most stable conformations of the syn type of the compounds of Example 1 and Reference Example 219. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] In this specification, the expressions "contain" and "comprise" include the concepts of "contain", "include", "consist essentially of" and "consist only of".

[0045] 1.Compound In one aspect, the present invention provides a compound represented by general formula (I):

[0046] [ka]

[0047] The present invention relates to a compound represented by the following formula (1):

[0048] In one aspect, the present invention relates to a compound represented by the general formula (II):

[0049] [ka]

[0050] The present invention relates to a compound having a lower polarity among two diastereomers having the carbon atom marked with * as an asymmetric carbon atom, a salt thereof, or a solvate thereof.

[0051] These will be explained below. In the present specification, the above may be collectively referred to as "the compound of the present invention".

[0052] <1-1.R 1 , R 1a , R 1b > R 1 represents an alkyl group.

[0053] R 1 The alkyl group represented by the formula (I) includes both linear and branched (preferably linear) ones. The number of carbon atoms in the alkyl group is not particularly limited, but is, for example, 1 to 4, preferably 1 to 3, more preferably 1 to 2, and further preferably 1. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, and the like.

[0054] R 1a and R 1b represents an alkyl group.

[0055] R 1a or R 1b The alkyl group represented by R 1 The alkyl group represented by R 1a and R 1b In one particularly preferred embodiment of the invention, R 1a and R 1b are both methyl groups.

[0056] <1-2.R 2 > R 2 represents an optionally substituted thienyl group.

[0057] Examples of the thienyl group include a 2-thienyl group and a 3-thienyl group, and preferably a 2-thienyl group.

[0058] Examples of the substituent that the thienyl group may have include an acyl group such as an acetyl group or a cycloalkanecarbonyl group, a sulfamoyl group, a cyano group, -R 21 -NR 22 R 23 (R 21 R represents a single bond, a carbonyl group, or an alkylene group. 22 and R 23 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, or R 22 and R 23 are bonded to each other to form an alkylene group, which forms a ring together with the adjacent nitrogen atom.) alkoxy group, halogen atom, alkyl group, etc. The position of the above-mentioned substituent is not particularly limited, and may be, for example, any of the ring-constituting atoms (carbon atom and sulfur atom) on the thiophene ring, and preferably a carbon atom on the thiophene ring. The number of the above-mentioned substituents is not particularly limited, and may be, for example, 0 to 4, preferably 0 to 2, and more preferably 1 to 2.

[0059] The acyl group as a substituent that the thienyl group may have is not particularly limited as long as it is a group obtained by removing a hydroxy group from a carboxylic acid, but is preferably -CO-R 24 (R 24 R represents an alkyl group or a cycloalkyl group (preferably an alkyl group). 24 The alkyl group represented by the formula (I) includes both linear and branched (preferably linear) alkyl groups. The number of carbon atoms in the alkyl group is not particularly limited, but is, for example, 1 to 8, preferably 1 to 6, more preferably 1 to 4, further preferably 1 to 2, and particularly preferably 1. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a neopentyl group, an n-hexyl group, and a 3-methylpentyl group. R 24The number of carbon atoms in the cycloalkyl group represented by the following formula is not particularly limited, and is, for example, 3 to 8, preferably 3 to 6, more preferably 3 to 4, and further preferably 3. Preferred examples of the acyl group as the substituent include an acetyl group and a cycloalkanecarbonyl group, and particularly from the viewpoint of Nrf2 activation activity, an acetyl group is particularly preferred.

[0060] -R as a substituent that the thienyl group may have 21 -NR 22 R 23 Configure R 21 R represents a single bond, a carbonyl group, or an alkylene group (preferably a carbonyl group). 21 The alkylene group represented by the formula (I) includes both linear and branched (preferably linear) alkylene groups. The number of carbon atoms in the alkylene group is not particularly limited, but is, for example, 1 to 8, preferably 1 to 6, more preferably 1 to 4, further preferably 1 to 2, and particularly preferably 1. Specific examples of the alkylene group include a methylene group, an ethylene group, a propylene group, and a butylene group. -R as the above-mentioned substituent 21 -NR 22 R 23 Configure R 22 and R 23 are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, or R 22 and R 23 are bonded to each other to form an alkylene group and form a ring together with the adjacent nitrogen atom (preferably R 22 and R 23 are the same or different and each is a hydrogen atom or an alkyl group, and more preferably R 22 and R 23 is preferably a hydrogen atom and the other is an alkyl group, and more preferably R 22 and R 23 are both hydrogen atoms. 22 or R 23The alkyl group represented by the formula (I) includes both linear and branched (preferably linear) groups. The number of carbon atoms in the alkyl group is not particularly limited, but is, for example, 1 to 8, preferably 1 to 6, more preferably 1 to 4, even more preferably 1 to 2, and particularly preferably 1. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a neopentyl group, an n-hexyl group, and a 3-methylpentyl group. Examples of the substituent that the alkyl group may have include an alkoxy group. The alkoxy group includes both linear and branched (preferably linear) groups. The number of carbon atoms in the alkoxy group is not particularly limited, but is, for example, 1 to 8, preferably 1 to 6, more preferably 1 to 4, even more preferably 1 to 2, and particularly preferably 1. Specific examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.

[0061] The alkoxy group as a substituent that the thienyl group may have includes both linear and branched (preferably linear) ones. The number of carbon atoms in the alkoxy group is not particularly limited, but is, for example, 1 to 8, preferably 1 to 6, more preferably 1 to 4, further preferably 1 to 2, and particularly preferably 1. Specific examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.

[0062] Examples of the halogen atom as a substituent that the thienyl group may have include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., preferably a fluorine atom, a chlorine atom, etc., more preferably a fluorine atom.

[0063] The alkyl group as a substituent that the thienyl group may have includes both linear and branched (preferably linear) ones. The number of carbon atoms in the alkyl group is not particularly limited, but is, for example, 1 to 4, preferably 1 to 3, more preferably 1 to 2, and further preferably 1. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, and the like.

[0064] In a preferred embodiment of the present invention, the substituent that the thienyl group may have preferably includes an electron-withdrawing group (i.e., when there is one substituent, the substituent is an electron-withdrawing group, and when there are two or more substituents, at least one of the substituents is an electron-withdrawing group), and more preferably, the substituent that the thienyl group may have includes an acyl group, a sulfamoyl group, or a cyano group (more preferably an acetyl group, a sulfamoyl group, a cyano group, or a cycloalkanecarbonyl group, and particularly preferably an acetyl group from the viewpoint of Nrf2 activation activity) (i.e., when there is one substituent, the substituent is any of these groups, and when there are two or more substituents, at least one of the substituents is any of these groups). In these embodiments, preferably, the number of substituents that the heterocycle-derived group has is 0 to 2 (preferably 1 to 2), and when the number of the substituents is 2 or more, at least one of the substituents is an alkyl group, a halogen atom, or an alkoxy group (preferably an alkoxy group).

[0065] In a preferred embodiment of the present invention, R 2 is preferably represented by the general formula (R2A):

[0066] [ka]

[0067] [In the formula, Y represents a hydrogen atom, an alkyl group, a halogen atom, or an alkoxy group. 3 is an acyl group, a hydrogen atom, a sulfamoyl group, a cyano group, or -R 21 -NR 22R 23 ] More preferably, the group represented by the general formula (R2Aa) or (R2Ab):

[0068] [ka]

[0069] [Wherein: Y and R 3 is the same as above.] Examples of the group include a group represented by the following formula:

[0070] R 3 The substituents represented by R 2 The substituents which the thienyl group represented by the following formula (I) may have are the same as those in the formula (I).

[0071] R 3 is preferably an acyl group (preferably -CO-R 24 (R 24 represents an alkyl group or a cycloalkyl group), a sulfamoyl group, a cyano group, and the like, more preferably an acetyl group, a sulfamoyl group, a cyano group, a cycloalkanecarbonyl group, and the like, and particularly from the viewpoint of Nrf2 activation activity, an acetyl group is particularly preferred.

[0072] <1-3.R 4 , R 5 > R 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group, or R 4 and R 5 combine with each other to form -NH-CH=N-.

[0073] R 4 or R 5The alkyl group represented by the formula (I) includes both linear and branched (preferably linear) ones. The number of carbon atoms in the alkyl group is not particularly limited, but is, for example, 1 to 4, preferably 1 to 3, more preferably 1 to 2, and further preferably 1. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, and the like.

[0074] R 4 or R 5 The substituent that the alkyl group represented by the following formula may have is, for example, a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The number of the substituents is not particularly limited and is, for example, 0 to 3, and is preferably 0.

[0075] "R 4 and R 5 are bonded to each other to form -NH-CH=N-" means the following partial structure in general formula (I):

[0076] [ka]

[0077] But the following structure:

[0078] [ka]

[0079] The key is to take

[0080] In a preferred embodiment of the present invention, preferably R 4 and R 5 are the same or different and each is a hydrogen atom or an alkyl group, and more preferably R 4 and R 5 one of R is an alkyl group and the other is a hydrogen atom, and more preferably R 4 is a hydrogen atom and R 5is an alkyl group.

[0081] <1-4.R 6 > R 6 represents an optionally substituted alkyl group.

[0082] R 6 The alkyl group represented by the formula (I) includes both linear and branched (preferably linear) alkyl groups. The number of carbon atoms in the alkyl group is not particularly limited, but is, for example, 1 to 8, preferably 1 to 6, more preferably 1 to 4, further preferably 1 to 2, and particularly preferably 2. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a neopentyl group, an n-hexyl group, and a 3-methylpentyl group.

[0083] R 6 Examples of the substituent that the alkyl group represented by the formula (I) may have include a hydroxyl group, an alkoxy group, an arylalkoxy group, an aryloxy group, -NR 61 R 62 (R 61 and R 62 are the same or different and represent a hydrogen atom or an alkyl group.) The position of the above-mentioned substituent is not particularly limited, but in one embodiment of the present invention, it is preferably the terminal of the above-mentioned alkyl group. The number of the above-mentioned substituents is not particularly limited, and is, for example, 0 to 3, preferably 0 to 1.

[0084] The alkoxy group as the above-mentioned substituent includes both linear and branched (preferably linear) ones. The number of carbon atoms of the alkoxy group is not particularly limited, but is, for example, 1 to 8, preferably 1 to 6, more preferably 1 to 4, further preferably 1 to 2, and particularly preferably 1. Specific examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.

[0085] The arylalkoxy group as the substituent is not particularly limited as long as it is the alkoxy group substituted with an aryl group. The number of carbon atoms of the aryl group is not particularly limited, but is, for example, 6 to 14, preferably 6 to 8. Specific examples of such aryl groups include phenyl, naphthyl, biphenyl, pentalenyl, indenyl, anthryl, tetracenyl, pentacenyl, pyrenyl, perylenyl, fluorenyl, and phenanthryl groups, and particularly preferably phenyl. The substitution position of the aryl group in the alkoxy group is not particularly limited, but in one embodiment of the present invention, it is preferably the terminal of the alkoxy group. Examples of the arylalkoxy group include benzyloxy and phenethyloxy groups.

[0086] The number of carbon atoms of the aryloxy group as the above-mentioned substituent is not particularly limited, but is, for example, 6 to 14, preferably 6 to 8. Specific examples of the aryl group constituting the aryloxy group include a phenyl group, a naphthyl group, a biphenyl group, a pentalenyl group, an indenyl group, an anthranyl group, a tetracenyl group, a pentacenyl group, a pyrenyl group, a perylenyl group, a fluorenyl group, and a phenanthryl group, and particularly preferably a phenyl group. Examples of the above-mentioned aryloxy group include a phenyloxy group.

[0087] -NR as the above substituent 61 R 62 Configure R 61 and R 62 R may be the same or different and represents a hydrogen atom or an alkyl group. 61 or R 62The alkyl group represented by the formula (I) includes both linear and branched (preferably linear) alkyl groups. The number of carbon atoms in the alkyl group is not particularly limited, but is, for example, 1 to 8, preferably 1 to 6, more preferably 1 to 4, further preferably 1 to 2, and particularly preferably 2. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a neopentyl group, an n-hexyl group, and a 3-methylpentyl group.

[0088] In a preferred embodiment of the present invention, preferably R 6 represents an alkyl group which may be substituted with a hydroxyl group, an alkoxy group, or an arylalkoxy group, more preferably an alkyl group which may be substituted with an arylalkoxy group, and even more preferably an alkyl group.

[0089] R 6 The configuration of is not particularly limited, and the configuration p:

[0090] [ka]

[0091] Or, configuration q:

[0092] [ka]

[0093] In a preferred embodiment of the present invention, R 6 The configuration of is configuration p.

[0094] <1-5.R 7 > R 7 is a hydroxy group, a hydrolyzable group, -NR 71 R 72 (R 71 and R 72are the same or different and each represents a hydrogen atom or -[C(=O)] 0-1 - represents a hydrocarbon group.

[0095] The hydrolyzable group is R 7 There are no particular limitations on the hydrolyzable group, so long as the ester bond formed with the carbonyl group adjacent to R is a group that is hydrolyzed (preferably under physiological conditions or by an enzyme such as esterase) to produce a hydroxy group. 7 A group that forms an ester bond with the adjacent carbonyl group (-OR x (R x is an optional substituent), specific examples of which include an alkoxy group, an aryloxy group (aryl group-O-), an arylalkoxy group (an alkoxy group substituted with an aryl group), an alkylaryloxy group (an aryloxy group substituted with an alkyl group), an aralkyloxy group (an alkoxy group substituted with an aryl group), an alkoxyalkoxy group (an alkoxy group substituted with an alkoxy group), an acyloxy group, and an acyloxyalkoxy group (an alkoxy group substituted with an acyloxy group).

[0096] 「-[C(=O)] 0-1 -Hydrocarbon group" is [C(=O)] 0 In the case of [C(=O)], it is a "-hydrocarbon group". 1 In the case of (a), it is "-C(=O)-hydrocarbon group".

[0097] R 71 and R 72 The "hydrocarbon group" in the definition is not particularly limited, and typical examples include an alkyl group, an aryl group, and the like.

[0098] R 7 is preferably a hydroxy group.

[0099] <1-6.A 1 , A 2 , A 3 , A 4 > A 1 , A2 , A 3 and A 4 are the same or different and represent CH or N (provided that N is 1 or less).

[0100] A 1 , A 2 , A 3 and A 4 If any one of is N, then preferably A 1 Or A 3 is N, more preferably A 3 is N.

[0101] In a preferred embodiment of the present invention, preferably, A 1 , A 2 and A 4 are all CH and A 3 is CH or N.

[0102] <1-7.Z> Z represents a hydrogen atom or a halogen atom.

[0103] Examples of the halogen atom represented by Z include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., preferably a fluorine atom, a chlorine atom, etc., more preferably a fluorine atom.

[0104] When Z is a halogen atom, the bonding position is A 1 , A 2 , A 3 and A 4 For example, A 4 It is.

[0105] In a preferred embodiment of the present invention, Z is preferably a hydrogen atom.

[0106] <1-8.Polarity> The compound of general formula (II) is the compound with the lower polarity of two diastereomers in which the carbon atom indicated by * in general formula (II) is an asymmetric carbon atom.

[0107] The two diastereomers having the carbon atom marked with * as an asymmetric carbon atom are, namely, R 2 The configuration of is configuration a:

[0108] [ka]

[0109] (diastereomer a) and R 2 The configuration of is configuration b:

[0110] [ka]

[0111] There are two diastereomers (diastereomer b) which are

[0112] In addition, each of the diastereomer a and the diastereomer b includes a diastereomer p (R 6 The configuration of the above is the configuration p) and the diastereomer q (R 6 The configuration of R includes the above configuration q). 2 The configuration of is configuration a and R 6 The diastereomer with the configuration p is denoted as diastereomer ap, and the others are denoted similarly. Therefore, diastereomer a includes diastereomers ap and aq, and diastereomer b includes diastereomers bp and bq. The "compound with the lower polarity of the two diastereomers" is the compound with the lower polarity R 6 When the configuration of is fixed (i.e., R 6 of the two diastereomers (when the configuration of is fixed to configuration p or configuration q), specifically, it means the compound with the lower polarity between diastereomer ap and diastereomer bp, and the compound with the lower polarity between diastereomer aq and diastereomer bq.

[0113] In a preferred embodiment of the present invention, the compound of general formula (II) is preferably an asymmetric carbon atom represented by * in the formula (II), particularly from the viewpoint of the compound having a lower cytotoxicity. 6 When a mixture of isomers containing two diastereomers (diastereomer ap and diastereomer bp, or diastereomer aq and diastereomer bq) with the configuration of the isomers fixed is subjected to column separation (column type: CHIRAL ART Cellulose-SC, elution solvent: a 40 / 60 / 0.1 mixed solvent of n-hexane / ethanol / trifluoroacetic acid), the compound that is eluted first (diastereomer ap or diastereomer bp, or diastereomer aq or diastereomer bq) is used. More specifically, this column separation is performed under the following conditions: flow rate: 2.35 mL / min, temperature: ambient, detection wavelength: UV at 293 nm, injection amount: 18 mg (13 mg / mL), system: Prominence (Shimadzu).

[0114] <1-9.General formula> In one embodiment of the present invention, among the general formula (I), preferably the general formula (IA):

[0115] [ka]

[0116] [In the formula: R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , A 1 , A 2 , A 3 , A 4 , Y and Z are the same as above.] More preferably, the compound represented by the general formula (IAA):

[0117] [ka]

[0118] [In the formula: R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , A 3 , Y and Z are the same as above.] More preferably, the compound represented by the general formula (IAAA):

[0119] [ka]

[0120] [In the formula: R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , A 3 and Y is the same as above.] and more preferably the general formula (IAAAA):

[0121] [ka]

[0122] [In the formula: R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , A 3 and Y is the same as above.] Examples include:

[0123] In one embodiment of the present invention, among the general formula (II), preferably the general formula (IIA):

[0124] [ka]

[0125] [In the formula: R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 , A 1 , A 2 , A 3 , A 4 , Y and Z are the same as above.] More preferably, the compound represented by the general formula (IIAA):

[0126] [ka]

[0127] [In the formula: R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 , A 3 , Y and Z are the same as above.] More preferably, the compound represented by the general formula (IIAAA):

[0128] [ka]

[0129] [In the formula: R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 and A 3 is the same as above.] More preferably, the compound represented by the general formula (IIAAAA):

[0130] [ka]

[0131] [In the formula: R 1a, R 1b , R 3 , R 4 , R 5 , R 6 and R 7 is the same as above.] Examples include:

[0132] In a preferred embodiment of the present invention, the R 2 is of the general formula (R2Aa):

[0133] [ka]

[0134] [In the formula: R 3 represents an acetyl group; Y represents a hydrogen atom, an alkyl group, a halogen atom or an alkoxy group. and R 4 is a hydrogen atom, R 5 is an alkyl group, R 6 is an optionally substituted ethyl group, R 7 is a hydroxy group, The above A 1 , the above A 2 , and the A 4 are all CH, and the A 3 is CH or N, and wherein Z is a hydrogen atom; It is preferred.

[0135] <1-10.Other> The salt of the compound is not particularly limited as long as it is a pharmaceutically acceptable salt. The salt may be either an acid salt or a basic salt. Examples of acid salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; organic acid salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, and paratoluenesulfonate; examples of basic salts include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt; salts with ammonia; salts with organic amines such as morpholine, piperidine, pyrrolidine, monoalkylamine, dialkylamine, trialkylamine, mono(hydroxyalkyl)amine, di(hydroxyalkyl)amine, and tri(hydroxyalkyl)amine.

[0136] The solvate of the compound is not particularly limited. Examples of the solvent constituting the solvate include water and pharma- ceutically acceptable organic solvents (e.g., ethanol, glycerol, acetic acid, etc.).

[0137] 2. Manufacturing method The compounds of the present invention can be prepared in a variety of ways.

[0138] The compounds of the present invention can be produced, for example, by the method shown in Scheme 1 below or a method analogous thereto.

[0139] [ka]

[0140] In step a, synthetic intermediate 2 and synthetic intermediate 3 are reacted in the presence of a catalyst and a base to produce synthetic intermediate 4. For synthetic intermediate 2, synthetic intermediate 3 can be used in, for example, 1 to 5 equivalents, preferably 1.2 to 3 equivalents, and the catalyst can be used in, for example, 0.05 to 0.5 equivalents, preferably 0.05 to 0.2 equivalents, and the base can be used in, for example, 1.5 to 5 equivalents, preferably 1.5 to 3 equivalents. The catalyst can be, for example, a rhodium complex, preferably [RhCl(cod)]. 2 Examples of the base include N,N-dicyclohexylmethylamine, triethylamine, pyridine, N,N-diisopropylethylamine, and the like, preferably triethylamine. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, and the like, preferably 1,4-dioxane. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 1 hour to 18 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 150°C, preferably 25°C to 100°C.

[0141] In step b, synthetic intermediate 4 is reacted with iodomethane in the presence of a base to produce synthetic intermediate 5. Lithium diisopropylamide can be used in an amount of, for example, 1 to 2 equivalents, preferably 1 to 1.8 equivalents, and iodomethane can be used in an amount of, for example, 1 to 20 equivalents, preferably 1 to 15 equivalents, relative to synthetic intermediate 4. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include tetrahydrofuran and the like. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 1 hour to 5 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually -78°C to 40°C, preferably -78°C to 25°C.

[0142] In step c, a deprotection reaction of the acetal of the synthetic intermediate 5 is carried out. An excess amount of hydrochloric acid is used relative to the synthetic intermediate 5. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include methanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, etc., and preferably methanol or tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 1 hour to 18 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 25°C to 150°C, preferably 25°C to 100°C.

[0143] In step d, the compound of the present invention is produced by hydrolysis of synthetic intermediate 4 or an ester equivalent thereto. For example, 5 to 20 equivalents, preferably 10 to 20 equivalents of a base can be used relative to synthetic intermediate 4. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and preferably sodium hydroxide or lithium hydroxide. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples include methanol, dichloromethane, tetrahydrofuran, and the like, and preferably methanol or tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 1 hour to 18 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 25°C to 150°C, and preferably 25°C to 140°C.

[0144] The compounds of the present invention can also be produced, for example, according to the method shown in the following Scheme 2 or a method analogous thereto.

[0145] [ka]

[0146] Step d of Scheme 2 is carried out according to Scheme 1.

[0147] In step e, synthetic intermediate 8 is produced from synthetic intermediate 6 and synthetic intermediate 7. For synthetic intermediate 6, synthetic intermediate 7 can be used in an amount of, for example, 1 to 1.5 equivalents, preferably 1 to 1.2 equivalents, and n-butyllithium can be used in an amount of, for example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include tetrahydrofuran and the like. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 10 hours, preferably 1 hour to 4 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually -80°C to 25°C, preferably -78°C to 25°C.

[0148] In step f, synthetic intermediate 9 is produced from synthetic intermediate 8. For synthetic intermediate 8, trichloroacetonitrile can be used in an amount of, for example, 1 to 3 equivalents, preferably 1 to 2 equivalents, 1,8-diazabicyclo[5,4,0]-7-undecene can be used in an amount of, for example, 0.01 to 0.1 equivalents, preferably 0.01 to 0.05 equivalents, dimethylketene methyltrimethylsilyl acetal can be used in an amount of, for example, 1 to 3 equivalents, preferably 1 to 2.5 equivalents, and bis(trifluoromethanesulfonyl)imide can be used in an amount of, for example, 0.01 to 0.1 equivalents, preferably 0.05 to 0.1 equivalents. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, tetrahydrofuran, acetonitrile, etc., and preferably acetonitrile. The reaction time varies depending on the reagent or solvent used, but is usually 1 to 10 hours, preferably 1 to 5 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 25°C, preferably 10°C to 25°C.

[0149] In step g, synthetic intermediate 10 is produced from synthetic intermediate 9. For synthetic intermediate 9, 2,3-dichloro-5,6-dicyano-p-benzoquinone can be used in an amount of, for example, 1 to 3 equivalents, preferably 1 to 2.5 equivalents. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and an example of the solvent is a mixed solvent of dichloromethane and water. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 5 hours, preferably 1 hour to 3 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 25°C, preferably 10°C to 25°C.

[0150] In step h, synthetic intermediate 12 is produced from synthetic intermediate 10 and synthetic intermediate 11. For synthetic intermediate 10, synthetic intermediate 11 can be used in an amount of, for example, 1 to 2 equivalents, preferably 1 to 1.2 equivalents, triphenylphosphine can be used in an amount of, for example, 1 to 2 equivalents, preferably 1 to 1.2 equivalents, and diethyl azodicarboxylate can be used in an amount of, for example, 1 to 1.5 equivalents, preferably 1 to 1.2 equivalents. Instead of diethyl azodicarboxylate, bis(2-methoxyethyl) azodicarboxylate, diisopropyl azodicarboxylate, cyanomethylene tributylphosphorane, etc. can also be used. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, N,N-dimethylformamide, etc., and preferably tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 5 hours to 8 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0° C. to 40° C., preferably 0° C. to 25° C.

[0151] The synthetic intermediates 2, 6, and 11 in Schemes 1 and 2 can be produced according to known methods, such as those described in Patent Document 1 (WO2015 / 092713) and WO2016 / 202253, or methods analogous thereto, for example, Scheme 3 below.

[0152] [ka]

[0153] Step h of Scheme 3 is carried out according to Scheme 2.

[0154] In step i, synthetic intermediate 14 is produced by an amination reaction of synthetic intermediate 13. An excess amount of aqueous ammonia is used relative to synthetic intermediate 13. The reaction time varies depending on the reagents or solvent used, but is usually 1 hour to 24 hours, preferably 1 hour to 18 hours. The reaction temperature varies depending on the reagents or solvent used, but is usually 25°C to 150°C, preferably 25°C to 40°C.

[0155] In step j, synthetic intermediate 14 and synthetic intermediate 15 are reacted to produce synthetic intermediate 11 via synthetic intermediate 16.

[0156] In the first step, synthetic intermediate 14 and synthetic intermediate 15 are reacted in the presence of a base. For example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents, of synthetic intermediate 14 can be used, and for example, 0.8 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents of synthetic intermediate 15 can be used. Examples of the base include potassium carbonate and sodium carbonate, and preferably potassium carbonate. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples include a mixed solvent of an organic solvent such as tetrahydrofuran or dimethylformamide and water, and preferably a mixed solvent of tetrahydrofuran and water. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, and preferably 1 hour to 3 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 25°C to 150°C, and preferably 25°C to 40°C.

[0157] In the second step, synthetic intermediate 11 is produced from synthetic intermediate 16 in the presence of a base. For example, 1 to 5 equivalents, preferably 2 to 3 equivalents of a base can be used relative to synthetic intermediate 16. Examples of the base include potassium tert-butoxide, potassium carbonate, potassium hydroxide, and the like, and preferably potassium tert-butoxide. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples include dimethyl sulfoxide, dimethylformamide, and the like, and preferably dimethyl sulfoxide. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, and preferably 1 hour to 3 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 25°C to 150°C, and preferably 60°C to 100°C.

[0158] In step k, synthetic intermediate 18 is produced by reduction reaction of synthetic intermediate 17. For example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents of a reducing agent can be used relative to synthetic intermediate 17. Examples of the reducing agent include borane-tetrahydrofuran complex and borane-dimethylsulfide complex. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and an example of the solvent is tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 40 hours, preferably 1 hour to 24 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 25°C to 150°C, preferably 25°C to 40°C.

[0159] In step 1, synthetic intermediate 19 is reacted with bis-pinacolatodiboron in the presence of a base and a catalyst to produce synthetic intermediate 2. For synthetic intermediate 19, for example, 1 to 3 equivalents, preferably 1 to 2.5 equivalents of base can be used, for example, 0.05 to 0.1 equivalents, preferably 0.05 to 0.08 equivalents of catalyst can be used, and for example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents of bis-pinacolatodiboron can be used. For example, potassium acetate can be used as the base. For example, PdCl 2 (dppf)2 -CH 2 Cl 2 , Pd 2 (dba) 3 Palladium catalysts such as PdCl 2 (dppf) 2 -CH 2 Cl 2 The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, and the like, and preferably 1,4-dioxane. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 5 hours to 8 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 60°C to 120°C, preferably 60°C to 100°C.

[0160] In step m, synthetic intermediate 20 is produced from synthetic intermediate 18. For synthetic intermediate 20, sodium hydride can be used in an amount of, for example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents, and p-methoxybenzyl chloride can be used in an amount of, for example, 1 to 2 equivalents, preferably 1 to 1.2 equivalents. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include tetrahydrofuran and N,N-dimethylformamide, and preferably N,N-dimethylformamide. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 5 hours to 15 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 60°C, preferably 0°C to 25°C.

[0161] In step n, synthetic intermediate 6 is produced from synthetic intermediate 20. For synthetic intermediate 20, n-butyllithium can be used in an amount of, for example, 1 to 1.5 equivalents, preferably 1 to 1.2 equivalents, and N,N-dimethylformamide can be used in an amount of, for example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include tetrahydrofuran and the like. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 10 hours, preferably 1 hour to 3 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually -80°C to 25°C, preferably -78°C to 25°C.

[0162] The synthetic intermediate 3 can be obtained, for example, by the methods shown in the following Schemes 4 to 7 or methods analogous thereto.

[0163] [ka]

[0164] In step o, synthetic intermediate 21 and N,O-dimethylhydroxylamine hydrochloride are reacted in the presence of a base, a condensing agent, and an additive to produce synthetic intermediate 22. N,O-dimethylhydroxylamine hydrochloride can be used in an amount of usually 1 to 3 equivalents, preferably 1.5 to 2 equivalents, relative to synthetic intermediate 21. Furthermore, a condensing agent can be used in an amount of usually 1 to 3 equivalents, preferably 1 to 2 equivalents, an additive can be used in an amount of usually 0.1 to 2 equivalents, preferably 1 to 2 equivalents, and a base can be used in an amount of usually 0.5 to 5 equivalents, preferably 2 to 4 equivalents, relative to synthetic intermediate 21. Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N Examples of the additive include 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxysuccinimide, and the like, and preferably 1-hydroxybenzotriazole. Examples of the base include triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, and the like, and preferably triethylamine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. The reaction is usually carried out in a solvent.The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, acetonitrile, N,N-dimethylformamide, and the like, and preferably includes dichloromethane or N,N-dimethylformamide. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 100°C, preferably 25°C to 40°C.

[0165] In step p, synthetic intermediate 23 or synthetic intermediate 25 is produced from synthetic intermediate 22 or synthetic intermediate 24 by bromination reaction. N-bromosuccinimide can be used usually in an amount of 1 to 5 equivalents, preferably 2 to 3 equivalents, and trifluoroacetic acid can be used usually in an amount of 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to synthetic intermediate 22 or synthetic intermediate 24. Concentrated sulfuric acid, concentrated hydrochloric acid, acetic acid, etc. can also be used instead of trifluoroacetic acid. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, chloroform, carbon tetrachloride, 1,2-dimethoxyethane, N,N-dimethylformamide, etc., and preferably N,N-dimethylformamide. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 100°C, preferably 25°C to 40°C.

[0166] In step q, synthetic intermediate 25 is produced from synthetic intermediate 23. For example, 1 to 3 equivalents, preferably 1 to 1.5 equivalents of methylmagnesium bromide can be used relative to synthetic intermediate 23. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, etc., and preferably tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 100°C, preferably 0°C to 40°C.

[0167] In step r, the synthetic intermediate 25 is reacted with ethylene glycol in the presence of an acid catalyst to produce a synthetic intermediate 26. For the synthetic intermediate 25, the acid catalyst can be used in an amount of, for example, 0.1 to 5 equivalents, preferably 0.1 to 0.5 equivalents, and ethylene glycol can be used in an amount of, for example, 5 to 20 equivalents, preferably 10 to 15 equivalents. Examples of the acid catalyst include p-toluenesulfonic acid monohydrate, hydrochloric acid, trifluoroacetic acid, and the like, and preferably p-toluenesulfonic acid monohydrate. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include toluene, benzene, and the like, and preferably toluene. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, and preferably 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 40°C to 150°C, and preferably 100°C to 130°C.

[0168] In step s, synthetic intermediate 25 or synthetic intermediate 26 is reacted with methyl acrylate in the presence of a catalyst, a base, and an additive to produce synthetic intermediate 27. For synthetic intermediate 25 or synthetic intermediate 26, the catalyst can be used in an amount of, for example, 0.05 to 0.2 equivalents, preferably 0.05 to 0.1 equivalents, the base can be used in an amount of, for example, 1.5 to 5 equivalents, preferably 1.5 to 3 equivalents, the additive can be used in an amount of, for example, 0.05 to 0.2 equivalents, preferably 0.05 to 0.1 equivalents, and the methyl acrylate can be used in an amount of, for example, 1.5 to 3 equivalents, preferably 1.5 to 2 equivalents. Examples of the catalyst include PdCl 2 (dppf) 2 CHCl 3 , Pd(OAc) 2 , PdCl 2 (PPh 3 ) 2 , Pd(PPh 3 ) 4 Palladium catalysts such as PdCl 2 (dppf) 2 CHCl 3 Examples of the base include N,N-dicyclohexylmethylamine, triethylamine, pyridine, N,N-diisopropylethylamine, and the like, and preferably N,N-dicyclohexylmethylamine. Examples of the additive include tetrabutylammonium chloride, tetrabutylammonium iodide, and the like, and preferably tetrabutylammonium chloride. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dimethylformamide, dimethylacetamide, and the like, and preferably dimethylacetamide. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 1 hour to 8 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 40°C to 150°C, preferably 100°C to 140°C, using microwaves.

[0169] [ka]

[0170] Scheme 5 is carried out similarly to steps o and s of Scheme 4, except that in step o, the corresponding amine is used instead of N,O-dimethylhydroxylamine hydrochloride.

[0171] [ka]

[0172] Step s of Scheme 6 is carried out according to Scheme 4.

[0173] In step t, synthetic intermediate 29 is produced from synthetic intermediate 28. For synthetic intermediate 28, 1 to 3 equivalents, preferably 1 to 1.5 equivalents of methylmagnesium bromide can be used. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, etc., and preferably tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 100°C, preferably 0°C to 40°C.

[0174] In step u, the synthetic intermediate 29 is oxidized with a sulfur trioxide-pyridine complex in the presence of a base to produce a synthetic intermediate 30. For example, 1 to 5 equivalents, preferably 1 to 3 equivalents, of the base can be used relative to the synthetic intermediate 29, and 1 to 3 equivalents, preferably 1 to 2.5 equivalents of the sulfur trioxide-pyridine complex can be used. Examples of the base include triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine, and preferably triethylamine can be used. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and preferably dimethyl sulfoxide can be used. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, preferably 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0° C. to 100° C., and preferably 0° C. to 40° C.

[0175] Furthermore, synthetic intermediate 3 can be produced according to a known method, for example, the method described in JP2008 / 273924, or a method analogous thereto, for example, Scheme 7 below.

[0176] [ka]

[0177] Steps p and s in Scheme 7 are carried out according to Scheme 4.

[0178] In step v, synthetic intermediate 31 is reacted with tert-butylamine and acetic acid to produce synthetic intermediate 32. For synthetic intermediate 31, tert-butylamine can be used in an amount of, for example, 1 to 3 equivalents, preferably 1 to 1.5 equivalents, and acetic acid can be used in an amount of, for example, 1 to 20 equivalents, preferably 2.5 to 5 equivalents. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, toluene, etc., and preferably dichloromethane. The reaction time varies depending on the reagent or solvent used, but is usually 1 to 5 hours, preferably 2 to 4 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 40°C, preferably 10 to 30°C.

[0179] In step w, synthetic intermediate 34 is produced by a deprotection reaction of tert-butylamine in synthetic intermediate 33. For synthetic intermediate 33, a mixed solvent of trifluoroacetic acid and water can be preferably used. The ratio of the mixed solvent is trifluoroacetic acid / water=10-20 / 1-5, preferably trifluoroacetic acid / water=10-12 / 1-2. The reaction time varies depending on the reagents or solvent used, but is usually 1-5 hours, preferably 2-4 hours. The reaction temperature varies depending on the reagents or solvent used, but is usually 0° C. to 150° C., preferably 90° C. to 110° C.

[0180] The compound of the present invention can also be produced by using synthetic intermediate 38 instead of synthetic intermediate 10 in Scheme 2. Synthetic intermediate 38 can also be produced, for example, according to the method shown in Scheme 8 below or a method analogous thereto.

[0181] [ka]

[0182] The steps of Scheme 8 are carried out in accordance with Schemes 1 to 3.

[0183] The compound of the present invention can also be produced by using synthetic intermediate 47 instead of synthetic intermediate 2 in Scheme 1. Synthetic intermediate 47 can also be produced, for example, according to the method shown in Scheme 9 below or a method analogous thereto.

[0184] [ka]

[0185] Step l of Scheme 9 is carried out according to Scheme 3.

[0186] In step x, synthetic intermediate 40 is produced from synthetic intermediate 39. Bromine can be used in an amount of, for example, 1 to 2 equivalents, preferably 1 to 1.2 equivalents, based on synthetic intermediate 39. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include acetic acid, trifluoroacetic acid, and the like, and acetic acid is preferably used. The reaction time varies depending on the reagent or solvent used, but is usually 0.5 to 3 hours, preferably 1 to 2 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 40°C, preferably 0°C to 25°C.

[0187] In step y, synthetic intermediate 41 is produced from synthetic intermediate 40. For example, 1 to 10 equivalents, preferably 2 to 5 equivalents of tin(II) chloride can be used relative to synthetic intermediate 40. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include methanol, ethanol, propanol, isopropanol, etc., and methanol is preferably used. The reaction time varies depending on the reagents or solvent used, but is usually 1 to 6 hours, preferably 1.5 to 4 hours. The reaction temperature varies depending on the reagents or solvent used, but is usually 0°C to 100°C, preferably 60°C to 80°C.

[0188] In step z, a synthetic intermediate 42 is produced from a synthetic intermediate 41. An excess amount of formic acid is used relative to the synthetic intermediate 41. The reaction time is usually 0.5 to 5 hours, preferably 1 to 2 hours. The reaction temperature is usually 25°C to 150°C, preferably 90°C to 110°C.

[0189] In step a-1, synthetic intermediate 43 is produced from synthetic intermediate 42. Trityl chloride can be used, for example, in an amount of 1 to 3 equivalents, preferably 1.1 to 1.3 equivalents, relative to synthetic intermediate 42, and a base can be used, for example, in an amount of 1 to 3 equivalents, preferably 1.1 to 1.7 equivalents. Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine, and preferably N-methylmorpholine or triethylamine. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, acetonitrile, and N,N-dimethylformamide, and preferably dichloromethane. The reaction time varies depending on the reagent or solvent used, but is usually 1 to 12 hours, and preferably 1 to 2 hours. The reaction temperature varies depending on the reagents or solvent used, but is usually 0°C to 100°C, preferably 40°C to 60°C.

[0190] In step a-2, synthetic intermediate 44 is produced from synthetic intermediate 43. For synthetic intermediate 43, for example, 1 to 5 equivalents, preferably 1.5 to 3 equivalents of a reducing agent can be used. Examples of the reducing agent include lithium borohydride, lithium aluminum hydride, lithium borohydride, and borane-tetrahydrofuran complex, and preferably lithium borohydride. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and preferably tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, but is usually 0.2 to 3 hours, and preferably 0.5 to 1.5 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0° C. to 60° C., and preferably 0° C. to 30° C.

[0191] In step a-3, methanesulfonyl chloride and lithium chloride are reacted in the presence of a base to produce a synthetic intermediate 45 from the synthetic intermediate 44. For the synthetic intermediate 44, methanesulfonyl chloride can be used in an amount of, for example, 1 to 5 equivalents, preferably 1.5 to 2.5 equivalents, lithium chloride can be used in an amount of, for example, 1 to 10 equivalents, preferably 3 to 5 equivalents, and a base can be used in an amount of, for example, 1 to 10 equivalents, preferably 3 to 8 equivalents. Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine, and N,N-diisopropylethylamine is preferred. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide, and preferred is dichloromethane. The reaction time varies depending on the reagent or solvent used, but is usually 1 to 24 hours, preferably 1 to 12 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0° C. to 40° C., preferably 0° C. to 25° C.

[0192] In step a-4, synthetic intermediate 45 is reacted with synthetic intermediate 11 and tetrabutylammonium iodide in the presence of a base to produce synthetic intermediate 46. For synthetic intermediate 45, synthetic intermediate 11 can be used in an amount of, for example, 1 to 3 equivalents, preferably 1 to 1.2 equivalents, tetrabutylammonium iodide can be used in an amount of, for example, 0.1 to 1 equivalents, preferably 0.1 to 0.2 equivalents, and a base can be used in an amount of, for example, 1 to 5 equivalents, preferably 1 to 3 equivalents. Examples of the base include potassium carbonate, sodium carbonate, and sodium hydrogen carbonate, and potassium carbonate is preferred. The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, and preferably N,N-dimethylformamide. The reaction time varies depending on the reagent or solvent used, but is usually 1 to 24 hours, preferably 1 to 18 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 60°C, preferably 25°C to 40°C.

[0193] The compounds of the present invention can also be produced, for example, according to the method shown in Scheme 10 below or a method analogous thereto.

[0194] [ka]

[0195] Steps a-3 and a-4 in Scheme 10 are carried out according to Scheme 9, and step d is carried out according to Scheme 1.

[0196] The compounds of the present invention can also be produced, for example, according to the method shown in the following Scheme 11 or a method analogous thereto.

[0197] [ka]

[0198] Steps c and d in Scheme 11 are carried out in accordance with Scheme 1, step g in accordance with Scheme 2, and steps a-3 and a-4 in Scheme 9.

[0199] <Process a-5> In step a-5, compound 49 is produced from compound 9. Tetrabutylammonium fluoride is used in an amount of 2 to 5 equivalents, preferably 2 to 3 equivalents, relative to compound 9. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include tetrahydrofuran and N,N-dimethylformamide, and preferably tetrahydrofuran is used. The reaction time varies depending on the reagent or solvent used, but is usually 1 to 24 hours, preferably 1 to 3 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 100°C, preferably 25°C to 40°C.

[0200] <Process a-6> In step a-6, compound 50 is produced from compound 49. Manganese dioxide is used in an amount of 10 to 50 equivalents, preferably 25 to 50 equivalents, relative to compound 49. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include dichloromethane, acetone, benzene, toluene, tetrahydrofuran, 1,4-dioxane, and the like, and dichloromethane is preferably used. The reaction time varies depending on the reagent or solvent used, but is usually 1 to 24 hours, preferably 2 to 24 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 100°C, preferably 25°C to 40°C.

[0201] <Process a-7> In step a-7, compound 52 is produced from compound 51. TMS ethanol is used in an amount of 1 to 5 equivalents, preferably 3 to 5 equivalents, relative to compound 51. A condensing agent is usually used in an amount of 1 to 3 equivalents, preferably 1.5 to 2 equivalents, and a base is usually used in an amount of 1 to 5 equivalents, preferably 2 to 5 equivalents. Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, diethyl cyanophosphate, diphenylphosphoryl azide, pentafluorophenyl trifluoroacetate, isopropyl chloroformate, and the like. Preferred is O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium. Examples of the base include hexafluorophosphate and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. Examples of the base include triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, and the like, and preferably triethylamine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, acetonitrile, N,N-dimethylformamide, and the like, and preferably dichloromethane or N,N-dimethylformamide. The reaction time varies depending on the reagent or solvent used, but is usually 1 hour to 24 hours, and preferably 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, but is usually 0°C to 100°C, preferably 25°C to 40°C.

[0202] The compound of general formula (I) can be prepared, for example, by reacting R 1 Configuration and R 2 The syn isomer mixture (S,S and R,R) is a syn isomer mixture of 1 Configuration and R 2 The compound of formula (I) can be obtained by separating the compound of formula (I) from the anti-isomer mixture (S,R and R,S) (separation 1), carrying out the synthesis reaction described in the subsequent scheme using the anti-isomer mixture, and separating the compound of formula (I) from the anti-isomer mixture in the final step (separation 2). Separation 1 can be carried out, for example, by silica gel column chromatography. In separation 1, the anti-isomer mixture has a longer retention time than, for example, the syn-isomer mixture. Separation 2 can be carried out, for example, by chromatography using a chiral column. The configuration of the separated product can be identified by analyzing the obtained separated product as in Test Example 2 described later.

[0203] The compound of general formula (II) can be separated and identified according to the description in "1-8. Polarity" above.

[0204] The compound of the present invention produced can be isolated or purified as a free form or as a salt formed by a conventional salt formation treatment. The isolation or purification method is not particularly limited, and for example, commonly used methods such as crystallization, recrystallization, distillation, liquid separation, and chromatography can be appropriately selected and combined. When multiple isomers are present, a single isomer or a mixture of multiple isomers can be obtained by purification. When multiple single isomers or multiple isomer mixtures are obtained by purification, each of them can be used as it is or mixed together as the compound of the present invention. The solvate can be obtained according to a method known per se. The structure of the product can be determined by elemental analysis, MS (ESI-MS) analysis, IR analysis, 1 H-NMR, 13 It can be identified by C-NMR, etc.

[0205] 3.Applications The compound of the present invention has an Nrf2 activating effect. Therefore, the compound of the present invention (sometimes referred to as the "active ingredient of the present invention" in this specification) can be used, for example, as a medicine, a reagent, etc. From this viewpoint, in one aspect, the present invention relates to a medicine (sometimes referred to as the "medicine of the present invention" in this specification) containing the active ingredient of the present invention.

[0206] The pharmaceutical agent of the present invention can be used as an Nrf2 activator, an oxidative stress defense gene expression activator, etc., based on the action of the active ingredient of the present invention.

[0207] The medicament of the present invention can be used for the prevention or treatment of various diseases. The target disease is not particularly limited as long as it can be prevented or treated based on the above-mentioned action of the active ingredient of the present invention. The medicament of the present invention can be used for the prevention or treatment of diseases in which Nrf2 is involved or diseases or symptoms related to the regulation of Nrf2 activity. The medicament of the present invention can be administered to patients who require activation of Nrf2, for example, patients suffering from diseases in which Nrf2 is involved. "Treatment" refers to preventing the deterioration of the condition when a disorder or disease develops, slowing the progression, and maintaining, alleviating, or eliminating the condition, and "prevention" refers to preventing the onset of a disorder or disease before it develops. Target diseases include, for example, ophthalmic diseases such as dry eye, diabetic retinopathy, retinitis pigmentosa, glaucoma, cataracts, age-related macular degeneration, proliferative vitreous retinopathy, retinal artery occlusion, retinal vein occlusion, uveitis, Leber's disease, retinopathy of prematurity, retinal detachment, retinal pigment epithelium detachment, optic nerve disorders caused by these diseases, optic nerve disorders caused by glaucoma, ischemic optic nerve disorders, postoperative inflammation suppression, pain suppression, and the like. In addition, examples of skin diseases include ultraviolet responsive skin damage, epidermolysis bullosa, psoriasis, atopic dermatitis, scleroderma, etc.; otorhinolaryngological diseases include noise-induced hearing loss and sensorineural hearing loss; brain diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, Batten disease, dementia, epilepsy, etc.; pulmonary diseases include asthma, bronchitis, chronic obstructive pulmonary disease, etc.; renal diseases include diabetic nephropathy, Alport syndrome, autosomal dominant polycystic kidney disease, focal segmental glomerulosclerosis, IgA nephropathy, etc.; and other systemic diseases include arteriosclerosis, hypertension, cancer, cardiac arrest, Friedreich's ataxia, amyotrophic lateral sclerosis, hepatitis, rheumatoid arthritis, pancreatitis, vasculitis, esophagitis, ulcerative colitis, neutropenia, cellular immunity, diabetes, mitochondrial myopathy, sickle cell anemia, multiple sclerosis, etc. Of these, preferred are ophthalmological diseases such as multiple sclerosis, psoriasis, Alzheimer's disease, retinitis pigmentosa, glaucoma, and cataracts.

[0208] The subjects to which the pharmaceutical agent of the present invention is administered are not particularly limited, and examples thereof include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).

[0209] The administration route of the medicament of the present invention is not particularly limited. For example, enteral administration such as oral administration, tube feeding, and enema administration; parenteral administration such as intravenous administration, intraarterial administration, intramuscular administration, intracardiac administration, subcutaneous administration, intradermal administration, and intraperitoneal administration; local administration such as local ocular administration (e.g., eye drop administration, intravitreal administration, subconjunctival administration, sub-Tenon administration, etc.), epicutaneous administration, inhalation administration, enema administration, ear drops, nasal administration, and vaginal administration can be adopted. Among these, preferred are local administration and parenteral administration. In addition, the medicament of the present invention is preferably in a formulation form suitable for these preferred administration routes, and from this viewpoint, a topical administration formulation and a parenteral administration formulation are preferred. In one embodiment, the medicament of the present invention can be an oral administration formulation, etc. In one embodiment, the medicament of the present invention can be an ophthalmic formulation, an otolaryngological formulation, a respiratory formulation, a dermatological formulation, etc. In addition, in this specification, "medical preparation" means a formulation applied to a disease, etc., that is treated in the medical department. In one embodiment, the pharmaceutical of the present invention can be an intravenous administration preparation, an intranasal administration preparation, a transdermal administration preparation, or the like.

[0210] The pharmaceutical of the present invention can be in a dosage form suitable for the administration route. Examples include eye drops, eye ointments, eye washes, injections, patches, lotions, creams, powders, granules, tablets, capsules, syrups, liquids, ointments, gels, liniments, suppositories, sprays, inhalants, sprays, and nasal drops. These can be prepared using conventional techniques commonly used in the field. In addition to these preparations, the active ingredient of the present invention can also be made into a preparation for intraocular implantation or a DDS (drug delivery system) such as microspheres.

[0211] The pharmaceutical of the present invention may consist of only the active ingredient of the present invention, or may be a composition containing a pharma- ceutically acceptable additive (sometimes simply referred to as "additive" in this specification) as necessary. The pharmaceutical of the present invention can be produced by mixing the active ingredient of the present invention together with at least one additive, etc., according to a method known per se in the technical field of pharmaceutical formulations. The additive can be appropriately selected according to the form of the formulation preferred for administration. The content of the active ingredient of the present invention in the pharmaceutical varies depending on the dosage form, dosage, etc., and can be appropriately selected. For example, it can usually be 0.01 to 99.9% by mass of the entire pharmaceutical, and preferably 0.1 to 80% by mass.

[0212] Examples of additives include bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, moisturizers, colorants, flavors, and chelating agents, etc. These can be appropriately selected depending on the administration route, dosage form, etc.

[0213] For example, when preparing an otolaryngological preparation containing the active ingredient of the present invention, water (purified or sterile water, distilled water for injection, etc.), physiological saline, glucose solution, water-soluble organic solvent (lower aliphatic alcohols such as ethanol and isopropanol, and polyalkylene glycols such as ethylene glycol, diethylene glycol, and polyethylene glycol), animal and vegetable oils (vegetable oils such as jojoba oil, olive oil, palm oil, and cottonseed oil; animal oils such as squalane), mineral oils (liquid paraffin, silicone oil, etc.), waxes (beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.), long-chain fatty acid esters (saturated or unsaturated fatty acid alkyl esters, esters of fatty acids and polyhydric alcohols (poly C2-4 alkylene glycol, glycerin, polyglycerin, etc.), hydrogenated oils, higher alcohols (saturated aliphatic alcohols such as stearyl alcohol, unsaturated aliphatic alcohols such as oleyl alcohol, etc.), higher fatty acids (stearic acid, oleic acid, etc.), etc. may also be added. Furthermore, antiseptics or preservatives (e.g., parabens such as methylparaben and butylparaben), odorants or fragrances (e.g., fragrances such as menthol), coolants, and analgesics (e.g., local anesthetics such as lidocaine), as well as active ingredients for treating infections and inflammation (e.g., antibacterial agents, antibiotics, anti-inflammatory agents, etc.) may also be blended. The amount of these additives to be added varies depending on the type and application of the additive, but it is sufficient to add a concentration that can achieve the purpose of the additive.

[0214] For example, when preparing a dermatological preparation containing the active ingredient of the present invention, the solvent may include purified water, ethanol, isopropanol, dipropylene glycol, etc., and one or more of these may be selected and used. The base may include animal and vegetable fats and oils such as olive oil, soybean oil, camellia oil, sesame oil, peanut oil, cacao butter, beef tallow, lard, etc.; waxes such as carnauba wax and beeswax; aliphatic alcohols such as octyldodecanol, cetanol, stearyl alcohol, etc.; fatty acids such as oleic acid, palmitic acid, stearic acid, etc.; oleaginous bases such as squalane, white petrolatum, liquid paraffin, ceresin, microcrystalline wax, etc., and hydrophilic bases such as gelatin and macrogol, and one or more of these may be selected and used. Other additives include excipients such as light anhydrous silicic acid, crystalline cellulose, and dextrin; solubilizing agents such as diisopropyl adipate, capric acid, crotamiton, and propylene carbonate; suspending agents such as propylene glycol alginate, sodium dioctyl sulfosuccinate, soybean lecithin, and povidone; surfactants or emulsifiers such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, glycerin monostearate, and sucrose fatty acid esters; carboxyvinyl polymers, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, and polyvinyl alcohol (partially ketones). Examples of the additives that can be added include thickeners such as ethylhexyl ether (ethyl acetate), ethyl acrylate (ethyl acrylate), and the like; plasticizers such as triacetin and isopropyl myristate; moisturizers such as glycerin, 1,3-butylene glycol, sodium DL-pyrrolidonecarboxylate and sodium hyaluronate; stabilizers such as sodium edetate, sorbitol, thymol and polyoxyethylene polyoxypropylene glycol; antioxidants such as ascorbic acid, sodium erythorbate, tocopherol acetate and dibutylhydroxytoluene; preservatives such as sorbic acid, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate and butyl parahydroxybenzoate; and pH adjusters such as hydrochloric acid, citric acid, sodium citrate, acetic acid, sodium acetate, sodium hydroxide and sodium hydrogen phosphate.The amount of these additives to be added varies depending on the type and application of the additive, but the additives should be added in a concentration that allows the additive to achieve its purpose.

[0215] For example, when preparing an ophthalmic preparation (topical application agent for the eye: eye drops, eye ointments, eye washes, etc.) containing the active ingredient of the present invention, stabilizers (e.g., sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutylhydroxytoluene, etc.), solubilizing agents (e.g., glycerin, propylene glycol, macrogol, polyoxyethylene hydrogenated castor oil, etc.), suspending agents (e.g., polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxymethylcellulose, sodium carboxymethylcellulose, etc.), emulsifiers (e.g., polyvinylpyrrolidone, soybean lecithin, egg yolk lecithin, polyoxyethylene hydrogenated castor oil, polysorbate 80, etc.), buffers (e.g., phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamic acid, epsilon aminocaproic acid, etc.), thickeners (e.g., methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), etc., may be used. Additives that can be added include water-soluble cellulose derivatives such as cellulose, carboxymethylcellulose, sodium chondroitin sulfate, sodium hyaluronate, carboxyvinyl polymers, polyvinyl alcohol, polyvinylpyrrolidone, macrogol, etc., preservatives (e.g., benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, paraoxybenzoic acid esters, sodium edetate, boric acid, etc.), isotonicity agents (e.g., sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, glucose, propylene glycol, etc.), pH adjusters (e.g., hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, boric acid, citric acid, etc.), refreshing agents (e.g., l-menthol, d-camphor, d-borneol, peppermint oil, etc.), ointment bases (white petrolatum, refined lanolin, liquid paraffin, vegetable oils (olive oil, camellia oil, peanut oil, etc.), etc.). The amount of these additives to be added varies depending on the type and application of the additive, but the additives should be added in a concentration that allows the additive to achieve its purpose.

[0216] When the pharmaceutical of the present invention is made into an otolaryngological composition such as ear drops or nasal liquid, it may be produced according to a method commonly used in the field of formulations, for example, it can be produced based on the method described in the 17th Edition of the Japanese Pharmacopoeia, General Provisions for Preparations, Section "Preparations to be Administered to the Ear" or Section "Preparations to be Applied to the Nose".

[0217] When the pharmaceutical of the present invention is used as a dermatological composition such as a skin topical agent, it may be produced according to a method commonly used in the pharmaceutical field, for example, the method described in the 17th Edition of the Japanese Pharmacopoeia, General Rules for Preparations, section "Preparations for Application to Skin, etc." When the pharmaceutical of the present invention is used as an ophthalmic composition such as eye drops or eye ointment, it may be produced according to a method commonly used in the pharmaceutical field, for example, the method described in the 17th Edition of the Japanese Pharmacopoeia, General Rules for Preparations, section "Drugs to be Administered to Eyes" (for example, the section on eye drops and the section on eye ointments).

[0218] The dosage of the medicament of the present invention varies depending on the target disease and cannot be generalized, but can be set so that the concentration of the active ingredient of the present invention in the target tissue to exert the effect is, for example, 0.001 nM to 100 μM, preferably 0.01 nM to 100 μM.

[0219] When the medicament of the present invention is used topically on the eye of an adult, it is advisable to apply, for example, a medicament containing 0.01 nM to 1000 μM, preferably 0.1 nM to 1000 μM, of the active ingredient of the present invention 1 to 8 times, preferably 1 to 5 times, per day. The application amount can be appropriately determined depending on the concentration and dosage form of the active ingredient of the present invention.

[0220] Furthermore, the pharmaceutical composition of the present invention may contain one or more other optional active ingredients as long as the effects of the present invention are not impaired. EXAMPLES

[0221] The present invention will be explained in more detail below by way of Reference Examples, Production Examples, Examples and Test Examples, but the present invention is not limited to these in any way.

[0222] In the Reference Examples, Preparations, Examples, and Test Examples, all temperatures are specified in degrees Celsius (°C) unless otherwise specified. All amounts and percentages are by weight unless otherwise specified. Reagents were purchased from reagent suppliers such as Sigma-Aldrich Corporation, Tokyo Chemical Industry Co., Ltd., Fujifilm Wako Pure Chemical Industries, Ltd., or Nacalai Tesque Inc., and were used without purification unless otherwise specified.

[0223] The operations in the Reference Examples, Production Examples, and Examples were generally carried out in anhydrous solvents under an argon atmosphere. The reaction was analyzed by TLC (Thin Layer Chromatography) and terminated based on the consumption of the starting material. TLC was carried out using silica gel 60F254 (Merck), developed with an appropriate solvent, and displayed at an appropriate position, with a UV detector used for detection. Elution in column chromatography in the Reference Examples, Production Examples, and Examples was carried out under observation by TLC, unless otherwise specified. As silica gel for column chromatography, SI silica gel (particle diameter 30-50 μm) or NH silica gel (particle diameter 60 μm) manufactured by Fuji Silysia Chemical, or silica gel (particle diameter 40 μm) or amino silica gel (particle diameter 40 μm) manufactured by Yamazen Corporation were used. Room temperature generally means a temperature of about 10° C. to 35° C.

[0224] The following abbreviations are used in the following Preparation Examples. mCPBA: Trichloroperbenzoic acid M: Molar concentration N: Normality CDCl 3 : deuterated chloroform CD 3 OD: deuterated methanol DMSO-d6: deuterated dimethyl sulfoxide 1 H NMR: proton nuclear magnetic resonance DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone DEAD: Diethyl azodicarboxylate DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMA: N,N-Dimethylacetamide DMSO: Dimethyl sulfoxide EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole LDA: Lithium diisopropylamide PdCl 2 (dppf) 2 -CH 2 Cl 2 : [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran p-TsOH-H 2 O: p-Toluenesulfonic acid monohydrate [RhCl(cod)] 2 : Chloro(1,5-cyclooctadiene)rhodium(I) (dimer) HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0225] 1 H NMR spectra were recorded on a Bruker instrument operating at 400 MHz. NMR spectra were analyzed using CDCl with chloroform as the reference standard (7.26 ppm) or internal tetramethylsilane (0.00 ppm) as appropriate. 3Obtained as solutions. Other NMR solvents were used as necessary. When reporting peak multiplicities, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), septd (septet), m (multiplet), br (broad), dd (doublet of doublet), dt (doublet of triplet), td (triplet of doublet). When coupling constants (J values) are given, they are reported in Hertz (Hz).

[0226] Compound synthesis 1 Reference example 1 Preparation of (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0227] [ka]

[0228] While stirring aqueous ammonia (approximately 28%) (84 mL), (R)-(+)-butylene oxide (5.0 mL, 58.2 mmol) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 22 hours. The solvent of the mixture was distilled off under reduced pressure, and the obtained oily substance was dissolved in THF / H 2The residue was dissolved in 2H2O (72 mL / 18 mL). Potassium carbonate (4.55 g, 32.9 mmol) and 2-fluorobenzenesulfonyl chloride (4.3 mL, 32.9 mmol) were added to this solution, and the mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in DMSO (130 mL), potassium tert-butoxide (11 g, 98 mmol) was added, and the mixture was stirred at 80 °C for 1 hour. The resulting solution was adjusted to pH ~5 with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Dichloromethane at 0 °C was added to the resulting residue, and the mixture was filtered. The residue was dried under reduced pressure to give the title compound (3.36 g, 45%) as a white solid. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 3 / 2 → 1 / 1) to obtain the title compound (2.93 g, 39%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.83 (1H, dd, J = 7.6, 1.6 Hz), 7.47 (1H, td, J = 7.6, 1.6 Hz), 7.19 (1H, td, J = 7.6, 1.2 Hz), 7.17 (1H, dd, J = 7.6, 1.2 Hz), 4.66 (1H, br s), 3.89-3.82 (1H, m), 3.70-3.62 (1H, m), 3.39 (1H, ddd, J =14.8, 5.2, 2.0 Hz), 1.83-1.71 (1H, m), 1.67-1.56 (1H, m), 1.13 (3H, t, J = 7.2 Hz).

[0229] Reference example 2 Preparation of (R)-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0230] [ka]

[0231] Using (R)-(-)-1-amino-2-propanol (2.89 g, 38.3 mmol), THF / water (125 mL / 31.3 mL), potassium carbonate (5.29 g, 38.3 mmol), 2-fluorobenzenesulfonyl chloride (5.0 mL, 38.3 mmol), DMSO (120 mL), and potassium tert-butoxide (10.0 g, 89.1 mmol) as raw materials, and operating in the same manner as in Step j of Reference Example 1, the title compound (6.42 g, 79%) was obtained as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.81 (1H, dd, J = 8.0, 1.6 Hz), 7.46 (1H, td, J = 8.0, 1.6 Hz), 7.19 (1H, td, J = 8.0, 1.2 Hz), 7.15 (1H, dd, J = 8.0, 1.2 Hz), 4.75 (1H, br s), 4.19-4.12 (1H, m), 3.67-3.59 (1H, m), 3.41 (1H, ddd, J = 14.8, 5.2, 2.0 Hz), 1.40 (3H, d, J = 6.4 Hz).

[0232] Reference example 3 Preparation of (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

[0233] [ka]

[0234] Ammonia water (about 28%) (2.9 mL), (R)-(+)-butylene oxide (172 μL, 2 mmol), THF / water (2.4 mL / 0.6 mL), potassium carbonate (163.1 mg, 1.18 mmol), 2-chloro-pyridine-3-sulfonyl chloride (250 mg, 1.18 mmol), DMSO (4.7 mL), and potassium tert-butoxide (397 mg, 3.54 mmol) were used as raw materials and treated in the same manner as in Reference Example 1 to obtain the title compound (210.4 mg, 78%) as a brown oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 8.40 (1H, dd, J = 4.8, 2.0 Hz), 8.15 (1H, dd, J = 7.6, 2.0 Hz), 7.19 (1H, dd, J = 7.6, 4.8 Hz), 6.34 (1H, br s), 4.26-4.21 (1H, m), 3.66-3.58 (1H, m), 3.50-3.44 (1H, m), 1.84-1.75 (1H, m), 1.71-1.65 (1H, m), 1.12 (3H, t, J = 7.6 Hz).

[0235] Reference example 4 Preparation of (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepine 1,1-dioxide

[0236] [ka]

[0237] Ammonia water (about 28%) (4.35 mL), (R)-(+)-butylene oxide (258 μL, 3 mmol), THF / water (2.5 mL / 1.0 mL), potassium carbonate (180 mg, 1.3 mmol), 4-chloro-pyridine-3-sulfonyl chloride (250 mg, 1.18 mmol), DMSO (8.0 mL), and potassium tert-butoxide (397 mg, 3.54 mmol) were used as starting materials and treated in the same manner as in Reference Example 1 to obtain the title compound (140.8 mg, 52%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 8.82 (1H, s), 8.53 (1H, d, J = 5.6 Hz), 7.04 (1H, d, J = 5.6, Hz), 5.98 (1H, br s), 4.29-4.23 (1H, m), 3.56-3.46 (2H, m), 1.81-1.74 (1H, m), 1.72-1.63 (1H, m), 1.10 (3H, t, J = 7.6 Hz).

[0238] Reference example 5 Preparation of (R)-2-fluoro-N-(2-hydroxybutyl)benzenesulfonamide

[0239] [ka]

[0240] To a solution of (R)-1-aminobutan-2-ol (127.6 mg, 1.4 mmol) in THF / water (4 / 1) (2.0 mL), potassium carbonate (203.0 mg, 1.5 mmol) and 2,6-difluorobenzenesulfonyl chloride (150 μL, 1.1 mmol) were added and stirred at room temperature for 2 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (318.1 mg, quant.) as a white solid. 1 H NMR (400 MHz, CDCl 3) δ 7.51 (1H, m), 7.04 (2H, t, J = 8.4 Hz), 3.73-3.67 (1H, m), 3.28 (1H, dd, J = 12.8, 3.2 Hz), 2.96 (1H, d, J = 12.8, 8.0 Hz), 1.55-1.41 (2H, m), 0.94 (3H, t, J =7.6 Hz).

[0241] Reference example 6 Preparation of (R)-4-ethyl-9-fluoro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0242] [ka]

[0243] A solution of (R)-2-fluoro-N-(2-hydroxybutyl)benzenesulfonamide (161.0 mg, 0.65 mmol) and potassium tert-butoxide (150.7 mg, 1.3 mmol) in DMSO (1.5 mL) was stirred at 100 °C for 2 hours using a microwave. The reaction solution was returned to room temperature, adjusted to pH 6 with 1 M hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 73 / 27 → 52 / 48) to obtain the title compound (113.2 mg, 71%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.33 (1H, m), 6.93-6.88 (2H, m), 5.26 (1H, br t, J = 6.0 Hz), 4.34-4.27 (1H, m), 3.54 (1H, ddd, J = 14.0, 6.4, 4.0 Hz), 3.23 (1H, ddd, J = 14.0, 11.2, 6.8 Hz), 1.78-1.58 (2H, m), 1.07 (3H, t, J = 7.6 Hz).

[0244] Reference example 7 Preparation of [(but-3-en-1-yloxy)methyl]benzene

[0245] [ka]

[0246] To a solution of sodium hydride (60%) (2.36 g, 59 mmol) in THF (25 mL), 3-buten-1-ol (2.5 mL, 29.5 mmol) was added at 0° C., and the mixture was warmed to room temperature and stirred for 30 minutes. Benzyl bromide (3.85 mL, 32.4 mmol) was added to this solution at 0° C., and the mixture was stirred at room temperature for 20 hours. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride to the mixture at 0° C., and the mixture was extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 100 / 0→91 / 9) to obtain the title compound (3.95 g, 83%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.26 (5H, m), 5.91-5.79 (1H, m), 5.15-5.07 (1H, m), 5.08-5.02 (1H, m), 4.53 (2H, s), 3.54 (2H, t, J = 6.8 Hz), 2.43-2.35 (2H, m).

[0247] Reference example 8 Preparation of 2-[2-(benzyloxy)ethyl]oxirane

[0248] [ka]

[0249] To a solution of [(but-3-en-1-yloxy)methyl]benzene (3.95 g, 24.3 mmol) in dichloromethane (79 mL) was added mCPBA (about 77%) (7.09 g, 31.6 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 14 hours. The reaction mixture was diluted with water, and a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium thiosulfate were added to quench the reaction. The mixture was extracted with dichloromethane, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 93 / 7 → 72 / 28) to obtain the title compound (4.11 g, 95%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.26 (5H, m), 4.54 (2H, s), 3.68-3.58 (2H, m), 3.12-3.06 (1H, m), 2.79 (1H, dd, J = 5.0, 4.2 Hz), 2.54 (1H, dd, J = 5.0, 3.7 Hz), 1.97-1.86 (1H, m), 1.84-1.73 (1H, m).

[0250] Reference example 9 Preparation of 1-amino-4-(benzyloxy)butan-2-ol

[0251] [ka]

[0252] 2-[2-(benzyloxy)ethyl]oxirane (4.11 g, 23.1 mmol) was added to aqueous ammonia (approximately 28%) (86 mL). The reaction mixture was stirred for 15 hours and then concentrated under reduced pressure to give the title compound (4.45 g, 99%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3) δ 7.37-7.26 (5H, m), 4.52 (2H, s), 3.77-3.63 (3H, m), 2.79 (1H, dd, J = 12.8, 3.6 Hz), 2.61 (1H, dd, J = 12.8, 7.6 Hz), 1.77-1.71 (2H, m).

[0253] Reference example 10 Preparation of 4-[2-(benzyloxy)ethyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0254] [ka]

[0255] To a solution of 1-amino-4-(benzyloxy)butan-2-ol (4.4475 g, 22.8 mmol) in THF (29 mL) and water (7.3 mL) were added potassium carbonate (2.06 g, 14.9 mmol) and 2-fluorobenzenesulfonyl chloride (1.95 mL, 14.9 mmol). The reaction mixture was stirred for 1 hour, and 1N hydrochloric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was dissolved in DMSO (135 mL), and potassium tert-butoxide (5.02 g, 44.7 mmol) was added to this solution. The reaction mixture was stirred at 80 °C for 1 hour, and 1N hydrochloric acid was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated saline, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 91 / 9 to 60 / 40) to obtain the title compound (3.88 g, 78%) as a colorless solid. 1 H NMR (400 MHz, CDCl 3)δ 7.83 (1H, d, J = 7.6 Hz), 7.42 (1H, td, J = 7.6, 1.6 Hz), 7.33-7.26 (5H, m), 7.20 (1H, t, J = 7.6 Hz), 6.96 (1H, d, J = 7.6 Hz), 4.63 (1H, br s), 4.55 (1H, d, J = 12.0 Hz), 4.49 (1H, d, J = 12.0 Hz), 4.11 (1H, br t, J = 9.6 Hz), 3.85-3.63 (3H, m), 3.39-3.35 (1H, m), 2.00-1.86 (2H, m).

[0256] Reference example 11 Preparation of (5-bromo-2-methylphenyl)methanol

[0257] [ka]

[0258] To a solution of 5-bromo-2-methylbenzoic acid (5.0 g, 25.3 mmol) in THF (50 mL), borane-tetrahydrofuran complex (about 0.9 mmol / L THF solution) (38.8 mL, 34.9 mmol) was added dropwise at 0° C. over 10 minutes, and the mixture was stirred at room temperature for 20 hours. Methanol (35 mL) was added to the resulting solution, and the mixture was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (5.0 g, 98%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.53 (1H, d, J = 2.0 Hz), 7.32 (1H, dd, J = 8.0, 2.0 Hz), 7.03 (1H, d, J = 8.0 Hz), 4.66 (2H, d, J = 5.6 Hz), 2.27 (3H, s), 1.64 (1H, t, J = 5.6 Hz).

[0259] Reference example 12 Preparation of (R)-2-(5-bromo-2-methylbenzyl)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0260] [ka]

[0261] To a solution of (5-bromo-2-methylphenyl)methanol (2.0 g, 9.95 mmol), (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (2.26 g, 9.95 mmol), and triphenylphosphine (2.61 g, 9.95 mmol) in THF (39 mL) was added 2.2M DEAD toluene solution (5.1 mL, 11.2 mmol) with stirring at 0 °C. The solution was stirred at room temperature for 7 hours, then diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 95 / 5→85 / 15) to obtain the title compound (3.46 g, 85%) as a white solid. 1 H NMR (400 MHz, CDCl 3)δ 7.89 (1H, dd, J = 7.6, 1.6 Hz), 7.52 (1H, td, J = 7.6, 1.6 Hz), 7.39 (1H, d, J = 2.0 Hz), 7.35 (1H, dd, J = 8.0, 2.0 Hz), 7.26 (1H, td, J = 7.6, 1.2 Hz), 7.21 (1H, dd, J = 7.6, 1.2 Hz), 7.06 (1H, d, J = 8.0 Hz), 4.51 (1H, d, J = 14.4 Hz), 4.08-4.02 (1H, m), 3.85 (1H, d, J =14.4 Hz), 3.76 (1H, dd, J = 15.2, 10.8 Hz), 3.06 (1H, dd, J = 15.2, 2.0 Hz), 2.29 (3H, s), 1.79-1.70 (1H, m), 1.56-1.50 (1H, m), 1.11 (3H, t, J = 7.2 Hz).

[0262] Reference example 13 Preparation of (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0263] [ka]

[0264] (R)-2-(5-bromo-2-methylbenzyl)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (3.4 g, 8.29 mmol), bis(pinacolato)diboron (3.15 g, 12.4 mmol), potassium acetate (2.44 g, 24.9 mmol), and PdCl 2 (dppf) 2 -CH 2 Cl 2(408 mg, 0.5 mmol) in 1,4-dioxane (36 mL) was stirred at 100 °C for 6 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 95 / 5 → 85 / 15) to obtain the title compound (3.28 g, 86%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.90 (1H, d, J = 7.6 Hz), 7.68 (1H, d, J = 7.6 Hz), 7.54 (1H, s), 7.52 (1H, t, J = 7.6 Hz), 7.25 (1H, t, J = 7.6 Hz), 7.22-7.20 (2H, m), 4.64 (1H, d, J = 13.6 Hz), 4.09-4.04 (1H, m), 3.83 (1H, d, J =13.6 Hz), 3.74 (1H, dd, J = 15.2, 10.8 Hz), 2.97 (1H, dd, J = 15.2, 1.2 Hz), 2.43 (3H, s), 1.77-1.70 (1H, m), 1.51-1.42 (1H, m), 1.32 (12H, s), 1.05 (3H, t, J = 7.2 Hz).

[0265] Reference example 14 Preparation of 4-bromo-2-{[(4-methoxybenzyl)oxy]methyl}-1-methylbenzene

[0266] [ka]

[0267] Sodium hydride (472 mg, 11.8 mmol) was added to a solution of (5-bromo-2-methylphenyl)methanol (2.16 g, 10.8 mmol) in DMF (16 mL). The solution was stirred at room temperature for 30 minutes, cooled to 0 °C, and 4-methoxybenzyl chloride (1.53 mL, 11.3 mmol) was added. The solution was stirred at room temperature for 2 hours, water was added to stop the reaction, and then extracted with diethyl ether. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 95 / 5 → 85 / 15) to obtain the title compound (1.77 g, 61%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.50 (1H, d, J = 2.0 Hz), 7.32-7.28 (3H, m), 7.02 (1H, d, J = 8.0 Hz), 6.90 (2H, d, J = 8.4 Hz), 4.51 (2H, s), 4.46 (2H, s), 3.81 (3H, s), 2.24 (3H, s).

[0268] Reference example 15 Preparation of 3-{[(4-methoxybenzyl)oxy]methyl}-4-methylbenzaldehyde

[0269] [ka]

[0270] 2.3 M n-butyllithium hexane solution (980 μL, 2.25 mmol) was added dropwise to a solution of 4-bromo-2-{[(4-methoxybenzyl)oxy]methyl}-1-methylbenzene (600 mg, 1.87 mmol) in THF (6 mL) at -78 °C under an argon atmosphere. The reaction mixture was stirred at -78 °C for 1 hour, DMF (290 μL, 3.75 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the mixture to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 99 / 1 → 90 / 10) to obtain the title compound (448.3 mg, 89%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 9.97 (1H, s), 7.87 (1H, d, J = 1.6 Hz), 7.72 (1H, dd, J = 8.0, 1.6 Hz), 7.33-7.26 (3H, m), 6.90 (2H, br d, J = 8.8 Hz), 4.56 (2H, s), 4.54 (2H, s), 3.82 (3H, s), 2.39 (3H, s).

[0271] Reference example 16 Preparation of 2-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0272] [ka]

[0273] 4-Bromo-2-{[(4-methoxybenzyl)oxy]methyl}-1-methylbenzene (6.67 g, 20.77 mmol), bis(pinacolato)diboron (5.54 g, 21.81 mmol), potassium acetate (6.12 g, 62.31 mmol), and PdCl 2(dppf) 2 -CH 2 Cl 2 A solution of (848.1 mg, 1.04 mmol) in 1,4-dioxane (68 mL) was stirred at 100 °C for 6 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 95 / 5 → 85 / 15) to obtain the title compound (6.63 g, 87%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.73 (1H, s), 7.65 (1H, dd, J = 7.2, 1.2 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.18 (1H, d, J = 7.2 Hz), 6.88 (2H, br d, J = 8.8 Hz), 4.52 (2H, s), 4.47 (2H, s), 3.81 (3H, s), 2.36 (3H, s), 1.34 (12H, s).

[0274] Reference example 17 Preparation of methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate

[0275] [ka]

[0276] Methyl (E)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate (3.30 g, 13.0 mmol), 2-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.39 g, 6.49 mmol), [RhCl(cod)] 2To a solution of (160 mg, 0.32 mmol) in 1,4-dioxane / water (9.6 mL / 960 μL) was added triethylamine (2.7 mL, 19.5 mmol). The reaction mixture was stirred at 50 °C for 2.5 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 9 / 1 → 7 / 3) to obtain the title compound (1.52 g, 47%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.28-7.24 (3H, m), 7.11-7.10 (2H, m), 6.88 (2H, br d, J = 8.4 Hz), 6.81 (1H, d, J = 3.6 Hz), 6.65 (1H, dd, J = 3.6, 0.8 Hz), 4.67 (1H, t, J = 7.6 Hz), 4.48 (2H, s), 4.46 (2H, s), 4.00-3.95 (2H, m), 3.94-3.89 (2H, m), 3.81 (3H, s), 3.59 (3H, s), 3.08 (1H, dd, J = 15.6, 7.6 Hz), 2.99 (1H, dd, J = 15.6, 7.6 Hz), 2.28 (3H, s), 1.71 (3H, s).

[0277] Reference example 18 Preparation of methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methyl-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate

[0278] [ka]

[0279] To a solution of methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate (1.40 g, 2.82 mmol) in THF (18 mL) was added 2M LDA THF / heptane / ethylbenzene solution (1.83 mL, 3.67 mmol) at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 30 minutes and then at -40 °C for 20 minutes. Iodomethane (2.6 mL, 42.3 mmol) was added, and the mixture was warmed to room temperature and stirred for 4 hours. Water was added to the mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 8%) to obtain the title compound. The title compound could be separated into two isomer mixtures, isomer mixture 1 (505.7 mg, 31%) with a shorter retention time and isomer mixture 2 (853.3 mg, 52%) with a longer retention time, as a pale yellow oily substance. Isomer mixture 2 was used in the next reaction. Isomer mixture 1: 1 H NMR (400 MHz, CDCl 3 )δ 7.28-7.26 (3H, m), 7.17-7.15 (1H, m), 7.06 (1H, d, J = 8.0 Hz), 6.89 (2H, br d, J = 8.8 Hz), 6.82 (1H, d, J = 3.6 Hz), 6.74 (1H, d, J = 3.6 Hz), 4.47 (2H, s), 4.43 (2H, s), 4.25 (1H, d, J = 10.8 Hz), 4.01-3.97 (2H, m), 3.96-3.90 (2H, m), 3.81 (3H, s), 3.43 (3H, s), 3.24-3.16 (1H, m), 2.25 (3H, s), 1.71 (3H, s), 1.20 (3H, d, J = 6.8 Hz). Isomer mixture 2: 1 H NMR (400 MHz, CDCl 3 )δ 7.28-7.23 (3H, m), 7.11-7.10 (2H, m), 6.89 (2H, br d, J = 8.8 Hz), 6.77 (1H, d, J = 3.6 Hz), 6.71 (1H, br d, J = 3.6 Hz), 4.48 (2H, s), 4.47 (2H, s), 4.27 (1H, d, J = 11.2 Hz), 3.99-3.95 (2H, m), 3.93-3.90 (2H, m), 3.82 (3H, s), 3.58 (3H, s), 3.21-3.16 (1H, m), 2.28 (3H, s), 1.69 (3H, s), 1.05 (3H, d, J = 6.8 Hz).

[0280] Reference example 19 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropanoate

[0281] [ka]

[0282] 2N hydrochloric acid (1.4 mL) was added to a solution of methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methyl-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate (Isomer mixture 2) (489 mg, 0.96 mmol) of Reference Example 18 in tetrahydrofuran (2.8 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was neutralized with a 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (390.8 mg, 87%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.46 (1H, d, J = 4.0 Hz), 7.29-7.24 (3H, m), 7.11 (2H, s), 6.92-6.89 (3H, m), 4.49 (2H, s), 4.48 (2H, s), 4.36 (1H, d, J = 11.2 Hz), 3.82 (3H, s), 3.60 (3H, s), 3.25-3.21 (1H, m), 2.46 (3H, s), 2.26 (3H, s), 1.08 (3H, d, J = 6.8 Hz).

[0283] Reference example 20 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2-methylpropanoate

[0284] [ka]

[0285] To a solution of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropanoate (700.9 mg, 1.5 mmol) in dichloromethane / water (10 / 1) (18.2 mL) was added DDQ (681 mg, 3.0 mmol) at 0 °C. The mixture was stirred at room temperature for 2.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 6 / 4 → 4 / 6) to obtain the title compound (436.3 mg, 84%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.46 (1H, d, J = 4.0 Hz), 7.28 (1H, br s), 7.13 (2H, br s), 6.93 (1H, d, J = 4.0 Hz), 4.68 (2H, d, J = 5.6 Hz), 4.37 (1H, d, J = 11.2 Hz), 3.60 (3H, s), 3.27-3.23 (1H, m), 2.46 (3H, s), 2.30 (3H, s), 1.09 (3H, d, J = 6.8 Hz).

[0286] Reference example 21 Preparation of 1-(5-bromothiophen-2-yl)ethan-1-ol

[0287] [ka]

[0288] Sodium borohydride (458.2 mg, 12 mmol) was added to a methanol solution (40 mL) of 2-acetyl-5-bromothiophene (1.16 g, 5.6 mmol) at 10°C, and the mixture was stirred at 10°C for 1 hour and 20 minutes. Water was added to the reaction solution, and the mixture was stirred at 0°C for 15 minutes. The reaction solution was concentrated under reduced pressure, and then ethyl acetate was added, followed by washing with water and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (1.16 g, 99%) as a colorless, transparent oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 6.90 (1H, d, J = 3.6 Hz), 6.72 (1H, d, J = 3.6 Hz), 5.04 (1H, dq, J = 5.6, 6.4 Hz), 1.97 (1H, d, J = 4.8 Hz), 1.57 (3H, d, J = 6.4 Hz).

[0289] Reference example 22 Preparation of [1-(5-bromothiophen-2-yl)ethoxy](tert-butyl)dimethylsilane

[0290] [ka]

[0291] A solution of 1-(5-bromothiophen-2-yl)ethan-1-ol (1.16 g, 5.6 mmol) in dichloromethane (12 mL) was added with 4-dimethylaminopyridine (76.8 mg, 0.6 mmol), TEA (3.2 mL, 23 mmol), and a solution of tert-butyldimethylchlorosilane (1.66 g, 11 mmol) in dichloromethane (5.0 mL) at 0 °C and stirred at room temperature overnight. 4-Dimethylaminopyridine (305.6 mg, 2.5 mmol) and tert-butyldimethylchlorosilane (981.6 mg, 6.5 mmol) were further added to the reaction solution and stirred at room temperature for 3 hours and 45 minutes. Ethyl acetate was added to the reaction solution, which was washed with water and saturated saline, and the obtained organic layer was dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 1 / 0 → 95 / 5) to obtain the title compound (1.28 g, 71%) as a colorless, transparent oily substance. 1 H NMR (400 MHz, CDCl 3 ), δ 6.86 (1H, d, J = 4.0 Hz), 6.58 (1H, d, J = 4.0 Hz), 5.01 (1H, q, J = 6.4 Hz), 1.47 (3H, d, J = 6.4 Hz), 0.91 (9H, s), 0.09 (3H, s), 0.06 (3H, s).

[0292] Reference example 23 Preparation of (5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}thiophen-2-yl)(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)methanol

[0293] [ka]

[0294] A solution of [1-(5-bromothiophen-2-yl)ethoxy](tert-butyl)dimethylsilane (540.9 mg, 1.7 mmol) in anhydrous THF (5.0 mL) was cooled to -78 °C, and then 2.5 M n-butyllithium (0.75 mL, 1.9 mmol) was added dropwise to the reaction solution, which was then stirred at -78 °C for 30 minutes. A solution of 3-{[(4-methoxybenzyl)oxy]methyl}-4-methylbenzaldehyde (478.1 mg, 1.8 mmol) in THF (5 mL) was added dropwise to the reaction solution, which was then stirred at -78 °C for 1 hour, and then at room temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting crude product was then purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 90 / 10 → 69 / 31) to obtain the title compound (740.4 mg, 86%) as a yellow transparent oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (1H, s), 7.29-7.26 (3H, m), 7.16 (1H, d, J = 7.6 Hz), 6.88 (1H, d, J = 8.4 Hz), 6.67 (2H, d, J = 4.4 Hz), 5.96 (1H, d, J = 4.0 Hz), 5.17 (1H, q, J = 6.4 Hz), 4.51 (2H, s), 4.48 (2H, s), 3.81 (3H, s), 2.32 (3H, s), 2.29 (1H, d, J = 4.0 Hz), 1.47 (3H, d, J = 6.4 Hz), 0.90 (9H, s), 0.07 (3H, s), 0.03 (3H, br s).

[0295] Reference example 24 Preparation of methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}thiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0296] [ka]

[0297] To a solution of ((5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}thiophen-2-yl)(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)methanol (110.7 mg, 0.2 mmol) in acetonitrile (2.0 mL), trichloroacetonitrile (40 μL, 0.4 mmol) and DBU (6 μL, 0.1 mmol) were added and stirred at room temperature for 30 min. Dimethylketene methyl trimethylsilyl acetal (120 μL, 0.6 mmol) and bis(trifluoromethanesulfonyl)imide (8.2 mg, 0.03 mmol) were added and stirred at room temperature for 1 h. The reaction was quenched by adding a saturated aqueous solution of sodium bicarbonate to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = The product was purified by elution with an elution solvent (95 / 5→74 / 26) to give the title compound (824.8 mg, 73%) as a yellow transparent oil. 1 H NMR (400 MHz, CDCl 3) δ 7.32 (1H, dd, J = 4.4, 1.2 Hz), 7.29-7.26 (2H, m), 7.21 (1H, td, J = 7.6, 1.6 Hz), 7.08 (1H, d, J = 7.6 Hz), 6.90 (1H, s), 6.88 (1H, s), 6.76-6.74 (1H, m), 6.64-6.63 (1H, m), 5.00 (1H, q, J = 6.4 Hz), 4.63-4.62 (1H, m), 4.49 (2H, s), 4.47 (2H, br s), 3.81 (3H, s), 3.56 (3H, s), 2.27 (3H, s), 1.45 (3H, d, J = 6.4 Hz), 1.29 (3H, s), 1.22 (3H, s), 0.89 (9H, br s), 0.05 (3H, s), 0.002 (3H, s).

[0298] Reference example 25 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropanoate

[0299] [ka]

[0300] DDQ (612.2 mg, 2.7 mmol) was added to a mixture of methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}thiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate (773 mg, 1.3 mmol) in dichloromethane (16 mL) and water (1.2 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 hour and 20 minutes. The reaction solution was added with a saturated aqueous solution of sodium bicarbonate to terminate the reaction, extracted with dichloromethane, and the organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 93 / 7 → 72 / 28 → 50 / 50) to obtain the title compound (204.1 mg, 44%) as a colorless, transparent oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (1H, d, J = 4.0 Hz), 7.34 (1H, d, J = 1.6 Hz), 7.20 (1H, dd, J = 7.6, 1.6 Hz), 7.11 (1H, d, J = 7.6 Hz), 6.97 (1H, d, J = 4.0 Hz), 4.17 (1H, s), 4.68 (2H, d, J = 5.6 Hz), 3.61 (3H, s), 2.49 (3H, s), 2.31 (3H, s), 1.32 (3H, s), 1.24 (3H, s).

[0301] Reference example 26 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropanoate

[0302] [ka]

[0303] To a suspension of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropanoate (204.1 mg, 0.57 mmol) and lithium chloride (123.1 mg, 2.9 mmol) in dichloromethane (6.0 mL), DIPEA (300 μL, 1.7 mmol) and methanesulfonyl chloride (88 μL, 1.1 mmol) were added and stirred at room temperature for 4.5 hours. Ethyl acetate was added to the reaction solution, which was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (218.3 mg, quant.) as a light brown transparent oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.51 (1H, d, J = 4.0 Hz), 7.31-7.24 (2H, m), 7.14 (1H, d, J = 8.0 Hz), 6.87 (1H, d, J = 4.0 Hz), 4.70 (1H, s), 4.57 (2H, s), 3.60 (3H, s), 2.50 (3H, s), 2.38 (3H, s), 1.31 (3H, s), 1.24 (3H, s).

[0304] Reference example 27 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0305] [ka]

[0306] A solution of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropanoate (29.8 mg, 0.079 mmol), (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (27.8 mg, 0.12 mmol), potassium carbonate (33.9 mg, 0.25 mmol), and tetrabutylammonium iodide (5.7 mg, 0.015 mmol) in DMF (0.50 mL) was stirred at 70 °C for 3 hours and 10 minutes. The reaction solution was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 73 / 27 → 52 / 48) to obtain the title compound (43.1 mg, 96%) as a white solid. 1 H NMR (400 Mz, CDCl 3 ) δ 7.87 (1H, dt, J = 7.6, 1.2 Hz), 7.55-7.50 (1H, m), 7.49 (1H, d, J = 4.0 Hz), 7.27-7.11 (5H, m), 6.97-6.95 (1H, m), 4.69 (1H, br s), 4.56-4.55 (1H, m), 3.83-3.80 (1H, m), 4.04-3.97 (1H, m), 3.73-3.71 (1H, m), 3.60 (3H, br s), 2.96-2.93 (1H, m), 2.49-2.48 (3H, m), 2.33 (3H, s), 1.81-1.56 (1H, m), 1.51-1.35 (1H, m), 1.29 (3H, br s), 1.23-1.21 (3H, m), 1.10-1.08 (3H, m).

[0307] Reference example 28 Preparation of methyl 2-amino-5-bromo-3-nitrobenzoate

[0308] [ka]

[0309] To a solution of methyl 2-amino-3-nitrobenzoate (5.30 g, 27 mmol) in acetic acid (30 mL), a solution of bromine (5.0 g, 32 mmol) in acetic acid (5.0 mL) was added and stirred at room temperature for 1 hour. Crushed ice and water were added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The precipitated solid was filtered, washed with water, dissolved in ethyl acetate, washed with 1 M aqueous sodium hydroxide solution and saturated saline, and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain the title compound (7.37 g, 99%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.51 (1H, d, J = 2.4 Hz), 8.44 (2H, br s), 8.32 (1H, d, J = 2.4 Hz), 3.93 (3H, s).

[0310] Reference example 29 Preparation of methyl 2,3-diamino-5-bromobenzoate

[0311] [ka]

[0312] Tin(II) chloride (13.6 g, 72 mmol) was added to a solution of methyl 2-amino-5-bromo-3-nitrobenzoate (3.97 g, 14 mmol) in methanol (100 mL), and the mixture was stirred at 75 °C for 1.5 hours. The reaction solution was returned to room temperature, concentrated under reduced pressure, and water was added. 1 M aqueous sodium hydroxide solution (100 mL) and solid sodium bicarbonate were added to adjust the pH to 9, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 70 / 30 → 49 / 51) to obtain the title compound (2.60 g, 73%) as a brown solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (1H, d, J = 1.6 Hz), 6.94 (1H d, J = 1.6 Hz), 5.55 (2H, br s), 3.87 (3H, s), 3.39 (2H, br s).

[0313] Reference example 30 Preparation of methyl 6-bromo-1H-benzo[d]imidazole-4-carboxylate

[0314] [ka]

[0315] A solution of methyl 2,3-diamino-5-bromobenzoate (1.02 g, 4.2 mmol) in formic acid (10 mL) was stirred at 100 °C for 1 hour. The reaction solution was returned to room temperature, and 1M aqueous sodium hydroxide and solid sodium bicarbonate were added to adjust the pH to 9, followed by extraction with ethyl acetate. The resulting organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (1.06 g, 99%) as a purple solid. 1 H NMR (400 MHz, CDCl 3 ) δ 10.5 (1H, br s), 8.18 (1H, d, J = 0.8 Hz), 8.14 (1H, s), 8.07 (1H, d, J = 0.8 Hz), 4.02 (3H, s).

[0316] Reference example 31 Preparation of (6-bromo-1-trityl-1H-benzo[d]imidazol-4-yl)methanol

[0317] [ka]

[0318] To a solution of methyl 6-bromo-1H-benzo[d]imidazole-4-carboxylate (854.6 mg, 3.4 mmol) in dichloromethane (16 mL), N-methylmorpholine (550 μL, 5.3 mmol) and trityl chloride (1.17 g, 4.2 mmol) were added and the mixture was stirred at 55 °C for 2 hours. The reaction solution was returned to room temperature, ethyl acetate was added, the mixture was washed with a saturated aqueous solution of sodium carbonate and saturated saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in THF (12 mL), and a 2M solution of lithium borohydride in THF (3.4 mL, 6.8 mmol) was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 72 / 28 → 7 / 93 → CH 2 Cl 2 / MeOH = 100 / 0 → 95 / 5) to obtain the title compound (1.17 g, 74%) as a pale purple solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (1H, s), 7.36-7.31 (9H, m), 7.21 (1H, s), 7.17-7.14 (6H, m), 6.50 (1H, s), 5.09 (2H, d, J = 6.4 Hz), 3.67 (1H, t, J = 6.4 Hz), Reference example 32 Preparation of (R)-2-[(6-bromo-1-trityl-1H-benzo[d]imidazol-4-yl)methyl]-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0319] [ka]

[0320] DIPEA (0.77 mL, 4.4 mmol) and methanesulfonyl chloride (115 μL, 1.5 mmol) were added to a solution of (6-bromo-1-trityl-1H-benzo[d]imidazol-4-yl)methanol (343.7 mg, 0.73 mmol) and lithium chloride (126.3 mg, 3.0 mmol) in dichloromethane (2.5 mL), and the mixture was stirred at 25 °C for 12 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in a mixed solvent of DMF (3.0 mL) and dichloromethane (1.0 mL), and (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (173.9 mg, 0.77 mmol), tetrabutylammonium iodide (55.8 mg, 0.15 mmol) and potassium carbonate (315.6 mg, 2.3 mmol) were added to the reaction solution. The reaction solution was stirred at 40 °C for 5.5 hours, and then cooled to room temperature, diluted with a mixed solvent of ethyl acetate / hexane (1 / 1), washed with water and saturated saline, dried over sodium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 69 / 31→48 / 52) to obtain the title compound (471.8 mg, 95%) as a pale orange solid. 1 H NMR (400 MHz, CDCl 3) δ 7.89 (1H, dd, J = 7.6, 1.6 Hz), 7.78 (1H, s), 7.49 (1H, td, J = 7.6, 1.6 Hz), 7.46 (1H, s), 7.34-7.30 (9H, m), 7.23 (1H, t, J = 8.0 Hz), 7.17-7.11 (7H, m), 6.50 (1H, d, J = 1.6 Hz), 4.77 (1H, d, J = 16.0 Hz), 4.55 (1H, d, J = 16.0 Hz), 4.05-3.96 (2H, m), 3.30 (1H, dt, J = 13.6, 6.8 Hz), 1.78-1.67 (1H, m), 1.54-1.44 (1H, m), 1.08 (3H, t, J = 7.2 Hz).

[0321] Reference example 33 Preparation of (R)-4-ethyl-2-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-benzo[d]imidazol-4-yl]methyl}-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0322] [ka]

[0323] (R)-2-[(6-bromo-1-trityl-1H-benzo[d]imidazol-4-yl)methyl]-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (202.2 mg, 0.30 mmol), bis(pinacolato)diboron (83.0 mg, 0.33 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2A solution of bis(pinacolato)diboron (12.8 mg, 0.016 mmol), and potassium acetate (90.8 mg, 0.93 mmol) in anhydrous 1,4-dioxane (2.0 mL) was stirred at 90 °C for 15.5 hours under an argon atmosphere. The reaction solution was returned to room temperature and filtered through Celite, and the solvent in the filtrate was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 76 / 24 → 55 / 45) to obtain the compound (170.6 mg), about half of which was unreacted. The compound obtained again (0.13 mmol), bis(pinacolato)diboron (83.0 mg, 0.33 mmol), and PdCl 2 (dppf) 2 -CH 2 Cl 2 A solution of 1,4-dioxane (2.0 mL) of 1,4-dioxane (12.8 mg, 0.016 mmol), potassium acetate (90.8 mg, 0.93 mmol) and 1,4-dioxane (2.0 mL) was stirred at 90 °C for 15.5 hours. The reaction solution was returned to room temperature and filtered through Celite, and the solvent of the obtained filtrate was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 76 / 24 → 55 / 45) to obtain the title compound (138.9 mg, 64%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (1H, d, J = 7.6 Hz), 7.84 (1H, s), 7.71 (1H, s), 7.46 (1H, t, J = 7.6 Hz), 7.32-7.28 (9H, m), 7.21 (1H, t, J = 7.6 Hz), 7.16-7.14 (7H, m). 6.77 (1H, s), 4.81 (1H, d, J = 14.8 Hz), 4.58 (1H, d, J = 14.8 Hz), 4.06-3.94 (2H, m), 3.27 (1H, d, J = 14.0 Hz), 1.72-1.62 (1H, m), 1.49-1.40 (1H, m), 1.20 (12H, s), 1.03 (3H, t, J = 7.2 Hz).

[0324] Reference example 34 Preparation of 5-bromo-3-methylthiophene-2-carbaldehyde

[0325] [ka]

[0326] Bromine (5.0 g, 31 mmol) was added to a solution of 3-methylthiophene-2-carboxaldehyde (3.75 g, 30 mmol) in dichloromethane (25 mL) at 0 °C, and the mixture was stirred at 65 °C for 1 hour. The reaction solution was returned to room temperature, diluted with dichloromethane, and washed with an aqueous solution of sodium thiosulfate, water, and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane / ethyl acetate (v / v) = 98 / 2 → 90 / 10) and then recrystallized from ethyl acetate / hexane to obtain the title compound (2.06 g, 33%) as pale yellow crystals. The filtrate was further concentrated, hexane was added, and the precipitate was collected by filtration to obtain the title compound (1.41 g, 23%) as a pale brown solid. 1 H NMR (400 MHz, CDCl 3 ) δ 9.90 (1H, s), 6.96 (1H, s), 2.53 (3H, s).

[0327] Reference example 35 Preparation of 5-bromo-3-methylthiophene-2-carboxylic acid

[0328] [ka]

[0329] A solution of 5-bromo-3-methylthiophene-2-carbaldehyde (317.1 mg, 1.6 mmol) in acetone (3.0 mL) was cooled to 0 °C and diluted with 2.5 M Jones reagent (3.75 mL, 3.8 mmol) (CrO 3 1.01 g, H2 SO 4 1.0 mL, H 2 To the reaction mixture was added 1.2 mL of ethyl acetate (O 3.0 mL), and the mixture was stirred at 0°C for 5 minutes, and then at 25°C for 2 hours and 15 minutes. Water was added to the reaction mixture to terminate the reaction, and ethyl acetate was added to separate the organic and aqueous layers. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (304.2 mg, 89%) as an orange solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.20 (1H, s), 2.43 (3H, s).

[0330] Reference example 36 Preparation of 5-bromo-N-methylfuran-2-carboxamide

[0331] [ka]

[0332] To a solution of 5-bromofuran-2-carboxylic acid (500 mg, 2.6 mmol), methylamine hydrochloride (212.3 mg, 3.1 mmol), EDCI (603 mg, 3.1 mmol), and HOBt (106.2 mg, 0.79 mmol) in acetonitrile (3.3 mL), TEA (439 μL, 3.1 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours, and then water was added and extracted with dichloromethane. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 70 / 30→50 / 50) to obtain the title compound (391.3 mg, 73%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.04 (1H, d, J = 3.6 Hz), 6.62 (1H, s), 6.42 (1H, d, J = 3.6 Hz), 2.96 (3H, d, J = 4.8 Hz).

[0333] Reference example 37 Preparation of (5-bromofuran-2-yl)(pyrrolidin-1-yl)methanone

[0334] [ka]

[0335] Using 5-bromofuran-2-carboxylic acid (1.0 g, 5.2 mmol), pyrrolidine (517 μL, 6.3 mmol), EDCI (1.2 g, 6.3 mmol), HOBt (212 mg, 1.6 mmol), acetonitrile (6.6 mL), and TEA (878 μL, 6.3 mmol) as raw materials, the title compound (748.8 mg, 58%) was obtained as a white solid by the procedure described in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.04 (1H, d, J = 3.6 Hz), 6.43 (1H, d, J = 3.6 Hz), 3.82 (2H, t, J = 6.8 Hz), 3.63 (2H, t, J = 6.8 Hz), 2.01 (2H, quin, J = 6.8 Hz), 1.90 (2H, quin, J = 6.8 Hz).

[0336] Reference example 38 Preparation of 5-bromo-N-isopropylfuran-2-carboxamide

[0337] [ka]

[0338] Using 5-bromofuran-2-carboxylic acid (1.0 g, 5.24 mmol), isopropylamine (540 μL, 6.3 mmol), EDCI (1.2 g, 6.3 mmol), HOBt (212 mg, 1.57 mmol), acetonitrile (6.6 mL), and TEA (878 μL, 6.3 mmol) as starting materials, the title compound (714.3 mg, 59%) was obtained as a colorless oily substance by the procedure described in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.04 (1H, d, J = 3.2 Hz), 6.43 (1H, d, J = 3.2 Hz), 6.09 (1H, br s), 4.24 (1H, septd, J = 6.4, 1.2 Hz), 1.26 (6H, d, J = 6.4 Hz).

[0339] Reference example 39 Preparation of 5-bromo-N-methylthiophene-2-carboxamide

[0340] [ka]

[0341] Using 5-bromothiophene-2-carboxylic acid (500 mg, 2.4 mmol), methylamine hydrochloride (325 mg, 4.8 mmol), EDCI (554 mg, 2.9 mmol), HOBt (97.7 mg, 0.72 mmol), acetonitrile (5.0 mL), and TEA (1.0 mL, 7.2 mmol) as starting materials, the title compound (239.8 mg, 45%) was obtained as a white solid by the procedure described in Reference Example 36. 1 H NMR (400 MHz, CD 3 OD)δ 7.40 (1H, d, J = 4.0 Hz), 7.13 (1H, d, J = 4.0 Hz), 2.86 (3H, s).

[0342] Reference example 40 Preparation of 5-bromo-N-(2-methoxyethyl)furan-2-carboxamide

[0343] [ka]

[0344] Using 5-bromofuran-2-carboxylic acid (300 mg, 1.6 mmol), 2-methoxyethylamine (340 μL, 5.2 mmol), EDCI (602 mg, 3.1 mmol), HOBt (212 mg, 1.6 mmol), acetonitrile (3.0 mL), and TEA (500 μL, 6.8 mmol) as starting materials, the title compound (339.9 mg, 87%) was obtained as a pale yellow oily substance by the procedure described in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.06 (1H, d, J = 3.6 Hz), 6.63 (1H, br s), 6.43 (1H, d, J = 3.6 Hz), 3.63-3.59 (2H, m), 3.55-3.53 (2H, m), 3.40 (3H, s).

[0345] Reference example 41 Preparation of N,3-dimethylfuran-2-carboxamide

[0346] [ka]

[0347] Using 3-methylfuran-2-carboxylic acid (720 mg, 5.7 mmol), methylamine hydrochloride (581 mg, 8.6 mmol), EDCI (1.3 g, 6.8 mmol), HOBt (459 mg, 3.4 mmol), acetonitrile (10 mL), and TEA (2.4 mL, 17 mmol) as starting materials, the title compound (693.6 mg, 87%) was obtained as a colorless oily substance by the procedure described in Reference Example 36. 1H NMR (400 MHz, CDCl 3 )δ 6.32 (1H, s), 6.28 (1H, br s), 2.95 (3H, d, J = 5.2 Hz), 2.40 (3H, s).

[0348] Reference example 42 Preparation of 4-bromo-N-methylthiophene-2-carboxamide

[0349] [ka]

[0350] Using 4-bromothiophene-2-carboxylic acid (1.0 g, 4.83 mmol), methylamine hydrochloride (652 mg, 9.7 mmol), EDCI (1.1 g, 5.8 mmol), HOBt (392 mg, 2.9 mmol), acetonitrile (15 mL), and TEA (2.0 mL, 15 mmol) as raw materials, the title compound (789.1 mg, 74%) was obtained as a white solid by the procedure described in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.37 (1H, d, J = 1.2 Hz), 7.35 (1H, d, J = 1.2 Hz), 5.93 (1H, br s), 3.00 (3H, d, J = 4.8 Hz).

[0351] Reference example 43 Preparation of N,4-dimethylthiophene-2-carboxamide

[0352] [ka]

[0353] Using 4-methylthiophene-2-carboxylic acid (1.0 g, 7.0 mmol), methylamine hydrochloride (945.3 mg, 14 mmol), EDCI (1.61 g, 8.4 mmol), HOBt (662 mg, 4.9 mmol), acetonitrile (5.0 mL), dichloromethane (5.0 mL) and TEA (2.94 mL, 21 mmol) as raw materials, the title compound (880.5 mg, 81%) was obtained as a white solid by the procedure described in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.45 (1H, d, J = 1.2 Hz), 7.29 (1H, br s), 7.00 (1H, br s), 2.96 (3H, d, J = 4.8 Hz), 2.20 (3H, d, J = 0.8 Hz).

[0354] Reference example 44 Preparation of N-methoxy-N,4-dimethylthiophene-2-carboxamide

[0355] [ka]

[0356] Using 4-methylthiophene-2-carboxylic acid (700 mg, 4.9 mmol), N,O-dimethylhydroxylamine hydrochloride (1.44 g, 15 mmol), EDCI (1.88 g, 9.8 mmol), HOBt (1.32 g, 9.8 mmol), dichloromethane (20 mL), and DIPEA (2.6 mL, 15 mmol) as starting materials, the title compound (831.5 mg, 91%) was obtained as a colorless oily substance by the procedure described in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.75 (1H, d, J = 1.6 Hz), 7.14 (1H, d, J = 1.6 Hz), 3.76 (3H, s), 3.36 (3H, s), 2.28 (3H, s).

[0357] Reference example 45 Preparation of 3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide

[0358] [ka]

[0359] 3-Fluorothiophene-2-carboxylic acid (500 mg, 3.4 mmol), N,O-dimethylhydroxylamine hydrochloride (1.0 g, 10 mmol), EDCI (1.31 g, 6.8 mmol), and HOBt (924.3 mg, 6.8 mmol), dichloromethane (20 mL), and DIPEA (1.84 mL, 10 mmol) were used as raw materials, and the title compound (604.6 mg, 94%) was obtained as a colorless oily substance by the same procedure as in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.38 (1H, dd, J = 5.6, 4.0 Hz), 6.84 (1H, d, J = 5.6 Hz), 3.74 (3H, s), 3.33 (3H, s).

[0360] Reference example 46 Preparation of 5-bromo-N-(2,4-dimethoxybenzyl)thiophene-2-carboxamide

[0361] [ka]

[0362] 5-Bromothiophene-2-carboxylic acid (400 mg, 1.9 mmol), 2,4-dimethoxybenzylamine (582 μL, 3.9 mmol), EDCI (1.31 g, 6.8 mmol), HOBt (924.3 mg, 6.8 mmol), dichloromethane (20 mL), and DIPEA (1.84 mL, 10 mmol) were used as raw materials, and the title compound (860.9 mg, quant.) was obtained as a colorless oily substance by the same procedure as in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.21 (1H, d, J = 8.0 Hz), 7.19 (1H, d, J = 4.0 Hz), 6.98 (1H, d, J = 4.0 Hz), 6.48 (1H, br s), 6.46 (1H, d, J = 2.4 Hz), 6.43 (1H, dd, J = 8.0, 2.4 Hz), 4.49 (2H, d, J = 5.6 Hz), 3.84 (3H, s), 3.79 (3H, s).

[0363] Reference example 47 Preparation of 5-bromo-N-methoxy-N-3-dimethylthiophene-2-carboxamide

[0364] [ka]

[0365] To a solution of 5-bromo-3-methylthiophene-2-carboxylic acid (302.3 mg, 1.4 mmol), N,O-dimethylhydroxylamine hydrochloride (267.4 mg, 2.7 mmol), and EDCI (397.6 mg, 2.1 mmol) in dichloromethane (5.0 mL), TEA (0.57 mL, 4.1 mmol) was added and stirred at 25 °C for 18 hours. The reaction solution was diluted with ethyl acetate, washed with 1M hydrochloric acid and saturated saline, dried over sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain the title compound (315.3 mg, 87%) as a brown oil. 1H NMR (400 MHz, CDCl 3 ) δ 6.87 (1H, s), 3.70 (3H, s), 3.29 (3H, s), 2.51 (3H, s).

[0366] Reference example 48 Bromo-N-methoxy-N-methylthiazole-5-carboxamide

[0367] [ka]

[0368] To a solution of 2-bromothiazole-5-carboxylic acid (707.9 mg, 3.4 mmol), N,O-dimethylhydroxylamine hydrochloride (667.5 mg, 6.8 mmol), and EDCI (977.9 mg, 5.1 mmol) in dichloromethane (17 mL) and DMF (3.0 mL), TEA (1.5 mL, 11 mmol) was added and the mixture was stirred at 25 °C for 13 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1M hydrochloric acid and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (519.1 mg, 61%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (1H, s), 3.78 (3H, s), 3.36 (3H, s).

[0369] Reference example 49 Preparation of 2-bromo-N-methoxy-N,4-dimethylthiazole-5-carboxamide

[0370] [ka]

[0371] To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (500.2 mg, 2.3 mmol), N,O-dimethylhydroxyamine hydrochloride (452.8 mg, 4.6 mmol), and EDCI (654.6 mg, 3.4 mmol) in dichloromethane (8.0 mL) and DMF (2.0 mL), TEA (1.0 mL, 7.2 mmol) was added and stirred at 25 °C for 8 hours. The reaction solution was diluted with ethyl acetate and washed with 1M hydrochloric acid and saturated saline. The organic layer was dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure to obtain the title compound (473.5 mg, 79%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.66 (3H, s), 3.26 (3H, s), 2.68 (3H, s).

[0372] Reference example 50 Preparation of 4-bromo-N-methoxy-N-methylthiophene-2-carboxamide

[0373] [ka]

[0374] Using 4-bromothiophene-2-carboxylic acid (500 mg, 2.4 mmol), NO-dimethylhydroxylamine hydrochloride (470 mg, 4.8 mmol), EDCI (924 mg, 4.8 mmol), HOBt (708 mg, 5.2 mmol), dichloromethane (20 mL), and DIPEA (1.29 mL, 7.2 mmol) as starting materials, the title compound (510.5 mg, 85%) was obtained as a colorless oily substance by the procedure described in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.83 (1H, d, J = 1.6 Hz), 7.44 (1H, d, J = 1.6 Hz), 3.78 (3H, s), 3.37 (3H, s).

[0375] Reference example 51 Preparation of 2-bromo-N-methoxy-N-methylthiophene-3-carboxamide

[0376] [ka]

[0377] 2-Bromothiophene-3-carboxylic acid (500 mg, 2.4 mmol), N,O-dimethylhydroxylamine hydrochloride (470 mg, 4.8 mmol), EDCI (924 mg, 4.8 mmol), HOBt (326 mg, 4.8 mmol), dichloromethane (20 mL) and DIPEA (1.29 mL, 7.2 mmol) were used as raw materials and operated in the same manner as in Reference Example 36 to obtain the title compound (606.7 mg, quant.) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.25 (1H, d, J = 6.0 Hz), 7.04 (1H, d, J = 6.0 Hz), 3.60 (3H, s), 3.34 (3H, s).

[0378] Reference example 52 Preparation of 5-bromo-N-methoxy-N-methylfuran-2-carboxamide

[0379] [ka]

[0380] Using 5-bromofuran-2-carboxylic acid (500 mg, 2.6 mmol), N,O-dimethylhydroxylamine hydrochloride (767 mg, 7.9 mmol), EDCI (1.0 g, 5.2 mmol), HOBt (708 mg, 5.2 mmol), dichloromethane (20 mL), and DIPEA (1.4 mL, 7.9 mmol) as starting materials, the title compound (555.3 mg, 90%) was obtained as a colorless oily substance by the procedure described in Reference Example 36. 1 H NMR (400 MHz, CDCl 3 )δ 7.08 (1H, d, J = 3.6 Hz), 6.44 (1H, d, J = 3.6 Hz), 3.77 (3H, s), 3.33 (3H, s).

[0381] Reference example 53 Preparation of N-[(5-bromofuran-2-yl)methyl]propan-2-amine

[0382] [ka]

[0383] Isopropylamine (514 μL, 6.0 mmol) and acetic acid (50 μL, 0.79 mmol) were added to a solution of 5-bromofuran-2-carbaldehyde (700 mg, 4.0 mmol) in methanol (7.0 mL), and the mixture was stirred at room temperature for 2 hours. Sodium borohydride (227 mg, 6.0 mmol) was added to the mixture, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (785.4 mg, 90%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ 6.21 (1H, d, J = 3.2 Hz), 6.15 (1H, d, J = 3.2 Hz), 3.75 (2H, s), 2.82 (1H, septd, J = 6.4 Hz), 1.38 (1H, br s), 1.06 (6H, d, J = 6.4 Hz).

[0384] Reference example 54 Preparation of 5-(tert-butyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one

[0385] [ka]

[0386] To a solution of 2,3-thiophenedicarboxaldehyde (4.14 g, 30 mmol) in anhydrous dichloromethane (260 mL), tert-butylamine (4.0 mL, 38 mmol) and acetic acid (8.5 mL, 149 mmol) were added at 0 °C, and the mixture was stirred at 0 °C for 15 minutes and then at room temperature for 3.5 hours. After the reaction was completed, the reaction solution was washed with 1M hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, and the resulting organic layer was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 84 / 16 → 63 / 37) to obtain the title compound (4.03 g, 70%) as a pale orange solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (1H, d, J = 4.8 Hz), 6.99 (1H, d, J = 4.8 Hz), 4.36 (2H, s), 1.54 (9H, s) Reference example 55 Preparation of 2-bromo-1,5,6,7-tetrahydro-4H-indol-4-one

[0387] [ka]

[0388] N-Bromosuccinimide (475.2 mg, 2.7 mmol) was added to a solution of 1,5,6,7-tetrahydro-4H-indol-4-one (300 mg, 2.2 mmol) in DMF (3.0 mL) and stirred at room temperature for 14 hours. 4N aqueous sodium hydroxide was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 6 / 4→5 / 5) to obtain the title compound (220.5 mg, 76%) as a white solid. 1 H NMR (400 MHz, CDCl3 )δ 8.49 (1H, br s), 6.51 (1H, d, J = 2.4 Hz), 2.79 (2H, t, J = 6.4 Hz), 2.48 (2H, t, J = 6.4 Hz), 2.15 (2H, quin, J = 6.4 Hz).

[0389] Reference example 56 Preparation of 5-bromo-N,3-dimethylfuran-2-carboxamide

[0390] [ka]

[0391] N,3-Dimethylfuran-2-carboxamide (310 mg, 2.2 mmol), DMF (2.3 mL), N-bromosuccinimide (477 mg, 2.7 mmol), and TFA (341 μL, 4.5 mmol) were used as starting materials, and the procedure was performed in the same manner as in Reference Example 55 to obtain the title compound (205.3 mg, 42%) as a yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 6.28 (1H, br s), 6.27 (1H, s), 2.95 (3H, d, J = 4.8 Hz), 2.37 (3H, s).

[0392] Reference example 57 Preparation of 5-bromo-N,4-dimethylthiophene-2-carboxamide

[0393] [ka]

[0394] N,4-Dimethylthiophene-2-carboxamide (600 mg, 3.9 mmol), dimethylformamide (6.0 mL), N-bromosuccinimide (822 mg, 4.6 mmol), and TFA (588 μL, 7.7 mmol) were used as raw materials and operated in the same manner as in Reference Example 55 to obtain the title compound (763.8 mg, 84%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.19 (1H, s), 6.23 (1H, br s), 2.95 (3H, d, J = 4.8 Hz), 2.18 (3H, s).

[0395] Reference example 58 Preparation of 1-(5-bromo-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one

[0396] [ka]

[0397] 1-(2,4-Dimethyl-1H-pyrrol-3-yl)ethan-1-one (500 mg, 3.6 mmol), DMF (5.0 mL), and N-bromosuccinimide (778 mg, 4.4 mmol) were used as starting materials, and the title compound (538.9 mg, 68%) was obtained as a red solid by the procedure described in Reference Example 55. 1 H NMR (400 MHz, CDCl 3 )δ 8.16 (1H, br s), 2.49 (3H, s), 2.42 (3H, s), 2.22 (3H, s).

[0398] Reference example 59 Preparation of 1-(5-bromo-4-methylthiophen-2-yl)ethan-1-one

[0399] [ka]

[0400] 1-(4-Methylthiophen-2-yl)ethan-1-one (100 mg, 0.71 mmol), DMF (1.0 mL), N-bromosuccinimide (152.4 mg, 0.86 mmol), and TFA (110 μL, 1.4 mmol) were used as raw materials, and the title compound (118.6 mg, 76%) was obtained as a pale yellow solid by the procedure described in Reference Example 55. 1 H NMR (400 MHz, CDCl 3 )δ 7.36 (1H, s), 2.48 (3H, s), 2.22 (3H, s).

[0401] Reference example 60 Preparation of 5-bromo-3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide

[0402] [ka]

[0403] To a solution of 3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (620 mg, 3.3 mmol) in DMF (6.0 mL), N-bromosuccinimide (1.17 g, 6.6 mmol) and TFA (1.0 mL, 13 mmol) were added. After stirring the reaction mixture at room temperature for 24 hours, 1N aqueous sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 100 / 0→80 / 20) to obtain the title compound (425.5 mg, 48%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δ 6.89 (1H, s), 3.75 (3H, s), 3.30 (3H, s).

[0404] Reference example 61 Preparation of 1-(5-bromo-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one

[0405] [ka]

[0406] 1-(2,4-Dimethyl-1H-pyrrol-3-yl)ethan-1-one (500 mg, 3.6 mmol), DMF (5.0 mL), and N-bromosuccinimide (778 mg, 4.4 mmol) were used as starting materials, and the title compound (538.9 mg, 68%) was obtained as a red solid by the procedure described in Reference Example 55. 1 H NMR (400 MHz, CDCl 3 )δ 8.16 (1H, br s), 2.49 (3H, s), 2.42 (3H, s), 2.22 (3H, s).

[0407] Reference example 62 Preparation of 1-(5-bromo-1-ethyl-1H-pyrrol-2-yl)ethan-1-one

[0408] [ka]

[0409] 1-(1-ethyl-1H-pyrrol-2-yl)ethan-1-one (600 μL, 4.3 mmol), DMF (6.0 mL), and N-bromosuccinimide (925 mg, 5.2 mmol) were used as starting materials, and the procedure was carried out in the same manner as in Reference Example 55 to obtain the title compound (752 mg, 80%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 6.91 (1H, d, J = 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 4.33 (2H, q, J = 7.2 Hz), 2.40 (3H, s), 1.35 (3H, t, J = 7.2 Hz).

[0410] Reference example 63 Preparation of (5-bromothiophen-2-yl)(cyclopropyl)methanone

[0411] [ka]

[0412] Cyclopropyl(thiophen-2-yl)methanone (593 μL, 4.6 mmol), DMF (5.8 mL), N-bromosuccinimide (979 mg, 5.5 mmol), and TFA (704 μL, 9.2 mmol) were used as starting materials, and the title compound (56.8 mg, 5%) was obtained as a pale red oily substance by the procedure described in Reference Example 55. 1 H NMR (400 MHz, CDCl 3 )δ 7.55 (1H, d, J = 4.0 Hz), 7.12 (1H, d, J = 4.0 Hz), 2.47-2.41 (1H, m), 1.25-1.21 (2H, m), 1.05-1.01 (2H, m).

[0413] Reference example 64 Preparation of 2-bromo-5-(tert-butyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one

[0414] [ka]

[0415] N-Bromosuccinimide (7.37 g, 41 mmol) and acetic acid (1.3 mL, 23 mmol) were added to a solution of 5-(tert-butyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one (4.03 g, 21 mmol) in DMF (100 mL) at 0 °C, and the mixture was stirred at room temperature for 8 hours. The reaction solution was quenched by adding a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate / hexane (1 / 1). The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 96 / 4 → 75 / 25) to obtain the title compound (4.27 g, 76%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.01(1H, s), 4.33 (2H, s), 1.53 (9H, s).

[0416] Reference example 65 Preparation of 4-bromo-1-methyl-1H-pyrrole-2-carbonitrile

[0417] [ka]

[0418] 1-Methyl-1H-pyrrole-2-carbonitrile (300 mg, 2.8 mmol), DMF (7.0 mL), and N-bromosuccinimide (604.5 mg, 3.4 mmol) were used as raw materials, and the title compound (212.5 mg, 41%) was obtained as a white solid by the procedure described in Reference Example 55. 1 H NMR (400 MHz, CDCl 3 )δ 6.81 (1H, d, J = 1.6 Hz), 6.75 (1H, d, J = 1.6 Hz), 3.76 (3H, s).

[0419] Reference example 66 Preparation of 2-bromo-1-methyl-1,5,6,7-tetrahydro-4H-indol-4-one

[0420] [ka]

[0421] A solution of 2-bromo-1,5,6,7-tetrahydro-4H-indol-4-one (200 mg, 0.93 mmol) and potassium tert-butoxide (113.6 mg, 1.0 mmol) in DMSO (4.0 mL) was stirred at 60 °C for 30 minutes. Iodomethane (86 μL, 1.4 mmol) was added and stirred at 60 °C for 7 hours. 1N hydrochloric acid was added to the mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 7 / 3 → 1 / 1) to obtain the title compound (170.1 mg, 80%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 6.52 (1H, s), 3.50 (3H, s), 2.73 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 6.4 Hz), 2.14 (2H, quin, J = 6.4 Hz).

[0422] Reference example 67 Preparation of 1-(5-bromo-1,2,4-trimethyl-1H-pyrrol-3-yl)ethan-1-one

[0423] [ka]

[0424] To a solution of sodium hydride (50.4 mg, 1.7 mmol) in DMF (4.0 mL), 1-(5-bromo-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one (300 mg, 1.4 mmol) was added. The mixture was stirred at room temperature for 1 hour, iodomethane (105 μL, 1.7 mmol) was added, and the mixture was stirred for 20 hours. Further iodomethane (86 μL, 1.4 mmol) was added, and the mixture was stirred at 60 °C for 7 hours. The reaction was stopped by adding water to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 0 → 9 / 1) to obtain the title compound (152.8 mg, 48%) as a pale red solid. 1 H NMR (400 MHz, CDCl 3 )δ 3.50 (3H, s), 2.50 (3H, s), 2.41 (3H, s), 2.24 (3H, s).

[0425] Reference example 68 Preparation of 1-(5-bromo-3-fluorothiophen-2-yl)ethan-1-one

[0426] [ka]

[0427] To a solution of 5-bromo-3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (425 mg, 1.6 mmol) in THF (8.0 mL) was added a solution of methylmagnesium bromide (3M, 2-methyltetrahydrofuran solution) (0.80 mL, 2.4 mmol) at 0 °C. After stirring the mixture at room temperature for 7.5 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted with diethyl ether. The organic layer was washed with saturated aqueous ammonium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (190.8 mg, 54%) as a colorless oil. 1 H NMR (400 MHz, CDCl3 )δ 6.90 (1H, d, J = 0.8 Hz), 2.52 (3H, d, J = 3.2 Hz).

[0428] Reference example 69 Preparation of 1-(4-methylthiophen-2-yl)ethan-1-one

[0429] [ka]

[0430] N-Methoxy-N,4-dimethylthiophene-2-carboxamide (400 mg, 2.2 mmol), THF (11 mL), and a solution of methylmagnesium bromide (3M, 2-methyltetrahydrofuran solution) (1.1 mL, 3.2 mmol) were used as starting materials, and the procedure was performed in the same manner as in Reference Example 68 to obtain the title compound (275.1 mg, 91%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.50 (1H, d, J = 0.8 Hz), 7.22 (1H, br d, J = 0.8 Hz), 2.53 (3H, s), 2.29 (3H, d, J = 0.8 Hz).

[0431] Reference example 70 Preparation of 1-(5-bromo-3-methylthiophen-2-yl)ethan-1-one

[0432] [ka]

[0433] Using 5-bromo-N-methoxy-N,3-dimethylthiophene-2-carboxamide (368 mg, 1.4 mmol), THF (7.0 mL), and a solution of methylmagnesium bromide (3M, 2-methyltetrahydrofuran solution) (0.70 mL, 2.1 mmol) as starting materials, the title compound (216.1 mg, 71%) was obtained as a yellow oily substance by the procedure of Reference Example 68. 1 H NMR (400 MHz, CDCl 3 )δ 6.93 (1H, s), 2.51 (3H, s), 2.47 (3H, s).

[0434] Reference example 71 Preparation of 1-(2-bromothiazol-5-yl)ethan-1-one

[0435] [ka]

[0436] A solution of 2-bromo-N-methoxy-N-methylthiazole-5-carboxamide (507.5 mg, 2.0 mmol) in THF (7.0 mL) was added with a solution of methylmagnesium bromide (3 M, 2-methyltetrahydrofuran solution) (0.68 mL, 2.0 mmol) and stirred at 25 °C for 1 hour. Further, methylmagnesium bromide (3 M, 0.15 mL, 0.45 mmol) was added and stirred at room temperature for 5 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (278 mg, 67%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.05, (1H, s), 2.56 (3H, s).

[0437] Reference example 72 Preparation of 1-(2-bromo-4-methylthiazol-5-yl)ethan-1-one

[0438] [ka]

[0439] A solution of 2-bromo-N-methoxy-N-4-dimethylthiazole-5-carboxamide (209.0 mg, 0.8 mmol) in THF (2.0 mL) was added with methylmagnesium bromide (3M, 2-methyltetrahydrofuran solution) (0.3 mL, 0.9 mmol) at 0 °C, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 82 / 18 → 61 / 39) to obtain the title compound (146.8 mg, 85%) as a yellow transparent oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 2.72 (3H, s), 2.51 (3H, s).

[0440] Reference example 73 Preparation of 1-(4-bromothiophen-2-yl)ethan-1-one

[0441] [ka]

[0442] Using 4-bromo-N-methoxy-N-methylthiophene-2-carboxamide (510 mg, 2.0 mmol), THF (10 mL), and a solution of methylmagnesium bromide (3M, 2-methyltetrahydrofuran solution) (1.0 mL, 3.0 mmol) as starting materials, the title compound (406.9 mg, 97%) was obtained as a colorless oily substance by the same procedure as in Reference Example 68. 1 H NMR (400 MHz, CDCl 3)δ 7.58 (1H, d, J = 1.2 Hz), 7.53 (1H, d, J = 1.2 Hz), 2.55 (3H, s).

[0443] Reference example 74 Preparation of 1-(2-bromothiophen-3-yl)ethan-1-one

[0444] [ka]

[0445] Using 2-bromo-N-methoxy-N-methylthiophene-3-carboxamide (550 mg, 2.2 mmol), THF (10 mL), and a solution of methylmagnesium bromide (3M, 2-methyltetrahydrofuran solution) (1.1 mL, 3.3 mmol) as starting materials, the title compound (128.8 mg, 29%) was obtained as a colorless oily substance by the procedure similar to that of Reference Example 68. 1 H NMR (400 MHz, CDCl 3 )δ 7.35 (1H, d, J = 5.6 Hz), 7.23 (1H, d, J = 5.6 Hz), 2.62 (3H, s).

[0446] Reference example 75 Preparation of 1-(5-bromofuran-2-yl)ethan-1-one

[0447] [ka]

[0448] Using 5-bromo-N-methoxy-N-methylfuran-2-carboxamide (332.6 mg, 1.4 mmol), THF (7.0 mL), and methylmagnesium bromide (3M, 2-methyltetrahydrofuran solution) (0.7 mL, 2 mmol) as raw materials, and operating in the same manner as in Reference Example 68, the title compound (223.3 mg, 78%) was obtained as a white solid. 1H NMR (400 MHz, CDCl 3 )δ 7.12 (1H, d, J = 3.6 Hz), 6.49 (1H, d, J = 3.6 Hz), 2.46 (3H, s).

[0449] Reference example 76 Preparation of 2-(5-bromothiophen-2-yl)-2-methyl-1,3-dioxolane

[0450] [ka]

[0451] A solution of 1-(5-bromothiophen-2-yl)ethan-1-one (500 mg, 2.4 mmol) in toluene (34 mL) was added with ethylene glycol (0.95 mL, 17 mmol), p-TsOH-H 2 O (130 mg, 0.68 mmol) was added and the mixture was stirred under heating and reflux for 25 hours. A saturated aqueous solution of sodium bicarbonate was added to this reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 95 / 5 → 9 / 1) to obtain the title compound (183.7 mg, 30%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 6.90 (1H, d, J = 4.0 Hz), 6.79 (1H, d, J = 4.0 Hz), 4.06-4.00 (m, 2H), 3.99-3.93 (m, 2H), 1.73(s, 3H).

[0452] Reference example 77 Preparation of 2-(5-bromo-3-methylthiophen-2-yl)-2-methyl-1,3-dioxolone

[0453] [ka]

[0454] A solution of 1-(5-bromo-3-methylthiophen-2-yl)ethan-1-one (491.5 mg, 2.2 mmol) in toluene (20 mL) was diluted with ethylene glycol (1.2 mL, 22 mmol) and p-TsOH-H 2 O (0.11 mmol) was added and the mixture was stirred under heating and reflux for 10 hours. The reaction solution was returned to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (577.9 mg, 98%) as a yellow transparent oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 6.74 (1H, s), 4.06-3.99 (2H, m), 3.96-3.90 (2H, m), 2.23 (3H, s), 1.71 (3H, s).

[0455] Reference example 78 Preparation of 2-bromo-5-(2-methyl-1,3-dioxolan-2-yl)thiazole

[0456] [ka]

[0457] A solution of 1-(2-bromothiazol-5-yl)ethan-1-one (278 mg, 1.3 mmol) in toluene (8.0 mL) was added with ethylene glycol (800 μL) and p-TsOH-H 2 O (12.7 mg, 0.067 mmol) was added and the mixture was stirred under heating and reflux for 14 hours. The reaction solution was returned to room temperature, and saturated aqueous sodium bicarbonate and ethyl acetate were added, and the organic layer and aqueous layer were separated. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (313.6 mg, 93%) as a yellow oily substance. 1 H NMR (400 MHz, CDCl 3) δ 7.49 (1H, s), 4.13-4.03 (2H, m), 3.99-3.91 (2H, m), 1.75 (3H, s).

[0458] Reference example 79 Preparation of 2-bromo-4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiazole

[0459] [ka]

[0460] A solution of 1-(2-bromo-4-methylthiazol-5-yl)ethan-1-one (146.8 mg, 0.67 mmol) in toluene (8.0 mL) was added with ethylene glycol (0.40 mL) and p-TsOH-H 2 HO (6.3 mg, 0.033 mmol) was added and the mixture was stirred under reflux for 21 hours. The reaction solution was returned to room temperature, saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, washed with saturated saline, and the solvent was removed by distillation under reduced pressure. Since the reaction had not proceeded completely, the residue was diluted with toluene (8.0 mL), ethylene glycol (0.80 mL), and p-TsOH-H 2 O (5.7 mg, 0.030 mmol) was added and the mixture was stirred under heating and reflux for 13 hours. The reaction solution was returned to room temperature, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, washed with saturated saline, and the solvent was removed by distillation under reduced pressure to obtain the title compound (172.2 mg, 98%) as an orange oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 4.09-4.01 (2H, m), 3.94-3.88 (2H, m), 2.43 (3H, s), 1.71 (3H, s).

[0461] Reference example 80 Preparation of 2-(5-bromofuran-2-yl)-2-methyl-1,3-dioxolane

[0462] [ka]

[0463] 1-(5-Bromofuran-2-yl)ethan-1-one (533.5 mg, 2.8 mmol), ethylene glycol (1.7 mL, 31 mmol), p-TsOH-H 2 O (27 mg, 0.14 mmol) and toluene (32 mL) were used as starting materials, and the procedure was performed in the same manner as in Reference Example 76 to obtain the title compound (496.3 mg, 76%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 6.29 (1H, d, J = 3.2 Hz), 6.23 (1H, d, J = 3.2 Hz), 4.07-4.03 (2H, m), 4.01-3.97 (2H, m), 1.71 (3H, s).

[0464] Reference example 81 Preparation of 2-(5-bromothiophen-3-yl)-2-methyl-1,3-dioxolane

[0465] [ka]

[0466] 1-(5-bromothiophen-3-yl)ethan-1-one (398 mg, 1.9 mmol), ethylene glycol (1.08 mL, 19. mmol), p-TsOH-H 2 O (18.5 mg, 0.097 mmol) and toluene (22 mL) were used as starting materials, and the procedure was performed in the same manner as in Reference Example 76 to obtain the title compound (322.2 mg, 67%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.17 (1H, d, J = 1.6 Hz), 7.02 (1H, d, J = 1.6 Hz), 4.07-3.98 (2H, m), 3.91-3.82 (2H, m), 1.64 (3H, s).

[0467] Reference example 82 Preparation of 1-(5-bromothiophen-3-yl)ethan-1-ol

[0468] [ka]

[0469] Methylmagnesium bromide (3M, 2-methyltetrahydrofuran solution) (907 μL, 2.7 mol) was added to a solution of 5-bromothiophene-3-carbaldehyde (200 μL, 1.8 mmol) in THF (8.0 mL) at 0° C., and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the mixture to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (503.8 mg, quant.) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 6.97 (1H, d, J = 0.8 Hz), 6.94 (1H, br s), 4.76 (1H, q, J = 6.4 Hz), 2.20 (1H, br s), 1.38 (3H, d, J = 6.4 Hz).

[0470] Reference example 83 Preparation of 1-(5-bromothiophen-3-yl)ethan-1-one

[0471] [ka]

[0472] To a solution of 1-(5-bromothiophen-3-yl)ethan-1-ol (503.8 mg, 1.8 mmol) in DMSO (8.0 mL), TEA (868 μL, 6.2 mmol) and pyridine-sulfur trioxide complex (832 mg, 5.2 mmol) were added and stirred at room temperature for 6 hours. This mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 95 / 5→80 / 20) to obtain the title compound (397.2 mg, quant.) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.91 (1H, d, J = 1.6 Hz), 7.49 (1H, d, J = 1.6 Hz), 2.49 (3H, s).

[0473] Reference example 84 Preparation of 5-(2-methyl-1,3-dioxolan-2-yl)thiazole-2-carbaldehyde

[0474] [ka]

[0475] A solution of 2-bromo-5-(2-methyl-1,3-dioxolan-2-yl)thiazole (215.2 mg, 0.86 mmol) in anhydrous THF (2.5 mL) was cooled to -78 °C, and n-butyllithium (1.6 M hexane solution) (0.6 mL, 0.96 mmol) was added and stirred at -78 °C for 30 minutes. Anhydrous DMF (240 μL, 3.1 mmol) was added to the reaction solution, and the mixture was stirred at -78 °C for 15 minutes, then heated to -60 °C and stirred for an additional 50 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution at -60 °C, extracted with diethyl ether, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (96.0 mg, 56%) as a yellow transparent oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 9.93 (1H, s), 8.01 (1H, s), 4.12-4.06 (2H, m), 3.99-3.93 (2H, m), 1.80 (3H, s).

[0476] Reference example 85 Preparation of 2-bromo-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one

[0477] [ka]

[0478] A solution of 2-bromo-5-(tert-butyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one (3.78 g, 14 mmol) in TFA (50 mL) and water (5.0 mL) was stirred at 105 °C for 19 hours. The reaction solution was cooled to room temperature and concentrated by distillation under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the resulting residue, which was extracted with ethyl acetate. The resulting organic layer was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure to obtain the title compound (3.25 g, quant.) as a brown solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.08 (1H, s), 6.16 (1H, br s), 4.36 (2H, s).

[0479] Reference example 86 Preparation of 1-(5-bromo-3-fluorothiophen-2-yl)ethan-1-ol

[0480] [ka]

[0481] Sodium borohydride (203.5 mg, 5.4 mmol) was added to a solution of 1-(5-bromo-3-fluorothiophen-2-yl)ethan-1-one (600.7 mg, 2.7 mmol) in methanol (3.6 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The reaction was quenched with 4N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (588.5 mg, 86%) as a pale red oil. 1 H NMR (400 MHz, CDCl 3 )δ 6.75 (1H, br s), 5.22-5.17 (1H, m), 2.00 (1H, d, J = 4.0 Hz), 1.54 (1H, d, J = 6.4 Hz).

[0482] Reference example 87 Preparation of [1-(5-bromo-3-fluorothiophen-2-yl)ethoxy](tert-butyl)dimethylsilane

[0483] [ka]

[0484] A solution of 1-(5-bromo-3-fluorothiophen-2-yl)ethan-1-ol (588.5 mg, 2.3 mmol) and imidazole (204.4 mg, 3.0 mmol) in DMF (1.5 mL) was added to a solution of tert-butyldimethylsilyl chloride (417.5 mg, 2.8 mmol) in DMF (4.1 mL) at 0 °C and stirred at room temperature for 23 hours. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 1 / 0 → 95 / 5) to obtain the title compound (581 mg, 74%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl3 )δ 6.70 (1H, br s), 5.13 (1H, qd, J = 6.4, 1.2 Hz), 1.45 (3H, d, J = 6.4 Hz), 0.91 (9H, s), 0.082 (3H, s), 0.036 (3H, s).

[0485] Reference example 88 Preparation of methyl (E)-3-[5-(methylcarbamoyl)furan-2-yl]acrylate

[0486] [ka]

[0487] 5-Bromo-N-methylfuran-2-carboxamide (163.3 mg, 0.80 mmol), tetrabutylammonium chloride (32.7 mg, 0.04 mmol), and PdCl 2 (dppf) 2 -CH 2 Cl 2 To a solution of (22.2 mg, 0.08 mmol) in DMA (1.4 mL), methyl acrylate (215 μL, 2.4 mmol) and N,N-dicyclohexylmethylamine (515 μL, 2.4 mmol) were added and stirred at 110 °C for 17 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 3 / 2 → 2 / 3) to obtain the title compound (103.8 mg, 62%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.41 (1H, d, J = 16.0 Hz), 7.13 (1H, d, J = 3.6 Hz), 6.67 (1H, d, J = 3.6 Hz), 6.52 (1H, br s), 6.41 (1H, d, J = 16.0 Hz), 3.80 (3H, s), 3.01 (3H, d, J = 4.8 Hz).

[0488] Reference example 89 Preparation of methyl (E)-3-[5-(pyrrolidine-1-carbamoyl)furan-2-yl]acrylate

[0489] [ka]

[0490] (5-Bromofuran-2-yl)(pyrrolidin-1-yl)methanone (583 mg, 2.4 mmol), tetrabutylammonium chloride (66.7 mg, 0.24 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (98 mg, 0.12 mmol), DMA (4.8 mL), methyl acrylate (643 μL, 7.2 mmol), and N,N-dicyclohexylmethylamine (761 μL, 3.6 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (478.2 mg, 80%) as a brown solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.44 (1H, d, J = 16.0 Hz), 7.14 (1H, d, J = 3.6 Hz), 6.71 (1H, d, J = 3.6 Hz), 6.37 (1H, d, J = 16.0 Hz), 3.90 (2H, t, J = 6.8 Hz), 3.80 (3H, s), 3.65 (2H, t, J = 6.8 Hz), 2.05 (2H, quin, J = 6.8 Hz), 1.92 (2H, quin, J = 6.8 Hz).

[0491] Reference example 90 Preparation of methyl (E)-3-[5-(isopropylcarbamoyl)furan-2-yl]acrylate

[0492] [ka]

[0493] 5-Bromo-N-isopropylfuran-2-carboxamide (546.2 mg, 2.4 mmol), tetrabutylammonium chloride (65.3 mg, 0.24 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (98 mg, 0.12 mmol), DMA (4.5 mL), methyl acrylate (632 μL, 7.1 mmol), and N,N-dicyclohexylmethylamine (748 μL, 3.5 mmol) were used as raw materials and treated in the same manner as in Reference Example 88 to obtain the title compound (411.6 mg, 74%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.43 (1H, d, J = 16.0 Hz), 7.13 (1H, d, J = 3.6 Hz), 6.68 (1H, d, J = 3.6 Hz), 6.43 (1H, d, J = 16.0 Hz), 6.15 (1H, br s), 4.27 (1H, septd, J = 6.4, 1.2 Hz), 3.82 (3H, s), 1.28 (6H, d, J = 6.4 Hz). Reference example 91 Preparation of methyl (E)-3-[5-(methylcarbamoyl)thiophen-2-yl]acrylate

[0494] [ka]

[0495] 5-Bromo-N-methylthiophene-2-carboxamide (239 mg, 1.1 mmol), tetrabutylammonium chloride (30.6 mg, 0.11 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2(44.5 mg, 0.05 mmol), DMA (2.2 mL), methyl acrylate (296 μL, 3.3 mmol), and N,N-dicyclohexylmethylamine (347 μL, 1.6 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (16.1 mg, 7%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.72 (1H, d, J = 15.6 Hz), 7.39 (1H, d, J = 3.6 Hz), 7.19 (1H, d, J = 3.6 Hz), 6.31 (1H, d, J = 15.6 Hz), 5.96 (1H, br s), 3.80 (3H, s), 3.01 (3H, d, J = 4.8 Hz).

[0496] Reference example 92 Preparation of methyl (E)-3-{5-[(2-methoxyethyl)carbamoyl]furan-2-yl}acrylate

[0497] [ka]

[0498] 5-Bromo-N-(2-methoxyethyl)furan-2-carboxamide (270 mg, 1.1 mmol), tetrabutylammonium chloride (27 mg, 0.097 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (40 mg, 0.049 mmol), DMA (2.2 mL), methyl acrylate (411 μL, 4.6 mmol), and N,N-dicyclohexylmethylamine (310 μL, 1.5 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (221.6 mg, 88%) as a brown oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.42 (1H, d, J = 16.0 Hz), 7.14 (1H, d, J = 3.6 Hz), 6.88 (1H, br s), 6.69 (1H, d, J = 3.6 Hz), 6.46 (1H, d, J = 16.0 Hz), 3.81 (3H, s), 3.66-3.62 (2H, m), 3.58-3.55 (2H, m), 3.41 (3H, s).

[0499] Reference example 93 Preparation of methyl (E)-3-(5-acetylthiophen-2-yl)acrylate

[0500] [ka]

[0501] 1-(5-bromothiophen-2-yl)ethan-1-one (700 mg, 3.4 mmol), tetrabutylammonium chloride (95 mg, 0.34 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (139.0 mg, 0.17 mmol), DMA (7.0 mL), methyl acrylate (457 μL, 0.17 mmol), and N,N-dicyclohexylmethylamine (1.1 mL, 5.1 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (304.8 mg, 43%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.73 (1H, d, J = 16.0 Hz), 7.60 (1H, d, J = 4.0 Hz), 7.24 (1H, d, J = 4.0 Hz), 6.39 (1H, d, J = 16.0 Hz), 3.81 (3H, s), 2.56 (3H, s).

[0502] Reference example 94 Preparation of methyl (E)-3-[4-methyl-5-(methylcarbamoyl)furan-2-yl]acrylate

[0503] [ka]

[0504] 5-Bromo-N,3-dimethylfuran-2-carboxamide (200 mg, 0.92 mmol), tetrabutylammonium chloride (26 mg, 0.092 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (38 mg, 0.046 mmol), DMA (1.5 mL), methyl acrylate (165 μL, 1.8 mmol), and N,N-dicyclohexylmethylamine (292 μL, 1.4 mmol) were used as raw materials and treated in the same manner as in Reference Example 88 to obtain the title compound (99.6 mg, 48%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ7.36 (1H, d, J = 15.6 Hz), 6.53 (1H, s), 6.36 (1H, d, J = 15.6 Hz), 6.34 (1H, br s), 3.80 (3H, s), 2.98 (3H, d, J = 5.2 Hz), 2.39 (3H, s).

[0505] Reference example 95 Preparation of methyl (E)-3-(5-sulfamoylthiophen-2-yl)acrylate

[0506] [ka]

[0507] 5-Bromothiophene-2-sulfonamide (593.2 mg, 2.5 mmol), tetrabutylammonium chloride (68.1 mg, 0.25 mmol), PdCl 2(dppf) 2 -CH 2 Cl 2 (100 mg, 0.12 mmol), DMA (4.0 mL), methyl acrylate (439 μL, 4.9 mmol), and N,N-dicyclohexylmethylamine (780 μL, 3.7 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (163.7 mg, 27%) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD)δ 7.80 (1H, d, J = 16.0 Hz), 7.55 (1H, d, J = 4.0 Hz), 7.37 (1H, d, J = 4.0 Hz), 6.42 (1H, d, J = 16.0 Hz), 3.81 (3H, s).

[0508] Reference example 96 Preparation of methyl (E)-3-(thiophen-2-yl)acrylate

[0509] [ka]

[0510] 2-Bromothiophene (235 μL, 2.5 mmol), tetrabutylammonium chloride (68.1 mg, 0.25 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (100 mg, 0.12 mmol), DMA (4.0 mL), methyl acrylate (439 μL, 4.9 mmol), and N,N-dicyclohexylmethylamine (780 μL, 3.7 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (332.9 mg, 81%) as a white solid. 1 H NMR (400 MHz, CDCl 3)δ 7.79 (1H, d, J = 16.0 Hz), 7.37 (1H, d, J = 5.2 Hz), 7.25 (1H, d, J = 3.6 Hz), 7.05 (1H, dd, J = 5.2, 3.6 Hz), 6.24 (1H, d, J = 16.0 Hz), 3.79 (3H, s).

[0511] Reference example 97 Preparation of methyl (E)-3-[5-(methylcarbamoyl)thiophen-3-yl]acrylate

[0512] [ka]

[0513] 4-Bromo-N-methylthiophene-2-carboxamide (500 mg, 2.3 mmol), tetrabutylammonium chloride (64 mg, 0.23 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (93.0 mg, 0.11 mmol), DMA (4.0 mL), methyl acrylate (407 μL, 4.5 mmol), and N,N-dicyclohexylmethylamine (723 μL, 3.4 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (213.7 mg, 42%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.63 (1H, s), 7.60 (1H, d, J = 16.0 Hz), 7.58 (1H, s), 6.27 (1H, d, J = 16.0 Hz), 6.04 (1H, br s), 3.80 (3H, s), 3.01 (3H, d, J = 4.8 Hz).

[0514] Reference example 98 Preparation of methyl (E)-3{-[5-(isopropylamino)methyl]furan-2-yl}acrylate

[0515] [ka]

[0516] N-[(5-bromofuran-2-yl)methyl]propan-2-amine (600 mg, 2.8 mmol), tetrabutylammonium chloride (78 mg, 0.28 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (112 mg, 0.14 mmol), DMA (4.5 mL), methyl acrylate (493 μL, 5.5 mmol), and N,N-dicyclohexylmethylamine (875 μL, 4.1 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (158 mg, 26%) as a brown oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.38 (1H, d, J = 15.6 Hz), 6.54 (1H, d, J = 3.2 Hz), 6.27 (1H, d, J = 15.6 Hz), 6.26 (1H, d, J = 3.2 Hz), 3.81 (2H, s), 3.78 (3H, s), 2.85 (1H, septd, J = 6.4 Hz), 1.09 (6H, d, J = 6.4 Hz).

[0517] Reference example 99 Preparation of methyl (E)-3-[3-methyl-5-(methylcarbamoyl)thiophen-2-yl]acrylate

[0518] [ka]

[0519] 5-Bromo-N,4-dimethylthiophene-2-carboxamide (200 mg, 0.85 mmol), tetrabutylammonium chloride (24 mg, 0.085 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (34.7 mg, 0.043 mmol), DMA (1.2 mL), methyl acrylate (152.5 μL, 1.7 mmol), and N,N-dicyclohexylmethylamine (270 μL, 1.3 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (171.5 mg, 84%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.76 (1H, d, J = 16.0 Hz), 7.34 (1H, s), 6.94 (1H, br s), 6.20 (1H, d, J = 16.0 Hz), 3.79 (3H, s), 2.98 (3H, d, J = 4.8 Hz), 2.28 (3H, s).

[0520] Reference example 100 Preparation of methyl (E)-3-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl)acrylate

[0521] [ka]

[0522] 2-Bromo-1-methyl-1,5,6,7-tetrahydro-4H-indol-4-one (170 mg, 2.3 mmol), tetrabutylammonium chloride (21 mg, 0.085 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2(31 mg, 0.038 mmol), DMA (0.90 mL), methyl acrylate (135 μL, 1.5 mmol), and N,N-dicyclohexylmethylamine (240 μL, 1.1 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (154.6 mg, 88%) as a brown solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.56 (1H, d, J = 15.6 Hz), 7.00 (1H, s), 6.23 (1H, d, J = 15.6 Hz), 3.78 (3H, s), 3.61 (3H, s), 2.79 (2H, t, J = 6.4 Hz), 2.47 (2H, t, J = 6.4 Hz), 2.17 (2H, quin, J = 6.4 Hz).

[0523] Reference example 101 Preparation of methyl (E)-3-(5-acetyl-1-methyl-1H-pyrrol-2-yl)acrylate

[0524] [ka]

[0525] 1-(5-bromo-1-methyl-1H-pyrrol-2-yl)ethan-1-one (402.7 mg, 1.8 mmol), tetrabutylammonium chloride (66 mg, 0.24 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (96.4 mg, 0.12 mmol), dimethylacetamide (1.8 mL), methyl acrylate (423 μL, 4.7 mmol), and N,N-dicyclohexylmethylamine (750 μL, 3.5 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 88 to obtain the title compound (153.1 mg, 17%) as a white solid. 1 H NMR (400 MHz, CDCl 3)δ 7.64 (1H, d, J = 15.6 Hz), 6.95 (1H, d, J = 4.4 Hz), 6.60 (1H, d, J = 4.4 Hz), 6.37 (1H, d, J = 15.6 Hz), 4.01 (3H, s), 3.81 (3H, s), 2.46 (3H, s).

[0526] Reference example 102 Preparation of methyl (E)-3-(5-acetyl-3-methylthiophen-2-yl)acrylate

[0527] [ka]

[0528] 1-(5-bromo-4-methylthiophen-2-yl)ethan-1-one (200 mg, 0.91 mmol), tetrabutylammonium chloride (25.4 mg, 0.091 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (37.6 mg, 0.046 mmol), DMA (1.6 mL), methyl acrylate (164 μL, 1.8 mmol), and N,N-dicyclohexylmethylamine (290 μL, 1.4 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (176.2 mg, 87%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.76 (1H, d, J = 15.6 Hz), 7.43 (1H, s), 6.29 (1H, d, J = 15.6 Hz), 3.80 (3H, s), 2.52 (3H, s), 2.34 (3H, s).

[0529] Reference example 103 Preparation of methyl (E)-3-(5-acetyl-4-fluorothiophen-2-yl)acrylate

[0530] [ka]

[0531] 1-(5-bromo-3-fluorothiophen-2-yl)ethan-1-one (140 mg, 0.46 mmol), tetrabutylammonium chloride (12.8 mg, 0.046 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (18.8 mg, 0.023 mmol), DMA (1.0 mL), methyl acrylate (82.5 μL, 0.92 mmol), and N,N-dicyclohexylmethylamine (146 μL, 0.69 mmol) were added and heated at 120 °C for 1.5 hours by microwave. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 9 / 1 → 7 / 3) to obtain the title compound (51.3 mg, 49%) as a brown powder. 1 H NMR (400 MHz, CDCl 3 )δ 7.60 (1H, d, J = 16.0 Hz), 7.00 (1H, s), 6.39 (1H, d, J = 16.0 Hz), 3.81 (3H, s), 2.58 (3H, d, J = 2.8 Hz).

[0532] Reference example 104 Preparation of methyl (E)-3-{5-[(2,4-dimethoxybenzyl)carbamoyl]thiophen-2-yl}acrylate

[0533] [ka]

[0534] 5-Bromo-N-(2,4-dimethoxybenzyl)thiophene-2-carboxamide (400 mg, 1.1 mmol), tetrabutylammonium chloride (31 mg, 0.11 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (45.7 mg, 0.11 mmol), DMA (2.0 mL), methyl acrylate (201 μL, 2.2 mmol), and N,N-dicyclohexylmethylamine (356 μL, 1.7 mmol) were used as raw materials and operated in the same manner as in Reference Example 103 to obtain the title compound (99.4 mg, 25%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.67 (1H, d, J = 16.0 Hz), 7.41 (1H, d, J = 4.0 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.13 (1H, d, J = 4.0 Hz), 6.85 (1H, t, J = 5.6 Hz), 6.43 (1H, d, J = 2.4 Hz), 6.41 (1H, dd, J = 8.0, 2.4 Hz), 6.26 (1H, d, J = 16.0 Hz),4.49 (2H, d, J = 5.6 Hz), 3.81 (3H, s), 3.77 (3H, s), 3.76 (3H, s).

[0535] Reference example 105 Preparation of methyl (E)-3-(5-acetyl-4-methylthiophen-2-yl)acrylate

[0536] [ka]

[0537] 1-(5-bromo-3-methylthiophen-2-yl)ethan-1-one (216 mg, 0.99 mmol), tetrabutylammonium chloride (14 mg, 0.049 mmol), PdCl 2 (dppf)2 -CH 2 Cl 2 (81 mg, 0.099 mmol), DMA (2.0 mL), methyl acrylate (177 μL, 2.0 mmol), and N,N-dicyclohexylmethylamine (314 μL, 1.5 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 103 to obtain the title compound (120.9 mg, 55%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.66 (1H, d, J = 16.0 Hz), 7.07 (1H, s), 6.35 (1H, d, J = 16.0 Hz), 3.81 (3H, s), 2.53 (3H, s), 2.52 (3H, s).

[0538] Reference example 106 Preparation of methyl (E)-3-(4-acetyl-1,3,5-trimethyl-1H-pyrrol-2-yl)acrylate

[0539] [ka]

[0540] 1-(5-bromo-1,2,4-trimethyl-1H-pyrrol-3-yl)ethan-1-one (120 mg, 0.52 mmol), tetrabutylammonium chloride (14.5 mg, 0.052 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (21.2 mg, 0.026 mmol), DMA (0.70 mL), methyl acrylate (93.3 μL, 1.0 mmol), and N,N-dicyclohexylmethylamine (165 μL, 0.78 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 103 to obtain the title compound (35.2 mg, 29%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3)δ 7.68 (1H, d, J = 16.0 Hz), 6.03 (1H, d, J = 16.0 Hz), 3.80 (3H, s), 3.59 (3H, s), 2.51 (3H, s), 2.46 (3H, s), 2.40 (3H, s).

[0541] Reference example 107 Preparation of methyl (E)-3-(5-acetyl-1-ethyl-1H-pyrrol-2-yl)acrylate

[0542] [ka]

[0543] 1-(5-bromo-1-ethyl-1H-pyrrol-2-yl)ethan-1-one (500 mg, 2.3 mmol), tetrabutylammonium chloride (64 mg, 0.23 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (94.3 mg, 0.12 mmol), DMA (3.5 mL), methyl acrylate (414 μL, 4.6 mmol), and N,N-dicyclohexylmethylamine (733 μL, 3.5 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 103 to obtain the title compound (23.2 mg, 5%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.54 (1H, d, J = 16.0 Hz), 7.12 (1H, d, J = 1.6 Hz), 7.08 (1H, d, J = 1.6 Hz), 6.16 (1H, d, J = 16.0 Hz), 4.35 (2H, q, J = 7.2 Hz), 3.77 (3H, s), 2.46 (3H, s), 1.37 (3H, t, J = 7.2 Hz).

[0544] Reference example 108 Preparation of methyl (E)-3-[5-(cyclopropanecarbonyl)thiophen-2-yl]acrylate

[0545] [ka]

[0546] (5-Bromothiophen-2-yl)(cyclopropyl)methanone (56 mg, 0.24 mmol), tetrabutylammonium chloride (3.4 mg, 0.012 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (20 mg, 0.024 mmol), DMA (0.60 mL), methyl acrylate (43.4 μL, 0.48 mmol), and N,N-dicyclohexylmethylamine (77 μL, 0.36 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 103 to obtain the title compound (34 mg, 60%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.74 (1H, d, J = 16.0 Hz), 7.72 (1H, d, J = 4.0 Hz), 7.27 (1H, d, J = 4.0 Hz), 6.39 (1H, d, J = 16.0 Hz), 3.81 (3H, s), 2.51 (1H, tt, J = 8.0, 4.4 Hz), 1.28-1.25 (2H, m), 1.08-1.04 (2H, m).

[0547] Reference example 109 Preparation of methyl (E)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate

[0548] [ka]

[0549] 2-(5-bromothiophen-2-yl)-2-methyl-1,3-dioxolane (180 mg, 0.72 mmol), tetrabutylammonium chloride (20 mg, 0.072 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (29.4 mg, 0.036 mmol), DMA (1.1 mL), methyl acrylate (129 μL, 1.4 mmol), and N,N-dicyclohexylmethylamine (232 μL, 1.1 mmol) were used as raw materials and treated in the same manner as in Reference Example 103 to obtain the title compound (135.5 mg, 74%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.71 (1H, d, J = 15.6 Hz), 7.10 (1H, d, J = 3.6 Hz), 6.97 (1H, d, J = 3.6 Hz), 6.18 (1H, d, J = 15.6 Hz), 4.08-4.02 (m, 2H), 3.98-3.95 (m, 2H), 3.78 (3H, s), 1.76 (s, 3H).

[0550] Reference example 110 Preparation of methyl (E)-3-(5-cyanothiophen-2-yl)acrylate

[0551] [ka]

[0552] 5-Bromothiophene-2-carbonitrile (289 μL, 2.7 mmol), tetrabutylammonium chloride (74 mg, 0.27 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2(109 mg, 0.13 mmol), DMA (3.3 mL), methyl acrylate (477 μL, 5.3 mmol), and N,N-dicyclohexylmethylamine (845 μL, 4.0 mmol) were used as raw materials and operated in the same manner as in Reference Example 103 to obtain the title compound (77.6 mg, 15%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.71 (1H, d, J = 16.0 Hz), 7.55 (1H, d, J = 4.0 Hz), 7.23 (1H, d, J = 4.0 Hz), 6.36 (1H, d, J = 16.0 Hz), 3.82 (3H, s).

[0553] Reference example 111 Preparation of methyl (E)-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate

[0554] [ka]

[0555] In a flask, add 2-(5-bromo-3-methylthiophen-2-yl)-2-methyl-1,3-dioxolone (306.1 mg, 1.2 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2(48.8 mg, 0.0060 mmol), tetrabutylammonium chloride (27.8 mg, 0.12 mmol), DMA (1.7 mL), N,N-dicyclohexylmethylamine (500 μL, 2.4 mmol) and methyl acrylate (210 μL, 2.3 mmol) were added, and the mixture was heated at 130 °C for 3 hours in a microwave oven. The mixture was further heated at 130 °C for 1 hour in a microwave oven, and the reaction solution was returned to room temperature. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 98 / 2 → 77 / 23) to obtain the title compound (160.8 mg, 52%) as a yellow transparent oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (1H, d, J = 15.6 Hz), 6.92 (1H, s), 6.11 (1H, d, J = 15.6 Hz), 4.07-3.98 (2H, m), 3.94-3.88 (2H, m), 3.74 (3H, s), 2.23 (3H, s), 1.70 (3H, s).

[0556] Reference example 112 Preparation of methyl (E)-3-(6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)acrylate

[0557] [ka]

[0558] 2-Bromo-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one (301.3 mg, 1.4 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2Methyl acrylate (250 μL, 2.8 mmol) and N,N-dicyclohexylamine (600 μL, 2.8 mmol) were added to a solution of tetrabutylammonium chloride (40.3 mg, 0.15 mmol) and DMA (1.8 mL) and the mixture was heated at 130 °C for 3 hours in a microwave oven. The reaction solution was cooled to room temperature, and ethyl acetate and 1M hydrochloric acid were added to separate the organic layer and the aqueous layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated saline and dried over sodium sulfate. After removing the solvent by distillation under reduced pressure, the product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 19 / 81 → 0 / 100) to obtain the title compound (171 mg, 55%) as an orange solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (1H, d, J = 15.6 Hz), 7.18 (1H, s), 6.54 (1H, br s), 6.37 (1H, d, J = 15.6 Hz), 4.38 (2H, s), 3.81 (3H, s).

[0559] Reference example 113 Preparation of methyl (E)-3-(5-acetylfuran-2-yl)acrylate

[0560] [ka]

[0561] 1-(5-bromofuran-2-yl)ethan-1-one (220 mg, 1.16 mmol), tetrabutylammonium chloride (16 mg, 0.058 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2(94 mg, 0.115 mmol), DMA (2.0 mL), methyl acrylate (206 μL, 2.3 mmol), and N,N-dicyclohexylmethylamine (364 μL, 1.72 mmol) were used as raw materials and operated in a similar manner to Reference Example 103 to obtain the title compound (90.0 mg, 40%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.43 (1H, d, J = 16.0 Hz), 7.17 (1H, d, J = 3.6 Hz), 6.69 (1H, d, J = 3.6 Hz), 6.54 (1H, d, J = 16.0 Hz), 3.79 (1H, s), 2.49 (3H, s).

[0562] Reference example 114 Preparation of methyl (E)-3-(5-acetylthiophen-3-yl)acrylate

[0563] [ka]

[0564] 1-(4-bromothiophen-2-yl)ethan-1-one (200 mg, 0.98 mmol), tetrabutylammonium chloride (13.6 mg, 0.049 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (80 mg, 0.098 mmol), DMA (2.0 mL), methyl acrylate (176 μL, 2.0 mmol), and N,N-dicyclohexylmethylamine (310 μL, 1.47 mmol) were used as raw materials and operated in the same manner as in Reference Example 103 to obtain the title compound (114.3 mg, 56%) as an orange solid. 1 H NMR (400 MHz, CDCl 3)δ 7.82 (1H, d, J = 1.2 Hz), 7.74 (1H, d, J = 1.2 Hz), 7.62 (1H, d, J = 16.0 Hz), 6.32 (1H, d, J = 16.0 Hz), 3.81 (3H, s), 2.59 (3H, s).

[0565] Reference example 115 Preparation of methyl (E)-3-(4-acetylthiophen-2-yl)acrylate

[0566] [ka]

[0567] 1-(5-bromothiophen-3-yl)ethan-1-one (380 mg, 1.9 mmol), tetrabutylammonium chloride (25.7 mg, 0.093 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (151 mg, 0.19 mmol), DMA (3.8 mL), methyl acrylate (344 μL, 3.7 mmol), and N,N-dicyclohexylmethylamine (586 μL, 2.8 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 103 to obtain the title compound (151.8 mg, 39%) as a pale green powder. 1 H NMR (400 MHz, CDCl 3 )δ 8.03 (1H, s), 7.73 (1H, d, J = 16.0 Hz), 7.64 (1H, br s), 6.27 (1H, d, J = 16.0 Hz), 3.80 (3H, s), 2.52 (3H, s).

[0568] Reference example 116 Preparation of methyl (E)-3-(5-cyano-1-methyl-1H-pyrrol-3-yl)acrylate

[0569] [ka]

[0570] 4-Bromo-1-methyl-1H-pyrrole-2-carbonitrile (131.9 mg, 0.71 mmol), tetrabutylammonium chloride (19.7 mg, 0.071 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (58 mg, 0.071 mmol), DMA (1.2 mL), methyl acrylate (128 μL, 1.4 mmol), and N,N-dicyclohexylmethylamine (227 μL, 1.1 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 103 to obtain the title compound (33.5 mg, 25%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.48 (1H, d, J = 16.0 Hz), 7.01 (1H, d, J = 1.6 Hz), 6.96 (1H, d, J = 1.6 Hz), 6.13 (1H, d, J = 16.0 Hz), 3.80 (3H, s), 3.77 (3H, s).

[0571] Reference example 117 Preparation of methyl (E)-3-(3-acetylthiophen-2-yl)acrylate

[0572] [ka]

[0573] 1-(2-bromothiophen-3-yl)ethan-1-one (128.8 mg, 0.63 mmol), tetrabutylammonium chloride (8.8 mg, 0.032 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2(51.4 mg, 0.065 mmol), DMA (1.3 mL), methyl acrylate (113 μL, 1.3 mmol), and N,N-dicyclohexylmethylamine (200 μL, 0.95 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 103 to obtain the title compound (62.1 mg, 47%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 8.51 (1H, d, J = 16.0 Hz), 7.40 (1H, d, J = 5.6 Hz), 7.28 (1H, d, J = 5.6 Hz), 6.34 (1H, d, J = 16.0 Hz), 3.78 (3H, s), 2.54 (3H, s).

[0574] Reference example 118 Preparation of methyl (E)-3-[5-(2-methyl-1,3-dioxolan-2-yl)furan-2-yl]acrylate

[0575] [ka]

[0576] 2-(5-Bromofuran-2-yl)-2-methyl-1,3-dioxolane (200 mg, 0.86 mmol), tetrabutylammonium chloride (12 mg, 0.043 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (70.1 mg, 0.086 mmol), DMA (2.0 mL), methyl acrylate (160 μL, 1.7 mmol), and N,N-dicyclohexylmethylamine (272 μL, 1.3 mmol) were used as raw materials and operated in the same manner as in Reference Example 103 to obtain the title compound (168.8 mg, 83%) as a yellow oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.39 (1H, d, J = 15.6 Hz), 6.52 (1H, d, J = 3.6 Hz), 6.39 (1H, d, J = 3.6 Hz), 6.32 (1H, d, J = 15.6 Hz), 4.09-4.05 (2H, m), 4.04-4.00 (2H, m), 3.78 (3H, s), 1.75 (3H, s).

[0577] Reference example 119 Preparation of methyl (E)-3-[4-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate

[0578] [ka]

[0579] 2-(5-bromothiophen-3-yl)-2-methyl-1,3-dioxolane (160 mg, 0.64 mmol), tetrabutylammonium chloride (8.9 mg, 0.032 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (52.4 mg, 0.064 mmol), DMA (1.3 mL), methyl acrylate (115 μL, 1.3 mmol), and N,N-dicyclohexylmethylamine (203 μL, 0.96 mmol) were used as raw materials and operated in the same manner as in Reference Example 103 to obtain the title compound (137.7 mg, 84%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.72 (1H, d, J = 15.6 Hz), 7.31 (1H, s), 7.21 (1H, s), 6.22 (1H, d, J = 15.6 Hz), 4.06-4.02 (2H, m), 3.89-3.86 (2H, m), 3.79 (3H, s), 1.66 (3H, s).

[0580] Reference example 120 Preparation of ethyl (E)-3-(thiazol-5-yl)acrylate

[0581] [ka]

[0582] A solution of potassium tert-butoxide (123.4 mg, 1.1 mmol) and triethyl phosphonoacetate (220 μL, 1.1 mmol) in THF (2.0 mL) was stirred at -5 °C for 30 minutes, and then thiazole-5-carbaldehyde (100 mg, 0.88 mmol) was added and the mixture was stirred at -5 °C for 2 hours and then at room temperature for 21 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 9 / 1 → 7 / 3) to obtain the title compound (143.5 mg, 89%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 8.80 (1H, s), 8.01 (1H, s), 7.82 (1H, d, J = 15.6 Hz), 6.26 (1H, d, J = 15.6 Hz), 4.26 (2H, q, J = 7.2 Hz), 1.33 (3H, t, J = 7.2 Hz).

[0583] Reference example 121 Preparation of methyl (E)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiazol-2-yl]acrylate

[0584] [ka]

[0585] Methyl (triphenylphosphoranylidene) acetate (424.2 mg, 1.3 mmol) was added to a solution of 5-(2-methyl-1,3-dioxolan-2-yl)thiazole-2-carbaldehyde (85.2 mg, 0.42 mmol) in toluene (1.5 mL), and the mixture was stirred at 120 °C for 1 hour. The reaction solution was returned to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 81 / 19→62 / 38) to obtain the title compound (111.5 mg, quant.) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (1H, s), 7.70 (1H, d, J = 15.6 Hz), 6.65 (1H, d, J = 15.6 Hz), 4.14-4.04 (2H, m), 3.99-3.91 (2H, m), 3.82 (3H, s), 1.78 (3H, s).

[0586] Reference example 122 Preparation of methyl (E)-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiazol-2-yl]acrylate

[0587] [ka]

[0588] Methyl (triphenylphosphoranylidene) acetate (160.7 mg, 0.48 mmol) was added to a solution of 4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiazole-2-carbaldehyde (32.5 mg, 0.15 mmol) in toluene (1.0 mL), and the mixture was stirred at 120 °C for 1.5 hours. The reaction solution was returned to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 86 / 14 → 65 / 35) to obtain the title compound (34.6 mg, 85%) as an orange transparent oily substance. 1H NMR (400 MHz, CDCl 3 ) δ 7.63 (1H, d, J = 15.6 Hz), 6.60 (1H, d, J = 15.6 Hz), 4.08-4.02 (2H, m), 3.94-3.86 (2H, m), 3.80 (3H, s), 2.49 (3H, s), 1.74 (3H, s).

[0589] Reference example 123 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(methylcarbamoyl)furan-2-yl]propanoate

[0590] [ka]

[0591] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (165 mg, 0.36 mmol), methyl (E)-3-[5-(methylcarbamoyl)furan-2-yl]acrylate (50 mg, 0.24 mmol), [RhCl(cod)] 2 To a solution of (5.9 mg, 0.012 mmol) in 1,4-dioxane / water (3 / 1) (1.0 mL), TEA (168 μL, 1.2 mmol) was added and the mixture was stirred under heating and reflux for 14 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 3 / 2→2 / 3) to obtain the title compound (22.9 mg, 18%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3)δ 7.88 (1H, d, J = 8.0 Hz), 7.53 (1H, td, J = 8.0, 1.6 Hz), 7.28-7.21 (3H, m), 7.14-7.07 (2H, m), 6.98 (1H, d, J = 3.2 Hz), 6.37 (1H, br s), 6.15 (1H, t, J = 3.2 Hz), 4.55-4.49 (2H, m), 4.04-3.99 (1H, m), 3.87-3.84 (1H, m), 3.80-3.73 (1H, m), 3.62 (3H, br s), 3.12-3.00 (3H, m), 2.95-2.94 (3H, m), 2.30 (3H, br s), 1.76-1.66 (1H, m), 1.53-1.41 (1H, m), 1.09 (3H, t, J = 7.2 Hz).

[0592] Reference example 124 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(pyrrolidine-1-carbonyl)furan-2-yl]propanoate

[0593] [ka]

[0594] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (240 mg, 0.52 mmol), methyl (E)-3-[5-(pyrrolidine-1-carbonyl)furan-2-yl]acrylate (84 mg, 0.34 mmol), [RhCl(cod)] 2(17.4 mg, 0.035 mmol), 1,4-dioxane / DMA / water (3 / 3 / 1) (0.7 mL), and TEA (74 μL, 0.53 mmol) were used as raw materials and treated in the same manner as in Reference Example 123 to obtain the title compound (85.0 mg, 50%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88(1H, d, J = 7.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.29-7.12 (5H, m), 6.97 (1H, d, J = 3.2 Hz), 6.11 (1H, d, J = 3.2 Hz), 4.57-4.53 (2H, m), 4.03-3.98 (1H, m), 3.81 (1H, d, J = 14.4 Hz), 3.78-3.67 (3H, m), 3.61-3.58 (5H, m), 3.14-3.10 (1H, m), 2.99-2.87 (2H, m), 2.32 (3H, s), 1.99-1.95 (2H, m), 1.88-1.85 (2H, m), 1.74-1.64 (1H, m), 1.50-1.42 (1H, m), 1.08 (3H, t, J = 7.2 Hz).

[0595] Reference example 125 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(isopropylcarbamoyl)furan-2-yl]propanoate

[0596] [ka]

[0597] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (206 mg, 0.45 mmol), methyl (E)-3-[5-(isopropylcarbamoyl)furan-2-yl]acrylate (70 mg, 0.3 mmol), [RhCl(cod)] 2 (15 mg, 0.030 mmol), 1,4-dioxane / water (6 / 1) (0.7 mL), and TEA (152 μL, 1.5 mmol) were used as raw materials and treated in the same manner as in Reference Example 123 to obtain the title compound (38.2 mg, 22%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.53 (1H, td, J = 8.0, 1.6 Hz), 7.26 (1H, t, J = 8.0 Hz), 7.21 (1H, d, J = 8.0 Hz), 7.16-7.08 (3H, m), 6.98 (1H, d, J = 3.6 Hz), 6.14-6.10 (1H, m), 6.05 (1H, br s), 4.56-4.51 (2H, m), 4.26-4.19 (1H, m), 4.03-4.00 (1H, m), 3.87-3.74 (2H, m), 3.64 (3H, s), 3.07-2.99 (2H, m), 2.88-2.85 (1H, m), 2.33 (3H, br s), 1.76-1.65 (1H, m), 1.51-1.42 (1H, m), 1.26-1.22 (6H, m), 1.09-1.08 (3H, m).

[0598] Reference example 126 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(methylcarbamoyl)thiophen-2-yl]propanoate

[0599] [ka]

[0600] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (240 mg, 0.52 mmol), methyl (E)-3-[5-(methylcarbamoyl)thiophen-2-yl]acrylate (79 mg, 0.35 mmol), [RhCl(cod)] 2 (17.4 mg, 0.035 mmol), 1,4-dioxane / DMA / water (3 / 3 / 1) (0.7 mL), and TEA (74 μL, 0.53 mmol) were used as raw materials and treated in the same manner as in Reference Example 123 to obtain the title compound (48.7 mg, 25%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, br t, J = 8.0 Hz), 7.29-7.19 (3H, m), 7.14 (2H, br s), 7.07 (1H, d, J = 6.8 Hz), 6.78-6.77 (1H, m), 5.99 (1H, br s), 4.69 (1H, t, J = 7.6 Hz), 4.56 (1H, dd, J = 14.0, 5.2 Hz), 4.02-3.95 (1H, m), 3.82-3.69 (2H, m), 3.60 (3H, s), 3.09 (1H, dd, J = 16.0, 7.6 Hz), 3.01-2.90 (5H, m), 2.34 (3H, br s), 1.69-1.62 (1H, m), 1.46-1.38 (1H, m), 1.06 (3H, t, J = 7.2 Hz).

[0601] Reference example 127 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-{5-[(2-methoxyethyl)carbamoyl]furan-2-yl}propanoate

[0602] [ka]

[0603] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (192 mg, 0.42 mmol), methyl (E)-3-{5-[(2-methoxyethyl)carbamoyl]furan-2-yl}acrylate (70 mg, 0.28 mmol), [RhCl(cod)] 2 (13.8 mg, 0.028 mmol), 1,4-dioxane / water (6 / 1) (0.7 mL), and TEA (60 μL, 0.42 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 123 to obtain the title compound (11.1 mg, 7%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, td, J = 8.0, 1.6 Hz), 7.26 (1H, t, J = 8.0 Hz), 7.23 (1H, d, J = 8.0 Hz), 7.16-7.09 (3H, m), 6.99 (1H, d, J = 3.6 Hz), 6.55 (1H, br s), 6.12 (1H, t, J = 3.6 Hz), 4.57-4.51 (2H, m), 4.04-4.00 (1H, m), 3.87-3.71 (2H, m), 3.63 (3H, s), 3.60-3.51 (4H, m), 3.37 (3H, s), 3.11-2.85 (3H, m), 2.33 (3H, br s), 1.78-1.67 (1H, m), 1.51-1.41 (1H, m), 1.08 (3H, t, J = 7.6 Hz).

[0604] Reference example 128 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0605] [ka]

[0606] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (274.4 mg, 0.6 mmol), methyl (E)-3-(5-acetylthiophen-2-yl)acrylate (105 mg, 0.5 mmol), [RhCl(cod)] 2(12.3 mg, 0.025 mmol), 1,4-dioxane / water (7 / 1) (1.0 mL), and TEA (210 μL, 1.5 mmol) were used as raw materials and treated in the same manner as in Reference Example 123 to obtain the title compound (138.0 mg, 50%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, td, J = 8.0, 1.6 Hz), 7.50 (1H, d, J = 4.0 Hz), 7.27-7.20 (2H, m), 7.17-7.12 (2H, m), 7.08 (1H, d, J = 8.4 Hz), 6.87 (1H, br t, J = 2.4 Hz), 4.72 (1H, t, J = 7.6 Hz), 4.58-4.56 (1H, m), 4.03-3.96 (1H, m), 3.83-3.69 (2H, m), 3.61 (3H, s), 3.13-2.91 (3H, m), 2.48 (3H, br s), 2.34 (3H, br s), 1.73-1.63 (1H, m), 1.47-1.39 (1H, m), 1.07 (3H, t, J = 7.6 Hz).

[0607] Reference example 129 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-methyl-5-(methylcarbamoyl)furan-2-yl]propanoate

[0608] [ka]

[0609] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (247 mg, 0.54 mmol), methyl (E)-3-[4-methyl-5-(methylcarbamoyl)furan-2-yl]acrylate (100 mg, 0.45 mmol), [RhCl(cod)] 2 (11.3 mg, 0.023 mmol), 1,4-dioxane / water (6 / 1) (1.0 mL), and TEA (189 μL, 1.4 mmol) were used as raw materials and treated in the same manner as in Reference Example 123 to obtain the title compound (48.2 mg, 19%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 7.6, 1.6 Hz), 7.53 (1H, td, J = 7.6, 1.6 Hz), 7.27-7.19 (3H, m), 7.13 (1H, d, J = 7.6 Hz), 7.10-7.06 (1H, m), 6.27 (1H, br s), 5.98 (1H, d, J = 3.2 Hz), 4.49-4.44 (2H, m), 4.05-3.98 (1H, m), 3.89-3.72 (2H, m), 3.63 (3H, s), 3.09-2.84 (6H, m), 2.34-2.30 (6H, m), 1.78-1.59 (1H, m), 1.52-1.41 (1H, m), 1.09 (3H, t, J = 7.2 Hz).

[0610] Reference example 130 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-(5-sulfamoylthiophen-2-yl)propanoate

[0611] [ka]

[0612] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (137.2 mg, 0.3 mmol), methyl (E)-3-(5-sulfamoylthiophen-2-yl)acrylate (50 mg, 0.2 mmol), [RhCl(cod)] 2 To a solution of (9.9 mg, 0.02 mmol) in 1,4-dioxane / water (1 / 1) (0.8 mL), TEA (84 μL, 0.6 mmol) was added and the mixture was stirred at 120 °C for 1 hour using a microwave. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 4 / 1 → 3 / 2) to obtain the title compound (98.9 mg, 85%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.84 (1H, br d, J = 8.0 Hz), 7.51 (1H, td, J = 8.0, 1.6 Hz), 7.42 (1H, d, J = 4.0 Hz), 7.27-7.19 (2H, m), 7.15-7.11 (3H, m), 6.78 (1H, d, J = 4.0 Hz), 4.71 (1H, t, J = 8.0 Hz), 4.51 (1H, d, J = 14.4 Hz), 4.03-3.97 (1H, m), 3.83-3.82 (1H, m), 3.77-3.69 (1H, m), 3.61 (3H, s), 3.11-2.95 (3H, m), 2.30 (3H, s), 1.74-1.63 (1H, m), 1.51-1.43 (1H, m), 1.08-1.07 (3H, m).

[0613] Reference example 131 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-(thiophen-2-yl)propanoate

[0614] [ka]

[0615] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (247 mg, 0.54 mmol), methyl (E)-3-(thiophen-2-yl)acrylate (76 mg, 0.45 mmol), [RhCl(cod)] 2 (11.3 mg, 0.023 mmol), 1,4-dioxane / water (3 / 1) (1.0 mL), and TEA (189 μL, 1.4 mmol) were used as raw materials and treated in the same manner as in Reference Example 123 to obtain the title compound (133 mg, 60%) as a white solid. 1 H NMR (400 MHz, CDCl 3)δ7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.51 (1H, td, J = 8.0, 1.6 Hz), 7.26-7.12 (5H, m), 7.03 (1H, d, J = 14.4 Hz), 6.89 (1H, br t, J = 4.0 Hz), 6.81 (1H, br t, J = 4.0 Hz), 4.71 (1H, t, J = 7.6 Hz), 4.60-4.57 (1H, m), 4.01-3.92 (1H, m), 3.80-3.68 (2H, m), 3.59 (3H, br s), 3.13-3.06 (1H, m), 3.02-2.87 (2H, m), 2.36 (3H, br s), 1.71-1.59 (1H, m), 1.44-1.32 (1H, m), 1.07-1.06 (3H, m).

[0616] Reference example 132 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(methylcarbamoyl)thiophen-3-yl]propanoate

[0617] [ka]

[0618] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (137.2 mg, 0.3 mmol), methyl (E)-3-[5-(methylcarbamoyl)thiophen-3-yl]acrylate (45.1 mg, 0.2 mmol), [RhCl(cod)] 2(9.9 mg, 0.02 mmol), 1,4-dioxane / water (1 / 1) (0.8 mL), and TEA (84 μL, 0.6 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (77.5 mg, 70%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.85 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, td, J = 8.0, 1.6 Hz), 7.31-7.30 (1H, m), 7.25 (1H, t, J = 8.0 Hz), 7.21 (1H, d, J = 8.0 Hz), 7.11-7.05 (4H, m), 6.37 (1H, br s), 4.51-4.47 (2H, m), 4.02-3.95 (1H, m), 3.84-3.70 (2H, m), 3.58 (3H, s), 3.05-2.92 (3H, m), 2.89 (3H, d, J = 4.8 Hz), 2.28 (3H, s), 1.74-1.61 (1H, m), 1.50-1.39 (1H, m), 1.08-1.07 (3H, m).

[0619] Reference example 133 Preparation of methyl 3-(3-(((R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-5-(methylcarbamoyl)thiophen-2-yl)propanoate

[0620] [ka]

[0621] (R)-4-Ethyl-2-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (226.4 mg, 0.5 mmol), methyl (E)-3-[3-methyl-5-(methylcarbamoyl)thiophen-2-yl]acrylate (80 mg, 0.3 mmol), [RhCl(cod)] 2 (16.3 mg, 0.03 mmol), 1,4-dioxane / water (1 / 1) (1.6 mL), and TEA (138.4 μL, 1.0 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (148.1 mg, 78%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.87 (1H, br d, J = 8.0 Hz), 7.52 (1H, br t, J = 8.0 Hz), 7.26 (1H, d, J = 8.0 Hz), 7.23-7.19 (1H, m), 7.17 (1H, br s), 7.14-7.11 (2H, m), 7.05 (1H, br d, J = 5.6 Hz), 6.08 (1H, br s), 4.72 (1H, t, J = 8.0 Hz), 4.56-4.55 (1H, m), 4.00-3.95 (1H, m), 3.78-3.68 (2H, m), 3.59 (3H, s), 2.99 (2H, dd, J = 7.6, 7.6 Hz), 2.94-2.90 (4H, m), 2.33 (3H, br s), 2.10 (3H, s), 1.73-1.60 (1H, m), 1.45-1.38 (1H, m), 1.07-1.06 (3H, m).

[0622] Reference example 134 Preparation of ethyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-(thiazol-5-yl)propanoate

[0623] [ka]

[0624] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (206 mg, 0.45 mmol), ethyl (E)-3-(thiazol-5-yl)acrylate (55 mg, 0.3 mmol), [RhCl(cod)] 2 (15 mg, 0.03 mmol), 1,4-dioxane / water (1 / 1) (1.0 mL), and TEA (126 μL, 0.9 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (97.3 mg, 63%) as a pale red solid. 1 H NMR (400 MHz, CDCl 3 )δ 8.80 (1H, s), 7.88 (1H, dd, J = 7.6, 1.6 Hz), 7.63 (1H, d, J = 3.6 Hz), 7.52 (1H, td, J = 7.6, 2.0 Hz), 7.25 (1H, td, J = 7.6, 1.2 Hz), 7.20 (1H, dd, J = 8.0, 0.8 Hz), 7.17-7.12 (2H, m), 7.08 (1H, d, J = 7.6 Hz), 4.77 (1H, t, J = 8.0 Hz), 4.57 (1H, dd, J = 14.0, 5.2 Hz), 4.09-3.98 (3H, m), 3.83-3.69 (2H, m), 3.11-2.91 (3H, m), 2.34 (3H, br s), 1.71-1.65 (1H, m), 1.46-1.40 (1H, m), 1.16 (3H, t, J = 7.2 Hz), 1.09-1.05 (3H, m).

[0625] Reference example 135 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl)propanoate

[0626] [ka]

[0627] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (206 mg, 0.5 mmol), methyl (E)-3-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl)acrylate (70 mg, 0.3 mmol), [RhCl(cod)] 2 (15 mg, 0.03 mmol), 1,4-dioxane / water (1 / 1) (1.0 mL), and TEA (126 μL, 0.9 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (149.8 mg, 91%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.87-7.82 (1H, m), 7.55-7.50 (1H, m), 7.28-7.19 (2H, m), 7.13-7.10 (1H, m), 7.06-7.01 (1H, m), 6.96 (1H, s), 6.48 (1H, d, J = 4.0 Hz), 4.52-4.51 (1H, m), 4.41 (1H, t, J = 8.0 Hz), 4.00-3.95 (1H, m), 3.80-3.72 (2H, m), 3.61 (1H, s), 3.23 (3H, br s), 3.04-2.87 (2H, m), 2.80-2.73 (1H, m), 2.67-2.62 (2H, m), 2.46-2.42 (2H, m), 2.34 (3H, br s), 2.14-2.10 (2H, m), 1.75-1.62 (1H, m), 1.50-1.39 (1H, m), 1.11-1.04 (3H, m).

[0628] Reference example 136 Preparation of methyl 3-(5-acetyl-1-methyl-1H-pyrrol-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0629] [ka]

[0630] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (206 mg, 0.5 mmol), methyl (E)-3-(5-acetyl-1-methyl-1H-pyrrol-2-yl)acrylate (62.2 mg, 0.3 mmol), [RhCl(cod)] 2(15 mg, 0.03 mmol), 1,4-dioxane / water (1 / 1) (1.0 mL), and TEA (126 μL, 0.9 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (129.3 mg, 80%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 7.6, 1.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.25 (1H, t, J = 7.6 Hz), 7.20 (1H, d, J = 7.6 Hz), 7.12-7.10 (1H, m), 7.02-6.92 (3H, m), 6.13 (1H, d, J = 4.4 Hz), 4.57-4.46 (2H, m), 4.00-3.93 (1H, m), 3.80-3.73 (1H, m), 3.68-3.65 (4H, m), 3.63 (3H, br s), 3.05-2.81 (3H, m), 2.39 (3H, s), 2.34-2.31 (3H, m), 1.74-1.61 (1H, m), 1.47-1.40 (1H, m), 1.09-1.05 (3H, m).

[0631] Reference example 137 Preparation of methyl 3-(5-acetyl-3-methylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0632] [ka]

[0633] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (206 mg, 0. 5 mmol), methyl (E)-3-(5-acetyl-3-methylthiophen-2-yl)acrylate (67.3 mg, 0.3 mmol), [RhCl(cod)] 2 (15 mg, 0.03 mmol), 1,4-dioxane / water (1 / 1) (2.0 mL), and TEA (126 μL, 0.9 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (123.3 mg, 74%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ7.87 (1H, dt, J = 8.0, 2.0 Hz), 7.52 (1H, br t, J = 8.0 Hz), 7.38 (1H, s), 7.28-7.20 (2H, m), 7.17-7.12 (2H, m), 7.05 (1H, d, J = 8.0 Hz), 4.74-4.73 (1H, m), 4.58-4.55 (1H, m), 4.03-3.95 (1H, m), 3.80-3.66 (2H, m), 3.60 (3H, br s), 3.07-2.86 (3H, m), 2.46 (3H, br s), 2.35 (3H, br s), 2.16 (3H, s), 1.74-1.60 (1H, m), 1.46-1.36 (1H, m), 1.08-1.07 (3H, m).

[0634] Reference example 138 Preparation of methyl 3-(5-acetyl-4-fluorothiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0635] [ka]

[0636] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (75.5 mg, 0.17 mmol), methyl (E)-3-(5-acetyl-4-fluorothiophen-2-yl)acrylate (51.3 mg, 0.23 mmol), [RhCl(cod)] 2 (5.4 mg, 0.011 mmol), 1,4-dioxane / water (1 / 1) (0.9 mL), and TEA (69 μL, 0.49 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (53.6 mg, 56%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, td, J = 8.0, 1.6 Hz), 7.26 (1H, td, J = 8.0, 1.2 Hz), 7.21 (1H, dd, J = 8.0, 1.2 Hz), 7.18-7.07 (3H, m), 6.64 (1H, s), 4.61-4.53 (2H, m), 4.06-3.98 (1H, m), 3.87-3.69 (2H, m), 3.63 (3H, s), 3.09-2.94 (3H, m), 2.50 (3H, br s), 2.35 (3H, br s), 1.74-1.65 (1H, m), 1.49-1.42 (1H, m), 1.08-1.07 (3H, m).

[0637] Reference example 139 Preparation of methyl 3-{5-[(2,4-dimethoxybenzyl)carbamoyl]thiophen-2-yl}-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0638] [ka]

[0639] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (150 mg, 0.328 mmol), methyl (E)-3-{5-[(2,4-dimethoxybenzyl)carbamoyl]thiophen-2-yl}acrylate (80 mg, 0.22 mmol), [RhCl(cod)] 2 (10.8 mg, 0.022 mmol), 1,4-dioxane / water (1 / 1) (1.0 mL), and TEA (92.2 μL, 0.66 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (112.4 mg, 74%) as a pale brown oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.86 (1H, dd, J = 8.0, 1.6 Hz), 7.51 (1H, br t, J = 8.0 Hz), 7.27-7.24 (2H, m), 7.22-7.18 (2H, m), 7.13 (2H, br s), 7.04 (1H, br d, J = 8.0 Hz), 6.76 (1H, br t, J = 3.6 Hz), 6.45-6.40 (3H, m), 4.67 (1H, t, J = 7.6 Hz), 4.56-4.55 (1H, m), 4.47 (2H, d, J = 5.6 Hz), 3.99-3.93 (1H, m), 3.84-3.67 (8H, m), 3.59 (3H, s), 3.09-2.88 (3H, m), 2.33 (3H, s), 1.67-1.58 (1H, m), 1.44-1.36 (1H, m), 1.04-1.03 (3H, m).

[0640] Reference example 140 Preparation of methyl 3-(5-acetyl-4-methylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0641] [ka]

[0642] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (150 mg, 0.3 mmol), methyl (E)-3-(5-acetyl-4-methylthiophen-2-yl)acrylate (50 mg, 0.2 mmol), [RhCl(cod)] 2 (10.8 mg, 0.02 mmol), 1,4-dioxane / water (1 / 1) (1.0 mL), and TEA (92.2 μL, 0.7 mmol) were used as raw materials and treated in a manner similar to that of Reference Example 130 to obtain the title compound (77.9 mg, 64%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.89-7.86 (1H, m), 7.52 (1H, br t, J = 8.0 Hz), 7.28-7.08 (5H, m), 6.69 (1H, br s), 4.66 (1H, t, J = 7.6 Hz), 4.60-4.48 (1H, m), 4.04-3.97 (1H, m), 3.85-3.70 (2H, m), 3.62-3.60 (3H, m), 3.12-2.87 (3H, m), 2.45-2.42 (3H, m), 2.35-2.31 (3H, m), 1.73-1.63 (1H, m), 1.47-1.39 (1H, m), 1.08-1.05 (3H, m).

[0643] Reference example 141 Preparation of methyl 3-(4-acetyl-1,3,5-trimethyl-1H-pyrrol-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0644] [ka]

[0645] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (93.3 mg, 0.20 mmol), methyl (E)-3-(4-acetyl-1,3,5-trimethyl-1H-pyrrol-2-yl)acrylate (30 mg, 0.14 mmol), [RhCl(cod)] 2 (7.0 mg, 0.014 mmol), 1,4-dioxane / water (1 / 1) (0.8 mL), and TEA (57 μL, 0.41 mmol) were used as raw materials and operated in the same manner as in Reference Example 130 to obtain the title compound (20.1 mg, 26%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.89-7.85 (1H, m), 7.52 (1H, td, J = 8.0, 1.6 Hz), 7.25 (1H, t, J = 8.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.11 (1H, br d, J = 8.0 Hz), 7.01-6.93 (2H, m), 4.85-4.80 (1H, m), 4.55-4.51 (1H, m), 3.99-3.94 (1H, m), 3.80-3.69 (2H, m), 3.65 (3H, br s), 3.25-3.17 (4H, m), 2.99-2.88 (2H, m), 2.43-2.42 (6H, m), 2.34-2.32 (3H, m), 2.22 (3H, s), 1.75-1.61 (1H, m), 1.48-1.32 (1H, m), 1.07-1.05 (3H, m).

[0646] Reference example 142 Preparation of methyl 3-(5-acetyl-1-ethyl-1H-pyrrol-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0647] [ka]

[0648] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (123.5 mg, 0.27 mmol), methyl (E)-3-(5-acetyl-1-ethyl-1H-pyrrol-2-yl)acrylate (40 mg, 0.18 mmol), [RhCl(cod)] 2(9.0 mg, 0.018 mmol), 1,4-dioxane / water (1 / 1) (0.8 mL), and TEA (75.5 μL, 0.54 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (37.2 mg, 37%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.89 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, td, J = 8.0, 1.6 Hz), 7.25 (1H, t, J = 8.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.15-7.08 (3H, m), 6.70 (1H, dd, J = 4.8, 2.0 Hz), 6.62 (1H, dd, J = 4.8, 2.0 Hz), 4.55 (1H, d, J = 14.0 Hz), 4.35 (1H, t, J = 8.0 Hz), 4.26 (1H, q, J = 7.2 Hz), 4.03-3.99 (1H, m), 3.84-3.70 (2H, m), 3.60 (3H, s), 3.00-2.93 (2H, m), 2.90-2.82 (1H, m), 2.36 (3H, s), 2.33 (3H, s), 1.73-1.63 (1H, m), 1.47-1.39 (1H, m), 1.30 (3H, t, J = 7.2 Hz), 1.07 (3H, t, J = 7.2 Hz).

[0649] Reference example 143 Preparation of methyl 3-[5-(cyclopropanecarbonyl)thiophen-2-yl]-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0650] [ka]

[0651] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (99 mg, 0.2 mmol), methyl (E)-3-[5-(cyclopropanecarbonyl)thiophen-2-yl]acrylate (34 mg, 0.14 mmol), [RhCl(cod)] 2 (7.1 mg, 0.014 mmol), 1,4-dioxane / water (1 / 1) (0.8 mL), and TEA (60 μL, 0.43 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (45.5 mg, 56%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 7.6, 1.6 Hz), 7.63 (1H, d, J = 3.6 Hz), 7.52 (1H, td, J = 7.6, 1.6 Hz), 7.25 (1H, dd, J = 7.6, 0.8 Hz), 7.22 (1H, br d, J = 7.6 Hz), 7.15 (2H, br s), 7.06 (1H, d, J = 10.4 Hz), 6.90-6.88 (1H, m), 4.73 (1H, t, J = 7.6 Hz), 4.60-4.54 (1H, m), 4.00-3.97 (1H, m), 3.81-3.77 (1H, m), 3.76-3.71 (1H, m), 3.61 (3H, s), 3.14-2.89 (3H, m), 2.47-2.43 (1H, m), 2.35 (3H, br s), 1.70-1.61 (1H, m), 1.44-1.39 (1H, m), 1.21-1.17 (2H, m), 1.06 (3H, t, J = 7.2 Hz), 1.00-0.96 (2H, m).

[0652] Reference example 144 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate

[0653] [ka]

[0654] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (216 mg, 0.47 mmol), methyl (E)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate (80 mg, 0.32 mmol), and [RhCl(cod)] 2 A solution of (15.5 mg, 0.032 mmol) in 1,4-dioxane / water (1 / 1) (1.7 mL) was placed in an argon atmosphere, TEA (132 μL, 0.95 mmol) was added, and the mixture was heated at 140 °C for 2 hours by microwave. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 9 / 1 → 7 / 3) to obtain the title compound (90.9 mg, 49%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.89 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, td, J = 8.0, 1.6 Hz), 7.26 (1H, br t, J = 8.0 Hz), 7.21 (1H, dd, J = 8.0, 1.6 Hz), 7.14 (2H, br s), 7.06 (1H, s), 6.81 (1H, d, J = 3.6 Hz), 6.62 (1H, d, J = 3.6 Hz), 4.63 (1H, t, J = 8.0 Hz), 4.58 (1H, d, J = 14.0 Hz), 4.03-3.96 (3H, m), 3.93-3.90 (2H, m), 3.81-3.77 (1H, m), 3.73 (1H, dd, J = 15.2, 10.8 Hz), 3.59 (3H, s), 3.10-3.07 (1H, m), 3.00-2.93 (2H, m), 2.35 (3H, s), 1.76-1.61 (1H, m), 1.70 (3H, s), 1.49-1.41 (1H, m), 1.11.06 (3H, m).

[0655] Reference example 145 Preparation of methyl 3-(5-cyanothiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0656] [ka]

[0657] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (137.2 mg, 0.3 mmol), methyl (E)-3-(5-cyanothiophen-2-yl)acrylate (38.6 mg, 0.2 mmol), [RhCl(cod)] 2(9.9 mg, 0.02 mmol), 1,4-dioxane / water (1 / 1) (0.8 mL), and TEA (83.9 μL, 0.6 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (22.2 mg, 21%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 7.6, 1.6 Hz), 7.53 (1H, td, J = 7.6, 1.6 Hz), 7.44 (1H, dd, J = 4.0, 0.8 Hz), 7.28-7.16 (3H, m), 7.13-7.10 (2H, m), 6.85 (1H, br d, J = 4.0 Hz), 4.73 (1H, t, J = 7.6 Hz), 4.58-4.52 (1H, m), 4.06-3.98 (1H, m), 3.88-3.81 (1H, m), 3.76-3.69 (1H, m), 3.63 (3H, s), 3.13-2.93 (3H, m), 2.34 (3H, br s), 1.77-1.64 (1H, m), 1.50-1.39 (1H, m), 1.12-1.06 (3H, m).

[0658] Reference example 146 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate

[0659] [ka]

[0660] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (499.7 mg, 1.1 mmol), methyl (E)-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate (146.8 mg, 1.1 mmol), and [RhCl(cod)] 2 (17.1 mg, 0.035 mmol) was replaced with an argon atmosphere, 1,4-dioxane / water (1 / 1) (1.2 mL) and TEA (250 μL, 1.8 mmol) were added, and the mixture was heated at 120 °C for 1.5 hours in a microwave oven. The reaction solution was returned to room temperature, diluted with ethyl acetate, washed with water and saturated saline, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane / TEA = 23 / 75 / 2) to obtain the title compound (204.3 mg, 62%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.28-7.24 (1H, m), 7.22 (1H, d, J = 8.0 Hz), 7.14 (2H, s), 7.06 (1H, s), 6.45 (1H, s), 4.60-4.53 (2H, m), 4.06-3.95 (3H, m), 3.92-3.86 (2H, m), 3.79 (1H, br d, J = 14.0 Hz), 3.74-3.72 (1H, m), 3.58 (3H, s), 3.05-3.01 (1H, m), 3.00-2.89 (2H, m), 2.35 (3H, s), 2.18 (3H, s), 1.74-1.64 (1H, m), 1.67 (3H, s), 1.52-1.42 (1H, m), 1.09-1.08 (3H, m).

[0661] Reference example 147 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiazol-2-yl]propanoate

[0662] [ka]

[0663] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (56.7 mg, 0.13 mmol), methyl (E)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiazol-2-yl]acrylate (21.8 mg, 0.085 mmol), and [RhCl(cod)] 2 To a solution of (7.1 mg, 0.016 mmol) in 1,4-dioxane / water (2 / 1) (0.5 mL), TEA (66 μL, 0.47 mmol) was added and the mixture was heated at 50 °C for 4 hours by microwave. The reaction solution was returned to room temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 91 / 9 → 70 / 30) to obtain the title compound (23.7 mg, 47%) as a colorless, transparent oily substance. 1 H NMR (400 MHz, CDCl 3) δ 7.89 (1H, dd, J = 7.6, 1.2 Hz), 7.56 (1H, s), 7.52 (1H, td, J = 8.0, 1.2 Hz), 7.24-7.24 (1H, m), 7.22-7.15 (3H, m), 7.13-7.12 (1H, m), 4.72 (1H, t, J = 7.6 Hz), 4.58-4.57 (1H, d, J = 14.0 Hz), 4.05-3.98 (2H, m), 3.94-3.88 (2H, m), 3.81-3.79 (1H, m), 3.74-3.71 (1H, m), 3.61 (3H, s), 3..42-3.35 (1H, ), 3.01-2.92 (2H, m), 2.36 (3H, s), 1.74-1.63 (1H, m), 1.70 (3H, s), 1.53-1.38 (1H, m), 1.09 (3H, t, J = 7.6 Hz). Reference example 148 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiazol-2-yl]propanoate

[0664] [ka]

[0665] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (62.6 mg, 0.1 mmol), methyl (E)-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiazol-2-yl]acrylate (13.7 mg, 0.05 mmol), [RhCl(cod)] 2To a solution of (6.3 mg, 0.01 mmol) in 1,4-dioxane / water (2 / 1) (0.5 mL), TEA (70 μL, 0.5 mmol) was added and the mixture was heated at 50 °C for 4 hours by microwave. The reaction solution was returned to room temperature, diluted with ethyl acetate, washed with water and saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 68 / 32 → 47 / 53) to obtain the title compound (32.8 mg, quant.) as a colorless, transparent oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (1H, d, J = 7.6 Hz), 7.52 (1H t, J = 7.2 Hz), 7.28-7.20 (3H, m), 7.17-7.14 (2H, m), 4.68-4.63 (1H, m), 4.58 (1H, d, J = 14.0 Hz) 4.06-3.94 (3H, m), 3.88-3.79 (3H, m), 3.76-3.70 (1H, m), 3.60 (3H, s), 3.35 (1H, dt, J = 16.0, 6.0 Hz), 3.00-2.93 (2H, m), 2.41 (3H, s), 2.36 (3H, s), 1.74-1.66 (4H, m), 1.51-1.45 (1H, m), 1.09 (3H, t, J = 7.2 Hz).

[0666] Reference example 149 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-(6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)propanoate

[0667] [ka]

[0668] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (64.6 mg, 0.1 mmol), methyl (E)-3-(oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrolo-2-yl)acrylate (16.2 mg, 0.07 mmol), [RhCl(cod)] 2 (7.6 mg, 0.02 mmol) in 1,4-dioxane / water (2 / 1) (0.7 mL) was added with TEA (100 μL, 0.7 mmol) and heated at 50 °C for 3 hours by microwave. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with water and saturated saline. The obtained organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 9 / 1 → 0 / 100) to obtain the title compound (20.1 mg, 50%) as a brown oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (1H, d, J = 7.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.27-7.18 (2H, m), 7.16 (2H, s), 7.11 (1H, d, J = 3.6 Hz), 6.80 (1H, s), 6.47 (1H, s), 4.75 (1H, t, J = 8.0 Hz), 4.56 (1H, d, J =14.4 Hz), 4.28 (2H, s), 4.04-3.97 (1H, m), 3.83-3.81 (1H, m), 3.75-3.68 (1H, m), 3.62 (3H, s), 3.12 (1H, dd, J = 15.6, 8.0 Hz), 3.03 (1H, dd, J = 15.6, 8.0 Hz), 2.96-2.94 (1H, m), 2.33 (3H, s), 1.73-1.64 (1H, m), 1.47-1.39 (1H, m), 1.07-1.06 (3H, m).

[0669] Reference example 150 Preparation of methyl 3-(5-acetylfuran-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0670] [ka]

[0671] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (120 mg, 0.3 mmol), methyl (E)-3-(5-acetylfuran-2-yl)acrylate (60.2 mg, 0.3 mmol), [RhCl(cod)] 2 (6.4 mg, 0.01 mmol), 1,4-dioxane / water (3 / 1) (0.4 mL), and TEA (109 μL, 0.8 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (29.9 mg, 22%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.88 (1H, dd, J = 7.6, 1.6 Hz), 7.52 (1H, td, J = 7.6, 1.6 Hz), 7.25 (1H, td, J = 7.6, 1.2 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.16-7.11 (3H, m), 7.07 (1H, d, J = 3.6 Hz), 6.16 (1H, t, J = 3.6 Hz), 4.59-4.52 (2H, m), 4.05-3.99 (1H, m), 3.83-3.81 (1H, m), 3.76-3.69 (1H, m), 3.62 (3H, s), 3.17-3.11 (1H, m), 3.00-2.88 (2H, m), 2.40 (3H, s), 2.32 (3H, br s), 1.74-1.66 (1H, m), 1.50-1.41 (1H, m), 1.08-1.07 (3H, m).

[0672] Reference example 151 Preparation of methyl 3-(5-acetylthiophen-3-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0673] [ka]

[0674] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (150 mg, 0.33 mmol), methyl (E)-3-(5-acetylthiophen-3-yl)acrylate (102.5 mg, 0.39 mmol), [RhCl(cod)] 2(8.1 mg, 0.016 mmol), 1,4-dioxane / water (3 / 1) (0.7 mL), and TEA (138 μL, 0.98 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (52.0 mg, 29%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.87 (1H, dd, J = 8.0, 1.6 Hz), 7.51 (1H, td, J = 8.0, 1.6 Hz), 7.45 (1H, dd, J = 3.2, 1.2 Hz), 7.29 (1H, br s), 7.24 (1H, td, J = 8.0, 1.2 Hz), 7.20 (1H, br d, J = 8.0 Hz), 7.14-7.12 (1H, m), 7.09-7.06 (2H, m), 4.55-4.51 (2H, m), 4.03-3.96 (1H, m), 3.84-3.66 (2H, m), 3.60 (3H, s), 3.06-3.00 (1H, m), 2.98-2.90 (2H, m), 2.48 (3H, s), 2.31 (3H, br s), 1.72-1.62 (1H, m), 1.46-1.37 (1H, m), 1.06 (3H, t, J = 7.2 Hz).

[0675] Reference example 152 Preparation of methyl 3-(4-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0676] [ka]

[0677] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (150 mg, 0.33 mmol), methyl (E)-3-(4-acetylthiophen-2-yl)acrylate (102.5 mg, 0.39 mmol), [RhCl(cod)] 2 (8.1 mg, 0.016 mmol), 1,4-dioxane / water (3 / 1) (0.7 mL), and TEA (138 μL, 0.98 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (25.5 mg, 14%) as a brown oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.84 (1H, d, J = 1.6 Hz), 7.52 (1H, br t, J = 8.0 Hz), 7.27-7.19 (3H, m), 7.16-7.11 (2H, m), 7.05 (1H, d, J = 10.4 Hz), 4.66 (1H, t, J = 7.6 Hz), 4.57-4.56 (1H, m), 4.00-3.97 (1H, m), 3.82-3.68 (2H, m), 3.61 (3H, s), 3.10 (1H, dd, J = 15.6, 7.6 Hz), 3.01-2.99 (2H, m), 2.46 (3H, s), 2.35 (3H, br s), 1.72-1.62 (1H, m), 1.48-1.36 (1H, m), 1.06 (3H, t, J = 7.6 Hz).

[0678] Reference example 153 Preparation of methyl 3-(5-cyano-1-methyl-1H-pyrrol-3-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0679] [ka]

[0680] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (150 mg, 0.33 mmol), methyl (E)-3-(5-cyano-1-methyl-1H-pyrrol-3-yl)acrylate (74 mg, 0.39 mmol), [RhCl(cod)] 2 (8.1 mg, 0.016 mmol), 1,4-dioxane / water (3 / 1) (0.7 mL), and TEA (138 μL, 0.98 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (52.4 mg, 30%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, td, J = 8.0, 1.6 Hz), 7.25 (1H, td, J = 8.0, 1.2 Hz), 7.21 (1H, d, J = 8.0 Hz), 7.12 (1H, d, J = 8.0 Hz), 7.08-7.04 (2H, m), 6.56-6.53 (2H, m), 4.54-4.53 (1H, m), 4.33 (1H, t, J = 8.0 Hz), 4.05-3.98 (1H, m), 3.86-3.69 (2H, m), 3.68 (3H, s), 3.60 (3H, s), 2.99-2.79 (3H, m), 2.32 (3H, s), 1.75-1.66 (1H, m), 1.51-1.39 (1H, m), 1.09-1.08 (3H, m).

[0681] Reference example 154 Preparation of methyl 3-(3-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0682] [ka]

[0683] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (110 mg, 0.2 mmol), methyl (E)-3-(3-acetylthiophen-2-yl)acrylate (61 mg, 0.3 mmol), [RhCl(cod)] 2 (5.9 mg, 0.01 mmol), 1,4-dioxane / water (9 / 1) (0.6 mL), and TEA (101 μL, 0.7 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (24.6 mg, 19%) as a pale brown oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, br t, J = 8.0 Hz), 7.34 (1H, d, J = 5.6 Hz), 7.27-7.20 (3H, m), 7.16-7.10 (3H, m), 5.65 (1H, dd, J = 8.0, 8.0 Hz), 4.61-4.59 (1H, m), 4.04-3.99 (1H, m), 3.80-3.72 (2H, m), 3.56 (3H, s), 3.13-3.07 (1H, m), 3.02-2.90 (2H, m), 2.49 (3H, s), 2.35 (3H, br s), 1.71-1.59 (1H, m), 1.51-1.42 (1H, m), 1.13-1.06 (3H, m).

[0684] Reference example 155 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)furan-2-yl]propanoate

[0685] [ka]

[0686] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (115 mg, 0.25 mmol), methyl (E)-3-[5-(2-methyl-1,3-dioxolan-2-yl)furan-2-yl]acrylate (60 mg, 0.25 mmol), [RhCl(cod)] 2 (6.2 mg, 0.013 mmol), 1,4-dioxane / water (9 / 1) (0.4 mL), and TEA (106 μL, 0.76 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (13.5 mg, 9%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.89 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, t, J = 8.0 Hz), 7.25 (1H, t, J = 8.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.13-7.12 (2H, m), 7.06 (1H, s), 6.17 (1H, d, J = 3.2 Hz), 5.85 (1H, d, J = 3.2 Hz), 4.56 (1H, d, J = 14.0 Hz), 4.48 (1H, t, J = 8.0 Hz), 4.04-3.93 (5H, m), 3.81-3.69 (2H, m), 3.60 (3H, s), 3.07 (1H, d, J = 15.2, 7.2 Hz), 2.97 (1H, d, J = 15.2 Hz), 2.88-2.80 (1H, m), 2.34 (3H, s), 1.75-1.65 (4H, m), 1.50-1.43 (1H, m), 1.08 (3H, t, J = 7.2 Hz).

[0687] Reference example 156 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate

[0688] [ka]

[0689] (R)-4-Ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (165 mg, 0.36 mmol), methyl (E)-3-[4-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate (137 mg, 0.54 mmol), [RhCl(cod)]2 (8.9 mg, 0.018 mmol), 1,4-dioxane / water (10 / 1) (0.77 mL), and TEA (151 μL, 1.08 mmol) were used as raw materials and treated in the same manner as in Reference Example 130 to obtain the title compound (83.4 mg, 40%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.89 (1H, dd, J = 8.0, 1.6 Hz), 7.51 (1H, td, J = 8.0, 1.6 Hz), 7.25 (1H, br t, J = 8.0 Hz), 7.20 (1H, br d, J = 8.0 Hz), 7.15-7.14 (2H, m), 7.07 (2H, br s), 6.77 (1H, dt, J = 4.8, 1.2 Hz), 4.64-4.62 (1H, m), 4.58-4.57 (1H, m), 4.03-3.96 (3H, m), 3.89-3.69 (4H, m), 3.59 (3H, s), 3.08 (1H, dd.

[0690] Reference example 157 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methyl-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate

[0691] [ka]

[0692] To a solution of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate (49.5 mg, 0.085 mmol) in THF (0.6 mL) was added 1M LDA THF / hexane (150 μL, 0.15 mmol) at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 30 minutes and at -40 °C for 20 minutes. Iodomethane (106 μL, 1.7 mmol) was added, and the mixture was warmed to room temperature and stirred for 3 hours. Water was added to the mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 9 / 1 → 7 / 3) to give the title compound (40.1 mg, 79%) as a colorless oil. The title compound could be separated into two isomer mixtures, isomer 1 with a short retention time and isomer 2 with a long retention time. Isomer 1: 1 H NMR (400 MHz, CDCl 3)δ 7.90 (1H, dd, J = 8.0, 1.6 Hz), 7.53 (1H, td, J = 8.0, 1.6 Hz), 7.26 (1H, br t, J = 8.0 Hz), 7.22 (1H, dd, J = 8.0, 1.6 Hz), 7.14 (2H, br s), 7.06 (1H, d, J = 11.2 Hz), 6.77 (1H, dd, J = 3.6, 0.8 Hz), 6.69 (1H, br d, J = 3.6 Hz), 4.60-4.57 (1H, m), 4.28-4.25 (1H, m), 4.02-3.88 (5H, m), 3.86-3.69 (2H, m), 3.59 (3H, s), 3.19-3.13 (1H, m), 2.95 (1H, dd, J = 15.2, 2.0 Hz), 2.36-2.34 (3H, m), 1.73-1.62 (4H, m), 1.46-1.38 (1H, m), 1.11-1.04 (6H, m)。 Isomer 2: 1 H NMR(400 MHz, CDCl 3 )δ 7.89 (1H, dd, J = 8.0, 1.6 Hz), 7.53 (1H, td, J = 8.0, 1.6 Hz), 7.26 (1H, br t, J = 8.0 Hz), 7.22 (1H, dd, J = 8.0, 1.6 Hz), 7.20-7.17 (1H, m), 7.11-7.07 (2H, m), 6.82 (1H, d, J = 3.6 Hz), 6.73 (1H, t, J = 3.6 Hz), 4.57 (1H, d, J = 14.0 Hz), 4.21 (1H, d, J = 11.2 Hz), 4.07-3.89 (5H, m), 3.79-3.68 (2H, m), 3.43 (3H, s), 3.21-3.10 (1H, m), 2.94 (1H, dd, J = 15.2, 8.8 Hz), 2.33 (3H, s), 1.73-1.65 (4H, m), 1.51-1.42 (1H, m), 1.20 (3H, d, J = 6.8 Hz), 1.15-1.07 (3H, m)。

[0693] Reference example 158 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methyl-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate

[0694] [ka]

[0695] A solution of diisopropylamine (30 μL, 0.21 mmol) in THF (200 μL) was cooled to -78 °C and stirred for 10 min. A 1.6 M solution of n-butyllithium in hexane (110 μL, 0.18 mmol) was added at -78 °C, the temperature was raised to -40 °C, and the mixture was stirred for 30 min. The mixture was cooled again to -78 °C, and a solution of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate (41.5 mg, 0.069 mmol) in THF (400 μL) was added dropwise to the reaction solution, and the mixture was stirred at -78 °C for 10 minutes, then heated to -40 °C and stirred for 10 minutes. Iodomethane (90 μL, 1.4 mmol) was added to the reaction solution, and the mixture was stirred at -40 °C for 15 minutes, then heated to room temperature and stirred for 2 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane / TEA (v / v) = 23 / 75 / 2) to give the title compound (31.2 mg, 74%) as a brown oily substance. 1 H NMR (400 MHz, CDCl 3) δ 7.89 (1H, d, J = 7.6 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.28-7.21 (2H, m), 7.18-7.04 (3H, m), 6.57-6.51 (1H, m), 4.59-4.57 (1H, m), 4.20-4.19 (1H, m), 4.07-3.94 (3H, m), 3.92-3.82 (3H, m), 3.78-3.69 (1H, m), 3.60-3.42 (3H, m), 3.16-3.08 (1H, m), 3.00-2.92 (1H, m), 2.37-2.33 (3H, m), 2.19-2.16 (3H, m), 1.74-1.62 (1H, m), 1.66-1.65 (3H, m), 1.53-1.37 (1H, m), 1.21-0.99 (6H, m).

[0696] Reference example 159 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methyl-3-[5-(2-methyl-1,3-dioxolan-2-yl)furan-2-yl]propanoate

[0697] [ka]

[0698] Methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)furan-2-yl]propanoate (55.7 mg, 0.098 mmol), 1M LDA THF / hexane solution (150 μL, 0.15 mmol), iodomethane (106 μL, 1.7 mmol), and THF (0.6 mL) were used as raw materials and operated in the same manner as in Reference Example 157 to obtain the title compound (40.1 mg, 79%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.89 (1H, br d, J = 8.0 Hz), 7.52 (1H, br t, J = 8.0 Hz), 7.28-7.23 (1H, m), 7.22-7.04 (4H, m), 6.18-6.14 (1H, m), 6.01-5.92 (1H, 2.98-2.93 (1H, m), 2.35-2.31 (3H, m), 1.69-1.66 (4H, m), 1.52-1.48 (1H, m), 1.16-0.98 (6H, m).

[0699] Reference example 160 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methyl-3-[4-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate

[0700] [ka]

[0701] Methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate (83 mg, 0.14 mmol), THF (0.9 mL), 2M LDA THF / heptane / ethylbenzene solution (92 μL, 0.18 mmol), and iodomethane (133 μL, 2.1 mmol) were used as raw materials, and the title compound (58.0 mg, 81%) was obtained as a colorless oily substance by the same procedure as in Reference Example 157. The title compound could be separated into two isomers by purification using silica gel column chromatography to give isomer 1 (17.0 mg) with a short retention time and isomer 2 (30.7 mg) with a long retention time as a colorless oil. Isomer 1: 1 H NMR (400 MHz, CDCl 3 )δ 7.89 (1H, dd, J = 7.6, 1.6 Hz), 7.53 (1H, br t, J = 8.0 Hz), 7.28-7.25 (1H, m), 7.24-7.18 (2H, m), 7.11-7.08 (3H, m), 6.86 (1H, dd, J = 6.0, 1.2 Hz), 4.57-4.56 (1H, m), 4.24-4.23 (1H, m), 4.03-3.99 (3H, m), 3.85-3.68 (4H, m), 3.43 (3H, s), 3.19-3.12 (1H, m), 2.96-2.91 (1H, m), 2.32 (3H, s), 1.73-1.69 (1H, m), 1.62 (3H, s), 1.51-1.44 (1H, m), 1.20-1.19 (3H, m), 1.24-1.09 (3H, m). Isomer 2: 1 H NMR (400 MHz, CDCl 3)δ 7.89 (1H, br d, J = 8.0 Hz), 7.53 (1H, td, J = 8.0, 1.6 Hz), 7.28-7.24 (1H, m), 7.22-7.19 (1H, m), 7.16-7.14 (2H, m), 7.09-7.07 (1H, m), 7.03 (1H, br s), 6.83 (1H, br s), 4.60-4.57 (1H, m), 4.28-4.27 (1H, m), 4.04-3.97 (3H, m), 3.87-3.69 (4H, m), 3.58 (3H, br s), 3.19-3.12 (1H, m), 2.97-2.93 (1H, m), 2.36-2.34 (3H, m), 1.71-1.67 (1H, m), 1.62-1.61 (3H, m), 1.46-1.37 (1H, m), 1.11-1.03 (6H, m).

[0702] Reference example 161 Preparation of methyl 3-[5-(dimethylcarbamoyl)furan-2-yl]-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0703] [ka]

[0704] To a solution of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(methylcarbamoyl)furan-2-yl]propanoate (43 mg, 0.08 mmol) in THF (2.0 mL) was added 1M LDA THF solution (96 μL, 0.096 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 20 minutes and at -40 °C for 15 minutes. Iodomethane (100 μL, 1.6 mmol) was added and the mixture was stirred at room temperature for 3.5 hours, after which the reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 3 / 7 → 1 / 1) to obtain the title compound (26.4 mg, 60%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.89 (1H, dd, J = 7.6, 1.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.26 (1H, t, J = 7.6 Hz), 7.21 (1H, d, J = 7.6 Hz), 7.15-7.10 (3H, m), 6.90 (1H, d, J = 3.6 Hz), 6.10 (1H, d, J = 3.6 Hz), 4.56-4.52 (2H, m), 4.04-3.99 (1H, m), 3.82 (1H, d, J = 14 Hz), 3.76-3.69 (1H, m), 3.61 (3H, s), 3.13-2.86 (9H, m), 2.32 (3H, s), 1.75-1.65 (1H, m), 1.52-1.42 (1H, m), 1.08 (3H, t, J = 7.2 Hz).

[0705] Reference example 162 Preparation of methyl 3-(5-carbamoylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0706] [ka]

[0707] Methyl 3-{5-[(2,4-dimethoxybenzyl)carbamoyl]thiophen-2-yl}-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate (83.4 mg, 0.12 mmol) in dichloromethane (1 mL) was added with TFA (750 μL, 9.8 mmol) under argon atmosphere and stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, and the residue was neutralized with 1N aqueous sodium hydroxide solution and extracted with methanol / dichloromethane (1 / 10). The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (99.4 mg, quant.) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3)δ 7.87 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, br t, J = 8.0 Hz), 7.35 (1H, d, J = 3.6 Hz), 7.25 (1H, t, J = 8.0 Hz), 7.20 (1H, br d, J = 8.0 Hz), 7.14 (2H, br s), 7.08 (1H, d, J = 8.4 Hz), 6.81-6.79 (1H, m), 6.01 (2H, br s), 4.70 (1H, t, J = 8.0 Hz), 4.57-4.55 (1H, m), 4.02-3.95 (1H, m), 3.82-3.69 (2H, m), 3.60 (3H, s), 3.09 (1H, dd, J = 15.6, 7.6 Hz), 3.02-2.91 (2H, m), 2.33 (3H, s), 1.72-1.62 (1H, m), 1.46-1.38 (1H, m), 1.07-1.06 (3H, m).

[0708] Reference example 163 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0709] [ka]

[0710] A solution of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropanoate (29.8 mg, 0.079 mmol), (R)-4-ethyl-3,4-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (27.8 mg, 0.12 mmol), potassium carbonate (33.9 mg, 0.25 mmol), and tetrabutylammonium iodide (5.7 mg, 0.015 mmol) in DMF (0.50 mL) was stirred at 70 °C for 3 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 73 / 27 → 52 / 48) to obtain the title compound (43.1 mg, 96%) as a white solid. 1 H NMR (400 Mz, CDCl 3 ) δ 7.87 (1H, dt, J = 7.6, 1.2 Hz), 7.55-7.50 (1H, m), 7.49 (1H, d, J = 4.0 Hz), 7.27-7.11 (5H, m), 6.97-6.95 (1H, m), 4.69-4.67 (1H, m), 4.56-4.55 (1H, m), 4.04-3.97 (1H, m), 3.83-3.69 (2H, m), 3.60 (3H, brs), 2.97-2.90 (1H, m), 2.49-2.48 (3H, m), 2.33 (3H, s), 1.81-1.56 (1H, m), 1.51-1.35 (1H, m), 1.29 (3H, br s), 1.23 / -1.21 (3H, m), 1.10-1.08 (3H, m).

[0711] Reference example 164 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-9-fluoro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0712] [ka]

[0713] Methyl 3-(5-acetylthiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropanoate (23.4 mg, 0.062 mmol), (R)-4-ethyl-9-fluoro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (18.3 mg, 0.075 mmol), potassium carbonate (27.2 mg, 0.20 mol) and tetrabutylammonium iodide (5.3 mg, 0.014 mmol) and DMF (1.0 mL) were used as raw materials, and the title compound (31.8 mg, 88%) was obtained as a white solid by operating in the same manner as in Reference Example 163. 1 H NMR (400 MHz, CDCl 3) δ 7.51 (1H, dd, J = 4.0, 1.6 Hz), 7.44-7.39 (1H, m), 7.29 / 7.28 (1H, m), 7.25-7.22 (1H, m), 7.14 (1H, br d, J = 8.0 Hz), 7.00-6.94 (3H, m), 4.72 (1H, s), 4.58-4.55 (1H, m), 4.50-4.43 (1H, m), 4.31-4.28 (1H, m), 3.62 (3H, s), 3.33 (1H, d, J = 14.4, 4.0 Hz), 3.10 (1H, d, J = 14.4, 1.2 Hz), 2.49 (3H, br s), 2.34 (3H, br s), 1.68-1.56 (1H, m), 1.55-1.45 (1H, m), 1.32 (3H, br s), 1.25 (3H, s), 1.02-1.01 (3H, m).

[0714] Reference example 165 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0715] [ka]

[0716] Methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropanoate (50 mg, 0.139 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (38.1 mg, 0.167 mmol), triphenylphosphine (73 mg, 0.278 mmol), THF (0.4 mL), and 2.2M DEAD toluene solution (126 μL, 0.278 mmol) were used as raw materials and operated in the same manner as in Reference Example 12 to obtain the title compound (39.4 mg, 50%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 8.51-8.49 (1H, m), 8.26 (1H, br d, J = 8.0 Hz), 7.51 (1H, d, J = 4.0 Hz), 7.30-7.24 (2H, m), 7.21 (1H, s), 7.14 (1H, d, J = 8.0 Hz), 6.98 (1H, t, J = 4.0 Hz), 4.69 (1H, d, J = 5.6 Hz), 4.47-4.42 (2H, m), 4.11-4.05 (1H, m), 3.62-3.59 (4H, m), 3.16 (1H, br d, J = 15.2 Hz), 2.50 (3H, s), 2.33 (3H, br s), 1.81-1.68 (1H, m), 1.60-1.52 (1H, m), 1.30 (3H, s), 1. 24 (3H, s), 1.09 (3H, t, J = 7.2 Hz).

[0717] Reference example 166 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-[3-({4-[2-(benzyloxy)ethyl]-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl}methyl)-4-methylphenyl]-2-methylpropanoate

[0718] [ka]

[0719] Methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropanoate (22 mg, 0.064 mmol), 4-[2-(benzyloxy)ethyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (23 mg, 0.070 mmol), triphenylphosphine (20.1 mg, 0.077 mmol), THF (0.27 mL), and 2.2M DEAD toluene solution (38 μL, 0.083 mmol) were used as raw materials and operated in the same manner as in Reference Example 12 to obtain the title compound (29.6 mg, 70%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, br d, J = 8.0 Hz), 7.49 (1H, br t, J = 8.0 Hz), 7.43 (1H, t, J = 4.0 Hz), 7.35-7.24 (6H, m), 7.14-7.09 (3H, m), 7.00 (1H, br t, J = 8.0 Hz), 6.89 (1H, br t, J = 4.0 Hz), 4.60-4.47 (3H, m), 4.36-4.31 (2H, m), 3.87-3.73 (3H, m), 3.66-3.61 (1H, m), 3.59 (3H, br s), 3.25-3.18 (1H, m), 2.93-2.88 (1H, m), 2.43 (3H, br s), 2.31 (3H, br s), 1.92-1.83 (1H, m), 1.67-1.60 (1H, m), 1.06 (3H, d, J = 7.2 Hz).

[0720] Reference example 167 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methylpropanoate

[0721] [ka]

[0722] Methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2-methylpropanoate (50 mg, 0.14 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepine 1,1-dioxide (38.1 mg, 0.17 mmol), triphenylphosphine (43.7 mg, 0.17 mmol), THF (3.7 mL), and 2.2M DEAD toluene solution (100 μL, 0.22 mmol) were used as raw materials and operated in the same manner as in Reference Example 12 to obtain the title compound (24.8 mg, 31%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 9.03 (1H, s), 8.66 (1H, dd, J = 5.6, 2.0 Hz), 7.47 (1H, dd, J = 4.0, 2.4 Hz), 7.17 (2H, s), 7.12-7.09 (2H, m), 6.93-6.92 (1H, m), 4.47-4.44 (1H, m), 4.38 (2H, d, J = 12.0 Hz), 4.21-4.09 (1H, m), 3.61 (3H, s), 3.51-3.41 (1H, m), 3.23-3.11 (2H, m), 2.47 (3H, br s), 2.33 (3H, s), 1.74-1.63 (1H, m), 1.56-1.47 (1H, m), 1.08-1.02 (6H, m).

[0723] Reference example 168 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[4-(2-hydroxyethyl)-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methylpropanoate

[0724] [ka]

[0725] Palladium carbon (35.7 mg) was added to a solution of methyl 3-(5-acetylthiophen-2-yl)-3-[3-({4-[2-(benzyloxy)ethyl]-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl}methyl)-4-methylphenyl]-2-methylpropanoate (126 mg, 0.19 mmol) in methanol / dichloromethane (0.6 mL / 0.4 mL) and stirred at room temperature for 32 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) =1 / 1→0 / 1) to obtain the title compound (44.4 mg, 41%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.89 (1H, dd, J = 8.0, 1.6 Hz), 7.69-7.44 (3H, m), 7.29-7.22 (1H, m), 7.17-7.10 (3H, m), 6.93 (1H, d, J = 4.0 Hz), 4.77-4.59 (1H, m), 4.44-4.33 (2H, m), 4.02-3.80 (4H, m), 3.60-3.55 (3H, m), 3.31-3.09 (1H, m), 2.92-2.81 (1H, m), 2.49-2.34 (6H, m), 1.96-1.77 (1H, m), 1.62-1.45 (1H, m), 1.07-1.00 (3H,m).

[0726] Reference example 169 Preparation of (5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)methanol

[0727] [ka]

[0728] To a solution of [1-(5-bromo-3-fluorothiophen-2-yl)ethoxy](tert-butyl)dimethylsilane (200 mg, 0.59 mmol) in THF (2.0 mL), 2M n-butyllithium cyclohexane solution (354 μL, 0.71 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 30 minutes, and a solution of 3-{[(4-methoxybenzyl)oxy]methyl}-4-methylbenzaldehyde (135.1 mg, 0.50 mmol) in THF (1.5 mL) was added. The reaction mixture was stirred at -78 °C for 1.5 hours and then warmed to room temperature. After stirring the mixture for 1.5 hours, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 1 / 0 → 95 / 5) to obtain the title compound (168.3 mg, 63%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3)δ 7.31 (1H, br s), 7.22-7.16 (3H, m), 7.10 (1H, d, J = 7.6 Hz), 6.82 (2H, br d, J = 8.8 Hz), 6.40 (1H, d, J = 20.8 Hz), 5.76 (1H, br s), 5.09 (1H, q, J = 6.4 Hz), 4.44-4.43 (4H, m), 3.74 (3H, s), 2.32 (1H, br s), 2.25 (3H, s), 1.39-1.38 (3H, m), 0.82 (9H, br s), 0.01 (3H, br s), -0.05 (3H, br s) s).

[0729] Reference example 170 Preparation of methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0730] [ka]

[0731] To a solution of (5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)(3-{[(4-methoxybenzyl)oxy)]methyl}-4-methylphenyl)methanol (210 mg, 0.40 mmol) in acetonitrile (4.8 mL), trichloroacetonitrile (80 μL, 0.79 mmol) and DBU (3 μL, 0.020 mmol) were added. The mixture was stirred at room temperature for 45 minutes, and a solution of dimethylketene methyltrimethylsilylacetal (201 μL, 0.99 mmol) and bis-(trifluoromethanesulfonyl)imide (11.1 mg, 0.040 mmol) in acetonitrile (111 μL) was added, followed by stirring at room temperature for 3.5 hours. A saturated aqueous solution of potassium carbonate was added to the mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 1 / 0 → 85 / 15) to obtain the title compound (184.3 mg, 76%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.25-7.22 (3H, m), 7.13 (1H, br t, J = 8.0 Hz), 7.04 (1H, dd, J = 8.0, 3.2 Hz), 6.84 (2H, br d, J = 8.8 Hz), 6.55 (1H, d, J = 19.6 Hz), 5.07 (1H, q, J = 6.4 Hz), 4.45-4.41 (5H, m), 3.77 (3H, s), 3.54 (3H, s), 2.23 (3H, s), 1.39-1.36 (3H, m), 1.24 (3H, s), 1.15 (3H, s), 0.82 (9H, br s), 0.001 (3H, br s), -0.07 (3H, br s).

[0732] Reference example 171 Preparation of methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropanoate

[0733] [ka]

[0734] Methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate (204 mg, 0.33 mmol), dichloromethane (2.9 mL), water (290 μL), and DDQ (82.6 mg, 0.36 mmol) were used as raw materials and operated in the same manner as in Reference Example 25 to obtain the title compound (109.3 mg, 66%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ7.31 (1H, s), 7.18 (1H, br t, J = 8.0 Hz), 7.10 (1H, dd, J = 8.0, 4.0 Hz), 6.60 (1H, d, J = 19.6 Hz), 5.12 (1H, q, J = 6.4 Hz), 4.67 (2H, br s), 4.50-4.47 (1H, m), 3.60 (3H, s), 2.31 (3H, s), 2.32 (3H, s), 1.59 (1H, br s), 1.43-1.42 (3H, m), 1.29 (3H, s), 1.20 (3H, br s), 0.87 (9H, br s), 0.054-0.051 (3H, m), 0.00--0.015 (3H, m).

[0735] Reference example 172 Preparation of methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0736] [ka]

[0737] Methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropanoate (65 mg, 0.13 mmol), (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (33 mg, 0.15 mmol), triphenylphosphine (38 mg, 0.15 mmol), THF (0.4 mL), and 2.2M DEAD toluene solution (78 μL, 0.17 mmol) were used as raw materials, and the title compound (66.2 mg, 71%) was obtained as a white solid by operating in the same manner as in Reference Example 12. 1 H NMR (400 MHz, CDCl 3)δ 7.84 (1H, d, J = 8.0 Hz), 7.47 (1H, br t, J = 8.0 Hz), 7.23-7.13 (3H, m), 7.11-7.07 (2H, m), 6.57-6.50 (1H, m), 5.09-5.06 (1H, m), 4.52-4.49 (1H, m), 4.42-4.38 (1H, m), 3.99-3.95 (1H, m), 3.80-3.65 (2H, m), 3.55 (3H, br s), 2.95-2.89 (1H, m), 2.29 (3H, br s), 1.69-1.59 (1H, m), 1.39-1.36 (4H, m), 1.22-1.21 (3H, m), 1.14-1.13 (3H, m), 1.06-1.02 (3H, m), 0.82-0.79 (9H, m), 0.004--0.009 (3H, m), -0.052--0.091 (3H, m).

[0738] Reference example 173 Preparation of 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-fluoro-5-(1-hydroxyethyl)thiophen-2-yl]-2,2-dimethylpropanoic acid

[0739] [ka]

[0740] Methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate (87.2 mg, 0.12 mmol) in methanol / 1,4-dioxane (0.5 mL / 0.5 mL) was added with 4N aqueous sodium hydroxide solution (310 μL, 1.2 mmol) and stirred at 100 °C for 1 hour by microwave. 1N hydrochloric acid was added to the mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (90.7 mg, quant.) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, br d, J = 8.0 Hz), 7.52 (1H, br t, J = 8.0 Hz), 7.27-7.20 (4H, m), 7.13-7.11 (1H, m), 6.69-6.64 (1H, m), 5.13 (1H, q, J = 6.4 Hz), 4.58-4.48 (2H, m), 4.02-4.00 (1H, m), 3.86-3.73 (2H, m), 3.01-2.96 (1H, m), 2.32 (3H, s), 1.73-1.60 (1H, m), 1.52-1.48 (3H, m), 1.45-1.41 (1H, m), 1.29 (3H, s), 1.18 (3H, s), 1.10-1.06 (3H, m).

[0741] Reference example 174 Preparation of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-fluoro-5-(1-hydroxyethyl)thiophen-2-yl]-2,2-dimethylpropanoate

[0742] [ka]

[0743] Methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate (66 mg, 0.094 mmol) in THF (0.2 mL) was added with 1N tetrabutylammonium fluoride THF solution (188 μL, 0.19 mmol) and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (62.1 mg, quant.) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.88 (1H, dd, J = 8.0, 1.6 Hz), 7.52 (1H, br t, J = 8.0 Hz), 7.27-7.17 (4H, m), 7.12 (1H, d, J = 7.6 Hz), 6.63-6.61 (1H, m), 5.15 (1H, q, J = 6.4 Hz), 4.54-4.50 (1H, m), 4.48 (1H, br s), 4.05-4.01 (1H, m), 3.83 (1H, d, J = 14.0 Hz), 3.76-3.70 (1H, m), 3.62 (3H, br s), 3.39-3.35 (1H, m), 3.00-2.95 (1H, m), 2.33 (3H, s), 1.72-1.66 (1H, m), 1.52-1.50 (3H, m), 1.48-1.42 (1H, m), 1.28 (3H, s), 1.19 (3H, br s), 1.09 (3H, t, J = 7.2 Hz).

[0744] Reference example 175 Preparation of methyl 3-(5-acetyl-4-fluorothiophen-2-yl) 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0745] [ka]

[0746] To a solution of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-fluoro-5-(1-hydroxyethyl)thiophen-2-yl]-2,2-dimethylpropanoate (62.1 mg, 0.094 mmol) in DMSO (0.4 mL), TEA (47 μL, 0.34 mmol) and pyridine-sulfur trioxide complex (32.9 mg, 0.21 mmol) were added. The reaction mixture was stirred at room temperature for 20 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (48.1 mg, 87%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3)δ 7.89 (1H, dt, J = 8.0, 1.6 Hz), 7.53 (1H, br t, J = 8.0 Hz), 7.29-7.14 (5H, m), 6.75 (1H, br d, J = 6.8 Hz), 4.57-4.54 (2H, m), 4.06-4.00 (1H, m), 3.85-3.82 (1H, m), 3.77-3.71 (1H, m), 3.64 (3H, br s), 3.00-2.93 (1H, m), 2.51 (3H, br s), 2.34 (3H, s), 1.71-1.65 (1H, m), 1.50-1.38 (1H, m), 1.30 (3H, s), 1.20 (3H, s), 1.09-1.08 (3H, m).

[0747] Reference example 176 Preparation of methyl 3-(4-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-1-trityl-1H-benzo[d]imidazol-6-yl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate

[0748] [ka]

[0749] A flask was charged with (R)-4-ethyl-2-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-benzo[d]imidazol-4-yl]methyl}-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (126.9 mg, 0.17 mmol), methyl (E)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate (88.4 mg, 0.35 mmol) and [RhCl(cod)]. 2(9.3 mg, 0.019 mmol) was added and the atmosphere was replaced with argon. Then, 1,4-dioxane / water (1 / 1) (0.8 mL) and TEA (75 μL, 0.54 mmol) were added and heated at 140 °C for 3 hours using a microwave. The reaction solution was returned to room temperature, diluted with ethyl acetate, washed with water and saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 71 / 29 → 1 / 1) to obtain the title compound (86.6 mg, 58%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (1H, d, J = 7.6 Hz), 7.78 (1H, s), 7.47-7.42 (1H, m), 7.31-7.26 (9H, m), 7.22-7.18 (1H, m), 7.15-7.11 (8H, m), 6.70 (1H, d, J = 2.0 Hz), 6.29-6.26 (2H, m), 4.77 (1H, d, J = 15.2 Hz), 4.55-4.54 (1H. m), 4.48 (1H, q, J = 7.2 Hz), 4.03-3.84 (6H, m), 3.53 (3H, s), 3.29-3.23 (1H, m),2.76-2.69 (1H, m), 2.59-2.51 (1H, m), 1.73-1.64 (1H, m), 1.68 (3H, s), 1.45-1.40 (1H, m), 1.03-1.02 (3H, m).

[0750] Reference example 177 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(4-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-1H-benzo[d]imidazol-6-yl)propanoate

[0751] [ka]

[0752] To a solution of methyl 3-(4-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-1-trityl-1H-benzo[d]imidazol-6-yl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate (49.8 mg, 0.058 mmol) in dichloromethane (0.9 mL), triethylsilane (0.1 mL) and TFA (1.0 mL) were added and stirred at room temperature for 30 minutes. The reaction solution was adjusted to basicity with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 → 95 / 5) and preparative thin-layer chromatography (dichloromethane / methanol = 97 / 3) to obtain the title compound (23.2 mg, 70%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 10.6 (1H, s), 8.11 (1H, s), 7.90 (1H, dd, J = 7.6, 1.2 Hz), 7.74 (1H, s), 7.56 (1H, t, J = 7.6 Hz), 7.52-7.48 (1H, m), 7.31-7.24 (2H, m), 6.91 (1H, s), 6.88 (1H, br s), 4.87 (1H, t, J = 7.6 Hz), 4.75-4.72 (1H, m), 4.15-4.07 (1H, m), 3.97-3.93 (1H, m), 3.74-3.71 (1H, m), 3.60 (3H, br s), 3.21-3.07 (3H, m), 2.47 (3H, s), 1.82-1.74 (1H, m), 1.59-1.51 (1H, m), 1.15-1.14 (3H, m).

[0753] Reference example 178 Preparation of methyl 3-(5-acetyl-4-methylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methylpropanoate

[0754] [ka]

[0755] To a solution of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2-methyl-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate (31.2 mg, 0.05 mmol) in THF (0.5 mL), 1 M hydrochloric acid (0.1 mL, 0.1 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain the title compound (26.7 mg, 92%) as a brown transparent oil. 1 H NMR (400 MHz, CDCl 3) δ 7.89 (1H, d, J = 7.6 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.26 (1H, t, J = 7.6 Hz), 7.22 (1H, d, J = 8.0 Hz), 7.17-7.07 (3H, m), 6.77-6.32 (1H, m), 4.60-4.53 (1H, m), 4.30-4.25 (1H, m), 4.06-3.98 (1H, m), 3.89-3.79 (1H, m), 3.75-3.68 (1H, m), 3.62-3.46 (3H, m), 3.24-3.14 (1H, m), 2.99-2.92 (1H, m), 2.47-2.42 (6H, m), 2.34-2.31 (3H, m), 1.73-1.62 (1H, m), 1.49-1.33 (1H, m), 1.11-1.04 (6H, m).

[0756] Reference example 179 Preparation of methyl 3-(5-acetylthiazol-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-propanoate

[0757] [ka]

[0758] To a solution of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiazol-2-yl]propanoate (23.7 mg, 0.040 mmol) in THF (0.5 mL), 1 M hydrochloric acid (0.1 mL) was added and stirred for 2 hours. Further, 6 M hydrochloric acid (0.1 mL) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain the title compound (19.0 mg, 89%) as a white oil. 1 H NMR (400MHz, CDCl 3 ) δ 8.17 (1H, br s), 7.89 (1H, dd, J = 7.6, 1.6 Hz), 7.52 (1H, td, J = 7.6, 1.6 Hz), 7.28-7.24 (1H, m), 7.22-7.14 (4H, m), 4.79 (1H, t, J = 7.6 Hz), 4.57-4.55 (1H, m), 4.07-3.97 (1H, m), 3.84-3.81 (1H, m), 3.76-3.66 (1H, m), 3.63 (3H, s), 3.43-3.42 (1H, m), 3.02-2.96 (2H, m), 2.52 (3H, s), 2.35 (3H, br s), 1.75-1.64 (1H, m), 1.51-1.39 (1H, m), 1.09-1.07 (3H, m).

[0759] Reference example 180 Preparation of methyl 3-(5-acetyl-4-methylthiazol-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-propanoate

[0760] [ka]

[0761] To a solution of methyl 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[4-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiazol-2-yl]propanoate (32.8 mg, 0.06 mmol) in THF (0.5 mL), 3M hydrochloric acid (0.1 mL, 0.3 mmol) was added and stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and saturated saline, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 1 → dichloromethane / methanol = 98 / 2) to obtain the title compound (24.8 mg, 82%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (1H, d, J = 7.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.28-7.24 (1H, m), 7.22-7.15 (4H, m), 4.73 (1H, t, J = 7.6 Hz), 4.58-4.56 (1H, m), 4.07-3.98 (1H, m), 3.85-3.82 (1H, m), 3.76-3.70 (1H, m), 3.62 (3H, s), 3.43-3.42 (1H, m), 3.01-2.94 (2H, m,), 2.68 (3H, s), 2.44 (3H, s), 2.36 (3H, br s), 1.77-1.62 (1H, m), 1.52-1.38 (1H, m), 1.11-1.05 (3H, m).

[0762] Reference example 181 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0763] [ka]

[0764] A solution of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropanoate (87.4 mg, 0.231 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepine 1,1-dioxide (52.7 mg, 0.231 mmol), potassium carbonate (96.0 mg, 0.693 mmol), and tetrabutylammonium iodide (17.1 mg, 0.046 mmol) in DMF (6.9 mL) was stirred at room temperature for 3.5 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 67 / 33 → 46 / 54) to obtain the title compound (181.0 mg, quant.) as a pale yellow oily substance. 1 H NMR (400 Mz, CDCl 3 ) δ 9.03 (1H, s), 8.66 (1H, dd, J = 5.6, 1.6 Hz), 7.51 (1H, dd, J = 4.0, 1.6 Hz), 7.24-7.20 (2H, m), 7.16-7.14 (1H, m), 7.12-7.08 (1H, m), 6.98-6.96 (1H, m), 4.70 / 4.69 (1H, s), 4.46-4.37 (2H, m), 4.22-4.16 (1H, m), 3.60 (3H, br s), 3.53-3.44 (1H, m), 3.18-3.12 (1H, m), 2.50 (3H, br s), 2.32 (3H, br s), 1.72-1.63 (1H, m), 1.54-1.47 (1H, m), 1.30 (3H, br s), 1.24-1.22 (3H, m), 1.07-1.02 (3H, m).

[0765] Reference example 182 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)propanoate

[0766] [ka]

[0767] To a solution of methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]propanoate (297.6 mg, 0.60 mmol) in tetrahydrofuran (1.8 mL), 2N hydrochloric acid (0.9 mL) was added and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (230.4 mg, 85%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ 7.49 (1H, d, J = 4.0 Hz), 7.28-7.24 (3H, m), 7.11 (2H, br s), 6.90-6.86 (3H, m), 4.74 (1H, t, J = 8.0 Hz), 4.48 (2H, s), 4.47 (2H, s), 3.82 (3H, s), 3.62 (3H, s), 3.15-3.00 (2H, m), 2.48 (3H, s), 2.27 (3H, s).

[0768] Reference example 183 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]propanoate

[0769] [ka]

[0770] To a solution of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)propanoate (230.4 mg, 0.509 mmol) in dichloromethane / water (10 / 1) (5.28 mL) was added DDQ (231.1 mg, 1.02 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 57 / 43 → 36 / 64) to obtain the title compound (149.6 mg, 85%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δ 7.49 (1H, d, J = 4.0 Hz), 7.29 (1H, br s), 7.10 (2H, br s), 6.87 (1H, br d, J = 4.0 Hz), 4.74 (1H, t, J = 8.0 Hz), 4.64 (2H, s), 3.60 (3H, s), 3.15-3.01 (2H, m), 2.46 (3H, s), 2.28 (3H, s).

[0771] Reference example 184 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]propanoate

[0772] [ka]

[0773] Methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]propanoate (150.0 mg, 0.45 mmol) and lithium chloride (38.4 mg, 0.91 mmol) were added to a suspension of dichloromethane (3.5 mL) with DIPEA (115.7 μL, 0.68 mmol) and methanesulfonyl chloride (41.8 μL, 0.54 mmol) and stirred at room temperature for 19 hours. Dichloromethane was added to the reaction solution, washed with saturated aqueous sodium bicarbonate and saturated saline, the organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 67 / 33→46 / 54) to obtain the title compound (105.0 mg, 67%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (1H, d, J = 4.0 Hz), 7.21 (1H, br s), 7.15 (2H, br s), 6.87 (1H, br d, J = 4.0 Hz), 4.74 (1H, t, J = 8.0 Hz), 4.56 (2H, s), 3.62 (3H, s), 3.15-3.00 (2H, m), 2.48 (3H, s), 2.38 (3H, s).

[0774] Reference example 185 Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)propanoate

[0775] [ka]

[0776] A solution of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]propanoate (35.0 mg, 0.10 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepine 1,1-dioxide (23.0 mg, 0.10 mmol), potassium carbonate (41.5 mg, 0.30 mmol), and tetrabutylammonium iodide (7.4 mg, 0.02 mmol) in DMF (3.0 mL) was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 55 / 45 → 36 / 64) to obtain the title compound (48.2 mg, 89%) as a colorless oily substance. 1 H NMR (400 Mz, CDCl 3 ) δ 9.02 (1H, s), 8.65 (1H, d, J = 5.6 Hz), 7.50 (1H, br d, J = 4.0 Hz), 7.17 (2H, br s), 7.11-7.08 (2H, m), 6.88 (1H, br d, J = 4.0 Hz), 4.73 (1H, t, J = 7.6 Hz), 4.45-4.37 (2H, m), 4.16-4.09 (1H, m), 3.62 (3H, s), 3.51-3.43 (1H, m), 3.17-3.09 (2H, m), 3.05-3.00 (1H, m), 2.49 (3H, s), 2.33 (3H, s), 1.74-1.65 (1H, m), 1.56-1.50 (1H, m), 1.04 (3H, br t, J = 7.6 Hz).

[0777] Reference example 186 Preparation of methyl 3-[4-fluoro-5-(1-hydroxyethyl)thiophen-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0778] [ka]

[0779] Methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate (131.8 mg, 0.21 mmol) in THF (2.0 mL) was added with 1N tetrabutylammonium fluoride THF solution (550 μL, 0.55 mmol) and stirred at room temperature for 1.5 hours. The solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 76 / 24 → 55 / 45) to obtain the title compound (95.5 mg, 94%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δ 7.29-7.27 (3H, m), 7.16 (1H, d, J = 8.0 Hz), 7.10 (1H, d, J = 8.0 Hz), 6.89 (2H, d, J = 8.4 Hz), 6.64, 6.63 (each 0.5H, s), 5.18-5.12 (1H, m), 4.51-4.48 (5H, m), 3.82 (3H, s), 3.61 (3H, s), 2.28 (3H, s), 1.87 (1H, br s), 1.51, 1.50 (each 1.5H, d, J = 6.4 Hz, thiophene β-CH 3 regioisomers), 1.30 (3H, s), 1.20 (3H, s).

[0780] Reference example 187 Preparation of methyl 3-[5-acetyl-4-fluorothiophen-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0781] [ka]

[0782] Manganese dioxide (822.2 mg, 9.45 mmol) was added to a solution of methyl 3-[4-fluoro-5-(1-hydroxyethyl)thiophen-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate (95.5 mg, 0.19 mmol) in dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 2.5 hours. Manganese dioxide (317.7 mg, 3.65 mmol) was further added and stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 86 / 14 → 65 / 35) to obtain the title compound (92.1 mg, 97%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.29-7.27 (3H, m), 7.15 (1H, dd, J = 7.6, 1.2 Hz), 7.11 (1H, d, J = 7.6 Hz), 6.90 (2H, d, J = 8.4 Hz), 6.75 (1H, s), 4.55 (1H, s), 4.49 (2H, s), 4.48 (2H, s), 3.82 (3H, s), 3.62 (3H, s), 2.51, 2.50 (each 1.5H, s), 2.28 (3H, s), 1.32 (3H, s), 1.21 (3H, s).

[0783] Reference example 188 Preparation of methyl 3-(5-acetyl-4-fluorothiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropanoate

[0784] [ka]

[0785] Methyl 3-[5-acetyl-4-fluorothiophen-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate (92.1 mg, 0.18 mmol), dichloromethane (2.5 mL), water (250 μL), and DDQ (63.9 mg, 0.28 mmol) were used as raw materials and operated in the same manner as in Reference Example 25 to obtain the title compound (65.7 mg, 94%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.31 (1H, d, J = 1.6 Hz), 7.15 (1H, dd, J = 8.0, 1.6 Hz), 7.11 (1H, d, J = 8.0 Hz), 6.75 (1H, s), 4.67 (2H, s), 4.55 (1H, s), 3.63 (3H, s), 2.50, 2.49 (each 1.5H, s, acetyl regioisomers), 2.29 (3H, s), 1.32 (3H, s), 1.20 (3H, s).

[0786] Reference example 189 Preparation of methyl 3-(5-acetyl-4-fluorothiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropanoate

[0787] [ka]

[0788] Methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]propanoate (65.7 mg, 0.17 mmol) and lithium chloride (40.1 mg, 0.95 mmol) were added to a suspension of dichloromethane (1.5 mL) with DIPEA (90 μL, 0.52 mmol) and methanesulfonyl chloride (27 μL, 0.35 mmol) and stirred at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (71.8 mg, quant.) as a light brown transparent oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (1H, d, J = 1.6 Hz), 7.21 (1H, dd, J = 8.0, 1.6 Hz), 7.15 (1H, d, J = 8.0 Hz), 6.76 (1H, s), 4.57 (2H, s), 4.44 (1H, s), 3.64 (3H, s), 2.514, 2.507 (each 1.5H, s), 2.39 (3H, s), 1.32 (3H, s), 1.22 (3H, s).

[0789] Reference example 190 Preparation of methyl 3-(5-acetyl-4-fluorothiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0790] [ka]

[0791] A solution of methyl 3-(5-acetyl-4-fluorothiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropanoate (0.17 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepine 1,1-dioxide (41.0 mg, 0.18 mmol), potassium carbonate (72.3 mg, 0.52 mmol), and tetrabutylammonium iodide (13.1 mg, 0.035 mmol) in DMF (1.0 mL) was stirred at room temperature for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 57 / 43 → 36 / 64) to obtain the title compound (93.7 mg, 92%) as a colorless oil. 1 H NMR (400 Mz, CDCl 3 ) δ 9.02 (1H, s), 8.65 (1H, dd, J = 5.6, 0.4 Hz), 7.21 (1H, dd, J = 7.6, 1.6 Hz), 7.17-7.14 (2H, m), 7.09 (1H, d, J = 5.6, 2.0 Hz), 6.76, 6.75 (each 0.5H, s), 4.55, 4.54 (each 0.5H, s), 4.47-4.36 (2H, m), 4.16, 4.14 (each 0.5H, d, J = 14.4 Hz), 3.640, 3.639 (each 1.5H, s), 3.51-3.43 (1H, m), 3.17 (1H, dt, J = 15.2, 2.8 Hz), 2.51, 2.50 (each 1.5H, s), 2.33, 2.32 (each 1.5H, s), 1.74-1.63 (1H, m), 1.60-1.49 (1H, m), 1.30, 1.29 (each 1.5H, s), 1.20 (3H, s), 1.05 (3H, t, J = 7.2 Hz).

[0792] Reference example 191 Preparation of 3-(5-acetyl-4-methoxythiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoic acid

[0793] [ka]

[0794] Methyl 3-[5-acetyl-4-fluorothiophen-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate (609.6 mg, 1.2 mmol), methanol / 1,4-dioxane (1 / 1) (10.0 mL), and 4N aqueous sodium hydroxide solution (5.0 mL, 20 mmol) were used as raw materials and operated in the same manner as in Production Example 43 to obtain the title compound (497.2 mg, 82%) as an orange solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.32 (1H, d, J = 2.0 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.21 (1H, dd, J = 8.0, 2.0 Hz), 7.10 (1H, d, J = 8.0 Hz), 6.89 (2H, d, J = 8.8 Hz), 6,73 (1H, s), 4.63 (1H, s), 4.48 (4H, s), 3.87 (3H, s), 3.81 (3H, s), 2.46 (3H, s), 2.27 (3H, s), 1.34 (3H, s), 1.25 (3H s).

[0795] Reference example 192 Preparation of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0796] [ka]

[0797] To a solution of 3-(5-acetyl-4-methoxythiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoic acid (491.7 mg, 1.0 mmol) and HBTU (568.4 mg, 1.5 mmol) in dimethylformamide (5.0 mL), 2-(trimethylsilyl)ethanol (520 μL, 3.0 mmol), DIPEA (430 μL, 3.0 mmol), and 4-dimethylaminopyridine (63.5 mg, 0.52 mmol) were added. After stirring at room temperature for 22 hours, DMAP (63.1 mg, 0.52 mmol) was added and stirred at room temperature for 3 hours. 2-(trimethylsilyl)ethanol (280 μL, 2.0 mmol) and DMAP (119.5 mg, 1.0 mmol) were added and stirred at room temperature for 19.5 hours. The reaction solution was diluted with hexane / ethyl acetate (1 / 1), washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated saline, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 86 / 14→65 / 35) to obtain the title compound (409.4 mg, 69%) as a yellow transparent oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.31-7.26 (3H, m), 7.18 (1H, dd, J = 7.6, 1.6 H), 7.10 (1H, d, J = 7.6 Hz), 6.89 (2H, d, J = 8.8 Hz), 6.71 (1H, s), 4.61 (1H, s), 4.48 (4H, s), 4.10-4.05 (2H, m), 3.89 (3H, s), 3.81 (3H, s), 2.46, (3H, s), 2.27 (3H, s), 1.32 (3H, s), 1.21 (3H, s), 0.89-0.86 (2H, m), 0.01 (9H, s).

[0798] Reference example 193 Preparation of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropanoate

[0799] [ka]

[0800] 2-(Trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropanoate (409.3 mg, 0.69 mmol), dichloromethane (6.0 mL), water (600 μL), and DDQ (188.4 mg, 0.83 mmol) were used as raw materials and operated in the same manner as in Reference Example 25 to obtain the title compound (316.9 mg, 97%) as a colorless oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.32 (1H, d, J = 2.0 Hz), 7.21 (1H, dd, J = 8.0, 2.0 Hz), 7.11 (1H, d, J = 8.0 Hz), 6.73 (1H, s), 4.67 (2H, d, J = 5.6 Hz), 4.62 (1H, s), 4.10-4.06 (2H, m), 3.91 (3H ,s), 2.46 (3H,s ), 2.31 (3H, s), 1.56 (1H, t, J = 5.6 Hz), 1.32 (3H, s), 1.22 (3H, s), 0.90-0.86 (2H, m), 0.02 (9H, s).

[0801] Reference example 194 Preparation of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropanoate

[0802] [ka]

[0803] 2-(Trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropanoate (101.8 mg, 0.22 mmol) and lithium chloride (49.6 mg, 1.2 mmol) were added to a suspension of dichloromethane (2.0 mL) with DIPEA (115 μL, 0.66 mmol) and methanesulfonyl chloride (34 μL, 0.44 mmol) and stirred at room temperature for 15.5 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (110.3 mg, quant.) as a light brown transparent oily substance. 1 H NMR (400 MHz, CDCl 3 ) δ 7.26-7.23 (2H, m), 7.12 (1H, d, J = 7.6 Hz), 6.72 (1H, s), 4.60 (1H, s), 4.56 (2H, s), 4.09-4.05 (2H, m), 3.91 (3H, s), 2.73 (3H, s), 2.46 (3H, s), 1.31 (3H, s), 1.22 (3H, s), 0.88-0.84 (2H, m), 0.10 (9H, s).

[0804] Reference example 195 Preparation of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophen-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropanoate

[0805] [ka]

[0806] 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropanoate (all amounts of the compound synthesized in Reference Example 194), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepine 1,1-dioxide (51.0 mg, 0.22 mmol), potassium carbonate (59.6 mg, 0.43 mmol), and tetrabutylammonium iodide (18.8 mg, 0.051 mmol) in DMF (1.0 mL) were stirred at 25 ° C for 1 hour, and then stirred at 40 ° C for 1 hour. The reaction solution was cooled to room temperature, hexane / ethyl acetate (1 / 1) was added, washed with water and saturated saline, the organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 63 / 37 → 42 / 58) to obtain the title compound (154.1 mg, quant.) as a colorless, transparent oily substance. 1 H NMR (400 Mz, CDCl 3) δ 9.01 (1H, s), 8.66, 8.65 (each 0.5H, d, J = 5.6 Hz), 7.24-7.22 (2H, m), 7.14 (1H, d, J = 8.0 Hz), 7.10, 7.09 (each 0.5H, d, J = 5.6 Hz), 6.76, 6.75 (each 0.5H, s), 4.60, 4.59 (each 0.5H, s), 4.45-4.36 (2H, m), 4.16-4.05 (3H, m), 3.933, 3.932 (each 1.5H, s), 3.53-3.44 (1H, m), 3.18-3.11 (1H, m), 2.46 (3H, s), 2.32 (3H, s), 1.73-1.61 (1H, m), 1.58-1.46 (1H, m), 1.30 (3H, s), 1.21, 1.20 (each 1.5H, s), 1.05, 1.03 (each 1.5H, t, J = 7.2 Hz), 0.90-0.86 (2H, m), 0.02, 0.01 (each 4.5H, s).

[0807] Reference example 196 Preparation of 2-(5-bromo-3-fluorothiophen-2-yl)-2-methyl-1,3-dioxolane

[0808] [ka]

[0809] 1-(5-Bromo-3-fluorothiophen-2-yl)ethan-1-one (350.0 mg, 1.57 mmol), ethylene glycol (0.957 mL, 17.3 mmol), p-TsOH H 2 O (15.0 mg, 0.08 mmol) and toluene (9.7 mL) were used as starting materials, and the procedure was performed in the same manner as in Reference Example 76 to obtain the title compound (386.9 mg, 92%) as a pale brown oily substance. 1 H NMR (400 MHz, CDCl 3)δ 6.78 (1H, br s), 4.07-4.03 (2H, m), 4.02-3.97 (2H, m), 1.77 (3H, s).

[0810] Reference example 197 Preparation of methyl (E)-3-[4-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate

[0811] [ka]

[0812] 2-(5-bromo-3-fluorothiophen-2-yl)-2-methyl-1,3-dioxolane (150 mg, 0.56 mmol), tetrabutylammonium chloride (7.8 mg, 0.028 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (45.9 mg, 0.056 mmol), DMA (0.74 mL), methyl acrylate (151 μL, 1.7 mmol), and N,N-dicyclohexylmethylamine (359 μL, 1.7 mmol) were used as raw materials and treated in a similar manner to Reference Example 88 to obtain the title compound (86.3 mg, 56%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.58 (1H, d, J = 16.0 Hz), 6.93 (1H, s), 6.20 (1H, d, J = 16.0 Hz), 4.10-4.03 (2H, m), 4.02-3.99 (2H, m), 3.79 (3H, s), 1.80 (3H, s).

[0813] Reference example 198 Preparation of methyl 3-[4-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)propanoate

[0814] [ka]

[0815] 2-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46.7 mg, 0.13 mmol), methyl (E)-3-[4-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl]acrylate (86.3 mg, 0.32 mmol), and [RhCl(cod)] 2 A solution of (6.3 mg, 0.013 mmol) in toluene (0.48 mL) was added with 2N potassium hydroxide solution (32 μL, 0.063 mmol) under argon atmosphere and heated at 100 °C for 1.5 hours. Water was added to this mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 87 / 13 → 66 / 34) to obtain the title compound (43.7 mg, 67%) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl 3 )δ 7.27 (2H, br d, J = 6.8 Hz), 7.21 (1H, br s), 7.13-7.07 (2H, m), 6.89 (2H, br d, J = 6.8 Hz), 6.52 (1H, br s), 4.55 (1H, t, J = 8.0 Hz), 4.48 (4H, br s), 4.01-3.91 (4H, m), 3.82 (3H, s), 3.61 (3H, s), 3.06-2.92 (2H, m), 2.28 (3H, s), 1.74 (3H, s).

[0816] Reference example 199 Preparation of methyl 3-[4-...

Claims

1. General formula (I): 【Chemistry 1】 [In the formula: R 1 R represents an alkyl group. 2 R represents an optionally substituted thienyl group. 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group, or R 4 and R 5 are bonded together to form -NH-CH=N-. R 6 R represents an optionally substituted alkyl group. 7 is a hydroxy group, a hydrolyzable group, or -NR 71 R 72 (R 71 and R 72 are the same or different and each represents a hydrogen atom or -[C(=O)] 0-1 - represents a hydrocarbon group. 1 , A 2 , A 3 and A 4 are the same or different and represent CH or N (however, the number of N is one or less). Z represents a hydrogen atom or a halogen atom. A compound represented by the formula:

2. General formula (II): 【Chemistry 2】 [In the formula: R 1a and R 1b R represents an alkyl group. 2 R represents an optionally substituted thienyl group. 4 and R 5 are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group, or R 4 and R 5 are bonded together to form -NH-CH=N-. R 6 R represents an optionally substituted alkyl group. 7 is a hydroxy group, a hydrolyzable group, or -NR 71 R 72 (R 71 and R 72 are the same or different and each represents a hydrogen atom or -[C(=O)] 0-1 - represents a hydrocarbon group. 1 , A 2 , A 3 and A 4 are the same or different and represent CH or N (however, the number of N is one or less). Z represents a hydrogen atom or a halogen atom. Of the two diastereomers in which the carbon atom marked with * in the formula is an asymmetric carbon atom, the compound with the lower polarity, its salt, or a solvate thereof.

3. The compound is a compound represented by the formula * in which the carbon atom is an asymmetric carbon atom. 6 The compound according to claim 2, its salt, or a solvate thereof, which is the first compound to be eluted when an isomeric mixture containing two diastereomers when the configuration of the compound is fixed is subjected to column separation (column type: CHIRAL ART Cellulose-SC, elution solvent: a 40 / 60 / 0.1 mixed solvent of n-hexane / ethanol / trifluoroacetic acid).

4. The compound, its salt, or a solvate thereof according to any one of claims 1 to 3, wherein the substituent that may be present on the thienyl group includes an electron-withdrawing group.

5. The compound, its salt, or a solvate thereof according to any one of claims 1 to 4, wherein the substituent which the thienyl group may have includes an acetyl group, a sulfamoyl group, a cyano group, or a cycloalkanecarbonyl group.

6. R 2 is of the general formula (R2Aa) or (R2Ab): 【Chemistry 3】 [In the formula: R 3 represents an acetyl group, a sulfamoyl group, a cyano group, or a cycloalkanecarbonyl group; Y represents a hydrogen atom, an alkyl group, a halogen atom, or an alkoxy group. The compound according to any one of claims 1 to 5, a salt thereof, or a solvate thereof, wherein

7. R 3 The compound according to claim 6 , a salt thereof, or a solvate thereof, wherein is an acetyl group.

8. R 4 and the above R 5 and are the same or different and each is a hydrogen atom or an alkyl group, or a salt thereof, or a solvate thereof according to claim 6 or 7.

9. R 2 Is of the general formula (R2Aa): 【Chemistry 4】 [In the formula: R 3 represents an acetyl group; Y represents a hydrogen atom, an alkyl group, a halogen atom or an alkoxy group. and R 4 is a hydrogen atom, R 5 is an alkyl group, R 6 is an optionally substituted ethyl group, R 7 is a hydroxy group, The above A 1 , the above A 2 , and the A 4 are all CH, and the A 3 is CH or N, and The Z is a hydrogen atom. The compound according to any one of claims 1 to 8, a salt thereof, or a solvate thereof.

10. A medicine comprising at least one selected from the group consisting of the compound according to any one of claims 1 to 9, a salt thereof, and a solvate thereof.

11. The pharmaceutical according to claim 10, which is an Nrf2 (NF-E2-related factor 2) activator.

12. The pharmaceutical composition according to claim 10 or 11, which is a topical administration formulation.

13. The pharmaceutical composition according to any one of claims 10 to 12, which is an ophthalmic formulation.

14. The pharmaceutical composition according to claim 10 or 11, which is a parenteral administration formulation.

15. The pharmaceutical composition according to claim 10, 11, or 14, which is an intravenous formulation.

16. The pharmaceutical composition according to any one of claims 10 to 15, which is a pharmaceutical composition for preventing or treating a brain disease, a lung disease, a skin disease, an otorhinolaryngological disease, a kidney disease, or an ophthalmological disease.

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