Nrf2-activating compounds

Abstract

The present invention provides compounds having Nrf2 activating effects. A compound represented by the general formula (I), or a group of compounds in which a carbon atom represented by * in the formula of the general formula (II) is a chiral carbon atom, out of 2 groups of diastereomers, a salt thereof, and a solvate thereof.

Description

Technical Field

[0001] This invention relates to Nrf2-activated compounds, etc. 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 and degraded by the proteasome through its interaction with Keap1 (Kelch-like ECH-associated protein 1). Therefore, inhibiting the interaction between Nrf2 and Keap1 can promote the translocation of Nrf2 into the nucleus, thereby activating the expression of oxidative stress defense genes. For example, Nrf2 activators are anticipated as therapeutic agents for various diseases in the systemic field, such as multiple sclerosis, psoriasis, and diabetic nephropathy. In ophthalmology, Nrf2 activators are anticipated as therapeutic agents for various diseases, such as dry eye, diabetic retinopathy, retinitis pigmentosa, and glaucoma.

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

[0004] Existing technical documents

[0005] Patent documents

[0006] Patent Document 1: International Publication No. 2015 / 092713 Summary of the Invention

[0007] The technical problem that the invention aims to solve

[0008] The objective of this invention is to provide compounds that have Nrf2 activating activity.

[0009] Technical solutions for solving technical problems

[0010] The inventors of this invention conducted in-depth research on the aforementioned issues and discovered that the compounds represented by general formula (I) described below, or the two groups of diastereomers of general formula (II) described below with lower polarity, their salts, and their solvates possess Nrf2 activating properties. Based on this discovery, further research was conducted, and this invention was completed.

[0011] That is, the present invention includes the following solutions.

[0012] Item 1. Compounds represented by general formula (I), their salts, or their solvates:

[0013]

[0014] [In the formula: R] 1 Indicates an alkyl group. R 2 Indicates a thiophene group that can be substituted. R 4 and R 5 Same or different, indicating a hydrogen atom or a substituted alkyl group, or R 4 and R 5 They combine to form -NH-CH=N-. R 6 Indicates an alkyl group that can be substituted. R 7 Indicates hydroxyl group, hydrolyzable group, or -NR 71 R 72 (R 71 and R 72 Same or different, representing a hydrogen atom or a -[C(=O)]0-1- hydrocarbon group. A 1 A 2 A 3 and A 4 Same or different, indicating CH or N (where N is one or less). Z represents a hydrogen atom or a halogen atom.

[0015] Item 2. Compounds, salts, or solvates thereof of two diastereomers of general formula (II) in which the carbon atom represented by * is a chiral carbon atom, having lower polarity.

[0016]

[0017] [In the formula: R] 1a and R 1b Indicates an alkyl group. R 2 Indicates a thiophene group that can be substituted. R 4 and R 5 Same or different, indicating a hydrogen atom or a substituted alkyl group, or R 4 and R 5 They combine to form -NH-CH=N-. R 6 Indicates an alkyl group that can be substituted. R 7 Indicates hydroxyl group, hydrolyzable group, or -NR 71 R 72 (R 71 and R 72 Same or different, representing hydrogen atoms or -[C(=O)] 0-1 - Hydrocarbon group. ). A 1 A 2 A 3 and A 4Same or different, indicating CH or N (where N is one or less). Z represents a hydrogen atom or a halogen atom.

[0018] Item 3. The compound, its salt, or its solvate as described in Item 2, wherein the compound comprises a chiral carbon atom represented by * in the formula and the above R 6 The compound initially eluted during column separation of a mixture of two diastereomers with a fixed stereoconfiguration (column type: CHIRAL ART Cellulose-SC, elution solvent: a 40 / 60 / 0.1 mixture of n-hexane / ethanol / trifluoroacetic acid).

[0019] Item 4. The compound, its salt or solvate thereof as described in any one of items 1 to 3, wherein the substituents that may be present on the thiophene group include electron-withdrawing groups.

[0020] Item 5. The compound, its salt, or its solvates as described in any one of items 1 to 4, wherein the thiophene group may have substituents comprising acetyl, aminosulfonyl, cyano, or cycloalkane carbonyl.

[0021] Item 6. The compound, its salt, or its solvate as described in any one of items 1 to 5, wherein the above-mentioned R 2 It is a group represented by the general formula (R2Aa) or (R2Ab).

[0022] or

[0023] [In the formula: R] 3 [This indicates an acetyl group, aminosulfonyl group, cyano group, or cycloalkane carbonyl group. Y represents a hydrogen atom, alkyl group, halogen atom, or alkoxy group.]

[0024] Item 7. The compound, its salt, or its solvate as described in Item 6, wherein the above-mentioned R 3 It is an acetyl group.

[0025] Item 8. The compound, its salt, or its solvate as described in Item 6 or 7, wherein the above-mentioned R 4 And the above R 5 The same or different, consisting of hydrogen atoms or alkyl groups.

[0026] Item 9. The compound, its salt, or its solvate as described in any one of items 1 to 8, wherein the above-mentioned R 2 The general formula is (R2Aa):

[0027]

[0028] [In the formula: R] 3This indicates an acetyl group. Y represents a hydrogen atom, alkyl group, halogen atom, or alkoxy group.

[0029] The above R 4 It is a hydrogen atom.

[0030] The above R 5 It is an alkyl group.

[0031] The above R 6 For substituted ethyl groups,

[0032] The above R 7 It is a hydroxyl group.

[0033] The above A 1 The above A 2 And the above A 4 All are CH, and the above A 3 It is CH or N, and

[0034] Z represents a hydrogen atom.

[0035] Item 9a. Any of the following compounds, their salts, or their solvates:

[0036] (2R,3S)-3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxy-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] -2-yl]methyl}-4-methylphenyl)-2-methylpropionic acid (compound A1),

[0037] (2R,3S)-3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxy-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza] -2-yl]methyl}-4-methylphenyl)-2-methylpropionic acid (compound B1),

[0038] (2R,3S)-3-(5-acetyl-4-methoxythiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxy-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza] [2-yl]methyl}-4-methylphenyl)-2-methylpropionic acid (compound C1).

[0039] Item 9b. 3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza When 2-[2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropionic acid is separated by column (column type: CHIRAL ART Cellulose-SC, elution solvent: 40 / 60 / 0.1 mixed solvent of n-hexane / ethanol / trifluoroacetic acid), the initially eluted compound (compound D1), its salt or their solvates are separated.

[0040] Item 10. A pharmaceutical product containing at least one of the compounds selected from any one of items 1 to 9, 9a and 9b, their salts, and their solvates.

[0041] Item 11. The pharmaceutical product as described in Item 10, which is an Nrf2 (NF-E2-related factor 2) activator.

[0042] Item 12. The pharmaceutical product as described in Item 10 or 11 is a topical administration preparation.

[0043] Item 13. The pharmaceutical product as described in any one of items 10 to 12 is an ophthalmic preparation.

[0044] Item 14. The pharmaceutical product as described in Item 10 or 11 is a non-oral administration preparation.

[0045] Item 15. The pharmaceutical product as described in Items 10, 11, or 14 is an intravenously administered preparation.

[0046] Item 16. The pharmaceutical product as described in any one of Items 10 to 15, which is a pharmaceutical product for the prevention or treatment of brain diseases, lung diseases, skin diseases, ear, nose and throat diseases, kidney diseases or eye diseases.

[0047] Item 17. A method for the prevention or treatment of a disease involving Nrf2, comprising administering to a patient at least one of a compound selected from any one of items 1-9, 9a and 9b, its salt, and its solvates.

[0048] Item 17a. The prevention or treatment method as described in Item 17, wherein the patient is a patient suffering from a disease involving Nrf2.

[0049] Item 17b. The prevention or treatment method as described in Item 17 or Item 17a, wherein the aforementioned disease is a brain disease, lung disease, skin disease, ear, nose and throat disease, kidney disease or eye disease.

[0050] Item 18. A substance selected from any one of items 1 to 9, 9a and 9b, its salts and their solvates, for use as a pharmaceutical product.

[0051] Item 19. At least one substance selected from any one of items 1 to 9, 9a and 9b, its salts and their solvates, for use in the prevention or treatment of diseases involving Nrf2.

[0052] Item 19a. A substance for use as described in Item 19, wherein the aforementioned disease is a brain disease, lung disease, skin disease, ear, nose and throat disease, kidney disease or eye disease.

[0053] Item 20. Use of at least one of the compounds, salts and solvates thereof selected from any one of items 1 to 9, 9a and 9b in the manufacture of pharmaceuticals.

[0054] Item 20a. As described in Item 20, the above-mentioned pharmaceutical product is an Nrf2 (NF-E2-related factor 2) activator.

[0055] Item 20b. As described in Item 20 or Item 20a, the above-mentioned pharmaceutical products are for the prevention or treatment of brain diseases, lung diseases, skin diseases, ear, nose and throat diseases, kidney diseases or eye diseases.

[0056] The effects of the invention

[0057] According to the present invention, compounds having Nrf2 activating activity, their salts, and their solvates can be provided. Furthermore, according to the present invention, pharmaceuticals comprising at least one of these, and more specifically, Nrf2 activators, topical formulations, and pharmaceuticals for the prevention or treatment of brain diseases, lung diseases, skin diseases, otolaryngological diseases, kidney diseases, eye diseases, etc., can be provided. Attached Figure Description

[0058] Figure 1 The ORTEP diagram showing the crystal structure of compound A1.

[0059] Figure 2 This represents the most stable anti-trans conformation of the compounds of Example 1 and Reference Example 219.

[0060] Figure 3 This represents the most stable conformation of the syn (cis) form of the compounds of Example 1 and Reference Example 219. Detailed Implementation

[0061] In this specification, expressions for “containing” and “including” include the concepts of “containing”, “including”, “substantially constituted by” and “consistent only by”.

[0062] 1. Compound

[0063] In one aspect, the present invention relates to compounds of general formula (I), their salts, or their solvates.

[0064]

[0065] Additionally, in one aspect, the present invention relates to compounds, salts thereof, or solvates thereof that are less polar within two diastereomers of general formula (II) in which the carbon atom represented by * is a chiral carbon atom.

[0066]

[0067] They will be described below. Furthermore, in this specification, the above combined is sometimes referred to as "the compounds of the present invention".

[0068] <1-1.R 1 R 1a R 1b >

[0069] R 1 Indicates alkyl group.

[0070] R 1 The alkyl group shown includes any alkyl group that is straight-chain or branched (preferably straight-chain). The number of carbon atoms in the alkyl group is not particularly limited, for example, 1 to 4, preferably 1 to 3, more preferably 1 to 2, and even more preferably 1. Specific examples of this alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.

[0071] R 1a and R 1b Indicates alkyl group.

[0072] R 1a Or R 1b The alkyl group shown is related to R. 1 The alkyl groups shown have the same meaning. R 1a and R 1b Generally the same. In a particularly preferred embodiment of the invention, R 1a and R 1b All are methyl groups.

[0073] <1-2.R 2 >

[0074] R 2 This indicates a thiophene group that can be substituted.

[0075] Examples of thiophene groups include 2-thiophene and 3-thiophene, with 2-thiophene being the preferred example.

[0076] Substituents that can be present on the thiophene group include, for example, acyl groups such as acetyl and cycloalkane carbonyl groups, aminosulfonyl groups, cyano groups, and -R groups. 21 -NR 22 R 23 (R 21 Indicates a single bond, carbonyl group, or alkylene group. R 22 and R 23 Same or different, consisting of hydrogen atoms, substituted alkyl groups, or R. 22 and R 23 These substituents combine to form alkylene groups, which together with adjacent nitrogen atoms form a ring. Other substituents include alkoxy groups, halogen atoms, and alkyl groups. The positions of these substituents are not particularly limited; for example, they can be at any position of the ring-forming atoms (carbon and sulfur atoms) on the thiophene ring, preferably the carbon atom on the thiophene ring. The number of these substituents is not particularly limited; for example, 0 to 4, preferably 0 to 2, and more preferably 1 to 2.

[0077] The acyl group that can be a substituent for the thiophene group is any group that is formed by removing the hydroxyl group from a carboxylic acid; there are no particular restrictions, but -CO-R is preferred. 24 (R 24 The group indicated is alkyl or cycloalkyl (preferably alkyl). R 24 The alkyl group shown includes any alkyl group that is straight-chain or branched (preferably straight-chain). The number of carbon atoms in the alkyl group is not particularly limited, 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 this alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, 3-methylpentyl, etc. 24 The number of carbon atoms in the cycloalkyl group is not particularly limited, for example, 3 to 8, preferably 3 to 6, more preferably 3 to 4, and even more preferably 3. Acyl groups, such as acetyl and cycloalkane carbonyl groups, are preferred as the substituents mentioned above, and acetyl groups are particularly preferred from the viewpoint of Nrf2 activation.

[0078] -R constitutes the substituents that thiophene groups can have. 21 -NR 22 R 23 R 21 Indicates a single bond, carbonyl group, or alkylene group (preferably carbonyl group). R 21 The alkylene group shown includes any alkylene group that is linear or branched (preferably linear). The number of carbon atoms in the alkylene group is not particularly limited, 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 this alkylene group include methylene, ethylene, propylene, butylene, etc. The -R group, which constitutes the above-mentioned substituent,... 21-NR 22 R 23 R 22 and R 23 Same or different, consisting of hydrogen atoms, substituted alkyl groups, or R. 22 and R 23 They combine to form alkylene groups and together with adjacent nitrogen atoms to form a ring (preferably R). 22 and R 23 Whether the atoms are the same or different, they are hydrogen atoms or alkyl groups, more preferably R. 22 and R 23 One of them is a hydrogen atom and the other is an alkyl group, more preferably R. 22 and R 23 Both sides are hydrogen atoms. ) R 22 Or R 23 The alkyl group shown includes any alkyl group that is straight-chain or branched (preferably straight-chain). The number of carbon atoms in the alkyl group is not particularly limited, 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 this alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, 3-methylpentyl, etc. Substituents that may be present in this alkyl group include, for example, alkoxy groups. The alkoxy group includes any alkoxy group that is straight-chain or branched (preferably straight-chain). The number of carbon atoms in the alkoxy group is not particularly limited, 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 this alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0079] The alkoxy group that can be a substituent of the thiophene group includes any alkoxy group that is straight-chain or branched (preferably straight-chain). The number of carbon atoms in this 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 this alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0080] Halogen atoms that can be substituents of the thiophene group include, for example, fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc., preferably fluorine atoms, chlorine atoms, etc., and more preferably fluorine atoms.

[0081] The alkyl groups that can be substituents of the thiophene group include any alkyl group that is straight-chain or branched (preferably straight-chain). 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 even more preferably 1. Specific examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.

[0082] In a preferred embodiment of the invention, the thiophene group preferably has substituents comprising electron-withdrawing groups (i.e., when there is one substituent, the substituent is an electron-withdrawing group; when there are two or more substituents, at least one substituent is an electron-withdrawing group). More preferably, the thiophene group may have substituents comprising acyl, aminosulfonyl, or cyano (further preferably acetyl, aminosulfonyl, cyano, or cycloalkanecarbonyl, and particularly preferably acetyl from the viewpoint of Nrf2 activation) (i.e., when there is one substituent, the substituent is any of these groups; when there are two or more substituents, at least one substituent is any of these groups). In these embodiments, it is preferred that the number of substituents from the heterocyclic group is 0 to 2 (preferably 1 to 2), and when the number of substituents is 2 or more, at least one of the substituents is an alkyl, halogen atom, or alkoxy (preferably alkoxy).

[0083] In a preferred embodiment of the invention, as R 2 Preferably, groups represented by the general formula (R2A) are listed.

[0084]

[0085] [In the formula: Y represents a hydrogen atom, alkyl group, halogen atom, or alkoxy group. R] 3 Represents acyl group, hydrogen atom, aminosulfonyl group, cyano group, or -R. 21 -NR 22 R 23 Further preferred examples include groups represented by the general formula (R2Aa) or (R2Ab).

[0086] or

[0087] [In the formula: Y and R] 3 Same meaning as above.

[0088] Regarding R 3 The substituents shown in Y, and the above "R" 2 The thiophene group shown can have the same substituents.

[0089] As R 3 Preferably, acyl groups (preferably -CO-R) are listed.24 (R 24 The group can be alkyl or cycloalkyl), aminosulfonyl, cyano, etc., and more preferably acetyl, aminosulfonyl, cyano, cycloalkane carbonyl, etc. In particular, from the viewpoint of Nrf2 activation, acetyl is especially preferred.

[0090] <1-3.R 4 R 5 >

[0091] R 4 and R 5 Same or different, indicating a hydrogen atom or a substituted alkyl group, or R 4 and R 5 They combine to form -NH-CH=N-.

[0092] R 4 Or R 5 The alkyl group shown includes any alkyl group that is straight-chain or branched (preferably straight-chain). The number of carbon atoms in the alkyl group is not particularly limited, for example, 1 to 4, preferably 1 to 3, more preferably 1 to 2, and even more preferably 1. Specific examples of this alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.

[0093] As R 4 Or R 5 The alkyl group shown may have substituents, such as halogen atoms. Examples of halogens include fluorine, chlorine, bromine, and iodine atoms. The number of substituents is not particularly limited, and is for example 0 to 3, preferably 0.

[0094] “R 4 and R 5 They combine to form the following partial structures in the general formula (I): -NH-CH=N-

[0095]

[0096] The following structure is adopted:

[0097]

[0098] In a preferred embodiment of the invention, R is preferred. 4 and R 5 Whether the atoms are the same or different, they are hydrogen atoms or alkyl groups, more preferably R. 4 and R 5 One of them is an alkyl group and the other is a hydrogen atom, further preferably R 4 It is a hydrogen atom and R 5 It is an alkyl group.

[0099] <1-4.R6 >

[0100] R 6 This indicates an alkyl group that can be substituted.

[0101] R 6 The alkyl group shown includes any alkyl group that is straight-chain or branched (preferably straight-chain). The number of carbon atoms in the alkyl group is not particularly limited, 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 this alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, 3-methylpentyl, etc.

[0102] As R 6 The alkyl group shown may have substituents, such as hydroxyl, alkoxy, arylalkoxy, aryloxy, -NR. 61 R 62 (R 61 and R 62 The same or different can refer to hydrogen atoms or alkyl groups. The position of the substituents is not particularly limited, but in one embodiment of the invention, the terminal of the alkyl group is preferred. The number of substituents is not particularly limited, for example, 0 to 3, preferably 0 to 1.

[0103] The alkoxy group used as the above-mentioned substituent includes any alkoxy group that is linear or branched (preferably linear). The number of carbon atoms in this alkoxy group is not particularly limited, 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 this alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0104] The arylalkoxy group used as the substituent is any alkoxy group formed by replacing an aryl group, and there is no particular limitation. The number of carbon atoms in the aryl group is not particularly limited, for example, 6 to 14, preferably 6 to 8. Specifically, examples of such aryl groups include phenyl, naphthyl, biphenyl, cyclopentadienyl, indene, anthracene, tetraphenyl, pentaphenyl, pyrene, peryl, fluorenyl, phenanthrene, etc., with phenyl being particularly preferred. The substitution position of the aryl group in the alkoxy group is not particularly limited; in one embodiment of the invention, the terminal position of the alkoxy group is preferred. Examples of arylalkoxy groups include benzyloxy and phenethoxy.

[0105] The number of carbon atoms in the aryloxy group that is a substituent is not particularly limited, and is, for example, 6 to 14, preferably 6 to 8. Specifically, examples of the aryl group constituting the aryloxy group include phenyl, naphthyl, biphenyl, cyclopentadienyl, indene, anthracene, tetraphenyl, pentaphenyl, pyrene, peryl, fluorenyl, phenanthrene, etc., with phenyl being particularly preferred. Examples of the aryloxy group include phenoxy.

[0106] -NR constitutes the above-mentioned substituent 61 R 62 R 61 and R 62 Same or different, indicating hydrogen atoms or alkyl groups. R 61 Or R 62 The alkyl group shown includes any alkyl group that is straight-chain or branched (preferably straight-chain). The number of carbon atoms in the alkyl group is not particularly limited, 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 this alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, 3-methylpentyl, etc.

[0107] In a preferred embodiment of the invention, R is preferred. 6 It is an alkyl group that can be substituted with hydroxyl, alkoxy, or arylalkoxy, more preferably an alkyl group that can be substituted with arylalkoxy, and even more preferably an alkyl group.

[0108] R 6 There are no particular restrictions on the three-dimensional configuration; it can be a three-dimensional configuration p:

[0109]

[0110] Or a three-dimensional configuration q:

[0111]

[0112] Any three-dimensional configuration. In a preferred embodiment of the invention, R 6 The three-dimensional configuration is the three-dimensional configuration p.

[0113] <1-5.R 7 >

[0114] R 7 Indicates hydroxyl group, hydrolyzable group, -NR 71 R 72 (R 71 and R 72 Same or different, representing hydrogen atoms or -[C(=O)] 0-1 - Hydrocarbon group.

[0115] Hydrolyzable groups are only those with R 7 Any group that produces a hydroxyl group by hydrolysis of the ester bond formed together with adjacent carbonyl groups (preferably under physiological conditions or by enzymes such as esterases) is acceptable; there are no particular restrictions. The hydrolyzable group is one that is associated with R... 7 Adjacent carbonyl groups together form ester bonds (-O-R) x (R x (The substituent can be any number of substituents). Specific examples include alkoxy, aryloxy (aryl-O-), arylalkoxy (alkoxy formed by substituted aryl), alkylaryloxy (aryloxy formed by substituted alkyl), aralkyloxy (alkoxy formed by substituted aryl), alkoxyalkoxy (alkoxy formed by substituted alkoxy), acyloxy, acyloxyalkoxy (alkoxy formed by substituted acyloxy), etc.

[0116] "-[C(=O)]" 0-1 The "-hydro group" is "-hydro group" in the case of [C(=O)]0 and "-C(=O)-hydro group" in the case of [C(=O)]1.

[0117] As R 71 and R 72 The definition of "hydrocarbon group" is not particularly limited, and typical examples include alkyl, aryl, etc.

[0118] R 7 Hydroxyl groups are preferred.

[0119] <1-6.A 1 A 2 A 3 A 4 >

[0120] A 1 A 2 A 3 and A 4 Same or different, indicated by CH or N (where N is one or less).

[0121] In A 1 A 2 A 3 and A 4 When any one of them is N, A is preferred. 1 Or A 3 For N, A is preferred. 3 Let N be the number of elements in the array.

[0122] In a preferred embodiment of the invention, A is preferred. 1 A 2 and A 4 All are CH and A 3 It can be CH or N.

[0123] <1-7.Z>

[0124] Z represents a hydrogen atom or a halogen atom.

[0125] The halogen atom represented by Z can be, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., preferably a fluorine atom, a chlorine atom, etc., and more preferably a fluorine atom.

[0126] When Z is a halogen atom, its bonding position can be A. 1 A 2 A 3 and A 4 Any position, for example, A 4 .

[0127] In a preferred embodiment of the invention, Z is preferably a hydrogen atom.

[0128] <1-8. Polarity>

[0129] Compounds of general formula (II) are compounds with lower polarity among the two diastereomers of general formula (II) in which the carbon atom represented by * is a chiral carbon atom.

[0130] The two diastereomers of R, where the carbon atom represented by * is a chiral carbon atom, are... 2 The three-dimensional configuration is three-dimensional configuration a:

[0131] The diastereomers (diastereomer a) and R 2 The three-dimensional configuration is three-dimensional configuration b:

[0132] Two diastereomers of the diastereomer (diastereomer b).

[0133] Furthermore, diastereomers a and b respectively include diastereomers p(R) with other carbon atoms in general formula (II) as chiral carbon atoms. 6 The stereo configuration is the above stereo configuration p) and the diastereomer q (R) 6 The three-dimensional configuration is the aforementioned three-dimensional configuration q). Wherein, R... 2 The three-dimensional configuration is three-dimensional configuration a and R 6 The diastereomer with stereoconfiguration p is labeled as diastereomer ap, and the others are labeled similarly. Therefore, diastereomer a includes diastereomer ap and diastereomer aq, and diastereomer b includes diastereomer bp and diastereomer bq. "Compounds with lower polarity among two diastereomers" refers to R... 6 When the three-dimensional configuration is fixed (i.e., R is fixed),6 When the stereoconfiguration is fixed as stereoconfiguration p or stereoconfiguration q, the compounds with lower polarity within the two diastereomers are specifically defined as compounds with lower polarity within the diastereomers ap and bp, and compounds with lower polarity within the diastereomers aq and bq.

[0134] In a preferred embodiment of the invention, particularly from the viewpoint of lower cytotoxicity of the compound, the compound of general formula (II) is preferably a compound containing the above-mentioned R, in which the carbon atom represented by * in general formula (II) is a chiral carbon atom. 6 This study describes column separation of a mixture of two diastereomers (two diastereomers of ap and bp, or two diastereomers of aq and bq) with a fixed stereoconfiguration. The column separation is performed using a CHIRAL ARTCellulose-SC column and an elution solvent of 40 / 60 / 0.1 g of hexane, ethanol, and trifluoroacetic acid. The first compound eluted (either diastereomer ap or bp, or diastereomer aq or bq) is identified. Specifically, the column separation is performed under the following conditions: flow rate: 2.35 mL / min; temperature: ambient; detection wavelength: UV at 293 nm; injection volume: 18 mg (13 mg / mL); system: Prominence (Shimadzu).

[0135] <1-9. General Formula>

[0136] In one aspect of the invention, in general formula (I), general formula (IA) is also preferably listed:

[0137]

[0138] [In the formula: R] 1 R 3 R 4 R 5 R 6 R 7 A 1 A 2 A 3 A 4 The meanings of Y and Z are the same as described above. More preferably, the general formula (IAA) is listed:

[0139]

[0140] [In the formula: R] 1 R 3 R 4 R 5 R 6R 7 A 3 The meanings of Y and Z are the same as described above. Further preferred examples include the general formula (IAAA):

[0141]

[0142] [In the formula: R] 1 R 3 R 4 R 5 R 6 R 7 A 3 The meanings of Y and Y are the same as described above. Furthermore, a more preferred example is the general formula (IAAAA):

[0143]

[0144] [In the formula: R] 1 R 3 R 4 R 5 R 6 R 7 A 3 The meanings of Y and Y are the same as described above.

[0145] In one aspect of the invention, general formula (IIA) is also preferably listed in general formula (II):

[0146]

[0147] [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 The meanings of Y and Z are the same as described above. More preferably, the general formula (IIAA) is listed:

[0148]

[0149] [In the formula: R] 1a R 1b R 3 R 4 R 5 R 6 R 7 A 3 The meanings of Y and Z are the same as described above. Further preferred examples include the general formula (IIAAA):

[0150]

[0151] [In the formula: R] 1a R 1b R 3 R 4 R 5 R 6 R 7 and A 3 The meaning is the same as above. Furthermore, a more preferred example is the general formula (IIAAAA):

[0152]

[0153] [In the formula: R] 1a R 1b R 3 R 4 R 5 R 6 and R 7 The meaning is the same as above.

[0154] In a preferred embodiment of the present invention, the above-described R is preferred. 2 The general formula is (R2Aa):

[0155]

[0156] [In the formula: R] 3 This indicates an acetyl group. Y represents a hydrogen atom, alkyl group, halogen atom, or alkoxy group.

[0157] The above R 4 It is a hydrogen atom.

[0158] The above R 5 It is an alkyl group.

[0159] The above R 6 For substituted ethyl groups,

[0160] The above R 7 It is a hydroxyl group.

[0161] The above A 1 The above A 2 And the above A 4 All are CH, and the above A 3 It is CH or N, and

[0162] Z represents a hydrogen atom.

[0163] <1-10. Others>

[0164] The salt of the compound can be any pharmaceutically acceptable salt, without particular restrictions. Any type of acidic or basic salt can be used. Examples of acidic 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 p-toluenesulfonate; examples of basic salts include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; salts with ammonia; and salts with organic amines such as morpholine, piperidine, pyrrolidine, monoalkylamines, dialkylamines, trialkylamines, mono(hydroxyalkyl)amines, di(hydroxyalkyl)amines, and tri(hydroxyalkyl)amines.

[0165] There are no particular limitations on the solvates of compounds. Examples of solvents that constitute solvates include water and pharmaceutically acceptable organic solvents (such as ethanol, glycerol, acetic acid, etc.).

[0166] 2. Manufacturing method

[0167] The compounds of the present invention can be manufactured by various methods.

[0168] The compounds of the present invention can be manufactured, for example, by the method shown in Scheme 1 or a method based thereon.

[0169] Scheme 1

[0170]

[0171] In step a, synthetic intermediate 2 is reacted with synthetic intermediate 3 in the presence of a catalyst and a base to produce synthetic intermediate 4. Relative to synthetic intermediate 2, synthetic intermediate 3 can be used in amounts of, for example, 1 to 5 equivalents, preferably 1.2 to 3 equivalents; a catalyst can be used in amounts of, for example, 0.05 to 0.5 equivalents, preferably 0.05 to 0.2 equivalents; and a base can be used in amounts of, for example, 1.5 to 5 equivalents, preferably 1.5 to 3 equivalents. Examples of catalysts include rhodium coordination compounds, preferably [RhCl(cod)]2. Examples of bases include, for example, N,N-dicyclohexylmethylamine, triethylamine, pyridine, N,N-diisopropylethylamine, etc., with triethylamine being 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; examples include, for example, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, etc., with 1,4-dioxane being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 hour to 24 hours, preferably from 1 hour to 18 hours. The reaction temperature also varies depending on the reagent or solvent used, typically ranging from 0°C to 150°C, preferably from 25°C to 100°C.

[0172] In step b, synthetic intermediate 4 is reacted with iodomethane in the presence of a base to produce synthetic intermediate 5. Relative to synthetic intermediate 4, 1 to 2 equivalents of diisopropylaminolithium, preferably 1 to 1.8 equivalents, can be used, and 1 to 20 equivalents of iodomethane, preferably 1 to 15 equivalents, can be used, for example. 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; examples include tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 1 hour to 5 hours. The reaction temperature varies depending on the reagent or solvent used, typically from -78°C to 40°C, preferably from -78°C to 25°C.

[0173] In step c, the deprotection reaction of the acetal of synthesis intermediate 5 is carried out. An excess of hydrochloric acid is used relative to synthesis intermediate 5. The solvent is not particularly limited as long as it does not adversely affect the reaction; examples include methanol, dichloromethane, tetrahydrofuran, and 1,4-dioxane, with methanol or tetrahydrofuran being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 hour to 24 hours, preferably from 1 hour to 18 hours. The reaction temperature varies depending on the reagent or solvent used, typically ranging from 25°C to 150°C, preferably from 25°C to 100°C.

[0174] In step d, the compound of the present invention is prepared by hydrolysis of synthetic intermediate 4 or its ester. A base can be used in amounts of, for example, 5 to 20 equivalents, preferably 10 to 20 equivalents, relative to synthetic intermediate 4. Examples of bases include lithium hydroxide, sodium hydroxide, and potassium hydroxide, with sodium hydroxide or lithium hydroxide being preferred. The reaction is typically carried out in a solvent. No particular solvent is specified as long as it does not adversely affect the reaction; examples include methanol, dichloromethane, and tetrahydrofuran, with methanol or tetrahydrofuran being preferred. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 1 hour to 18 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 25°C to 150°C, preferably from 25°C to 140°C.

[0175] The compounds of the present invention can also be manufactured, for example, according to the method shown in or based on Scheme 2 below.

[0176] Scheme2

[0177]

[0178] Step d in Scheme 2 shall be performed in accordance with Scheme 1.

[0179] In step e, synthetic intermediate 8 is prepared from synthetic intermediate 6 and synthetic intermediate 7. Synthetic intermediate 7 can be used in amounts of, for example, 1 to 1.5 equivalents, preferably 1 to 1.2 equivalents, relative to synthetic intermediate 6, and n-butyllithium can be used in amounts 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; examples include tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 10 hours, preferably from 1 hour to 4 hours. The reaction temperature varies depending on the reagent or solvent used, typically from -80°C to 25°C, preferably from -78°C to 25°C.

[0180] In step f, synthetic intermediate 9 is prepared from synthetic intermediate 8. Relative to synthetic intermediate 8, trichloroacetonitrile can be used in amounts of, for example, 1 to 3 equivalents, preferably 1 to 2 equivalents; 1,8-diazabicyclo[5,4,0]-7-undecene can be used in amounts of, for example, 0.01 to 0.1 equivalents, preferably 0.01 to 0.05 equivalents; dimethyl ketene methyltrimethylsilyl acetal can be used in amounts of, for example, 1 to 3 equivalents, preferably 1 to 2.5 equivalents; and bis(trifluoromethanesulfonyl)imide can be used in amounts 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; examples include dichloromethane, tetrahydrofuran, and acetonitrile, with acetonitrile being a preferred example. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 hour to 10 hours, preferably from 1 hour to 5 hours. The reaction temperature varies depending on the reagents or solvents used, and is usually 0℃ to 25℃, preferably 10℃ to 25℃.

[0181] In step g, synthetic intermediate 10 is prepared from synthetic intermediate 9. 2,3-Dichloro-5,6-dicyano-p-benzoquinone can be used, for example, in amounts of 1 to 3 equivalents, preferably 1 to 2.5 equivalents, relative to synthetic intermediate 9. The reaction is usually carried out in a solvent. No particular limitation is made as long as it does not adversely affect the reaction; a mixture of dichloromethane and water is an example. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 5 hours, preferably from 1 hour to 3 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 0°C to 25°C, preferably from 10°C to 25°C.

[0182] In step h, synthetic intermediate 12 is prepared from synthetic intermediate 10 and synthetic intermediate 11. Relative to synthetic intermediate 10, synthetic intermediate 11 can be used in amounts of, for example, 1 to 2 equivalents, preferably 1 to 1.2 equivalents; triphenylphosphine can be used in amounts of, for example, 1 to 2 equivalents, preferably 1 to 1.2 equivalents; and diethyl azodicarbonate can be used in amounts of, for example, 1 to 1.5 equivalents, preferably 1 to 1.2 equivalents. Instead of diethyl azodicarbonate, bis(2-methoxyethyl) azodicarbonate, diisopropyl azodicarbonate, cyanomethylenetributylphosphonane, 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; examples include dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, N,N-dimethylformamide, etc., with tetrahydrofuran being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 hour to 24 hours, preferably 5 to 8 hours. The reaction temperature varies depending on the reagents or solvents used, and is usually 0℃ to 40℃, preferably 0℃ to 25℃.

[0183] Synthetic intermediates 2, 6 and 11 of Schemes 1 to 2 can be manufactured according to known methods, such as those described in Patent Document 1 (WO2015 / 092713) and WO2016 / 202253, or methods based thereon, such as Scheme 3 below.

[0184] Scheme3

[0185]

[0186] The procedure h in Scheme 3 shall be performed in accordance with Scheme 2.

[0187] In step i, synthetic intermediate 14 is produced by the amination reaction of synthetic intermediate 13. Excess ammonia is used relative to synthetic intermediate 13. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 1 hour to 18 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 25°C to 150°C, preferably from 25°C to 40°C.

[0188] In step j, synthetic intermediate 14 is reacted with synthetic intermediate 15, and then synthetic intermediate 16 is used to produce synthetic intermediate 11.

[0189] In the first step, synthetic intermediate 14 and synthetic intermediate 15 are reacted in the presence of a base. The base used relative to synthetic intermediate 14 can be, for example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents, and the base used can be, for example, 0.8 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents. Examples of bases include potassium carbonate and sodium carbonate, with potassium carbonate being 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; examples include mixtures of organic solvents such as tetrahydrofuran or dimethylformamide with water, with a mixture of tetrahydrofuran and water being preferred. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 1 hour to 3 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 25°C to 150°C, preferably from 25°C to 40°C.

[0190] In the second step, synthetic intermediate 11 is produced from synthetic intermediate 16 in the presence of a base. The base used relative to synthetic intermediate 16 can be, for example, 1 to 5 equivalents, preferably 2 to 3 equivalents. Examples of bases include potassium tert-butoxide, potassium carbonate, and potassium hydroxide, with potassium tert-butoxide being preferred. The reaction is usually carried out in a solvent. No particular solvent is specified as long as it does not adversely affect the reaction; examples include dimethyl sulfoxide and dimethylformamide, with dimethyl sulfoxide being preferred. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 1 hour to 3 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 25°C to 150°C, preferably from 60°C to 100°C.

[0191] In step k, synthetic intermediate 18 is produced by reducing synthetic intermediate 17. A reducing agent, for example, can be used in amounts of 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to synthetic intermediate 17. Examples of reducing agents include borane-tetrahydrofuran coordination compounds and borane-dimethyl sulfide coordination compounds. The reaction is usually carried out in a solvent. No particular limitation is made to the solvent, as long as it does not adversely affect the reaction; tetrahydrofuran is an example. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 40 hours, preferably from 1 hour to 24 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 25°C to 150°C, preferably from 25°C to 40°C.

[0192] In step 1, synthetic intermediate 19 is reacted with dipinane diboron in the presence of a base and a catalyst to produce synthetic intermediate 2. The base used can be, for example, 1 to 3 equivalents, preferably 1 to 2.5 equivalents, the catalyst can be, for example, 0.05 to 0.1 equivalents, preferably 0.05 to 0.08 equivalents, and the dipinane diboron can be, for example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents. Potassium acetate, for example, can be used as the base. Palladium catalysts such as PdCl2(dppf)2-CH2Cl2 and Pd2(dba)3 can be used, with PdCl2(dppf)2-CH2Cl2 being 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; examples include 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, and N,N-dimethylformamide, with 1,4-dioxane being preferred. The reaction time varies depending on the reagents or solvents used, typically ranging from 1 to 24 hours, preferably from 5 to 8 hours. The reaction temperature also varies depending on the reagents or solvents used, typically ranging from 60°C to 120°C, preferably from 60°C to 100°C.

[0193] In step m, synthetic intermediate 20 is prepared from synthetic intermediate 18. Sodium hydride can be used in amounts of, for example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to synthetic intermediate 20, and p-methoxybenzyl chloride can be used in amounts 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; examples include tetrahydrofuran and N,N-dimethylformamide, with N,N-dimethylformamide being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 hour to 24 hours, preferably 5 to 15 hours. The reaction temperature varies depending on the reagent or solvent used, typically ranging from 0°C to 60°C, preferably 0°C to 25°C.

[0194] In step n, synthetic intermediate 6 is prepared from synthetic intermediate 20. Relative to synthetic intermediate 20, 1 to 1.5 equivalents of n-butyllithium, preferably 1 to 1.2 equivalents, can be used, for example, and 1 to 2 equivalents of N,N-dimethylformamide, preferably 1 to 1.5 equivalents, 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; examples include tetrahydrofuran. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 10 hours, preferably from 1 hour to 3 hours. The reaction temperature varies depending on the reagent or solvent used, typically from -80°C to 25°C, preferably from -78°C to 25°C.

[0195] Synthetic intermediate 3 can be obtained by, for example, the methods shown in Schemes 4 to 7 below, or methods based thereon.

[0196] Scheme4

[0197]

[0198] In step o, synthetic intermediate 21 is reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of a base, a condensing agent, and an additive to produce synthetic intermediate 22. Relative to synthetic intermediate 21, 1 to 3 equivalents, preferably 1.5 to 2 equivalents, of N,O-dimethylhydroxylamine hydrochloride can typically be used. Furthermore, relative to synthetic intermediate 21, 1 to 3 equivalents, preferably 1 to 2 equivalents, of a condensing agent can typically be used; 0.1 to 2 equivalents, preferably 1 to 2 equivalents, of an additive can typically be used; and 0.5 to 5 equivalents, preferably 2 to 4 equivalents, of a base can typically be used. Examples of condensing agents include N,N'-dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride, benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, diethyl cyanophosphate, diphenyl azidophosphate, pentafluorophenyl trifluoroacetate, and isopropyl chloroformate. Preferably, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate is also mentioned. Examples of additives include 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and N-hydroxysuccinimide, with 1-hydroxybenzotriazole being a preferred choice. Examples of bases include triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine, with triethylamine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine being preferred. The reaction is usually carried out in a solvent. No particular solvent is specified as long as it does not adversely affect the reaction; examples include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, acetonitrile, and N,N-dimethylformamide, with dichloromethane or N,N-dimethylformamide being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 hour to 24 hours, preferably from 3 hours to 24 hours. The reaction temperature varies depending on the reagents or solvents used, and is usually 0℃ to 100℃, preferably 25℃ to 40℃.

[0199] In step p, synthetic intermediate 23 or synthetic intermediate 25 is produced from synthetic intermediate 22 or synthetic intermediate 24 via a bromination reaction. Relative to synthetic intermediate 22 or synthetic intermediate 24, 1 to 5 equivalents of N-bromosuccinimide, preferably 2 to 3 equivalents, are typically used, and 1 to 3 equivalents of trifluoroacetic acid, preferably 1 to 2 equivalents, are typically used. 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; examples include dichloromethane, chloroform, carbon tetrachloride, 1,2-dimethoxyethane, N,N-dimethylformamide, etc., with N,N-dimethylformamide being preferred. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 0°C to 100°C, preferably from 25°C to 40°C.

[0200] In step q, synthetic intermediate 25 is prepared from synthetic intermediate 23. Methylmagnesium bromide can be used in amounts of, for example, 1 to 3 equivalents, preferably 1 to 1.5 equivalents, 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; examples include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, etc., with tetrahydrofuran being preferred. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 0°C to 100°C, preferably from 0°C to 40°C.

[0201] In step r, synthetic intermediate 25 is reacted with ethylene glycol in the presence of an acid catalyst to produce synthetic intermediate 26. The acid catalyst can be used in amounts of, for example, 0.1 to 5 equivalents, preferably 0.1 to 0.5 equivalents, relative to synthetic intermediate 25, and the ethylene glycol can be used in amounts of, for example, 5 to 20 equivalents, preferably 10 to 15 equivalents. Examples of acid catalysts include p-toluenesulfonic acid monohydrate, hydrochloric acid, and trifluoroacetic acid, with p-toluenesulfonic acid monohydrate being 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; examples include toluene and benzene, with toluene being preferred. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 40°C to 150°C, preferably from 100°C to 130°C.

[0202] 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. Relative to synthetic intermediate 25 or synthetic intermediate 26, the catalyst can be used in amounts of, for example, 0.05 to 0.2 equivalents, preferably 0.05 to 0.1 equivalents; the base can be used in amounts of, for example, 1.5 to 5 equivalents, preferably 1.5 to 3 equivalents; the additive can be used in amounts of, for example, 0.05 to 0.2 equivalents, preferably 0.05 to 0.1 equivalents; and the methyl acrylate can be used in amounts of, for example, 1.5 to 3 equivalents, preferably 1.5 to 2 equivalents. Examples of catalysts include palladium catalysts such as PdCl2(dppf)2-CHCl3, Pd(OAc)2, PdCl2(PPh3)2, and Pd(PPh3)4, with PdCl2(dppf)2-CHCl3 being a preferred example. Examples of bases include N,N-dicyclohexylmethylamine, triethylamine, pyridine, and N,N-diisopropylethylamine, with N,N-dicyclohexylmethylamine being the most preferred. Examples of additives include tetrabutylammonium chloride and tetrabutylammonium iodide, with tetrabutylammonium chloride being the most preferred. The reaction is usually carried out in a solvent. No particular solvent is specified as long as it does not adversely affect the reaction; examples include dimethylformamide and dimethylacetamide, with dimethylacetamide being the most preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 hour to 24 hours, preferably from 1 hour to 8 hours. The reaction temperature varies depending on the reagent or solvent used, typically using microwaves, and is between 40°C and 150°C, preferably between 100°C and 140°C.

[0203] Scheme 5

[0204]

[0205] Scheme 5 follows steps o and s of Scheme 4, except that in step o, N,O-dimethylhydroxylamine hydrochloride is replaced with the corresponding amine.

[0206] Scheme 6

[0207]

[0208] The procedures in Scheme 6 shall be performed in accordance with Scheme 4.

[0209] In step t, synthetic intermediate 29 is prepared from synthetic intermediate 28. Methylmagnesium bromide can be used in amounts of, for example, 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to synthetic intermediate 28. 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; examples include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, etc., with tetrahydrofuran being preferred. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 0°C to 100°C, preferably from 0°C to 40°C.

[0210] In step u, an oxidation reaction of the synthetic intermediate 29, which is a sulfur trioxide-pyridine coordination compound, is carried out in the presence of a base to produce synthetic intermediate 30. The base used can be, for example, 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to synthetic intermediate 29, and the sulfur trioxide-pyridine coordination compound can be, for example, 1 to 3 equivalents, preferably 1 to 2.5 equivalents. Examples of bases include triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine, with triethylamine being 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; dimethyl sulfoxide is preferred. The reaction time varies depending on the reagent or solvent used, typically from 1 hour to 24 hours, preferably from 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, typically from 0°C to 100°C, preferably from 0°C to 40°C.

[0211] In addition, synthetic intermediate 3 can be manufactured according to known methods, such as those described in JP2008 / 273924, or methods based thereon, such as Scheme 7 below.

[0212] Scheme7

[0213]

[0214] Procedures p and s in Scheme 7 shall be performed in accordance with Scheme 4.

[0215] In step v, synthetic intermediate 31 is reacted with tert-butylamine and acetic acid to produce synthetic intermediate 32. The amount of tert-butylamine used relative to synthetic intermediate 31 can be, for example, 1 to 3 equivalents, preferably 1 to 1.5 equivalents, and the amount of acetic acid used can be, 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; examples include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, toluene, etc., with dichloromethane being preferred. The reaction time varies depending on the reagent or solvent used, and is typically 1 to 5 hours, preferably 2 to 4 hours. The reaction temperature varies depending on the reagent or solvent used, and is typically 0°C to 40°C, preferably 10 to 30°C.

[0216] In step w, synthetic intermediate 34 is prepared by deprotection reaction of tert-butylamine in the synthesis of intermediate 33. For synthetic intermediate 33, a mixed solvent of trifluoroacetic acid and water is 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 reagent or solvent used, typically 1–5 hours, preferably 2–4 hours. The reaction temperature varies depending on the reagent or solvent used, typically 0°C–150°C, preferably 90°C–110°C.

[0217] Alternatively, the compounds of the present invention can also be manufactured in Scheme 2 using synthetic intermediate 38 instead of synthetic intermediate 10. Synthetic intermediate 38 can also be manufactured, for example, according to the method shown in or based on Scheme 8 below.

[0218] Scheme8

[0219]

[0220] Each step in Scheme 8 shall be performed in accordance with Schemes 1 to 3.

[0221] Alternatively, the compounds of the present invention can also be manufactured in Scheme 1 using synthetic intermediate 47 instead of synthetic intermediate 2. Synthetic intermediate 47 can also be manufactured, for example, according to the method shown in or based on Scheme 9 below.

[0222] Scheme9

[0223]

[0224] The procedure in Scheme 9 shall be performed in accordance with Scheme 3.

[0225] In step x, synthetic intermediate 40 is prepared from synthetic intermediate 39. Bromine can be used in an amount of, for example, 1 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to 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; examples include acetic acid and trifluoroacetic acid, with acetic acid being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 0.5 to 3 hours, preferably 1 to 2 hours. The reaction temperature varies depending on the reagent or solvent used, typically ranging from 0°C to 40°C, preferably from 0°C to 25°C.

[0226] In step y, synthetic intermediate 41 is prepared from synthetic intermediate 40. Relative to synthetic intermediate 40, 1 to 10 equivalents of tin(II) chloride, preferably 2 to 5 equivalents, can be used. The reaction is typically carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction; examples include methanol, ethanol, propanol, and isopropanol, with methanol being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 to 6 hours, preferably 1.5 to 4 hours. The reaction temperature varies depending on the reagent or solvent used, typically ranging from 0°C to 100°C, preferably 60°C to 80°C.

[0227] In step z, synthetic intermediate 42 is prepared from synthetic intermediate 41. An excess of formic acid is used relative to synthetic intermediate 41. The reaction time is typically 0.5 to 5 hours, preferably 1 to 2 hours. The reaction temperature is typically 25°C to 150°C, preferably 90°C to 110°C.

[0228] In step a-1, synthetic intermediate 43 is prepared from synthetic intermediate 42. Relative to synthetic intermediate 42, triphenylmethyl chloride can be used in amounts of, for example, 1 to 3 equivalents, preferably 1.1 to 1.3 equivalents, and a base can be used in amounts of, for example, 1 to 3 equivalents, preferably 1.1 to 1.7 equivalents. Examples of bases include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc., with N-methylmorpholine or triethylamine being 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; examples include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, acetonitrile, N,N-dimethylformamide, etc., with dichloromethane being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 hour to 12 hours, preferably 1 to 2 hours. The reaction temperature varies depending on the reagents or solvents used, and is usually 0℃ to 100℃, preferably 40℃ to 60℃.

[0229] In step a-2, synthetic intermediate 44 is prepared from synthetic intermediate 43. A reducing agent can be used relative to synthetic intermediate 43, for example, in amounts of 1 to 5 equivalents, preferably 1.5 to 3 equivalents. Examples of reducing agents include lithium borohydride, lithium aluminum hydride, lithium borohydride, and borane-tetrahydrofuran coordination compounds, with lithium borohydride being preferred. The reaction is usually carried out in a solvent. No particular solvent is specified as long as it does not adversely affect the reaction; examples include tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane, with tetrahydrofuran being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 0.2 to 3 hours, preferably 0.5 to 1.5 hours. The reaction temperature varies depending on the reagent or solvent used, typically ranging from 0°C to 60°C, preferably 0°C to 30°C.

[0230] In step a-3, methanesulfonyl chloride and lithium chloride are reacted in the presence of a base to produce synthetic intermediate 45 from synthetic intermediate 44. Methanesulfonyl chloride can be used in amounts of, for example, 1 to 5 equivalents, preferably 1.5 to 2.5 equivalents, lithium chloride can be used in amounts of, for example, 1 to 10 equivalents, preferably 3 to 5 equivalents, and a base can be used in amounts of, for example, 1 to 10 equivalents, preferably 3 to 8 equivalents. Examples of bases include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, etc., with N,N-diisopropylethylamine being 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; examples include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, etc., with dichloromethane being preferred. The reaction time varies depending on the reagent or solvent used, and is typically 1 to 24 hours, preferably 1 to 12 hours. The reaction temperature varies depending on the reagents or solvents used, and is usually 0℃ to 40℃, preferably 0℃ to 25℃.

[0231] In step a-4, in the presence of a base, synthetic intermediate 45 is reacted with synthetic intermediate 11 and tetrabutylammonium iodide to produce synthetic intermediate 46. Relative to synthetic intermediate 45, synthetic intermediate 11 can be used in amounts of, for example, 1 to 3 equivalents, preferably 1 to 1.2 equivalents; tetrabutylammonium iodide can be used in amounts of, for example, 0.1 to 1 equivalent, preferably 0.1 to 0.2 equivalents; and a base can be used in amounts of, for example, 1 to 5 equivalents, preferably 1 to 3 equivalents. Examples of bases include potassium carbonate, sodium carbonate, and sodium bicarbonate, with potassium carbonate being 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; examples include dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide, with N,N-dimethylformamide being preferred. The reaction time varies depending on the reagent or solvent used, and is typically 1 to 24 hours, preferably 1 to 18 hours. The reaction temperature varies depending on the reagents or solvents used, and is usually 0℃ to 60℃, preferably 25℃ to 40℃.

[0232] The compounds of the present invention can also be manufactured, for example, according to the method shown in or based on Scheme 10 below.

[0233] Scheme10

[0234]

[0235] Procedures a-3 and a-4 of Scheme 10 shall be performed in accordance with Scheme 9, and procedure d shall be performed in accordance with Scheme 1.

[0236] The compounds of the present invention can also be manufactured according to, for example, the method shown in Scheme 11 below or a method based thereon.

[0237] Scheme11

[0238]

[0239] Procedures c and d of Scheme 11 shall be performed in accordance with Scheme 1, procedure g shall be performed in accordance with Scheme 2, and procedures a-3 and a-4 shall be performed in accordance with Scheme 9.

[0240] <Process a-5>

[0241] In step a-5, compound 49 is produced from compound 9. Relative to compound 9, 2 to 5 equivalents of tetrabutylammonium fluoride are used, preferably 2 to 3 equivalents. The solvent is not particularly limited as long as it does not adversely affect the reaction; examples include tetrahydrofuran and N,N-dimethylformamide, with tetrahydrofuran being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 to 24 hours, preferably 1 to 3 hours. The reaction temperature varies depending on the reagent or solvent used, typically ranging from 0°C to 100°C, preferably 25°C to 40°C.

[0242] <Process a-6>

[0243] In step a-6, compound 50 is produced from compound 49. Relative to compound 49, 10 to 50 equivalents of manganese dioxide are used, preferably 25 to 50 equivalents. The solvent is not particularly limited as long as it does not adversely affect the reaction; examples include dichloromethane, acetone, benzene, toluene, tetrahydrofuran, and 1,4-dioxane, with dichloromethane being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 to 24 hours, preferably 2 to 24 hours. The reaction temperature varies depending on the reagent or solvent used, typically ranging from 0°C to 100°C, preferably 25°C to 40°C.

[0244] <Process a-7>

[0245] In step a-7, compound 52 is produced from compound 51. Relative to compound 51, 1 to 5 equivalents of TMS ethanol are used, preferably 3 to 5 equivalents. A condensing agent is typically used in 1 to 3 equivalents, preferably 1.5 to 2 equivalents, and a base is typically used in 1 to 5 equivalents, preferably 2 to 5 equivalents. Examples of condensing agents include N,N'-dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride, benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, diethyl cyanophosphate, diphenyl azidophosphate, pentafluorophenyl trifluoroacetate, isopropyl chloroformate, etc., with preferred examples being O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate. Examples of bases include triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine, with triethylamine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine being preferred. As for solvents, any solvent that does not adversely affect the reaction is acceptable and is not particularly limited; examples include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, acetonitrile, and N,N-dimethylformamide, with dichloromethane or N,N-dimethylformamide being preferred. The reaction time varies depending on the reagent or solvent used, typically ranging from 1 hour to 24 hours, preferably from 3 hours to 24 hours. The reaction temperature varies depending on the reagent or solvent used, typically ranging from 0°C to 100°C, preferably from 25°C to 40°C.

[0246] Compounds of general formula (I) can be isolated into R by, for example, at any stage of the above-described schemes. 1 The three-dimensional configuration and R 2 The stereochemical configuration is a mixture of cis (S,S and R,R) cis isomers, and R 1 The three-dimensional configuration and R 2 A mixture of trans (S,R and R,S) trans isomers (Separation 1) with the trans isomer mixture is used to carry out the synthetic reaction described in the subsequent scheme, and the compound of general formula (I) is isolated from the trans isomer mixture in the final stage (Separation 2). Separation 1 can be performed, for example, by silica gel column chromatography. In Separation 1, the trans isomer mixture has a longer retention time, for example, than the cis isomer mixture. Separation 2 can be performed, for example, by chromatography using a chiral column. The obtained isolates are analyzed as described in Experimental Example 2 below, thereby identifying the stereoconfiguration of the isolates.

[0247] Compounds of general formula (II) were isolated and identified in accordance with the description in "1-8. Polarity" above.

[0248] The compounds of the present invention obtained can be separated or purified as free entities or as salts by conventional salting processes. The separation or purification methods are not particularly limited; for example, commonly used methods such as crystallization, recrystallization, distillation, separation, and chromatography can be appropriately selected, and combinations of these methods are also possible. In the presence of multiple isomers, purification can yield a single isomer or a mixture of multiple isomers. When multiple single isomers or a mixture of multiple isomers are obtained through purification, they can be used directly or in combination as compounds of the present invention. Solvents can be obtained according to methods known per se. Furthermore, the structure of the product can be determined by elemental analysis, MS (ESI-MS) analysis, IR analysis, etc. 1 H-NMR, 13 Identification was performed using C-NMR and other methods.

[0249] 3. Uses

[0250] The compounds of the present invention exhibit Nrf2 activating activity. Therefore, the compounds of the present invention (sometimes referred to in this specification as "the active ingredient of the present invention") can be used, for example, as medicines, reagents, etc. From this viewpoint, the present invention relates, in one embodiment, to pharmaceutical products containing the active ingredient of the present invention (sometimes referred to in this specification as "the pharmaceutical product of the present invention").

[0251] The pharmaceutical products of the present invention can be used as Nrf2 activators, oxidative stress defense gene expression activators, etc., based on the effects of the active ingredients of the present invention.

[0252] The pharmaceutical products of the present invention can be used for the prevention or treatment of various diseases. The target disease is any disease that can be prevented or treated by the above-described effects of the active ingredient according to the present invention, without particular limitation. The pharmaceutical products of the present invention can be used for the prevention or treatment of diseases or symptoms involving Nrf2 or related to the regulation of Nrf2 activity. The pharmaceutical products of the present invention can be administered to patients requiring Nrf2 activation, such as patients suffering from Nrf2-related diseases. "Treatment" refers to preventing the deterioration of a disorder or disease at the onset of its condition, delaying its progression, maintaining its current state, alleviating or resolving it; "prevention" refers to preventing the onset of a disorder or disease before its onset. As for the diseases being addressed, for example, in ophthalmology, examples include dry eye syndrome, diabetic retinopathy, retinitis pigmentosa, glaucoma, cataracts, age-related macular degeneration, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, uveitis, Leber's disease, retinopathy of prematurity, retinal detachment, retinal pigment epithelium detachment, optic nerve damage caused by these diseases, optic nerve damage caused by glaucoma, ischemic optic neuropathy, postoperative inflammation suppression, and pain suppression. Additionally, in skin diseases, examples include ultraviolet-reactive skin damage, bullous epidermolysis, psoriasis, atopic dermatitis, and scleroderma. In otolaryngology, examples include noise-induced hearing loss and sensorineural hearing loss. In brain diseases, examples include Alzheimer's disease, Parkinson's disease, Huntington's disease, Barton's disease, dementia, and epilepsy. In lung diseases, examples include asthma, bronchitis, and chronic obstructive pulmonary disease. In kidney diseases, examples include... Examples of diseases that can be listed include diabetic nephropathy, Alport syndrome, autosomal dominant polycystic kidney disease, focal segmental glomerulosclerosis, and IgA nephropathy. Other systemic diseases that can be listed include arteriosclerosis, hypertension, cancer, cardiac arrest, Friedreich ataxia, amyotrophic lateral sclerosis (ALS), hepatitis, rheumatoid arthritis, pancreatitis, vasculitis, esophagitis, ulcerative colitis, neutropenia, cellular immunity, diabetes, mitochondrial myopathy, sickle cell anemia, and multiple sclerosis. Among these, ophthalmic diseases such as multiple sclerosis, psoriasis, Alzheimer's disease, retinitis pigmentosa, glaucoma, and cataracts are particularly noteworthy.

[0253] There are no particular limitations on the target of administration of the pharmaceutical product of the present invention. Examples of such targets include mammals (e.g., humans, mice, rats, hamsters, rabbits, cats, dogs, pigs, sheep, monkeys, etc.).

[0254] The route of administration for the pharmaceutical product of the present invention is not particularly limited. It can be administered via enteral methods such as oral administration, tube feeding, and enema; non-oral administration such as intravenous administration, arterial administration, intramuscular administration, intracardiac administration, subcutaneous administration, intradermal administration, and intraperitoneal administration; and local administration such as ocular administration (e.g., eye drops, intravitreal administration, subconjunctival administration, sub-Tenon administration), skin administration, inhalation administration, enema administration, ear drops, nasal administration, and vaginal administration. Among these, local administration and non-oral administration are preferred. Furthermore, the pharmaceutical product of the present invention is preferably configured as a formulation suitable for these preferred routes of administration; from this viewpoint, local administration formulations and non-oral administration formulations are preferred. In one embodiment, the pharmaceutical product of the present invention can be an oral administration formulation. In another embodiment, the pharmaceutical product of the present invention can be an ophthalmic formulation, an otolaryngological formulation, a respiratory formulation, a dermatological formulation, etc. In addition, in this specification, "~departmental formulation" refers to a formulation suitable for diseases treated in that department. The pharmaceutical product of the present invention can be an intravenous administration preparation, a nasal administration preparation, a transdermal administration preparation, etc. in one embodiment.

[0255] The pharmaceutical products of the present invention can be formulated in dosage forms suitable for administration routes. Examples include eye drops, eye ointments, eye washes, injections, patches, lotions, creams, powders, granules, tablets, capsules, syrups, liquids, ointments, gels, liniments, suppositories, sprays, inhalers, nasal sprays, etc. They can be prepared using conventional techniques in the field. Furthermore, the active ingredients of the present invention, in addition to these formulations, can also be formulated into intraocular implantable formulations or DDS (drug delivery system) formulations such as microspheres.

[0256] The pharmaceutical products of the present invention may consist solely of the active ingredient of the present invention, or may be compositions comprising, as needed, pharmaceutically acceptable additives (sometimes referred to simply as "additives" in this specification). The pharmaceutical products of the present invention can be manufactured by mixing the active ingredient of the present invention with at least one additive, etc., according to methods known in the field of pharmaceutical formulation. The additives may be appropriately selected depending on the preferred form of the formulation for administration. The content of the active ingredient of the present invention in the pharmaceutical product varies depending on the dosage form, dosage, etc., and may be appropriately selected. For example, it can generally be set to 0.01 to 99.9% by mass of the total pharmaceutical product, and is preferably set to 0.1 to 80% by mass.

[0257] Examples of additives include bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, humectants, colorants, fragrances, and chelating agents. These can be appropriately selected based on the route of administration, dosage form, etc.

[0258] For example, in preparing otolaryngological preparations containing the active ingredients of the present invention, water (purified or sterile water, distilled water for injection, etc.) or physiological saline, glucose solution, water-soluble organic solvents (lower aliphatic alcohols such as ethanol and isopropanol, or polyalkylene glycols such as ethylene glycol, diethylene glycol, and polyethylene glycol, etc.), plant and animal oils (plant oils such as jojoba oil, olive oil, coconut oil, and cottonseed oil; animal oils such as squalane, etc.) or 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 polyols (poly-C2-4 alkylene glycols, glycerol, or polyglycerol, 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. In addition, it can be combined with preservatives or preservatives (paraben esters such as methylparaben and butylparaben), deodorants or fragrances (aromatic agents such as menthol), cooling agents, analgesics (local anesthetics such as lidocaine), and effective ingredients used to treat infections or inflammation (antibacterial agents, antibiotics, anti-inflammatory agents, etc.). The amount of these additives added varies depending on the type and purpose of the additive; the concentration added should be sufficient to achieve the intended purpose of the additive.

[0259] For example, in the preparation of dermatological formulations containing the active ingredients of the present invention, one or more solvents can be selected from purified water, ethanol, isopropanol, dipropylene glycol, etc. As base agents, one or more animal and vegetable oils such as olive oil, soybean oil, camellia oil, sesame oil, peanut oil, cocoa butter, tallow, and lard can be selected from; waxes such as carnauba wax and beeswax; aliphatic alcohols such as octyl dodecanol, hexadecyl alcohol, and stearyl alcohol; fatty acids such as oleic acid, palmitic acid, and stearic acid; hydrocarbons such as squalane, white petrolatum, liquid paraffin, ceresin, and microcrystalline wax; and hydrophilic base agents such as gelatin and polyethylene glycol can be selected from. In addition, as other additives, it can be added as excipients such as light silicic anhydride, crystalline cellulose, and dextrin; as a solubilizer such as diisopropyl adipate, decanoic acid, clomiphene, and propylene carbonate; as a suspending agent such as propylene glycol alginate, sodium dioctyl sulfosuccinate, soybean lecithin, and povidone; as a surfactant or emulsifier such as polyoxyethylene hydrogenated castor oil, polyoxyethylene dehydrated sorbitol monolaurate, polyoxyethylene dehydrated sorbitol monolaurate, polyoxyethylene dehydrated sorbitol monooleate, glyceryl monolaurate, and sucrose fatty acid esters; and as a carboxyvinyl polymer, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, and polyethylene. Thickeners such as alcohols (partially saponified); plasticizers such as glyceryl triacetate and isopropyl myristate; humectants such as glycerin, 1,3-butanediol, sodium DL-pyrrolidone carboxylate, and sodium hyaluronate; stabilizers such as sodium edetate, sorbitol, thymol, and polyoxyethylene polyoxypropylene glycol; antioxidants such as ascorbic acid, sodium isoascorbate, tocopheryl acetate, and butylated hydroxytoluene; preservatives such as sorbic acid, sodium dehydroacetate, methylparaben, ethylparaben, and butylparaben; 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 added varies depending on the type and intended use of the additive; the concentration added should be sufficient to achieve the intended purpose of the additive.

[0260] For example, in preparing ophthalmic preparations (topical ophthalmic agents: eye drops, eye ointments, eye washes, etc.) containing the active ingredients of this invention, stabilizers (e.g., sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, butylated hydroxytoluene, etc.), solubilizers (e.g., glycerin, propylene glycol, polyethylene glycol, polyoxyethylene hydrogenated castor oil, etc.), suspending agents (e.g., polyvinylpyrrolidone, hydroxypropyl methylcellulose, 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, glutamate, ε-aminocaproic acid, etc.), and thickeners (e.g., methylcellulose) can be added. Additives include water-soluble cellulose derivatives such as cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose; sodium chondroitin sulfate; sodium hyaluronate; carboxyvinyl polymers; polyvinyl alcohol; polyvinylpyrrolidone; polyethylene glycol; etc.; preservatives (e.g., benzalkonium chloride, benzyl chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, parabens, sodium edetate, boric acid, etc.); isotonic 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.); cooling agents (e.g., L-menthol, D-camphor, D-isoborneol, peppermint oil, etc.); and ointment bases (white petrolatum, purified lanolin, liquid paraffin, vegetable oils (olive oil, camellia oil, peanut oil, etc.)). The amount of these additives added varies depending on the type and purpose of the additive; the concentration added should be sufficient to achieve the intended purpose of the additive.

[0261] When the pharmaceutical product of the present invention is formulated into an otolaryngological composition such as an ear drop or nasal drop, it can be manufactured according to methods commonly used in the pharmaceutical field, for example, according to the methods described in the 17th revised edition of the Japanese Pharmacopoeia, General Principles of Pharmaceutical Preparations, under the section "Ear Drug Delivery Preparations" or "Preparations Applicable to the Nose".

[0262] When the pharmaceutical product of the present invention is formulated into a dermatological composition such as a topical skin preparation, it can be manufactured according to methods commonly used in the pharmaceutical field, for example, according to the methods described in the 17th revised edition of the Japanese Pharmacopoeia, General Principles of Pharmaceutical Preparations, "Preparations Applicable to the Skin, etc." When the pharmaceutical product of the present invention is formulated into an ophthalmic composition such as an eye drop or ointment, it can be manufactured according to methods commonly used in the pharmaceutical field, for example, according to the methods described in the 17th revised edition of the Japanese Pharmacopoeia, General Principles of Pharmaceutical Preparations, "Ocular Drugs" (e.g., the sections on eye drops and ointments).

[0263] The dosage of the pharmaceutical product of the present invention varies depending on the disease to which it is intended and cannot be generalized. It can be set such that the concentration of the active ingredient of the present invention in the target tissue to exert its effect is, for example, 0.001 nM to 100 μM, preferably 0.01 nM to 100 μM.

[0264] When the pharmaceutical product of the present invention is applied topically to the eyes of adults, for example, the pharmaceutical product containing 0.01 nM to 1000 μM, preferably 0.1 nM to 1000 μM, of the active ingredient of the present invention may be applied 1 to 8 times, preferably 1 to 5 times, per day. The dosage can be appropriately set according to the concentration and dosage form of the active ingredient according to the present invention.

[0265] Furthermore, the pharmaceutical products of the present invention may contain one or more other active pharmaceutical ingredients, as long as they do not impair the effects of the present invention.

[0266] Example

[0267] The following examples, manufacturing examples, embodiments, and test examples are provided to illustrate the present invention in more detail, but the present invention is not limited by these examples.

[0268] In the reference examples, manufacturing examples, examples, and test examples, unless otherwise specified, the temperature is specified in degrees Celsius (°C). Unless otherwise specified, all quantities and percentages are expressed by weight. Reagents were purchased from reagent suppliers such as Sigma-Aldrich, Tokyo Chemical Industry Co., Ltd., Fujifilm and Koden Chemical Co., Ltd., or Nacalai Tesque Co., Ltd., and unless otherwise specified, no further purification is required for use.

[0269] The operations in the reference examples, manufacturing examples, and embodiments are generally carried out in an anhydrous solvent under an argon atmosphere. The reaction is analyzed by TLC (Thin Layer Chromatography), and termination is determined by the consumption of the starting material. TLC uses silica gel 60F254 (Merck), developed with a suitable solvent, displayed at appropriate locations, and detected using a UV detector. Elution in the column chromatography of the reference examples, manufacturing examples, and embodiments is performed under TLC observation unless otherwise specified. For column chromatography, SI silica gel (30-50 μm particle size) or NH silica gel (60 μm particle size) manufactured by Fuji Silysia Chemical Co., Ltd., or silica gel (40 μm particle size) or amino silica gel (40 μm particle size) manufactured by Yamazen Co., Ltd., is used. Room temperature generally refers to a temperature of approximately 10°C to 35°C.

[0270] The following abbreviations are used in the manufacturing examples below.

[0271] mCPBA: m-chloroperoxybenzoic acid

[0272] M: molar concentration

[0273] N: Equivalent concentration

[0274] CDCl3: Deuterated chloroform

[0275] CD3OD: Deuterated methanol

[0276] DMSO-d6: Deuterated dimethyl sulfoxide

[0277] 1 H NMR: Proton nuclear magnetic resonance

[0278] DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

[0279] DDQ: 2,3-Dichloro-5,6-dicyano-p-benzoquinone

[0280] DEAD: Diethyl azodicarbonate

[0281] DIPEA: N,N-Diisopropylethylamine

[0282] DMF: N,N-dimethylformamide

[0283] DMA: N,N-dimethylacetamide

[0284] DMSO: Dimethyl sulfoxide

[0285] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0286] HOBt: 1-Hydroxybenzotriazole

[0287] LDA: Lithium diisopropylamide

[0288] PdCl2(dppf)2-CH2Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane adduct

[0289] TEA: Triethylamine

[0290] TFA: Trifluoroacetic acid

[0291] THF: Tetrahydrofuran

[0292] p-TsOH-H2O: p-Toluenesulfonic acid monohydrate

[0293] [RhCl(cod)]2: Chloro(1,5-cyclooctadiene)rhodium(I) (dimer)

[0294] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0295] 1 ¹H NMR spectra were recorded using a Bruker instrument operating at 400 MHz. NMR spectra were obtained using chloroform (7.26 ppm) as a reference standard, or tetramethylsilane (0.00 ppm) as an internal solution, as appropriate, as a CDCl₃ solution. Other NMR solvents may also be used as needed. When reporting peak multiplicity, the following abbreviations are used: s (singleton), d (doublet), t (triplet), q (quartet), quin (quintet), septd (septet), m (multipleton), br (broad peak), dd (doublet of doublet), dt (doublet of triplet), td (triplet of doublet). When expressing the coupling constant (J value), it is reported in Hertz (Hz).

[0296] Compound Synthesis 1

[0297] Reference Example 1

[0298] (R)-4-Ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Preparation of 1,1-dioxide

[0299]

[0300] (R)-(+)-epoxybutane (5.0 mL, 58.2 mmol) was added dropwise to 84 mL of ammonia (approximately 28%) over 10 minutes with stirring, and the mixture was stirred at room temperature for 22 hours. The solvent in the mixture was removed by distillation under reduced pressure, and the resulting oily substance was dissolved in THF / H₂O (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 brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The 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 then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. Dichloromethane at 0°C was added to the 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 give the title compound (2.93 g, 39%) as a white solid.

[0301] 1 H NMR (400MHz, CDCl3) δ7.83(1H,dd,J=7.6,1.6Hz),7.47(1H,td,J=7.6,1.6Hz),7.19(1H,td,J=7.6,1.2Hz),7.17(1H,dd,J=7.6,1.2Hz),4.66(1H,br s),3.89-3.82(1H,m),3.70-3.62(1H,m),3.39(1H,ddd,J=14.8,5.2,2.0Hz),1.83-1.71(1H,m),1.67-1.56(1H,m),1.13(3H,t,J=7.2Hz).

[0302] See Example 2

[0303] (R)-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Preparation of 1,1-dioxide

[0304]

[0305] 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 starting materials, the procedure was performed in the same manner as in step j of Reference Example 1, and the title compound (6.42 g, 79%) was obtained as a pale yellow solid.

[0306] 1 H NMR (400MHz, CDCl3) δ7.81(1H,dd,J=8.0,1.6Hz),7.46(1H,td,J=8.0,1.6Hz),7.19(1H,td,J=8.0,1.2Hz),7.15(1H,dd,J=8.0,1.2Hz),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, 2.0Hz), 1.40 (3H, d, J = 6.4Hz).

[0307] See Example 3

[0308] (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiaza Preparation of 1,1-dioxide

[0309]

[0310] Using ammonia (approximately 28%) (2.9 mL), (R)-(+)-epoxybutane (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) as starting materials, the same procedure as in Reference Example 1 was followed to obtain the title compound (210.4 mg, 78%) as an amber-colored oily substance.

[0311] 1H NMR (400MHz, CDCl3) δ8.40(1H,dd,J=4.8,2.0Hz),8.15(1H,dd,J=7.6,2.0Hz),7.19(1H,dd,J=7.6,4.8Hz),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=7.6Hz).

[0312] See Example 4

[0313] (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza Preparation of 1,1-dioxide

[0314]

[0315] Using ammonia (approximately 28%) (4.35 mL), (R)-(+)-epoxybutane (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) as starting materials, the procedure was performed in the same manner as in Reference Example 1, and the title compound (140.8 mg, 52%) was obtained as a colorless oil.

[0316] 1 H NMR (400MHz, CDCl3) δ8.82(1H,s),8.53(1H,d,J=5.6Hz),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=7.6Hz).

[0317] See Example 5

[0318] Manufacturing of (R)-2-fluoro-N-(2-hydroxybutyl)benzenesulfonamide

[0319]

[0320] Potassium carbonate (203.0 mg, 1.5 mmol) and 2,6-difluorobenzenesulfonyl chloride (150 μL, 1.1 mmol) were added to a 2.0 mL solution of (R)-1-aminobutane-2-ol (127.6 mg, 1.4 mmol) in THF / water (4 / 1) (2.0 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and the solvent was removed by vacuum distillation to give the title compound (318.1 mg, quant.) as a white solid.

[0321] 1 H NMR (400MHz, CDCl3) δ7.51 (1H, m), 7.04 (2H, t, J = 8.4Hz), 3.73-3.67 (1H, m), 3.28 (1H, dd ,J=12.8,3.2Hz),2.96(1H,d,J=12.8,8.0Hz),1.55-1.41(2H,m),0.94(3H,t,J=7.6Hz).

[0322] See Example 6

[0323] (R)-4-ethyl-9-fluoro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Preparation of 1,1-dioxide

[0324]

[0325] 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 in a microwave oven at 100 °C for 2 hours. The reaction solution was allowed to return to room temperature, adjusted to pH 6 with 1 M hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 73 / 27 → 52 / 48) to give the title compound (113.2 mg, 71%) as a white solid.

[0326] 1 H NMR (400MHz, CDCl3) δ7.38-7.33(1H,m),6.93-6.88(2H,m),5.26(1H,br t,J=6.0Hz),4.34-4.27(1H,m),3.54(1H,ddd,J=14.0,6.4,4.0Hz),3.23(1H,ddd,J=14.0,11.2,6.8Hz),1.78-1.58(2H,m),1.07(3H,t,J=7.6Hz).

[0327] See Example 7

[0328] Manufacturing of [(but-3-en-1-yloxy)methyl]benzene

[0329]

[0330] 3-Buten-1-ol (2.5 mL, 29.5 mmol) was added to a solution of sodium hydride (60%) (2.36 g, 59 mmol) in THF (25 mL) at 0 °C, and the mixture was allowed to return to room temperature and stirred for 30 min. 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 h. 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 layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 100 / 0 → 91 / 9) to give the title compound (3.95 g, 83%) as a colorless oil.

[0331] 1 H NMR (400MHz, CDCl3) δ7.38-7.26(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=6.8Hz),2.43-2.35(2H,m).

[0332] See Example 8

[0333] Production of 2-[2-(benzyloxy)ethyl]ethylene oxide

[0334]

[0335] In a solution of [(but-3-en-1-yloxy)methyl]benzene (3.95 g, 24.3 mmol) in dichloromethane (79 mL), mCPBA (approximately 77%) (7.09 g, 31.6 mmol) was added at 0 °C. The mixture was brought to room temperature and stirred for 14 hours. The reaction mixture was diluted with water, and the reaction was stopped by adding saturated aqueous solutions of sodium bicarbonate and sodium thiosulfate. 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 give the title compound (4.11 g, 95%) as a colorless oil.

[0336] 1H NMR(400MHz, CDCl3)δ7.38-7.26(5H,m),4.54(2H,s),3.68-3.58(2H,m),3.12-3.06(1H,m),2 .79(1H,dd,J=5.0,4.2Hz),2.54(1H,dd,J=5.0,3.7Hz),1.97-1.86(1H,m),1.84-1.73(1H,m).

[0337] See Example 9

[0338] Preparation of 1-amino-4-(benzyloxy)butane-2-ol

[0339]

[0340] 2-[2-(benzyloxy)ethyl]ethylene oxide (4.11 g, 23.1 mmol) was added to ammonia water (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.

[0341] 1 H NMR (400MHz, CDCl3) δ7.37-7.26(5H,m),4.52(2H,s),3.77-3.63(3H,m),2.79(1H,dd,J=12.8,3.6Hz),2.61(1H,dd,J=12.8,7.6Hz),1.77-1.71(2H,m).

[0342] See Example 10

[0343] 4-[2-(benzyloxy)ethyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Preparation of 1,1-dioxide

[0344]

[0345] Potassium carbonate (2.06 g, 14.9 mmol) and 2-fluorobenzenesulfonyl chloride (1.95 mL, 14.9 mmol) were added to a solution of 1-amino-4-(benzyloxy)butane-2-ol (4.4475 g, 22.8 mmol) in THF (29 mL) and water (7.3 mL). The reaction mixture was stirred for 1 hour, and the reaction was stopped by adding 1 N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was dissolved in DMSO (135 mL), and potassium tert-butoxide (5.02 g, 44.7 mmol) was added to the solution. The reaction mixture was stirred at 80 °C for 1 hour, and the reaction was stopped by adding 1 N hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 91 / 9 → 60 / 40) to give the title compound (3.88 g, 78%) as a colorless solid.

[0346] 1 H NMR (400MHz, CDCl3) δ7.83(1H,d,J=7.6Hz),7.42(1H,td,J=7.6,1.6Hz),7.33-7.26(5H,m),7.20(1H,t,J=7.6Hz),6.96(1H,d,J=7.6Hz),4.63(1H,br s), 4.55 (1H, d, J = 12.0Hz), 4.49 (1H, d, J = 12.0Hz), 4.11 (1H, br t, J = 9.6Hz), 3.85-3.63 (3H, m), 3.39-3.35 (1H, m), 2.00-1.86 (2H, m).

[0347] See Example 11

[0348] Production of (5-bromo-2-methylphenyl)methanol

[0349]

[0350] In a solution of 5-bromo-2-methylbenzoic acid (5.0 g, 25.3 mmol) in THF (50 mL), a borane-tetrahydrofuran complex (approximately 0.9 mmol / L THF solution) (38.8 mL, 34.9 mmol) was added dropwise over 10 minutes at 0 °C, followed by stirring at room temperature for 20 hours. Methanol (35 mL) was added to the resulting solution, and after stirring at room temperature for 2 hours, the solvent was removed by distillation under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, yielding the title compound (5.0 g, 98%) as a pale yellow oil.

[0351] 1H NMR (400MHz, CDCl3) δ7.53 (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).

[0352] See Example 12

[0353] (R)-2-(5-bromo-2-methylbenzyl)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathazaza Preparation of 1,1-dioxide

[0354]

[0355] In (5-bromo-2-methylphenyl)methanol (2.0 g, 9.95 mmol), (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza In a THF (39 mL) solution of 1,1-dioxide (2.26 g, 9.95 mmol) and triphenylphosphine (2.61 g, 9.95 mmol), 2.2 M DEAD toluene solution (5.1 mL, 11.2 mmol) was added while stirring at 0 °C. The solution was stirred at room temperature for 7 hours, diluted with water, and 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) = 95 / 5 → 85 / 15) to give the title compound (3.46 g, 85%) as a white solid.

[0356] 1H NMR (400MHz, CDCl3) δ7.89 (1H, dd, J = 7.6, 1.6Hz), 7.52 (1H, td, J = 7.6, 1.6Hz), 7.39 (1H, d, J = 2.0Hz), 7 .35(1H,dd,J=8.0,2.0Hz),7.26(1H,td,J=7.6,1.2Hz),7.21(1H,dd,J=7.6,1.2Hz),7.06(1H,d,J=8.0 Hz), 4.51 (1H, d, J = 14.4Hz), 4.08-4.02 (1H, m), 3.85 (1H, d, J = 14.4Hz), 3.76 (1H, dd, J = 15.2, 10.8Hz), 3.06(1H,dd,J=15.2,2.0Hz),2.29(3H,s),1.79-1.70(1H,m),1.56-1.50(1H,m),1.11(3H,t,J=7.2Hz).

[0357] See Example 13

[0358] (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Preparation of 1,1-dioxide

[0359]

[0360] (R)-2-(5-bromo-2-methylbenzyl)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza A 1,1-dioxane solution (36 mL) of 1,1-dioxide (3.4 g, 8.29 mmol), bis(pinacol)diboron (3.15 g, 12.4 mmol), potassium acetate (2.44 g, 24.9 mmol), and PdCl2(dppf)2-CH2Cl2 (408 mg, 0.5 mmol) was stirred at 100 °C for 6 hours. The reaction solution was filtered through diatomaceous earth, 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 give the title compound (3.28 g, 86%) as a white solid.

[0361] 1H NMR (400MHz, CDCl3) δ7.90(1H,d,J=7.6Hz),7.68(1H,d,J=7.6Hz),7.54(1H,s),7.52(1H, t,J=7.6Hz),7.25(1H,t,J=7.6Hz),7.22-7.20(2H,m),4.64(1H,d,J=13.6Hz),4.09-4.04( 1H,m),3.83(1H,d,J=13.6Hz),3.74(1H,dd,J=15.2,10.8Hz),2.97(1H,dd,J=15.2,1.2Hz ),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=7.2Hz).

[0362] See Example 14

[0363] Preparation of 4-bromo-2-{[(4-methoxybenzyl)oxy]methyl}-1-methylbenzene

[0364]

[0365] 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, then 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, and after the reaction was stopped by adding water, it was extracted with diethyl ether. The organic layer was washed with saturated brine, 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) = 95 / 5 → 85 / 15) to give the title compound (1.77 g, 61%) as a colorless oil.

[0366] 1 H NMR (400MHz, CDCl3) δ7.50 (1H, d, J = 2.0Hz), 7.32-7.28 (3H, m), 7.02 (1H, d, J = 8. 0Hz), 6.90(2H,d,J=8.4Hz), 4.51(2H,s), 4.46(2H,s), 3.81(3H,s), 2.24(3H,s).

[0367] See Example 15

[0368] Manufacturing of 3-{[(4-methoxybenzyl)oxy]methyl}-4-methylbenzaldehyde

[0369]

[0370] A solution of 2.3 M n-butyllithium hexane (980 μL, 2.25 mmol) was added dropwise to a THF (6 mL) solution of 4-bromo-2-{[(4-methoxybenzyl)oxy]methyl}-1-methylbenzene (600 mg, 1.87 mmol) at -78 °C under an argon atmosphere. The reaction mixture was stirred at -78 °C for 1 h, and DMF (290 μL, 3.75 mmol) was added. The mixture was then heated to room temperature and stirred for 1 h. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, 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) = 99 / 1 → 90 / 10) to give the title compound (448.3 mg, 89%) as a colorless oil.

[0371] 1 H NMR (400MHz, CDCl3) δ9.97 (1H, s), 7.87 (1H, d, J = 1.6Hz), 7.72 (1H, dd, J = 8.0, 1.6Hz), 7.33-7.26 (3H, m), 6.90 (2H, br d,J=8.8Hz),4.56(2H,s),4.54(2H,s),3.82(3H,s),2.39(3H,s).

[0372] See Example 16

[0373] Preparation of 2-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane

[0374]

[0375] A 1,4-dioxane solution (68 mL) of 4-bromo-2-{[(4-methoxybenzyl)oxy]methyl}-1-methylbenzene (6.67 g, 20.77 mmol), bis(pinacol)diboron (5.54 g, 21.81 mmol), potassium acetate (6.12 g, 62.31 mmol), and PdCl2(dppf)2-CH2Cl2 (848.1 mg, 1.04 mmol) was stirred at 100 °C for 6 hours. The reaction solution was filtered through diatomaceous earth, 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 give the title compound (6.63 g, 87%) as a pale yellow oil.

[0376] 1H NMR (400MHz, CDCl3) δ7.73(1H,s),7.65(1H,dd,J=7.2,1.2Hz),7.27(2H,d,J=8.8Hz),7.18(1H,d,J=7.2Hz),6.88(2H,br d,J=8.8Hz),4.52(2H,s),4.47(2H,s),3.81(3H,s),2.36(3H,s),1.34(12H,s).

[0377] See Example 17

[0378] Preparation of methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxapentane-2-yl)thiophen-2-yl]propionate

[0379]

[0380] In a solution of (E)-3-[5-(2-methyl-1,3-dioxapentane-2-yl)thiophen-2-yl]methyl acrylate (3.30 g, 13.0 mmol), 2-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane (2.39 g, 6.49 mmol), and [RhCl(cod)]2 (160 mg, 0.32 mmol) in 1,4-dioxane / water (9.6 mL / 960 μL), triethylamine (2.7 mL, 19.5 mmol) was added. The reaction mixture was stirred at 50 °C for 2.5 h. Water was added to the mixture, 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. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 9 / 1 → 7 / 3) to give the title compound (1.52 g, 47%) as a pale yellow oil.

[0381] 1H NMR(400MHz, CDCl3)δ7.28-7.24(3H,m),7.11-7.10(2H,m),6.88(2H,br d,J=8.4Hz),6.81(1H,d,J=3.6Hz),6.65(1H,dd,J=3.6,0.8Hz),4.67(1H,t,J=7.6Hz),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=15.6,7.6Hz),2.99(1H,dd,J=15.6,7.6Hz),2.28(3H,s),1.71(3H,s).

[0382] See Example 18

[0383] Preparation of methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methyl-3-[5-(2-methyl-1,3-dioxapentane-2-yl)thiophen-2-yl]propionate

[0384]

[0385] A 2M LDA THF / heptane / ethylbenzene solution (1.83 mL, 3.67 mmol) was added to a THF (18 mL) solution of methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxapentyl-2-yl)thiophene-2-yl]propionate (1.40 g, 2.82 mmol) under argon atmosphere at -78 °C. The reaction mixture was stirred at -78 °C for 30 min, then at -40 °C for 20 min. Iodomethane (2.6 mL, 42.3 mmol) was added, and the mixture was heated to room temperature and stirred for 4 h. Water was added to the mixture to stop the reaction, 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. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 8%) to give the title compound. The title compound can be separated into two isomer mixtures, which are obtained as a pale yellow oily substance: 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. Isomer mixture 2 is used in the following reaction.

[0386] Isomer mixture 1: 1H NMR (400MHz, CDCl3) δ7.28-7.26(3H,m),7.17-7.15(1H,m),7.06(1H,d,J=8.0Hz),6.89(2H,br d,J=8.8Hz),6.82(1H,d,J=3.6Hz),6.74(1H,d,J=3.6Hz),4.47(2H,s),4.43(2H,s),4.25(1H,d,J=10.8Hz),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=6.8Hz).

[0387] Isomer mixture 2: 1 H NMR (400MHz, CDCl3) δ7.28-7.23(3H,m),7.11-7.10(2H,m),6.89(2H,br d,J=8.8Hz),6.77(1H,d,J=3.6Hz),6.71(1H,br d,J=3.6Hz),4.48(2H,s),4.47(2H,s),4.27(1H,d,J=11.2Hz),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=6.8Hz).

[0388] See Example 19

[0389] Preparation of methyl 3-(5-acetylthiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionate

[0390]

[0391] In a solution of methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methyl-3-[5-(2-methyl-1,3-dioxapentyl-2-yl)thiophen-2-yl]propionate (Isomer mixture 2) (489 mg, 0.96 mmol) in tetrahydrofuran (2.8 mL), 2N hydrochloric acid (1.4 mL) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was neutralized with 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (390.8 mg, 87%) as a pale yellow oil.

[0392] 1 H NMR(400MHz, CDCl3)δ7.46(1H,d,J=4.0Hz),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=11.2Hz), 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=6.8Hz).

[0393] See Example 20

[0394] Preparation of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2-methylpropionate

[0395]

[0396] DDQ (681 mg, 3.0 mmol) was added to a solution of methyl 3-(5-acetylthiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionate (700.9 mg, 1.5 mmol) in dichloromethane / water (10 / 1) (18.2 mL) at 0 °C. The mixture was stirred at room temperature for 2.5 h. 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 brine, 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) = 6 / 4 → 4 / 6) to give the title compound (436.3 mg, 84%) as a pale yellow oil.

[0397] 1H NMR (400MHz, CDCl3) δ7.46 (1H, d, J = 4.0Hz), 7.28 (1H, br s), 7.13 (2H, br s), 6.93 (1H, d, J = 4.0Hz), 4.68 (2H, d, J = 5.6Hz), 4.37 (1H, d, J = 11.2Hz), 3.6 0(3H,s),3.27-3.23(1H,m),2.46(3H,s),2.30(3H,s),1.09(3H,d,J=6.8Hz).

[0398] See Example 21

[0399] Preparation of 1-(5-bromothiophen-2-yl)ethane-1-ol

[0400]

[0401] 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 ethyl acetate was added. The solution was washed with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation, yielding the title compound (1.16 g, 99%) as a colorless, transparent oil.

[0402] 1 H NMR (400MHz, CDCl3) δ6.90 (1H,d,J=3.6Hz), 6.72 (1H,d,J=3.6Hz), 5.04 (1H,dq,J=5.6,6.4Hz), 1.97 (1H,d,J=4.8Hz), 1.57 (3H,d,J=6.4Hz).

[0403] See Example 22

[0404] Preparation of [1-(5-bromothiophene-2-yl)ethoxy](tert-butyl)dimethylsilane

[0405]

[0406] In a solution of 1-(5-bromothiophene-2-yl)ethane-1-ol (1.16 g, 5.6 mmol) in 12 mL of dichloromethane, 4-dimethylaminopyridine (76.8 mg, 0.6 mmol), TEA (3.2 mL, 23 mmol), and tert-butyldimethylchlorosilane (1.66 g, 11 mmol) in 5.0 mL of dichloromethane were added at 0 °C, and the mixture was stirred overnight at room temperature. Further addition of 4-dimethylaminopyridine (305.6 mg, 2.5 mmol) and tert-butyldimethylchlorosilane (981.6 mg, 6.5 mmol) to the reaction solution followed by stirring at room temperature for 3 hours and 45 minutes. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and saturated brine. The resulting organic layer was dried over sodium sulfate. After removing the solvent by vacuum distillation, the residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 1 / 0 → 95 / 5) to give the title compound (1.28 g, 71%) as a colorless, transparent oil.

[0407] 1 H NMR (400MHz, CDCl3), δ6.86 (1H, d, J = 4.0Hz), 6.58 (1H, d, J = 4.0Hz), 5.01 (1H ,q,J=6.4Hz),1.47(3H,d,J=6.4Hz),0.91(9H,s),0.09(3H,s),0.06(3H,s).

[0408] See Example 23

[0409] Production of (5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}thiophen-2-yl)(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)methanol

[0410]

[0411] A 5.0 mL solution of anhydrous THF containing [1-(5-bromothiophene-2-yl)ethoxy](tert-butyl)dimethylsilane (540.9 mg, 1.7 mmol) was cooled to -78 °C, and 0.75 mL (1.9 mmol) of 2.5 M n-butyllithium was added dropwise. The mixture was stirred at -78 °C for 30 minutes. A 5 mL solution of THF containing 3-{[(4-methoxybenzyl)oxy]methyl}-4-methylbenzaldehyde (478.1 mg, 1.8 mmol) was added dropwise to the reaction solution. The mixture was stirred at -78 °C for 1 hour, and then stirred at room temperature for 30 minutes. The reaction was stopped with a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried with sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was then purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 90 / 10 → 69 / 31) to give the title compound (740.4 mg, 86%) as a yellow transparent oil.

[0412] 1 H NMR (400MHz, CDCl3) δ7.41 (1H, s), 7.29-7.26 (3H, m), 7.16 (1H, d, J = 7.6Hz) ,6.88(1H,d,J=8.4Hz),6.67(2H,d,J=4.4Hz),5.96(1H,d,J=4.0Hz),5.17(1 H,q,J=6.4Hz),4.51(2H,s),4.48(2H,s),3.81(3H,s),2.32(3H,s),2.29(1 H,d,J=4.0Hz),1.47(3H,d,J=6.4Hz),0.90(9H,s),0.07(3H,s),0.03(3H,br s).

[0413] See Example 24

[0414] Manufacturing of methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}thiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[0415]

[0416] In 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 the mixture was stirred at room temperature for 30 minutes. Then, dimethyl ketene methyltrimethylsilyl acetal (120 μL, 0.4 mmol) was added to the reaction solution. 0.6 mmol) and bis(trifluoromethanesulfonyl)imide (8.2 mg, 0.03 mmol) were stirred at room temperature for 1 hour. The reaction was stopped by adding a saturated aqueous sodium bicarbonate solution 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 vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 95 / 5 → 74 / 26) to give the title compound (824.8 mg, 73%) as a yellow, transparent oil.

[0417] 1 H NMR (400MHz, CDCl3) δ7.32 (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=6.4Hz),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=6.4Hz),1.29(3H,s),1.22(3H,s),0.89(9H,br s),0.05(3H,s),0.002(3H,s).

[0418] See Example 25

[0419] Preparation of methyl 3-(5-acetylthiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropionate

[0420]

[0421] 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-dimethylpropionate (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 was stopped by adding saturated sodium bicarbonate solution 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 vacuum distillation. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 93 / 7 → 72 / 28 → 50 / 50) to give the title compound (204.1 mg, 44%) as a colorless, transparent oil.

[0422] 1 H NMR (400MHz, CDCl3) δ7.50 (1H, d, J = 4.0Hz), 7.34 (1H, d, J = 1.6Hz), 7.20 (1H, dd, J = 7.6, 1.6Hz), 7.11 (1H, d, J = 7.6Hz), 6. 97(1H,d,J=4.0Hz), 4.17(1H,s), 4.68(2H,d,J=5.6Hz), 3.61(3H,s), 2.49(3H,s), 2.31(3H,s), 1.32(3H,s), 1.24(3H,s).

[0423] See Example 26

[0424] Preparation of methyl 3-(5-acetylthiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropionate

[0425]

[0426] DIPEA (300 μL, 1.7 mmol) and methanesulfonyl chloride (88 μL, 1.1 mmol) were added to a suspension of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropionate (204.1 mg, 0.57 mmol) and lithium chloride (123.1 mg, 2.9 mmol) in dichloromethane (6.0 mL), and the mixture was stirred at room temperature for 4.5 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation, yielding the title compound (218.3 mg, quant.) as a pale brown, transparent oil.

[0427] 1 H NMR (400MHz, CDCl3) δ7.51 (1H, d, J = 4.0Hz), 7.31-7.24 (2H, m), 7.14 (1H, d, J = 8.0Hz), 6.87 (1H, d, J = 4.0Hz),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).

[0428] See Example 27

[0429] 3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2,2-dimethylpropionate (-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[0430]

[0431] Methyl 3-(5-acetylthiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropionate (29.8 mg, 0.079 mmol), (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza A solution of 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 brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 73 / 27 → 52 / 48) to give the title compound (43.1 mg, 96%) as a white solid.

[0432] 1H NMR (400Mz, CDCl3) δ7.87(1H,dt,J=7.6,1.2Hz),7.55-7.50(1H,m),7.49(1H,d,J=4.0Hz),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).

[0433] See Example 28

[0434] Manufacturing of methyl 2-amino-5-bromo-3-nitrobenzene

[0435]

[0436] In a solution of methyl 2-amino-3-nitrobenzene (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 the mixture was 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. To obtain the precipitated solid, the mixture was filtered, washed with water, dissolved in ethyl acetate, washed with 1 M sodium hydroxide aqueous solution and saturated brine, and dried over sodium sulfate. The solvent was removed by vacuum distillation, yielding the title compound (7.37 g, 99%) as a yellow solid.

[0437] 1 H NMR (400MHz, CDCl3) δ 8.51 (1H, d, J = 2.4Hz), 8.44 (2H, br s), 8.32 (1H, d, J = 2.4Hz), 3.93 (3H, s).

[0438] See Example 29

[0439] Manufacturing of methyl 2,3-diamino-5-bromobenzoate

[0440]

[0441] Tin(II) chloride (13.6 g, 72 mmol) was added to a methanol (100 mL) solution of methyl 2-amino-5-bromo-3-nitrobenzene (3.97 g, 14 mmol), and the mixture was stirred at 75 °C for 1.5 h. The reaction solution was allowed to return to room temperature, concentrated under reduced pressure, and water was added. A 1 M sodium hydroxide aqueous solution (100 mL) and solid sodium bicarbonate were added to adjust the pH to 9. The solution was extracted with ethyl acetate. The resulting organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 70 / 30 → 49 / 51) to give the title compound (2.60 g, 73%) as a brown solid.

[0442] 1 H NMR (400MHz, CDCl3) δ7.58 (1H, d, J = 1.6Hz), 6.94 (1H d, J = 1.6Hz), 5.55 (2H, br s), 3.87 (3H, s), 3.39 (2H, br s).

[0443] See Example 30

[0444] Preparation of methyl 6-bromo-1H-benzo[d]imidazol-4-carboxylic acid

[0445]

[0446] 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 allowed to return to room temperature, and 1 M aqueous sodium hydroxide solution and solid sodium bicarbonate were added to adjust the pH to 9. The solution was then extracted with ethyl acetate. The resulting organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation to give the title compound (1.06 g, 99%) as a purple solid.

[0447] 1 H NMR (400MHz, CDCl3) δ10.5 (1H, br s), 8.18 (1H, d, J = 0.8Hz), 8.14 (1H, s), 8.07 (1H, d, J = 0.8Hz), 4.02 (3H, s).

[0448] See Example 31

[0449] Production of (6-bromo-1-triphenylmethyl-1H-benzo[d]imidazol-4-yl)methanol

[0450]

[0451] In a solution of methyl 6-bromo-1H-benzo[d]imidazolium-4-carboxylate (854.6 mg, 3.4 mmol) in dichloromethane (16 mL), N-methylmorpholine (550 μL, 5.3 mmol) and triphenylmethyl chloride (1.17 g, 4.2 mmol) were added, and the mixture was stirred at 55 °C for 2 hours. The reaction solution was allowed to return to room temperature, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium carbonate solution and saturated brine. The solution was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was dissolved in THF (12 mL), and a 2 M lithium borohydride THF solution (3.4 mL, 6.8 mmol) was added. 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 vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 72 / 28 → 7 / 93 → CH2Cl2 / MeOH = 100 / 0 → 95 / 5) to give the title compound (1.17 g, 74%) as a pale purple solid.

[0452] 1 H NMR (400MHz, CDCl3) δ7.85(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=6.4Hz), 3.67(1H,t,J=6.4Hz),

[0453] See Example 32

[0454] (R)-2-[(6-bromo-1-triphenylmethyl-1H-benzo[d]imidazol-4-yl)methyl]-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathazaza Preparation of 1,1-dioxide

[0455]

[0456] DIPEA (0.77 mL, 4.4 mmol) and methanesulfonyl chloride (115 μL, 1.5 mmol) were added to a solution of (6-bromo-1-triphenylmethyl-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 brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The 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]oxathiaza 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 h, and after returning to room temperature, it was diluted with a 1 / 1 mixture of ethyl acetate and hexane, washed with water and saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 69 / 31 → 48 / 52) to give the title compound (471.8 mg, 95%) as a pale orange solid.

[0457] 1 H NMR (400MHz, CDCl3) δ7.89 (1H, dd, J = 7.6, 1.6 Hz), 7.78 (1H, s), 7.49 (1H, td, J = 7.6, 1. 6Hz),7.46(1H,s),7.34-7.30(9H,m),7.23(1H,t,J=8.0Hz),7.17-7.11(7H,m),6.50(1 H,d,J=1.6Hz),4.77(1H,d,J=16.0Hz),4.55(1H,d,J=16.0Hz),4.05-3.96(2H,m),3.3 0(1H,dt,J=13.6,6.8Hz),1.78-1.67(1H,m),1.54-1.44(1H,m),1.08(3H,t,J=7.2Hz).

[0458] See Example 33

[0459] (R)-4-ethyl-2-{[6-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)-1-triphenylmethyl-1H-benzo[d]imidazol-4-yl]methyl}-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Preparation of 1,1-dioxide

[0460]

[0461] (R)-2-[(6-bromo-1-triphenylmethyl-1H-benzo[d]imidazol-4-yl)methyl]-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza A solution of 1,1-dioxane (202.2 mg, 0.30 mmol), bis(pinacol)diboron (83.0 mg, 0.33 mmol), PdCl2(dppf)2-CH2Cl2 (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 under an argon atmosphere for 15.5 h. The reaction solution was allowed to return to room temperature and filtered through diatomaceous earth. The solvent in the filtrate was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 76 / 24 → 55 / 45) to give the compound (170.6 mg), but approximately half of it was unreacted. The obtained compound (0.13 mmol), bis(pinacol)diboron (83.0 mg, 0.33 mmol), PdCl2(dppf)2-CH2Cl2 (12.8 mg, 0.016 mmol), and potassium acetate (90.8 mg, 0.93 mmol) in anhydrous 1,4-dioxane (2.0 mL) were stirred at 90 °C for 15.5 h. The reaction solution was allowed to return to room temperature and filtered through diatomaceous earth. The solvent in the filtrate was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 76 / 24 → 55 / 45) to give the title compound (138.9 mg, 64%) as a white solid.

[0462] 1 H NMR(400MHz, CDCl3)δ7.92(1H,d,J=7.6Hz),7.84(1H,s),7.71(1H,s),7.46(1H,t, J=7.6Hz),7.32-7.28(9H,m),7.21(1H,t,J=7.6Hz),7.16-7.14(7H,m).6.77(1H,s) ,4.81(1H,d,J=14.8Hz),4.58(1H,d,J=14.8Hz),4.06-3.94(2H,m),3.27(1H,d,J=1 4.0Hz), 1.72-1.62(1H,m), 1.49-1.40(1H,m), 1.20(12H,s), 1.03(3H,t,J=7.2Hz).

[0463] See Example 34

[0464] Manufacturing of 5-bromo-3-methylthiophene-2-carboxaldehyde

[0465]

[0466] Bromine (5.0 g, 31 mmol) was added to a solution of 3-methylthiophene-2-carboxaldehyde (3.75 g, 30 mmol) in 25 mL of dichloromethane at 0 °C, and the mixture was stirred at 65 °C for 1 hour. The reaction solution was allowed to return to room temperature, diluted with dichloromethane, and washed with an aqueous solution of sodium thiosulfate, water, and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel chromatography (hexane / ethyl acetate (v / v) = 98 / 2 → 90 / 10), and recrystallized from ethyl acetate / hexane to give the title compound (2.06 g, 33%) as pale yellow crystals. The filtrate was then concentrated, and the precipitate was filtered off with hexane to give the title compound (1.41 g, 23%) as a pale brown solid.

[0467] 1 H NMR (400MHz, CDCl3) δ9.90 (1H,s), 6.96 (1H,s), 2.53 (3H,s).

[0468] See Example 35

[0469] Production of 5-bromo-3-methylthiophene-2-carboxylic acid

[0470]

[0471] A solution of 5-bromo-3-methylthiophene-2-carboxaldehyde (317.1 mg, 1.6 mmol) in acetone (3.0 mL) was cooled to 0 °C. 2.5 M Jones' reagent (3.75 mL, 3.8 mmol) (CrO3 1.01 g, H2SO4 1.0 mL, H2O 3.0 mL) was added, and the mixture was stirred at 0 °C for 5 minutes, then at 25 °C for 2 hours and 15 minutes. Water was added to the reaction solution to stop the reaction. Ethyl acetate was added, and the mixture was separated into an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation to give the title compound (304.2 mg, 89%) as an orange solid.

[0472] 1 H NMR (400MHz, DMSO-d6) δ7.20 (1H, s), 2.43 (3H, s).

[0473] See Example 36

[0474] Manufacturing of 5-bromo-N-methylfuran-2-carboxamide

[0475]

[0476] TEA (439 μL, 3.1 mmol) was added 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). The reaction mixture was stirred at room temperature for 14 hours, then water was added, 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 residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 70 / 30 → 50 / 50) to give the title compound (391.3 mg, 73%) as a white solid.

[0477] 1 H NMR (400MHz, CDCl3) δ7.04 (1H,d,J=3.6Hz), 6.62 (1H,s), 6.42 (1H,d,J=3.6Hz), 2.96 (3H,d,J=4.8Hz).

[0478] See Example 37

[0479] Preparation of (5-bromofuran-2-yl)(pyrrolidone-1-yl)methyl ketone

[0480]

[0481] 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 starting materials, the procedure was the same as in Reference Example 36, and the title compound (748.8 mg, 58%) was obtained as a white solid.

[0482] 1 H NMR (400MHz, CDCl3) δ7.04 (1H, d, J = 3.6Hz), 6.43 (1H, d, J = 3.6Hz), 3.82 (2H, t, J = 6 .8Hz), 3.63(2H,t,J=6.8Hz), 2.01(2H,quin,J=6.8Hz), 1.90(2H,quin,J=6.8Hz).

[0483] See Example 38

[0484] Manufacturing of 5-bromo-N-isopropylfuran-2-carboxamide

[0485]

[0486] 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 procedure was the same as in Reference Example 36, and the title compound (714.3 mg, 59%) was obtained as a colorless oil.

[0487] 1 H NMR (400MHz, CDCl3) δ7.04 (1H, d, J = 3.2Hz), 6.43 (1H, d, J = 3.2Hz), 6.09 (1H, br s), 4.24 (1H, septd, J = 6.4, 1.2Hz), 1.26 (6H, d, J = 6.4Hz).

[0488] See Example 39

[0489] Manufacturing of 5-bromo-N-methylthiophene-2-carboxamide

[0490]

[0491] 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 procedure was the same as in Reference Example 36, and the title compound (239.8 mg, 45%) was obtained as a white solid.

[0492] 1 H NMR (400MHz, CD3OD) δ7.40 (1H,d,J=4.0Hz), 7.13 (1H,d,J=4.0Hz), 2.86 (3H,s).

[0493] See Example 40

[0494] Preparation of 5-bromo-N-(2-methoxyethyl)furan-2-carboxamide

[0495]

[0496] 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 procedure was the same as in Reference Example 36, and the title compound (339.9 mg, 87%) was obtained as a pale yellow oil.

[0497] 1 H NMR (400MHz, CDCl3) δ7.06 (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).

[0498] See Example 41

[0499] Manufacturing of N,3-dimethylfuran-2-carboxamide

[0500]

[0501] 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 procedure was the same as in Reference Example 36, and the title compound (693.6 mg, 87%) was obtained as a colorless oil.

[0502] 1 H NMR (400MHz, CDCl3) δ6.32 (1H, s), 6.28 (1H, br s), 2.95 (3H, d, J = 5.2Hz), 2.40 (3H, s).

[0503] See Example 42

[0504] Manufacturing of 4-bromo-N-methylthiophene-2-carboxamide

[0505]

[0506] 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 starting materials, the procedure was the same as in Reference Example 36, and the title compound (789.1 mg, 74%) was obtained as a white solid.

[0507] 1 H NMR (400MHz, CDCl3) δ7.37 (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).

[0508] See Example 43

[0509] Manufacturing of N,4-dimethylthiophene-2-carboxamide

[0510]

[0511] 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 starting materials, the procedure was the same as in Reference Example 36, and the title compound (880.5 mg, 81%) was obtained as a white solid.

[0512] 1 H NMR (400MHz, CDCl3) δ7.45 (1H, d, J = 1.2Hz), 7.29 (1H, br s), 7.00 (1H, br s), 2.96 (3H, d, J = 4.8Hz), 2.20 (3H, d, J = 0.8Hz).

[0513] See Example 44

[0514] Manufacturing of N-methoxy-N,4-dimethylthiophene-2-carboxamide

[0515]

[0516] 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 procedure was the same as in Reference Example 36, and the title compound (831.5 mg, 91%) was obtained as a colorless oil.

[0517] 1 H NMR (400MHz, CDCl3) δ7.75(1H,d,J=1.6Hz), 7.14(1H,d,J=1.6Hz), 3.76(3H,s), 3.36(3H,s), 2.28(3H,s).

[0518] See Example 45

[0519] Manufacturing of 3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide

[0520]

[0521] Using 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), HOBt (924.3 mg, 6.8 mmol), dichloromethane (20 mL), and DIPEA (1.84 mL, 10 mmol) as starting materials, the procedure was performed in the same manner as in Reference Example 36, and the title compound (604.6 mg, 94%) was obtained as a colorless oil.

[0522] 1 H NMR (400MHz, CDCl3) δ7.38 (1H, dd, J = 5.6, 4.0 Hz), 6.84 (1H, d, J = 5.6 Hz), 3.74 (3H, s), 3.33 (3H, s).

[0523] See Example 46

[0524] Preparation of 5-bromo-N-(2,4-dimethoxybenzyl)thiophene-2-carboxamide

[0525]

[0526] Using 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) as starting materials, the procedure was the same as in Reference Example 36, to obtain the title compound (860.9 mg, quant.) as a colorless oil.

[0527] 1 H NMR (400MHz, CDCl3) δ7.21 (1H, d, J = 8.0Hz), 7.19 (1H, d, J = 4.0Hz), 6.98 (1H, d, J = 4.0Hz), 6.48 (1H, br s), 6.46 (1H, d, J = 2.4Hz), 6.43 (1H, dd, J = 8.0, 2.4Hz), 4.49 (2H, d, J = 5.6Hz), 3.84 (3H, s), 3.79 (3H, s).

[0528] See Example 47

[0529] Preparation of 5-bromo-N-methoxy-N-3-dimethylthiophene-2-carboxamide

[0530]

[0531] TEA (0.57 mL, 4.1 mmol) was added 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), and the mixture was stirred at 25 °C for 18 hours. The reaction solution was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation to give the title compound (315.3 mg, 87%) as a brownish oily substance.

[0532] 1 H NMR (400MHz, CDCl3) δ6.87(1H,s),3.70(3H,s),3.29(3H,s),2.51(3H,s).

[0533] See Example 48

[0534] Bromo-N-methoxy-N-methylthiazol-5-carboxamide

[0535]

[0536] TEA (1.5 mL, 11 mmol) was added to a solution of 2-bromothiazol-5-carboxylic acid (707.9 mg, 3.4 mmol), N,O-dimethylhydroxylamine hydrochloride (667.5 mg, 6.8 mmol), EDCI (977.9 mg, 5.1 mmol) in dichloromethane (17 mL) and DMF (3.0 mL), 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 1 M hydrochloric acid and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation to give the title compound (519.1 mg, 61%) as a pale yellow solid.

[0537] 1 H NMR (400MHz, CDCl3) δ8.32(1H,s),3.78(3H,s),3.36(3H,s).

[0538] See Example 49

[0539] Preparation of 2-bromo-N-methoxy-N,4-dimethylthiazol-5-carboxamide

[0540]

[0541] TEA (1.0 mL, 7.2 mmol) was added to a solution of 2-bromo-4-methylthiazol-5-carboxylic acid (500.2 mg, 2.3 mmol), N,O-dimethylhydroxylamine hydrochloride (452.8 mg, 4.6 mmol), EDCI (654.6 mg, 3.4 mmol) in dichloromethane (8.0 mL) and DMF (2.0 mL), and the mixture was stirred at 25 °C for 8 hours. The reaction solution was diluted with ethyl acetate and washed with 1 M hydrochloric acid and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation to give the title compound (473.5 mg, 79%) as a white solid.

[0542] 1 H NMR (400MHz, CDCl3) δ3.66(3H,s), 3.26(3H,s), 2.68(3H,s).

[0543] See Example 50

[0544] Preparation of 4-bromo-N-methoxy-N-methylthiophene-2-carboxamide

[0545]

[0546] Using 4-bromothiophene-2-carboxylic acid (500 mg, 2.4 mmol), N,O-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 procedure was the same as in Reference Example 36, to obtain the title compound (510.5 mg, 85%) as a colorless oil.

[0547] 1 H NMR (400MHz, CDCl3) δ7.83(1H,d,J=1.6Hz), 7.44(1H,d,J=1.6Hz), 3.78(3H,s), 3.37(3H,s).

[0548] See Example 51

[0549] Manufacturing of 2-bromo-N-methoxy-N-methylthiophene-3-carboxamide

[0550]

[0551] Using 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) as starting materials, the procedure was the same as in Reference Example 36, to obtain the title compound (606.7 mg, quant.) as a colorless oil.

[0552] 1 H NMR (400MHz, CDCl3) δ7.25 (1H,d,J=6.0Hz), 7.04 (1H,d,J=6.0Hz), 3.60 (3H,s), 3.34 (3H,s).

[0553] See Example 52

[0554] Preparation of 5-bromo-N-methoxy-N-methylfuran-2-carboxamide

[0555]

[0556] 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 procedure was the same as in Reference Example 36, and the title compound (555.3 mg, 90%) was obtained as a colorless oil.

[0557] 1 H NMR (400MHz, CDCl3) δ7.08 (1H,d,J=3.6Hz), 6.44 (1H,d,J=3.6Hz), 3.77 (3H,s), 3.33 (3H,s).

[0558] See Example 53

[0559] Preparation of N-[(5-bromofuran-2-yl)methyl]propane-2-amine

[0560]

[0561] Isopropylamine (514 μL, 6.0 mmol) and acetic acid (50 μL, 0.79 mmol) were added to a methanol (7.0 mL) solution of 5-bromofuran-2-carboxaldehyde (700 mg, 4.0 mmol), and the mixture was stirred at room temperature for 2 hours. Sodium borohydride (227 mg, 6.0 mmol) was then added to the mixture, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with a 1 N aqueous solution of sodium hydroxide and extracted with dichloromethane. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (785.4 mg, 90%) as a pale yellow oil.

[0562] 1 H NMR (400MHz, CDCl3) δ6.21 (1H, d, J = 3.2Hz), 6.15 (1H, d, J = 3.2Hz), 3.75 (2H, s), 2.82 (1H, septd, J = 6.4Hz), 1.38 (1H, br s), 1.06 (6H, d, J = 6.4Hz).

[0563] See Example 54

[0564] Preparation of 5-(tert-butyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrole-6-one

[0565]

[0566] In a solution of 4.14 g (30 mmol) of 2,3-thiophene dicarboxaldehyde 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. The mixture was stirred at 0 °C for 15 minutes, and then stirred at room temperature for 3.5 hours. After the reaction was complete, the reaction solution was washed with 1 M hydrochloric acid and saturated sodium bicarbonate aqueous solution. The resulting organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 84 / 16 → 63 / 37) to give the title compound (4.03 g, 70%) as a pale orange solid.

[0567] 1 H NMR (400MHz, CDCl3) δ7.56 (1H, d, J = 4.8Hz), 6.99 (1H, d, J = 4.8Hz), 4.36 (2H, s), 1.54 (9H, s)

[0568] See Example 55

[0569] Preparation of 2-bromo-1,5,6,7-tetrahydro-4H-indole-4-one

[0570]

[0571] N-bromosuccinimide (475.2 mg, 2.7 mmol) was added to a DMF (3.0 mL) solution of 1,5,6,7-tetrahydro-4H-indol-4-one (300 mg, 2.2 mmol), and the mixture was stirred at room temperature for 14 hours. An aqueous solution of 4N 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 6 / 4 → 5 / 5) to give the title compound (220.5 mg, 76%) as a white solid.

[0572] 1 H NMR (400MHz, CDCl3) δ8.49 (1H, br s), 6.51 (1H, d, J = 2.4Hz), 2.79 (2H, t, J = 6.4Hz), 2.48 (2H, t, J = 6.4Hz), 2.15 (2H, quin, J = 6.4Hz).

[0573] See Example 56

[0574] Preparation of 5-bromo-N,3-dimethylfuran-2-carboxamide

[0575]

[0576] Using 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) as starting materials, the procedure was the same as in Reference Example 55, and the title compound (205.3 mg, 42%) was obtained as a yellow oil.

[0577] 1 H NMR (400MHz, CDCl3) δ6.28 (1H, br s), 6.27 (1H, s), 2.95 (3H, d, J = 4.8Hz), 2.37 (3H, s).

[0578] See Example 57

[0579] Preparation of 5-bromo-N,4-dimethylthiophene-2-carboxamide

[0580]

[0581] Using 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) as starting materials, the procedure was the same as in Reference Example 55, and the title compound (763.8 mg, 84%) was obtained as a white solid.

[0582] 1 H NMR (400MHz, CDCl3) δ7.19 (1H, s), 6.23 (1H, br s), 2.95 (3H, d, J = 4.8Hz), 2.18 (3H, s).

[0583] See Example 58

[0584] Preparation of 1-(5-bromo-2,4-dimethyl-1H-pyrrolo-3-yl)ethane-1-one

[0585]

[0586] Using 1-(2,4-dimethyl-1H-pyrrolo-3-yl)ethane-1-one (500 mg, 3.6 mmol), DMF (5.0 mL), and N-bromosuccinimide (778 mg, 4.4 mmol) as starting materials, the procedure was the same as in Reference Example 55, and the title compound (538.9 mg, 68%) was obtained as a red solid.

[0587] 1H NMR (400MHz, CDCl3) δ8.16(1H,br s),2.49(3H,s),2.42(3H,s),2.22(3H,s).

[0588] See Example 59

[0589] Preparation of 1-(5-bromo-4-methylthiophen-2-yl)ethane-1-one

[0590]

[0591] Using 1-(4-methylthiophen-2-yl)ethane-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) as starting materials, the procedure was the same as in Reference Example 55, and the title compound (118.6 mg, 76%) was obtained as a pale yellow solid.

[0592] 1 H NMR (400MHz, CDCl3) δ7.36(1H,s),2.48(3H,s),2.22(3H,s).

[0593] See Example 60

[0594] Manufacturing of 5-bromo-3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide

[0595]

[0596] N-bromosuccinimide (1.17 g, 6.6 mmol) and TFA (1.0 mL, 13 mmol) were added to a DMF (6.0 mL) solution of 3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (620 mg, 3.3 mmol). The reaction mixture was stirred at room temperature for 24 hours, then extracted with ethyl acetate after adding 1 N aqueous sodium hydroxide solution. The organic layer was washed with water, 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) = 100 / 0 → 80 / 20) to give the title compound (425.5 mg, 48%) as a colorless oil.

[0597] 1 H NMR (400MHz, CDCl3) δ6.89(1H,s),3.75(3H,s),3.30(3H,s).

[0598] See Example 61

[0599] Preparation of 1-(5-bromo-2,4-dimethyl-1H-pyrrolo-3-yl)ethane-1-one

[0600]

[0601] Using 1-(2,4-dimethyl-1H-pyrrolo-3-yl)ethane-1-one (500 mg, 3.6 mmol), DMF (5.0 mL), and N-bromosuccinimide (778 mg, 4.4 mmol) as starting materials, the procedure was the same as in Reference Example 55, and the title compound (538.9 mg, 68%) was obtained as a red solid.

[0602] 1 H NMR (400MHz, CDCl3) δ8.16(1H,br s),2.49(3H,s),2.42(3H,s),2.22(3H,s).

[0603] See Example 62

[0604] Preparation of 1-(5-bromo-1-ethyl-1H-pyrrole-2-yl)ethane-1-one

[0605]

[0606] Using 1-(1-ethyl-1H-pyrrolo-2-yl)ethane-1-one (600 μL, 4.3 mmol), DMF (6.0 mL), and N-bromosuccinimide (925 mg, 5.2 mmol) as starting materials, the procedure was the same as in Reference Example 55, to obtain the title compound (752 mg, 80%) as a colorless oil.

[0607] 1 H NMR (400MHz, CDCl3) δ6.91 (1H, d, J = 1.6Hz), 6.85 (1H, d, J = 1.6Hz), 4.33 (2H, q, J = 7.2Hz), 2.40 (3H, s), 1.35 (3H, t, J = 7.2Hz).

[0608] See Example 63

[0609] Manufacturing of (5-bromothiophene-2-yl)(cyclopropyl) methyl ketone

[0610]

[0611] Using cyclopropyl(thiophen-2-yl) methyl ketone (593 μL, 4.6 mmol), DMF (5.8 mL), N-bromosuccinimide (979 mg, 5.5 mmol) and TFA (704 μL, 9.2 mmol) as starting materials, the procedure was the same as in Reference Example 55, and the title compound (56.8 mg, 5%) was obtained as a pale red oil.

[0612] 1 H NMR (400MHz, CDCl3) δ7.55(1H,d,J=4.0Hz), 7.12(1H,d,J=4.0Hz), 2.47-2.41(1H,m), 1.25-1.21(2H,m), 1.05-1.01(2H,m).

[0613] See Example 64

[0614] Preparation of 2-bromo-5-(tert-butyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrole-6-one

[0615]

[0616] N-bromosuccinimide (7.37 g, 41 mmol) and acetic acid (1.3 mL, 23 mmol) were added to a DMF (100 mL) solution of 5-(tert-butyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrole-6-one (4.03 g, 21 mmol) at 0 °C, and the mixture was stirred at room temperature for 8 hours. The reaction was stopped by adding a saturated aqueous sodium bicarbonate solution to the reaction solution, and the mixture was extracted with ethyl acetate / hexane (1 / 1). The resulting organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 96 / 4 → 75 / 25) to give the title compound (4.27 g, 76%) as a pale yellow solid.

[0617] 1 H NMR (400MHz, CDCl3) δ7.01 (1H,s), 4.33 (2H,s), 1.53 (9H,s).

[0618] See Example 65

[0619] Preparation of 4-bromo-1-methyl-1H-pyrrole-2-onitrile

[0620]

[0621] Using 1-methyl-1H-pyrrolo-2-onitrile (300 mg, 2.8 mmol), DMF (7.0 mL), and N-bromosuccinimide (604.5 mg, 3.4 mmol) as starting materials, the procedure was the same as in Reference Example 55, and the title compound (212.5 mg, 41%) was obtained as a white solid.

[0622] 1 H NMR (400MHz, CDCl3) δ6.81 (1H,d,J=1.6Hz), 6.75 (1H,d,J=1.6Hz), 3.76 (3H,s).

[0623] See Example 66

[0624] Preparation of 2-bromo-1-methyl-1,5,6,7-tetrahydro-4H-indol-4-one

[0625]

[0626] 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 min. Iodomethane (86 μL, 1.4 mmol) was added, and the mixture was stirred at 60 °C for 7 h. 1 N hydrochloric acid was added to the mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, 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) = 7 / 3 → 1 / 1) to give the title compound (170.1 mg, 80%) as a pale yellow solid.

[0627] 1 H NMR (400MHz, CDCl3) δ6.52 (1H, s), 3.50 (3H, s), 2.73 (2H, t, J = 6.4Hz), 2.41 (2H, t, J = 6.4Hz), 2.14 (2H, quin, J = 6.4Hz).

[0628] See Example 67

[0629] Preparation of 1-(5-bromo-1,2,4-trimethyl-1H-pyrrolo-3-yl)ethane-1-one

[0630]

[0631] 1-(5-bromo-2,4-dimethyl-1H-pyrrolo-3-yl)ethane-1-one (300 mg, 1.4 mmol) was added to a solution of sodium hydride (50.4 mg, 1.7 mmol) in DMF (4.0 mL). The mixture was stirred at room temperature for 1 hour, and iodomethane (105 μL, 1.7 mmol) was added, followed by stirring for 20 hours. Iodomethane (86 μL, 1.4 mmol) was added further, and the mixture was stirred at 60 °C for 7 hours. Water was added to the mixture to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 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) = 0 → 9 / 1) to give the title compound (152.8 mg, 48%) as a pale red solid.

[0632] 1 H NMR (400MHz, CDCl3) δ3.50(3H,s),2.50(3H,s),2.41(3H,s),2.24(3H,s).

[0633] See Example 68

[0634] Preparation of 1-(5-bromo-3-fluorothiophene-2-yl)ethane-1-one

[0635]

[0636] A solution of methyl magnesium bromide (3M, 2-methyltetrahydrofuran) (0.80 mL, 2.4 mmol) was added to a THF (8.0 mL) solution of 5-bromo-3-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (425 mg, 1.6 mmol) at 0 °C. The mixture was stirred at room temperature for 7.5 hours, and the reaction was stopped with a saturated aqueous ammonium chloride solution. The mixture was then extracted with diethyl ether. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (190.8 mg, 54%) as a colorless oil.

[0637] 1 H NMR (400MHz, CDCl3) δ6.90 (1H,d,J=0.8Hz), 2.52 (3H,d,J=3.2Hz).

[0638] See Example 69

[0639] Preparation of 1-(4-methylthiophen-2-yl)ethane-1-one

[0640]

[0641] Using N-methoxy-N,4-dimethylthiophene-2-carboxamide (400 mg, 2.2 mmol), THF (11 mL), and methyl magnesium bromide (3 M, 2-methyltetrahydrofuran solution) (1.1 mL, 3.2 mmol) as starting materials, the procedure was the same as in Reference Example 68, and the title compound (275.1 mg, 91%) was obtained as a colorless oil.

[0642] 1 H NMR (400MHz, CDCl3) δ7.50 (1H, d, J = 0.8Hz), 7.22 (1H, br d, J = 0.8Hz), 2.53 (3H, s), 2.29 (3H, d, J = 0.8Hz).

[0643] See Example 70

[0644] Preparation of 1-(5-bromo-3-methylthiophen-2-yl)ethane-1-one

[0645]

[0646] Using 5-bromo-N-methoxy-N,3-dimethylthiophene-2-carboxamide (368 mg, 1.4 mmol), THF (7.0 mL), and methyl magnesium bromide (3 M, 2-methyltetrahydrofuran solution) (0.70 mL, 2.1 mmol) as starting materials, the procedure was the same as in Reference Example 68, and the title compound (216.1 mg, 71%) was obtained as a yellow oil.

[0647] 1 H NMR (400MHz, CDCl3) δ6.93(1H,s),2.51(3H,s),2.47(3H,s).

[0648] See Example 71

[0649] Preparation of 1-(2-bromothiazol-5-yl)ethane-1-one

[0650]

[0651] A solution of methyl magnesium bromide (3M, 2-methyltetrahydrofuran solution) (0.68 mL, 2.0 mmol) was added to a THF solution of 2-bromo-N-methoxy-N-methylthiazol-5-carboxamide (507.5 mg, 2.0 mmol) in 7.0 mL of THF, and the mixture was stirred at 25 °C for 1 hour. Magnesium methyl bromide (3M, 0.15 mL, 0.45 mmol) was then added, and the mixture was 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 brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation to give the title compound (278 mg, 67%) as a pale yellow solid.

[0652] 1 H NMR (400MHz, CDCl3) δ8.05, (1H, s), 2.56 (3H, s).

[0653] See Example 72

[0654] Preparation of 1-(2-bromo-4-methylthiazo-5-yl)ethane-1-one

[0655]

[0656] A solution of methyl magnesium bromide (3M, 2-methyltetrahydrofuran) (0.3 mL, 0.9 mmol) in THF (2.0 mL) was added to the reaction solution at 0 °C, and the mixture was stirred at room temperature for 10 min. The reaction was stopped by adding saturated ammonium chloride aqueous solution, 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 vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 82 / 18 → 61 / 39) to give the title compound (146.8 mg, 85%) as a yellow, transparent oil.

[0657] 1 H NMR (400MHz, CDCl3) δ2.72(3H,s),2.51(3H,s).

[0658] See Example 73

[0659] Preparation of 1-(4-bromothiophen-2-yl)ethane-1-one

[0660]

[0661] Using 4-bromo-N-methoxy-N-methylthiophene-2-carboxamide (510 mg, 2.0 mmol), THF (10 mL), and methyl magnesium bromide (3 M, 2-methyltetrahydrofuran solution) (1.0 mL, 3.0 mmol) as starting materials, the procedure was the same as in Reference Example 68, and the title compound (406.9 mg, 97%) was obtained as a colorless oil.

[0662] 1 H NMR (400MHz, CDCl3) δ7.58 (1H,d,J=1.2Hz), 7.53 (1H,d,J=1.2Hz), 2.55 (3H,s).

[0663] See Example 74

[0664] Preparation of 1-(2-bromothiophen-3-yl)ethane-1-one

[0665]

[0666] Using 2-bromo-N-methoxy-N-methylthiophene-3-carboxamide (550 mg, 2.2 mmol), THF (10 mL), and methyl magnesium bromide (3 M, 2-methyltetrahydrofuran solution) (1.1 mL, 3.3 mmol) as starting materials, the procedure was the same as in Reference Example 68, and the title compound (128.8 mg, 29%) was obtained as a colorless oil.

[0667] 1 H NMR (400MHz, CDCl3) δ7.35 (1H, d, J = 5.6Hz), 7.23 (1H, d, J = 5.6Hz), 2.62 (3H, s).

[0668] See Example 75

[0669] Preparation of 1-(5-bromofuran-2-yl)ethane-1-one

[0670]

[0671] Using 5-bromo-N-methoxy-N-methylfuran-2-carboxamide (332.6 mg, 1.4 mmol), THF (7.0 mL), and methyl magnesium bromide (3 M, 2-methyltetrahydrofuran solution) (0.7 mL, 2 mmol) as starting materials, the procedure was the same as in Reference Example 68, and the title compound (223.3 mg, 78%) was obtained as a white solid.

[0672] 1H NMR (400MHz, CDCl3) δ7.12 (1H,d,J=3.6Hz), 6.49 (1H,d,J=3.6Hz), 2.46 (3H,s).

[0673] See Example 76

[0674] Preparation of 2-(5-bromothiophene-2-yl)-2-methyl-1,3-dioxapentane

[0675]

[0676] Ethylene glycol (0.95 mL, 17 mmol) and p-TsOH-H₂O (130 mg, 0.68 mmol) were added to a toluene (34 mL) solution of 1-(5-bromothiophene-2-yl)ethane-1-one (500 mg, 2.4 mmol), and the mixture was stirred under reflux for 25 hours. A saturated aqueous solution of sodium bicarbonate 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 95 / 5 → 9 / 1) to give the title compound (183.7 mg, 30%) as a white solid.

[0677] 1 H NMR (400MHz, CDCl3) δ6.90 (1H, d, J = 4.0Hz), 6.79 (1H, d, J = 4.0Hz), 4.06-4.00 (m, 2H), 3.99-3.93 (m, 2H), 1.73 (s, 3H).

[0678] See Example 77

[0679] Preparation of 2-(5-bromo-3-methylthiophen-2-yl)-2-methyl-1,3-dioxanepentadienone

[0680]

[0681] Ethylene glycol (1.2 mL, 22 mmol) and p-TsOH-H2O (0.11 mmol) were added to a toluene (20 mL) solution of 1-(5-bromo-3-methylthiophen-2-yl)ethane-1-one (491.5 mg, 2.2 mmol), and the mixture was stirred under reflux for 10 hours. The reaction solution was allowed to return to room temperature, and a saturated aqueous solution of sodium bicarbonate was added. 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 vacuum distillation, yielding the title compound (577.9 mg, 98%) as a yellow, transparent oil.

[0682] 1H NMR (400MHz, CDCl3) δ6.74(1H,s),4.06-3.99(2H,m),3.96-3.90(2H,m),2.23(3H,s),1.71(3H,s).

[0683] See Example 78

[0684] Preparation of 2-bromo-5-(2-methyl-1,3-dioxapentan-2-yl)thiazole

[0685]

[0686] Ethylene glycol (800 μL) and p-TsOH-H₂O (12.7 mg, 0.067 mmol) were added to a toluene (8.0 mL) solution of 1-(2-bromothiazol-5-yl)ethane-1-one (278 mg, 1.3 mmol), and the mixture was stirred under reflux for 14 hours. The reaction solution was allowed to return to room temperature, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to separate the organic and aqueous layers. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and the solvent was removed by vacuum distillation to give the title compound (313.6 mg, 93%) as a yellow oil.

[0687] 1 H NMR (400MHz, CDCl3) δ7.49(1H,s),4.13-4.03(2H,m),3.99-3.91(2H,m),1.75(3H,s).

[0688] See Example 79

[0689] Preparation of 2-bromo-4-methyl-5-(2-methyl-1,3-dioxapentan-2-yl)thiazole

[0690]

[0691] Ethylene glycol (0.40 mL) and p-TsOH-H₂O (6.3 mg, 0.033 mmol) were added to a toluene (8.0 mL) solution of 1-(2-bromo-4-methylthiazo-5-yl)ethane-1-one (146.8 mg, 0.67 mmol), and the mixture was stirred under reflux for 21 hours. The reaction solution was allowed to return to room temperature, and a saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was removed by vacuum distillation. Since the reaction did not proceed completely, toluene (8.0 mL), ethylene glycol (0.80 mL), and p-TsOH-H₂O (5.7 mg, 0.030 mmol) were added to the residue, and the mixture was stirred under reflux for 13 hours. The reaction solution was allowed to return to room temperature, and a saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was removed by vacuum distillation, yielding the title compound (172.2 mg, 98%) as an orange oil.

[0692] 1 H NMR (400MHz, CDCl3) δ4.09-4.01(2H,m),3.94-3.88(2H,m),2.43(3H,s),1.71(3H,s).

[0693] See Example 80

[0694] Preparation of 2-(5-bromofuran-2-yl)-2-methyl-1,3-dioxapentane

[0695]

[0696] Using 1-(5-bromofuran-2-yl)ethane-1-one (533.5 mg, 2.8 mmol), ethylene glycol (1.7 mL, 31 mmol), p-TsOH-H2O (27 mg, 0.14 mmol), and toluene (32 mL) as starting materials, the procedure was the same as in Reference Example 76, to obtain the title compound (496.3 mg, 76%) as a colorless oil.

[0697] 1 H NMR (400MHz, CDCl3) δ6.29(1H,d,J=3.2Hz), 6.23(1H,d,J=3.2Hz), 4.07-4.03(2H,m), 4.01-3.97(2H,m), 1.71(3H,s).

[0698] See Example 81

[0699] Preparation of 2-(5-bromothiophene-3-yl)-2-methyl-1,3-dioxapentane

[0700]

[0701] Using 1-(5-bromothiophene-3-yl)ethane-1-one (398 mg, 1.9 mmol), ethylene glycol (1.08 mL, 19 mmol), p-TsOH-H2O (18.5 mg, 0.097 mmol), and toluene (22 mL) as starting materials, the procedure was the same as in Reference Example 76, to obtain the title compound (322.2 mg, 67%) as a colorless oil.

[0702] 1 H NMR (400MHz, CDCl3) δ7.17(1H,d,J=1.6Hz), 7.02(1H,d,J=1.6Hz), 4.07-3.98(2H,m), 3.91-3.82(2H,m), 1.64(3H,s).

[0703] See Example 82

[0704] Preparation of 1-(5-bromothiophene-3-yl)ethane-1-ol

[0705]

[0706] In a solution of 5-bromothiophene-3-carboxaldehyde (200 μL, 1.8 mmol) in 8.0 mL of THF, 907 μL (2.7 mol) of methyl magnesium bromide (3 M, 2-methyltetrahydrofuran solution) was added at 0 °C, and the mixture was stirred at room temperature for 1.5 h. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride, 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 by distillation under reduced pressure to give the title compound (503.8 mg, quant.) as a white solid.

[0707] 1 H NMR (400MHz, CDCl3) δ6.97 (1H, d, J = 0.8Hz), 6.94 (1H, br s), 4.76 (1H, q, J = 6.4Hz), 2.20 (1H, br s), 1.38 (3H, d, J = 6.4Hz).

[0708] See Example 83

[0709] Preparation of 1-(5-bromothiophen-3-yl)ethane-1-one

[0710]

[0711] A solution of 1-(5-bromothiophene-3-yl)ethane-1-ol (503.8 mg, 1.8 mmol) in DMSO (8.0 mL) was mixed with TEA (868 μL, 6.2 mmol) and a pyridine-sulfur trioxide complex (832 mg, 5.2 mmol) and stirred at room temperature for 6 hours. The mixture was diluted with water and 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. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 95 / 5 → 80 / 20) to give the title compound (397.2 mg, quant.) as a white solid.

[0712] 1 H NMR (400MHz, CDCl3) δ7.91 (1H,d,J=1.6Hz), 7.49 (1H,d,J=1.6Hz), 2.49 (3H,s).

[0713] See Example 84

[0714] Preparation of 5-(2-methyl-1,3-dioxapentan-2-yl)thiazolyl-2-carboxaldehyde

[0715]

[0716] A solution of 2-bromo-5-(2-methyl-1,3-dioxapentane-2-yl)thiazole (215.2 mg, 0.86 mmol) in anhydrous THF (2.5 mL) was cooled to -78 °C, and 0.6 mL (0.96 mmol) of n-butyllithium (1.6 M hexane solution) was added. The mixture was stirred at -78 °C for 30 min. Anhydrous DMF (240 μL, 3.1 mmol) was added to the reaction solution, and the mixture was stirred at -78 °C for 15 min, then heated to -60 °C and stirred for another 50 min. A saturated aqueous solution of ammonium chloride was added to the reaction solution at -60 °C, and the mixture was extracted with diethyl ether, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to give the title compound (96.0 mg, 56%) as a yellow, transparent oil.

[0717] 1 H NMR (400MHz, CDCl3) δ9.93(1H,s),8.01(1H,s),4.12-4.06(2H,m),3.99-3.93(2H,m),1.80(3H,s).

[0718] See Example 85

[0719] Preparation of 2-bromo-4,5-dihydro-6H-thieno[2,3-c]pyrrole-6-one

[0720]

[0721] A solution of 3.78 g, 14 mmol of 2-bromo-5-(tert-butyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrolo-6-one (TFA) in 50 mL of water was stirred at 105 °C for 19 hours. The reaction solution was cooled to room temperature, concentrated by vacuum distillation, and the residue was extracted with ethyl acetate after adding a saturated aqueous solution of sodium bicarbonate. The resulting organic layer was dried over sodium sulfate and the solvent was removed by vacuum distillation, yielding the title compound (3.25 g, quant.) as a brown solid.

[0722] 1 H NMR (400MHz, CDCl3) δ7.08 (1H, s), 6.16 (1H, br s), 4.36 (2H, s).

[0723] See Example 86

[0724] Preparation of 1-(5-bromo-3-fluorothiophene-2-yl)ethane-1-ol

[0725]

[0726] Sodium borohydride (203.5 mg, 5.4 mmol) was added to a methanol (3.6 mL) solution of 1-(5-bromo-3-fluorothiophene-2-yl)ethane-1-one (600.7 mg, 2.7 mmol), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated under reduced pressure. The reaction was stopped with an aqueous solution of 4N sodium hydroxide and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (588.5 mg, 86%) as a pale red oil.

[0727] 1 H NMR (400MHz, CDCl3) δ6.75 (1H, br s), 5.22-5.17 (1H, m), 2.00 (1H, d, J = 4.0Hz), 1.54 (1H, d, J = 6.4Hz).

[0728] See Example 87

[0729] Preparation of [1-(5-bromo-3-fluorothiophene-2-yl)ethoxy](tert-butyl)dimethylsilane

[0730]

[0731] A solution of tert-butyldimethylchlorosilane (417.5 mg, 2.8 mmol) in DMF (4.1 mL) was added to a solution of 1-(5-bromo-3-fluorothiophene-2-yl)ethane-1-ol (588.5 mg, 2.3 mmol) and imidazole (204.4 mg, 3.0 mmol) in DMF (1.5 mL) at 0 °C, and the mixture was 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 brine, 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) = 1 / 0 → 95 / 5) to give the title compound (581 mg, 74%) as a colorless oil.

[0732] 1 H NMR (400MHz, CDCl3) δ6.70 (1H, br s), 5.13 (1H, qd, J = 6.4, 1.2Hz), 1.45 (3H, d, J = 6.4Hz), 0.91 (9H, s), 0.082 (3H, s), 0.036 (3H, s).

[0733] See Example 88

[0734] Manufacturing of (E)-3-[5-(methylcarbamoyl)furan-2-yl]methyl acrylate

[0735]

[0736] A solution of 5-bromo-N-methylfuran-2-carboxamide (163.3 mg, 0.80 mmol), tetrabutylammonium chloride (32.7 mg, 0.04 mmol), and PdCl2(dppf)2-CH2Cl2 (22.2 mg, 0.08 mmol) in DMA (1.4 mL) was mixed with methyl acrylate (215 μL, 2.4 mmol) and N,N-dicyclohexylmethylamine (515 μL, 2.4 mmol) and stirred at 110 °C for 17 h. 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 3 / 2 → 2 / 3) to give the title compound (103.8 mg, 62%) as a pale yellow solid.

[0737] 1H NMR (400MHz, CDCl3) δ7.41 (1H, d, J = 16.0Hz), 7.13 (1H, d, J = 3.6Hz), 6.67 (1H, d, J = 3.6Hz), 6.52 (1H, br s), 6.41 (1H, d, J = 16.0Hz), 3.80 (3H, s), 3.01 (3H, d, J = 4.8Hz).

[0738] See Example 89

[0739] Manufacturing of (E)-3-[5-(pyrrolidine-1-carbamoyl)furan-2-yl]methyl acrylate

[0740]

[0741] Using (5-bromofuran-2-yl)(pyrrolidine-1-yl) methyl ketone (583 mg, 2.4 mmol), tetrabutylammonium chloride (66.7 mg, 0.24 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was performed in the same manner as in Reference Example 88, and the title compound (478.2 mg, 80%) was obtained as an amber solid.

[0742] 1 H NMR (400MHz, CDCl3) δ7.44(1H,d,J=16.0Hz), 7.14(1H,d,J=3.6Hz), 6.71(1H,d,J=3.6Hz), 6.37(1H,d,J=16.0Hz ), 3.90(2H,t,J=6.8Hz), 3.80(3H,s), 3.65(2H,t,J=6.8Hz), 2.05(2H,quin,J=6.8Hz), 1.92(2H,quin,J=6.8Hz).

[0743] Reference Example 90

[0744] Manufacturing of (E)-3-[5-(isopropylcarbamoyl)furan-2-yl]methyl acrylate

[0745]

[0746] Using 5-bromo-N-isopropylfuran-2-carboxamide (546.2 mg, 2.4 mmol), tetrabutylammonium chloride (65.3 mg, 0.24 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was performed in the same manner as in Reference Example 88, and the title compound (411.6 mg, 74%) was obtained as a white solid.

[0747] 1 H NMR (400MHz, CDCl3) δ7.43 (1H, d, J = 16.0Hz), 7.13 (1H, d, J = 3.6Hz), 6.68 (1H, d, J = 3.6Hz), 6.43 (1H, d, J = 16.0Hz), 6.15 (1H, br s), 4.27 (1H, septd, J = 6.4, 1.2Hz), 3.82 (3H, s), 1.28 (6H, d, J = 6.4Hz).

[0748] See Example 91

[0749] Manufacturing of (E)-3-[5-(methylcarbamoyl)thiophen-2-yl]methyl acrylate

[0750]

[0751] Using 5-bromo-N-methylthiophene-2-carboxamide (239 mg, 1.1 mmol), tetrabutylammonium chloride (30.6 mg, 0.11 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 88, and the title compound (16.1 mg, 7%) was obtained as a white solid.

[0752] 1 H NMR (400MHz, CDCl3) δ7.72(1H,d,J=15.6Hz),7.39(1H,d,J=3.6Hz),7.19(1H,d,J=3.6Hz),6.31(1H,d,J=15.6Hz),5.96(1H,br s), 3.80 (3H, s), 3.01 (3H, d, J = 4.8Hz).

[0753] See Example 92

[0754] Manufacturing of (E)-3-{5-[(2-methoxyethyl)carbamoyl]furan-2-yl}methyl acrylate

[0755]

[0756] Using 5-bromo-N-(2-methoxyethyl)furan-2-carboxamide (270 mg, 1.1 mmol), tetrabutylammonium chloride (27 mg, 0.097 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was performed in the same manner as in Reference Example 88, and the title compound (221.6 mg, 88%) was obtained as an amber-colored oil.

[0757] 1 H NMR (400MHz, CDCl3) δ7.42 (1H, d, J = 16.0Hz), 7.14 (1H, d, J = 3.6Hz), 6.88 (1H, br s), 6.69 (1H, d, J = 3.6Hz), 6.46 (1H, d, J = 16.0Hz), 3.81 (3H, s), 3.66-3.62 (2H, m), 3.58-3.55 (2H, m), 3.41 (3H, s).

[0758] See Example 93

[0759] Manufacturing of (E)-3-(5-acetylthiophene-2-yl)methyl acrylate

[0760]

[0761] Using 1-(5-bromothiophene-2-yl)ethane-1-one (700 mg, 3.4 mmol), tetrabutylammonium chloride (95 mg, 0.34 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was performed in the same manner as in Reference Example 88, and the title compound (304.8 mg, 43%) was obtained as a white solid.

[0762] 1H NMR (400MHz, CDCl3) δ7.73 (1H,d,J=16.0Hz), 7.60 (1H,d,J=4.0Hz), 7.24 (1H,d,J=4.0Hz), 6.39 (1H,d,J=16.0Hz), 3.81 (3H,s), 2.56 (3H,s).

[0763] See Example 94

[0764] Manufacturing of (E)-3-[4-methyl-5-(methylcarbamoyl)furan-2-yl]methyl acrylate

[0765]

[0766] Using 5-bromo-N,3-dimethylfuran-2-carboxamide (200 mg, 0.92 mmol), tetrabutylammonium chloride (26 mg, 0.092 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was performed in the same manner as in Reference Example 88, and the title compound (99.6 mg, 48%) was obtained as a white solid.

[0767] 1 H NMR (400MHz, CDCl3) δ7.36 (1H,d,J=15.6Hz), 6.53 (1H,s), 6.36 (1H,d,J=15.6Hz), 6.34 (1H,br s), 3.80 (3H,s), 2.98 (3H,d,J=5.2Hz), 2.39 (3H,s).

[0768] See Example 95

[0769] Manufacturing of (E)-3-(5-aminosulfonylthiophene-2-yl)methyl acrylate

[0770]

[0771] Using 5-bromothiophene-2-sulfonamide (593.2 mg, 2.5 mmol), tetrabutylammonium chloride (68.1 mg, 0.25 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 88, and the title compound (163.7 mg, 27%) was obtained as a yellow solid.

[0772] 1 H NMR (400MHz, CD3OD) δ7.80 (1H,d,J=16.0Hz), 7.55 (1H,d,J=4.0Hz), 7.37 (1H,d,J=4.0Hz), 6.42 (1H,d,J=16.0Hz), 3.81 (3H,s).

[0773] See Example 96

[0774] Manufacturing of (E)-3-(thiophene-2-yl)methyl acrylate

[0775]

[0776] Using 2-bromothiophene (235 μL, 2.5 mmol), tetrabutylammonium chloride (68.1 mg, 0.25 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was performed in the same manner as in Reference Example 88, and the title compound (332.9 mg, 81%) was obtained as a white solid.

[0777] 1 H NMR (400MHz, CDCl3) δ7.79 (1H, d, J = 16.0Hz), 7.37 (1H, d, J = 5.2Hz), 7.25 (1H, d, J = 3.6Hz), 7.05 (1H, dd, J = 5.2, 3.6Hz), 6.24 (1H, d, J = 16.0Hz), 3.79 (3H, s).

[0778] See Example 97

[0779] Manufacturing of (E)-3-[5-(methylcarbamoyl)thiophen-3-yl]methyl acrylate

[0780]

[0781] Using 4-bromo-N-methylthiophene-2-carboxamide (500 mg, 2.3 mmol), tetrabutylammonium chloride (64 mg, 0.23 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 88, and the title compound (213.7 mg, 42%) was obtained as a white solid.

[0782] 1 H NMR (400MHz, CDCl3) δ7.63(1H,s),7.60(1H,d,J=16.0Hz),7.58(1H,s),6.27(1H,d,J=16.0Hz),6.04(1H,br s),3.80(3H,s),3.01(3H,d,J=4.8Hz).

[0783] See Example 98

[0784] Manufacturing of (E)-3{-[5-(isopropylamino)methyl]furan-2-yl}methyl acrylate

[0785]

[0786] Using N-[(5-bromofuran-2-yl)methyl]propane-2-amine (600 mg, 2.8 mmol), tetrabutylammonium chloride (78 mg, 0.28 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was performed in the same manner as in Reference Example 88, and the title compound (158 mg, 26%) was obtained as an amber-colored oil.

[0787] 1 H NMR (400MHz, CDCl3) δ7.38 (1H, d, J = 15.6Hz), 6.54 (1H, d, J = 3.2Hz), 6.27 (1H, d, J = 15.6Hz), 6.2 6(1H,d,J=3.2Hz), 3.81(2H,s), 3.78(3H,s), 2.85(1H,septd,J=6.4Hz), 1.09(6H,d,J=6.4Hz).

[0788] See Example 99

[0789] Manufacturing of (E)-3-[3-methyl-5-(methylcarbamoyl)thiophen-2-yl]methyl acrylate

[0790]

[0791] Using 5-bromo-N,4-dimethylthiophene-2-carboxamide (200 mg, 0.85 mmol), tetrabutylammonium chloride (24 mg, 0.085 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 88, and the title compound (171.5 mg, 84%) was obtained as a yellow solid.

[0792] 1 H NMR (400MHz, CDCl3) δ7.76 (1H,d,J=16.0Hz), 7.34 (1H,s), 6.94 (1H,br s), 6.20 (1H,d,J=16.0Hz), 3.79 (3H,s), 2.98 (3H,d,J=4.8Hz), 2.28 (3H,s).

[0793] Reference Example 100

[0794] Preparation of (E)-3-(1-methyl-4-oxa-4,5,6,7-tetrahydro-1H-indole-2-yl)methyl acrylate

[0795]

[0796] Using 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), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 88, and the title compound (154.6 mg, 88%) was obtained as an amber solid.

[0797] 1 H NMR(400MHz, CDCl3) δ7.56(1H,d,J=15.6Hz),7.00(1H,s),6.23(1H,d,J=15.6Hz),3.78(3 H, s), 3.61 (3H, s), 2.79 (2H, t, J = 6.4Hz), 2.47 (2H, t, J = 6.4Hz), 2.17 (2H, quin, J = 6.4Hz).

[0798] See Example 101

[0799] Manufacturing of (E)-3-(5-acetyl-1-methyl-1H-pyrrole-2-yl)methyl acrylate

[0800]

[0801] Using 1-(5-bromo-1-methyl-1H-pyrrolo-2-yl)ethane-1-one (402.7 mg, 1.8 mmol), tetrabutylammonium chloride (66 mg, 0.24 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 88, and the title compound (153.1 mg, 17%) was obtained as a white solid.

[0802] 1 H NMR (400MHz, CDCl3) δ7.64 (1H, d, J = 15.6Hz), 6.95 (1H, d, J = 4.4Hz), 6.60 (1H ,d,J=4.4Hz), 6.37(1H,d,J=15.6Hz), 4.01(3H,s), 3.81(3H,s), 2.46(3H,s).

[0803] See Example 102

[0804] Manufacturing of (E)-3-(5-acetyl-3-methylthiophene-2-yl)methyl acrylate

[0805]

[0806] Using 1-(5-bromo-4-methylthiophen-2-yl)ethane-1-one (200 mg, 0.91 mmol), tetrabutylammonium chloride (25.4 mg, 0.091 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 88, and the title compound (176.2 mg, 87%) was obtained as a yellow solid.

[0807] 1 H NMR (400MHz, CDCl3) δ7.76 (1H,d,J=15.6Hz), 7.43 (1H,s), 6.29 (1H,d,J=15.6Hz), 3.80 (3H,s), 2.52 (3H,s), 2.34 (3H,s).

[0808] See Example 103

[0809] Manufacturing of (E)-3-(5-acetyl-4-fluorothiophene-2-yl)methyl acrylate

[0810]

[0811] Add 1-(5-bromo-3-fluorothiophene-2-yl)ethane-1-one (140 mg, 0.46 mmol), tetrabutylammonium chloride (12.8 mg, 0.046 mmol), PdCl2(dppf)2-CH2Cl2 (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), and microwave at 120 °C for 1.5 h. Dilute the resulting solution with water and extract with ethyl acetate. Wash the organic layer with water, dry with sodium sulfate, and remove the solvent by distillation under reduced pressure. Purify the residue by silica gel column chromatography (hexane / ethyl acetate (v / v) = 9 / 1 → 7 / 3) to give the title compound (51.3 mg, 49%) as amber powder.

[0812] 1 H NMR (400MHz, CDCl3) δ7.60 (1H,d,J=16.0Hz), 7.00 (1H,s), 6.39 (1H,d,J=16.0Hz), 3.81 (3H,s), 2.58 (3H,d,J=2.8Hz).

[0813] See Example 104

[0814] Manufacturing of (E)-3-{5-[(2,4-dimethoxybenzyl)carbamoyl]thiophen-2-yl}methyl acrylate

[0815]

[0816] Using 5-bromo-N-(2,4-dimethoxybenzyl)thiophene-2-carboxamide (400 mg, 1.1 mmol), tetrabutylammonium chloride (31 mg, 0.11 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (99.4 mg, 25%) was obtained as a white solid.

[0817] 1H NMR (400MHz, CDCl3) δ7.67 (1H, d, J = 16.0Hz), 7.41 (1H, d, J = 4.0Hz), 7.19 (1H, d, J = 8.4Hz), 7.13 (1H, d, J = 4.0Hz), 6.85 (1H, t, J = 5.6Hz), 6.43(1H,d,J=2.4Hz), 6.41(1H,dd,J=8.0,2.4Hz), 6.26(1H,d,J=16.0Hz), 4.49(2H,d,J=5.6Hz), 3.81(3H,s), 3.77(3H,s), 3.76(3H,s).

[0818] See Example 105

[0819] Manufacturing of (E)-3-(5-acetyl-4-methylthiophene-2-yl)methyl acrylate

[0820]

[0821] Using 1-(5-bromo-3-methylthiophen-2-yl)ethane-1-one (216 mg, 0.99 mmol), tetrabutylammonium chloride (14 mg, 0.049 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (120.9 mg, 55%) was obtained as a yellow solid.

[0822] 1 H NMR (400MHz, CDCl3) δ7.66 (1H,d,J=16.0Hz), 7.07 (1H,s), 6.35 (1H,d,J=16.0Hz), 3.81 (3H,s), 2.53 (3H,s), 2.52 (3H,s).

[0823] See Example 106

[0824] Manufacturing of (E)-3-(4-acetyl-1,3,5-trimethyl-1H-pyrrole-2-yl)methyl acrylate

[0825]

[0826] Using 1-(5-bromo-1,2,4-trimethyl-1H-pyrrolo-3-yl)ethane-1-one (120 mg, 0.52 mmol), tetrabutylammonium chloride (14.5 mg, 0.052 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (35.2 mg, 29%) was obtained as a pale yellow solid.

[0827] 1 H NMR (400MHz, CDCl3) δ7.68(1H,d,J=16.0Hz), 6.03(1H,d,J=16.0Hz), 3.80(3H,s), 3.59(3H,s), 2.51(3H,s), 2.46(3H,s), 2.40(3H,s).

[0828] See Example 107

[0829] Manufacturing of (E)-3-(5-acetyl-1-ethyl-1H-pyrrole-2-yl)methyl acrylate

[0830]

[0831] Using 1-(5-bromo-1-ethyl-1H-pyrrolo-2-yl)ethane-1-one (500 mg, 2.3 mmol), tetrabutylammonium chloride (64 mg, 0.23 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was performed in the same manner as in Reference Example 103, and the title compound (23.2 mg, 5%) was obtained as a pale yellow solid.

[0832] 1 H NMR (400MHz, CDCl3) δ7.54 (1H, d, J = 16.0Hz), 7.12 (1H, d, J = 1.6Hz), 7.08 (1H, d, J = 1.6Hz), 6. 16(1H,d,J=16.0Hz), 4.35(2H,q,J=7.2Hz), 3.77(3H,s), 2.46(3H,s), 1.37(3H,t,J=7.2Hz).

[0833] See Example 108

[0834] Manufacturing of (E)-3-[5-(cyclopropanecarbonyl)thiophen-2-yl]methyl acrylate

[0835]

[0836] Using (5-bromothiophene-2-yl)(cyclopropyl) methyl ketone (56 mg, 0.24 mmol), tetrabutylammonium chloride (3.4 mg, 0.012 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was performed in the same manner as in Reference Example 103, and the title compound (34 mg, 60%) was obtained as a pale yellow solid.

[0837] 1 H NMR (400MHz, CDCl3) δ7.74(1H,d,J=16.0Hz),7.72(1H,d,J=4.0Hz),7.27(1H,d,J=4.0Hz),6.39( 1H,d,J=16.0Hz),3.81(3H,s),2.51(1H,tt,J=8.0,4.4Hz),1.28-1.25(2H,m),1.08-1.04(2H,m).

[0838] See Example 109

[0839] Manufacturing of (E)-3-[5-(2-methyl-1,3-dioxapentane-2-yl)thiophene-2-yl]methyl acrylate

[0840]

[0841] Using 2-(5-bromothiophene-2-yl)-2-methyl-1,3-dioxapentane (180 mg, 0.72 mmol), tetrabutylammonium chloride (20 mg, 0.072 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (135.5 mg, 74%) was obtained as a white solid.

[0842] 1H NMR (400MHz, CDCl3) δ7.71 (1H, d, J = 15.6Hz), 7.10 (1H, d, J = 3.6Hz), 6.97 (1H, d, J = 3.6Hz) ,6.18(1H,d,J=15.6Hz),4.08-4.02(m,2H),3.98-3.95(m,2H), 3.78(3H,s),1.76(s,3H).

[0843] See Example 110

[0844] Manufacturing of (E)-3-(5-cyanothiophene-2-yl)methyl acrylate

[0845]

[0846] Using 5-bromothiophene-2-onitrile (289 μL, 2.7 mmol), tetrabutylammonium chloride (74 mg, 0.27 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (77.6 mg, 15%) was obtained as a white solid.

[0847] 1 H NMR (400MHz, CDCl3) δ7.71 (1H,d,J=16.0Hz), 7.55 (1H,d,J=4.0Hz), 7.23 (1H,d,J=4.0Hz), 6.36 (1H,d,J=16.0Hz), 3.82 (3H,s).

[0848] See Example 111

[0849] Manufacturing of (E)-3-[4-methyl-5-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]methyl acrylate

[0850]

[0851] In a flask, 2-(5-bromo-3-methylthiophene-2-yl)-2-methyl-1,3-dioxanepentadienone (306.1 mg, 1.2 mmol), PdCl2(dppf)2-CH2Cl2 (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. The mixture was then heated in a microwave oven at 130 °C for 3 hours. The mixture was then further heated in a microwave oven at 130 °C for 1 hour to allow the reaction solution to return to room temperature. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 98 / 2 → 77 / 23) to give the title compound (160.8 mg, 52%) as a yellow, transparent oil.

[0852] 1 H NMR (400MHz, CDCl3) δ7.61 (1H, d, J = 15.6Hz), 6.92 (1H, s), 6.11 (1H, d, J = 15.6Hz) ),4.07-3.98(2H,m),3.94-3.88(2H,m),3.74(3H,s),2.23(3H,s),1.70(3H,s).

[0853] See Example 112

[0854] Manufacturing of (E)-3-(6-oxa-5,6-dihydro-4H-thieno[2,3-c]pyrrolo-2-yl)methyl acrylate

[0855]

[0856] A solution of 2-bromo-4,5-dihydro-6H-thieno[2,3-c]pyrrole-6-one (301.3 mg, 1.4 mmol), PdCl2(dppf)2-CH2Cl2 (59.4 mg, 0.073 mmol), and tetrabutylammonium chloride (40.3 mg, 0.15 mmol) in DMA (1.8 mL) was added, along with methyl acrylate (250 μL, 2.8 mmol) and N,N-dicyclohexylamine (600 μL, 2.8 mmol). The mixture was then microwaved at 130 °C for 3 hours. The reaction solution was cooled to room temperature, and ethyl acetate and 1 M hydrochloric acid were added. The mixture was separated into an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. After removing the solvent by vacuum distillation, the compound was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 19 / 81 → 0 / 100) to give the title compound (171 mg, 55%) as an orange solid.

[0857] 1 H NMR (400MHz, CDCl3) δ7.77(1H,d,J=15.6Hz), 7.18(1H,s), 6.54(1H,br s), 6.37(1H,d,J=15.6Hz), 4.38(2H,s), 3.81(3H,s).

[0858] See Example 113

[0859] Manufacturing of (E)-3-(5-acetylfuran-2-yl)methyl acrylate

[0860]

[0861] Using 1-(5-bromofuran-2-yl)ethane-1-one (220 mg, 1.16 mmol), tetrabutylammonium chloride (16 mg, 0.058 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (90.0 mg, 40%) was obtained as a pale yellow solid.

[0862] 1 H NMR (400MHz, CDCl3) δ7.43 (1H,d,J=16.0Hz), 7.17 (1H,d,J=3.6Hz), 6.69 (1H,d,J=3.6Hz), 6.54 (1H,d,J=16.0Hz), 3.79 (1H,s), 2.49 (3H,s).

[0863] See Example 114

[0864] Manufacturing of (E)-3-(5-acetylthiophene-3-yl)methyl acrylate

[0865]

[0866] Using 1-(4-bromothiophene-2-yl)ethane-1-one (200 mg, 0.98 mmol), tetrabutylammonium chloride (13.6 mg, 0.049 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (114.3 mg, 56%) was obtained as an orange solid.

[0867] 1 H NMR (400MHz, CDCl3) δ7.82 (1H,d,J=1.2Hz), 7.74 (1H,d,J=1.2Hz), 7.62 (1H,d,J=16.0Hz), 6.32 (1H,d,J=16.0Hz), 3.81 (3H,s), 2.59 (3H,s).

[0868] See Example 115

[0869] Manufacturing of (E)-3-(4-acetylthiophene-2-yl)methyl acrylate

[0870]

[0871] Using 1-(5-bromothiophene-3-yl)ethane-1-one (380 mg, 1.9 mmol), tetrabutylammonium chloride (25.7 mg, 0.093 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (151.8 mg, 39%) was obtained as a pale green powder.

[0872] 1 H NMR (400MHz, CDCl3) δ8.03 (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).

[0873] See Example 116

[0874] Manufacturing of (E)-3-(5-cyano-1-methyl-1H-pyrrole-3-yl)methyl acrylate

[0875]

[0876] Using 4-bromo-1-methyl-1H-pyrrole-2-onitrile (131.9 mg, 0.71 mmol), tetrabutylammonium chloride (19.7 mg, 0.071 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (33.5 mg, 25%) was obtained as a pale yellow solid.

[0877] 1 H NMR (400MHz, CDCl3) δ7.48 (1H,d,J=16.0Hz), 7.01 (1H,d,J=1.6Hz), 6.96 (1H,d,J=1.6Hz), 6.13 (1H,d,J=16.0Hz), 3.80 (3H,s), 3.77 (3H,s).

[0878] See Example 117

[0879] Manufacturing of (E)-3-(3-acetylthiophene-2-yl)methyl acrylate

[0880]

[0881] Using 1-(2-bromothiophene-3-yl)ethane-1-one (128.8 mg, 0.63 mmol), tetrabutylammonium chloride (8.8 mg, 0.032 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (62.1 mg, 47%) was obtained as a pale yellow solid.

[0882] 1H NMR (400MHz, CDCl3) δ8.51 (1H,d,J=16.0Hz), 7.40 (1H,d,J=5.6Hz), 7.28 (1H,d,J=5.6Hz), 6.34 (1H,d,J=16.0Hz), 3.78 (3H,s), 2.54 (3H,s).

[0883] See Example 118

[0884] Manufacturing of (E)-3-[5-(2-methyl-1,3-dioxapentan-2-yl)furan-2-yl]methyl acrylate

[0885]

[0886] Using 2-(5-bromofuran-2-yl)-2-methyl-1,3-dioxapentane (200 mg, 0.86 mmol), tetrabutylammonium chloride (12 mg, 0.043 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (168.8 mg, 83%) was obtained as a yellow oil.

[0887] 1 H NMR (400MHz, CDCl3) δ7.39 (1H, d, J = 15.6Hz), 6.52 (1H, d, J = 3.6Hz), 6.39 (1H, d, J = 3.6Hz) ,6.32(1H,d,J=15.6Hz),4.09-4.05(2H,m),4.04-4.00(2H,m),3.78(3H,s),1.75(3H,s).

[0888] See Example 119

[0889] Manufacturing of (E)-3-[4-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]methyl acrylate

[0890]

[0891] Using 2-(5-bromothiophene-3-yl)-2-methyl-1,3-dioxapentane (160 mg, 0.64 mmol), tetrabutylammonium chloride (8.9 mg, 0.032 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 103, and the title compound (137.7 mg, 84%) was obtained as a colorless oil.

[0892] 1 H NMR(400MHz, CDCl3)δ7.72(1H,d,J=15.6Hz),7.31(1H,s),7.21(1H,s),6.22(1H ,d,J=15.6Hz),4.06-4.02(2H,m),3.89-3.86(2H,m),3.79(3H,s),1.66(3H,s).

[0893] See Example 120

[0894] Manufacturing of (E)-3-(thiazolyl-5-yl)ethyl acrylate

[0895]

[0896] 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 min. Thiazole-5-carboxaldehyde (100 mg, 0.88 mmol) was added, and the mixture was stirred at -5 °C for 2 hours, followed by stirring at room temperature for 21 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, 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) = 9 / 1 → 7 / 3) to give the title compound (143.5 mg, 89%) as a white solid.

[0897] 1 H NMR (400MHz, CDCl3) δ 8.80 (1H, s), 8.01 (1H, s), 7.82 (1H, d, J = 15.6Hz), 6.26 (1H, d, J = 15.6Hz), 4.26 (2H, q, J = 7.2Hz), 1.33 (3H, t, J = 7.2Hz).

[0898] See Example 121

[0899] Manufacturing of (E)-3-[5-(2-methyl-1,3-dioxapentan-2-yl)thiazolyl-2-yl]methyl acrylate

[0900]

[0901] A solution of 5-(2-methyl-1,3-dioxapentyl-2-yl)thiazolyl-2-carboxaldehyde (85.2 mg, 0.42 mmol) in toluene (1.5 mL) was mixed with methyl (triphenylphosphine) acetate (424.2 mg, 1.3 mmol) and stirred at 120 °C for 1 hour. The reaction solution was allowed to return to room temperature, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 81 / 19 → 62 / 38) to give the title compound (111.5 mg, quant.) as a white solid.

[0902] 1 H NMR (400MHz, CDCl3) δ7.79 (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).

[0903] See Example 122

[0904] Manufacturing of (E)-3-[4-methyl-5-(2-methyl-1,3-dioxapentan-2-yl)thiazolyl-2-yl]methyl acrylate

[0905]

[0906] A solution of 4-methyl-5-(2-methyl-1,3-dioxapentyl-2-yl)thiazolyl-2-carboxaldehyde (32.5 mg, 0.15 mmol) in toluene (1.0 mL) was mixed with methyl (triphenylphosphine) acetate (160.7 mg, 0.48 mmol) and stirred at 120 °C for 1.5 h. The reaction solution was allowed to return to room temperature, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 86 / 14 → 65 / 35) to give the title compound (34.6 mg, 85%) as an orange transparent oil.

[0907] 1H NMR (400MHz, CDCl3) δ7.63(1H,d,J=15.6Hz), 6.60(1H,d,J=15.6Hz), 4.08-4.02(2H,m), 3.94-3.86(2H,m), 3.80(3H,s), 2.49(3H,s), 1.74(3H,s).

[0908] See Example 123

[0909] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 2-[-2-yl]methyl}-4-methylphenyl)-3-[5-(methylcarbamoyl)furan-2-yl]propionate

[0910]

[0911] In (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza A solution of 1,1-dioxane (165 mg, 0.36 mmol), (E)-3-[5-(methylcarbamoyl)furan-2-yl]acrylate (50 mg, 0.24 mmol), and [RhCl(cod)]2 (5.9 mg, 0.012 mmol) in 1,4-dioxane / water (3 / 1) (1.0 mL) was mixed with TEA (168 μL, 1.2 mmol) and stirred under 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 3 / 2 → 2 / 3) to give the title compound (22.9 mg, 18%) as a colorless oil.

[0912] 1H NMR (400MHz, CDCl3) δ7.88(1H,d,J=8.0Hz),7.53(1H,td,J=8.0,1.6Hz),7.28-7.21(3H,m),7.14-7.07(2H,m),6.98(1H,d,J=3.2Hz),6.37(1H,br s),6.15(1H,t,J=3.2Hz),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=7.2Hz).

[0913] See Example 124

[0914] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 3-[5-(pyrrolidine-1-carbonyl)furan-2-yl]propionate

[0915]

[0916] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (240 mg, 0.52 mmol), (E)-3-[5-(pyrrolidine-1-carbonyl)furan-2-yl]methyl 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) as starting materials, the procedure was the same as in Reference Example 123, and the title compound (85.0 mg, 50%) was obtained as a colorless oil.

[0917] 1H NMR (400MHz, CDCl3) δ7.88 (1H, d, J = 7.6Hz), 7.52 (1H, t, J = 7.6Hz), 7.29-7.12 (5H, m), 6.97 (1H, d,J=3.2Hz),6.11(1H,d,J=3.2Hz),4.57-4.53(2H,m),4.03-3.98(1H,m),3.81(1H,d,J=14.4Hz ),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),1.9 9-1.95(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=7.2Hz).

[0918] See Example 125

[0919] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 3-[5-(isopropylcarbamoyl)furan-2-yl]propionate

[0920]

[0921] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (206 mg, 0.45 mmol), (E)-3-[5-(isopropylcarbamoyl)furan-2-yl]methyl 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) as starting materials, the procedure was performed in the same manner as in Reference Example 123, and the title compound (38.2 mg, 22%) was obtained as a pale yellow oil.

[0922] 1H NMR(400MHz, CDCl3) δ7.88(1H,dd,J=8.0,1.6Hz),7.53(1H,td,J=8.0,1.6Hz),7.26(1H,t,J=8.0H z),7.21(1H,d,J=8.0Hz),7.16-7.08(3H,m),6.98(1H,d,J=3.6Hz),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).

[0923] See Example 126

[0924] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 3-[5-(methylcarbamoyl)thiophen-2-yl]propionate

[0925]

[0926] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (240 mg, 0.52 mmol), (E)-3-[5-(methylcarbamoyl)thiophen-2-yl]methyl 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) as starting materials, the same procedure as in Reference Example 123 was followed to obtain the title compound (48.7 mg, 25%) as a pale yellow oil.

[0927] 1H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 8.0, 1.6Hz), 7.52 (1H, br t, J = 8.0Hz), 7.29-7.19 (3H, m), 7.14 (2H, br s),7.07(1H,d,J=6.8Hz),6.78-6.77(1H,m),5.99(1H,brs),4.69(1H,t,J=7.6Hz),4.56(1H,dd,J=14.0,5.2Hz) ,4.02-3.95(1H,m),3.82-3.69(2H,m),3.60(3H,s),3.09(1H,dd,J=16.0,7.6Hz),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=7.2Hz).

[0928] See Example 127

[0929] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 2-[(2-methyl]methyl}-4-methylphenyl)-3-{5-[(2-methoxyethyl)carbamoyl]furan-2-yl}propionate

[0930]

[0931] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (192 mg, 0.42 mmol), (E)-3-{5-[(2-methoxyethyl)carbamoyl]furan-2-yl}methyl 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) as starting materials, the procedure was performed in the same manner as in Reference Example 123, and the title compound (11.1 mg, 7%) was obtained as a pale yellow oil.

[0932] 1H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 8.0, 1.6Hz), 7.52 (1H, td, J = 8.0, 1.6Hz), 7.26 (1H, t,J=8.0Hz),7.23(1H,d,J=8.0Hz),7.16-7.09(3H,m),6.99(1H,d,J=3.6Hz),6.55(1H,br s),6.12(1H,t,J=3.6Hz),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=7.6Hz).

[0933] See Example 128

[0934] 3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[0935]

[0936] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (274.4 mg, 0.6 mmol), (E)-3-(5-acetylthiophen-2-yl)methyl 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) as starting materials, the same procedure as in Reference Example 123 was followed to obtain the title compound (138.0 mg, 50%) as a pale yellow oil.

[0937] 1H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 8.0, 1.6Hz), 7.52 (1H, td, J = 8.0, 1.6Hz), 7.50 (1H ,d,J=4.0Hz),7.27-7.20(2H,m),7.17-7.12(2H,m),7.08(1H,d,J=8.4Hz),6.87(1H,br t,J=2.4Hz),4.72(1H,t,J=7.6Hz),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, brs), 1.73-1.63 (1H, m), 1.47-1.39 (1H, m), 1.07 (3H, t, J = 7.6Hz).

[0938] See Example 129

[0939] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 3-[4-methyl-5-(methylcarbamoyl)furan-2-yl]propionate

[0940]

[0941] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (247 mg, 0.54 mmol), (E)-3-[4-methyl-5-(methylcarbamoyl)furan-2-yl]methyl 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) as starting materials, the procedure was performed in the same manner as in Reference Example 123, and the title compound (48.2 mg, 19%) was obtained as a pale yellow oil.

[0942] 1H NMR (400MHz, CDCl3) δ7.88(1H,dd,J=7.6,1.6Hz),7.53(1H,td,J=7.6,1.6Hz),7.27-7.19(3H,m),7.13(1H,d,J=7.6Hz),7.10-7.06(1H,m),6.27(1H,br s),5.98(1H,d,J=3.2Hz),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=7.2Hz).

[0943] See Example 130

[0944] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 2-(2-yl)methyl(-4-methylphenyl)-3-(5-aminosulfonylthiophene-2-yl)propionate

[0945]

[0946] In (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza A solution of 1,1-dioxane (137.2 mg, 0.3 mmol), (E)-3-(5-aminosulfonylthiophene-2-yl)acrylate (50 mg, 0.2 mmol), and [RhCl(cod)]2 (9.9 mg, 0.02 mmol) in 1,4-dioxane / water (1 / 1) (0.8 mL) was mixed with TEA (84 μL, 0.6 mmol) and microwaved at 120 °C for 1 hour. 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 4 / 1 → 3 / 2) to give the title compound (98.9 mg, 85%) as a white solid.

[0947] 1H NMR(400MHz,CDCl3)δ7.84(1H,br d,J=8.0Hz),7.51(1H,td,J=8.0,1.6Hz),7.42(1H,d,J=4.0Hz),7.27-7.19(2H,m) ,7.15-7.11(3H,m),6.78(1H,d,J=4.0Hz),4.71(1H,t,J=8.0Hz),4.51(1H,d,J=14. 4Hz),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).

[0948] See Example 131

[0949] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 3-(thiophen-2-yl)propionate (-4-methylphenyl)-3-(thiophen-2-yl)propionate

[0950]

[0951] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Starting with 1,1-dioxide (247 mg, 0.54 mmol), (E)-3-(thiophen-2-yl)methyl 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), the procedure was the same as in Reference Example 123, and the title compound (133 mg, 60%) was obtained as a white solid.

[0952] 1H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 8.0, 1.6Hz), 7.51 (1H, td, J = 8.0, 1.6Hz), 7.26-7.12 (5H, m), 7.03 (1H, d, J = 14.4Hz), 6.89 (1H, br t,J=4.0Hz),6.81(1H,brt,J=4.0Hz),4.71(1H,t,J=7.6Hz),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).

[0953] See Example 132

[0954] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 3-[5-(methylcarbamoyl)thiophen-3-yl]propionate

[0955]

[0956] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Starting with 1,1-dioxide (137.2 mg, 0.3 mmol), (E)-3-[5-(methylcarbamoyl)thiophen-3-yl]methyl 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), the procedure was the same as in Reference Example 130, and the title compound (77.5 mg, 70%) was obtained as a white solid.

[0957] 1H NMR (400MHz, CDCl3) δ7.85 (1H, dd, J = 8.0, 1.6Hz), 7.52 (1H, td, J = 8.0, 1.6Hz), 7.31-7. 30(1H,m),7.25(1H,t,J=8.0Hz),7.21(1H,d,J=8.0Hz),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=4.8Hz),2.28(3H,s),1.74-1.61(1H,m),1.50-1.39(1H,m),1.08-1.07(3H,m).

[0958] See Example 133

[0959] 3-(3-(((R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine) Manufacturing of methyl 2-(3-methyl-5-(methylcarbamoyl)thiophen-2-yl)propionate

[0960]

[0961] Using (R)-4-ethyl-2-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dihexocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Starting with 1,1-dioxide (226.4 mg, 0.5 mmol), (E)-3-[3-methyl-5-(methylcarbamoyl)thiophen-2-yl]methyl 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), the procedure was the same as in Reference Example 130, and the title compound (148.1 mg, 78%) was obtained as a white solid.

[0962] 1H NMR (400MHz, CDCl3) δ7.87 (1H, br d, J = 8.0Hz), 7.52 (1H, br t, J = 8.0Hz), 7.26 (1H, d, J = 8.0Hz), 7.23-7.19 (1H, m), 7.17 (1H, br s),7.14-7.11(2H,m),7.05(1H,brd,J=5.6Hz),6.08(1H,br s),4.72(1H,t,J=8.0Hz),4.56-4.55(1H,m),4.00-3.95(1H,m),3.78-3.68(2 H,m),3.59(3H,s),2.99(2H,dd,J=7.6,7.6Hz),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).

[0963] See Example 134

[0964] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Production of ethyl 2-yl]methyl}-4-methylphenyl)-3-(thiazolyl-5-yl)propionate

[0965]

[0966] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Starting with 1,1-dioxide (206 mg, 0.45 mmol), ethyl (E)-3-(thiazolyl-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), the procedure was the same as in Reference Example 130, and the title compound (97.3 mg, 63%) was obtained as a pale red solid.

[0967] 1H NMR(400MHz, CDCl3) δ8.80(1H,s),7.88(1H,dd,J=7.6,1.6Hz),7.63(1H,d,J=3.6Hz ),7.52(1H,td,J=7.6,2.0Hz),7.25(1H,td,J=7.6,1.2Hz),7.20(1H,dd,J=8.0,0.8 Hz),7.17-7.12(2H,m),7.08(1H,d,J=7.6Hz),4.77(1H,t,J=8.0Hz),4.57(1H,dd,J =14.0,5.2Hz),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=7.2Hz),1.09-1.05(3H,m).

[0968] See Example 135

[0969] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Preparation of methyl methyl 3-(1-methyl-4-oxa-4,5,6,7-tetrahydro-1H-indol-2-yl)propionate

[0970]

[0971] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Starting with 1,1-dioxide (206 mg, 0.5 mmol), (E)-3-(1-methyl-4-oxa-4,5,6,7-tetrahydro-1H-indol-2-yl)methyl 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), the procedure was the same as in Reference Example 130, and the title compound (149.8 mg, 91%) was obtained as a pale yellow oil.

[0972] 1H NMR(400MHz, CDCl3)δ7.87-7.82(1H,m),7.55-7.50(1H,m),7.28-7.19(2H,m),7.13-7.10(1H,m),7.06-7.0 1(1H,m),6.96(1H,s),6.48(1H,d,J=4.0Hz),4.52-4.51(1H,m),4.41(1H,t,J=8.0Hz),4.00-3.95(1H,m),3 .80-3.72(2H,m),3.61(1H,s),3.23(3H,brs),3.04-2.87(2H,m),2.80-2.73(1H,m),2.67-2.62(2H,m),2.4 6-2.42(2H,m),2.34(3H,brs),2.14-2.10(2H,m),1.75-1.62(1H,m),1.50-1.39(1H,m),1.11-1.04(3H,m).

[0973] See Example 136

[0974] 3-(5-acetyl-1-methyl-1H-pyrrolo-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[0975]

[0976] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (206 mg, 0.5 mmol), (E)-3-(5-acetyl-1-methyl-1H-pyrrolo-2-yl)methyl 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) as starting materials, the procedure was performed in the same manner as in Reference Example 130, and the title compound (129.3 mg, 80%) was obtained as a colorless oil.

[0977] 1H NMR (400MHz, CDCl3) δ7.88(1H,dd,J=7.6,1.6Hz),7.52(1H,t,J=7.6Hz),7.25(1H,t,J=7.6Hz),7.20(1H,d,J=7.6Hz),7.12-7.10(1H, m),7.02-6.92(3H,m),6.13(1H,d,J=4.4Hz),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).

[0978] See Example 137

[0979] 3-(5-acetyl-3-methylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[0980]

[0981] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (206 mg, 0.5 mmol), (E)-3-(5-acetyl-3-methylthiophen-2-yl)methyl 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) as starting materials, the procedure was performed in the same manner as in Reference Example 130, and the title compound (123.3 mg, 74%) was obtained as a pale yellow oil.

[0982] 1H NMR (400MHz, CDCl3) δ7.87 (1H, dt, J = 8.0, 2.0Hz), 7.52 (1H, br t,J=8.0Hz),7.38(1H,s),7.28-7.20(2H,m),7.17-7.12(2H,m),7.05(1H,d,J=8.0Hz), 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).

[0983] See Example 138

[0984] 3-(5-acetyl-4-fluorothiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[0985]

[0986] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Starting with 1,1-dioxide (75.5 mg, 0.17 mmol), (E)-3-(5-acetyl-4-fluorothiophene-2-yl)methyl 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), the procedure was the same as in Reference Example 130, and the title compound (53.6 mg, 56%) was obtained as a pale yellow solid.

[0987] 1H NMR (400MHz, CDCl3) δ7.88(1H,dd,J=8.0,1.6Hz),7.52(1H,td,J=8.0,1.6Hz),7.26(1H,td,J=8.0,1.2Hz),7.21(1H,dd,J=8.0,1.2Hz) ,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).

[0988] See Example 139

[0989] 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]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[0990]

[0991] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (150 mg, 0.328 mmol), (E)-3-{5-[(2,4-dimethoxybenzyl)carbamoyl]thiophen-2-yl}methyl 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) as starting materials, the same procedure as in Reference Example 130 was followed to obtain the title compound (112.4 mg, 74%) as a light brown oily substance.

[0992] 1H NMR (400MHz, CDCl3) δ7.86(1H,dd,J=8.0,1.6Hz),7.51(1H,br t,J=8.0Hz),7.27-7.24(2H,m),7.22-7.18(2H,m),7.13(2H,br s),7.04(1H,br d,J=8.0Hz),6.76(1H,br t,J=3.6Hz),6.45-6.40(3H,m),4.67(1H,t,J=7.6Hz),4.56-4.55(1H,m),4.47(2H,d,J=5.6Hz),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).

[0993] See Example 140

[0994] 3-(5-acetyl-4-methylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[0995]

[0996] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Starting with 1,1-dioxide (150 mg, 0.3 mmol), (E)-3-(5-acetyl-4-methylthiophene-2-yl)methyl 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), the procedure was the same as in Reference Example 130, and the title compound (77.9 mg, 64%) was obtained as a pale yellow solid.

[0997] 1H NMR (400MHz, CDCl3) δ7.89-7.86(1H,m),7.52(1H,br t,J=8.0Hz),7.28-7.08(5H,m),6.69(1H,br s),4.66(1H,t,J=7.6Hz),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).

[0998] See Example 141

[0999] 3-(4-acetyl-1,3,5-trimethyl-1H-pyrrolo-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1000]

[1001] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Starting with 1,1-dioxide (93.3 mg, 0.20 mmol), (E)-3-(4-acetyl-1,3,5-trimethyl-1H-pyrrolo-2-yl)methyl 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), the same procedure as in Reference Example 130 was followed to obtain the title compound (20.1 mg, 26%) as a colorless oil.

[1002] 1H NMR (400MHz, CDCl3) δ7.89-7.85(1H,m),7.52(1H,td,J=8.0,1.6Hz),7.25(1H,t,J=8.0Hz),7.20(1H,d,J=8.0Hz),7.11(1H,br d,J=8.0Hz),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).

[1003] See Example 142

[1004] 3-(5-acetyl-1-ethyl-1H-pyrrolo-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1005]

[1006] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (123.5 mg, 0.27 mmol), (E)-3-(5-acetyl-1-ethyl-1H-pyrrolo-2-yl)methyl 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) as starting materials, the procedure was performed in the same manner as in Reference Example 130, and the title compound (37.2 mg, 37%) was obtained as a pale yellow oil.

[1007] 1H NMR (400MHz, CDCl3) δ7.89(1H,dd,J=8.0,1.6Hz),7.52(1H,td,J=8.0,1.6Hz),7.25(1H,t,J=8.0Hz),7.20(1H,d,J=8 .0Hz),7.15-7.08(3H,m),6.70(1H,dd,J=4.8,2.0Hz),6.62(1H,dd,J=4.8,2.0Hz),4.55(1H,d,J=14.0Hz),4.35(1H, t,J=8.0Hz),4.26(1H,q,J=7.2Hz),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=7.2Hz),1.07(3H,t,J=7.2Hz).

[1008] See Example 143

[1009] 3-[5-(cyclopropanecarbonyl)thiophen-2-yl]-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1010]

[1011] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (99 mg, 0.2 mmol), (E)-3-[5-(cyclopropanecarbonyl)thiophen-2-yl]methyl 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) as starting materials, the procedure was the same as in Reference Example 130, and the title compound (45.5 mg, 56%) was obtained as a colorless oil.

[1012] 1H NMR (400MHz, CDCl3) δ7.88(1H,dd,J=7.6,1.6Hz),7.63(1H,d,J=3.6Hz),7.52(1H,td,J=7.6,1.6Hz),7.25(1H,dd,J=7.6,0.8Hz),7.22(1H,br d,J=7.6Hz),7.15(2H,br s),7.06(1H,d,J=10.4Hz),6.90-6.88(1H,m),4.73(1H,t,J=7.6Hz),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=7.2Hz),1.00-0.96(2H,m).

[1013] See Example 144

[1014] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 5-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]propionate

[1015]

[1016] In (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dihexocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza A mixture of 1,1-dioxane (216 mg, 0.47 mmol), (E)-3-[5-(2-methyl-1,3-dioxapentyl-2-yl)thiophen-2-yl)]methyl acrylate (80 mg, 0.32 mmol), and [RhCl(cod)]2 (15.5 mg, 0.032 mmol) in 1,4-dioxane / water (1 / 1) (1.7 mL) was heated with TEA (132 μL, 0.95 mmol) under argon atmosphere and microwaved at 140 °C for 2 h. Water was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, 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 (90.9 mg, 49%) as a colorless oil.

[1017] 1 H NMR (400MHz, CDCl3) δ7.89 (1H, dd, J = 8.0, 1.6Hz), 7.52 (1H, td, J = 8.0, 1.6Hz), 7.26 (1H, br t, J = 8.0Hz), 7.21 (1H, dd, J = 8.0, 1.6Hz), 7.14 (2H, br s),7.06(1H,s),6.81(1H,d,J=3.6Hz),6.62(1H,d,J=3.6Hz),4.63(1H,t,J=8.0Hz ),4.58(1H,d,J=14.0Hz),4.03-3.96(3H,m),3.93-3.90(2H,m),3.81-3.77(1H,m) ,3.73(1H,dd,J=15.2,10.8Hz),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).

[1018] See Example 145

[1019] 3-(5-Cyanothiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1020]

[1021] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Starting with 1,1-dioxide (137.2 mg, 0.3 mmol), (E)-3-(5-cyanothiophene-2-yl)methyl 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), the procedure was the same as in Reference Example 130, and the title compound (22.2 mg, 21%) was obtained as a white solid.

[1022] 1 H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 7.6, 1.6 Hz), 7.53 (1H, td, J = 7.6, 1.6 Hz), 7.44(1H,dd,J=4.0,0.8Hz),7.28-7.16(3H,m),7.13-7.10(2H,m),6.85(1H,br d,J=4.0Hz),4.73(1H,t,J=7.6Hz),4.58-4.52(1H,m),4.06-3.98(1H,m),3.8 8-3.81(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).

[1023] See Example 146

[1024] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl propionate (-2-yl]methyl}-4-methylphenyl)-3-[4-methyl-5-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]propionate

[1025]

[1026] (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza 1,1-dioxide (499.7 mg, 1.1 mmol), (E)-3-[4-methyl-5-(2-methyl-1,3-dioxapentane-2-yl)thiophen-2-yl]methyl acrylate (146.8 mg, 1.1 mmol), and [RhCl(cod)]₂ (17.1 mg, 0.035 mmol) were used to replace the atmosphere with argon. 1,4-dioxane / water (1 / 1) (1.2 mL) and TEA (250 μL, 1.8 mmol) were added, and the mixture was heated in a microwave oven at 120 °C for 1.5 h. The reaction solution was allowed to return to room temperature, diluted with ethyl acetate, washed with water and saturated brine, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane / TEA = 23 / 75 / 2) to give the title compound (204.3 mg, 62%) as a pale yellow solid.

[1027] 1 H NMR (400MHz, CDCl3) δ7.89(1H,dd,J=8.0,1.6Hz),7.52(1H,t,J=7.6Hz),7.28-7.24(1H,m),7.22(1H,d,J=8.0H z),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=14.0Hz),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).

[1028] See Example 147

[1029] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl propionate (-2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxapentan-2-yl)thiazolyl-2-yl]propionate

[1030]

[1031] In (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dihexocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza A solution of 1,1-dioxane (56.7 mg, 0.13 mmol), (E)-3-[5-(2-methyl-1,3-dioxapentyl-2-yl)thiazolyl-2-yl]acrylate (21.8 mg, 0.085 mmol), and [RhCl(cod)]2 (7.1 mg, 0.016 mmol) in 1,4-dioxane / water (2 / 1) (0.5 mL) was heated with TEA (66 μL, 0.47 mmol) at 50 °C using microwave heating for 4 hours. The reaction solution was allowed to return to room temperature, diluted with ethyl acetate, washed with water, 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) = 91 / 9 → 70 / 30) to give the title compound (23.7 mg, 47%) as a colorless, transparent oil.

[1032] 1 H NMR(400MHz, CDCl3) δ7.89(1H,dd,J=7.6,1.2Hz),7.56(1H,s),7.52(1H,td,J=8.0,1.2Hz),7.24-7.24( 1H,m),7.22-7.15(3H,m),7.13-7.12(1H,m),4.72(1H,t,J=7.6Hz),4.58-4.57(1H,d,J=14.0Hz),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=7.6Hz).

[1033] See Example 148

[1034] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl propionate (-2-yl]methyl}-4-methylphenyl)-3-[4-methyl-5-(2-methyl-1,3-dioxapentan-2-yl)thiazolyl]propionate

[1035]

[1036] In (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dihexocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza A solution of 1,1-dioxane (62.6 mg, 0.1 mmol), (E)-3-[4-methyl-5-(2-methyl-1,3-dioxapentyl-2-yl)thiazolyl-2-yl]acrylate (13.7 mg, 0.05 mmol), and [RhCl(cod)]2 (6.3 mg, 0.01 mmol) in 1,4-dioxane / water (2 / 1) (0.5 mL) was heated with TEA (70 μL, 0.5 mmol) at 50 °C using microwave heating for 4 hours. The reaction solution was allowed to return to room temperature, diluted with ethyl acetate, washed with water and saturated brine, 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) = 68 / 32 → 47 / 53) to give the title compound (32.8 mg, quant.) as a colorless, transparent oil.

[1037] 1 H NMR (400MHz, CDCl3) δ7.90 (1H, d, J = 7.6Hz), 7.52 (1H t,J=7.2Hz),7.28-7.20(3H,m),7.17-7.14(2H,m),4.68-4.63(1H,m),4.5 8(1H,d,J=14.0Hz)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=16.0,6.0Hz),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=7.2Hz).

[1038] See Example 149

[1039] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 3-(6-oxa-5,6-dihydro-4H-thieno[2,3-c]pyrrolo-2-yl)propionate

[1040]

[1041] In (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dihexocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza 1,1-dioxide (64.6 mg, 0.1 mmol), (E)-3-(oxa-5,6-dihydro-4H-thieno[2,3-c]pyrrolo-2-yl)methyl acrylate (16.2 mg, 0.07 mmol), [RhCl(cod)]2 (7.6 mg, 0.02 mmol), and 1,4-dioxane / water (2 / 1) (0.7 mL) were mixed with TEA (100 μL, 0.7 mmol) and heated in a microwave oven at 50 °C for 3 hours. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate, washed with water and saturated brine, and the resulting organic layer was dried over sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 9 / 1 → 0 / 100) to give the title compound (20.1 mg, 50%) as a brownish oil.

[1042] 1 H NMR (400MHz, CDCl3) δ7.88(1H,d,J=7.6Hz),7.52(1H,t,J=7.6Hz),7.27-7.18(2H,m),7.16(2H,s),7.11(1 H,d,J=3.6Hz),6.80(1H,s),6.47(1H,s),4.75(1H,t,J=8.0Hz),4.56(1H,d,J=14.4Hz),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=15.6,8.0Hz),3.03(1H,dd ,J=15.6,8.0Hz),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).

[1043] See Example 150

[1044] 3-(5-acetylfuran-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxy-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1045]

[1046] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (120 mg, 0.3 mmol), (E)-3-(5-acetylfuran-2-yl)methyl 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) as starting materials, the procedure was the same as in Reference Example 130, and the title compound (29.9 mg, 22%) was obtained as a colorless oil.

[1047] 1 H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 7.6, 1.6 Hz), 7.52 (1H, td, J = 7.6, 1.6 Hz), 7.25 (1 H,td,J=7.6,1.2Hz),7.20(1H,d,J=8.4Hz),7.16-7.11(3H,m),7.07(1H,d,J=3.6Hz),6 .16(1H,t,J=3.6Hz),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).

[1048] See Example 151

[1049] 3-(5-acetylthiophene-3-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1050]

[1051] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (150 mg, 0.33 mmol), (E)-3-(5-acetylthiophene-3-yl)methyl 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) as starting materials, the title compound (52.0 mg, 29%) was obtained as a pale yellow oily substance, as described in Reference Example 130.

[1052] 1 H NMR (400MHz, CDCl3) δ7.87(1H,dd,J=8.0,1.6Hz),7.51(1H,td,J=8.0,1.6Hz),7.45(1H,dd,J=3.2,1.2Hz),7.29(1H,br s),7.24(1H,td,J=8.0,1.2Hz),7.20(1H,br d,J=8.0Hz),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=7.2Hz).

[1053] See Example 152

[1054] 3-(4-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1055]

[1056] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (150 mg, 0.33 mmol), (E)-3-(4-acetylthiophen-2-yl)methyl 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) as starting materials, the title compound (25.5 mg, 14%) was obtained as an amber oil.

[1057] 1 H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 8.0, 1.6Hz), 7.84 (1H, d, J = 1.6Hz), 7.52 (1H, br t,J=8.0Hz),7.27-7.19(3H,m),7.16-7.11(2H,m),7.05(1H,d,J=10.4Hz),4.66(1H,t,J=7.6Hz),4.57-4.56(1H,m),4.0 0-3.97(1H,m),3.82-3.68(2H,m),3.61(3H,s),3.10(1H,dd,J=15.6,7.6Hz),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=7.6Hz).

[1058] See Example 153

[1059] 3-(5-cyano-1-methyl-1H-pyrrolo-3-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1060]

[1061] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (150 mg, 0.33 mmol), (E)-3-(5-cyano-1-methyl-1H-pyrrolo-3-yl)methyl 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) as starting materials, the procedure was performed in the same manner as in Reference Example 130, and the title compound (52.4 mg, 30%) was obtained as a pale yellow oil.

[1062] 1 H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 8.0, 1.6Hz), 7.52 (1H, td, J = 8.0, 1.6Hz), 7.25 (1H, td, J = 8. 0,1.2Hz),7.21(1H,d,J=8.0Hz),7.12(1H,d,J=8.0Hz),7.08-7.04(2H,m),6.56-6.53(2H,m),4. 54-4.53(1H,m),4.33(1H,t,J=8.0Hz),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).

[1063] See Example 154

[1064] 3-(3-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1065]

[1066] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (110 mg, 0.2 mmol), (E)-3-(3-acetylthiophen-2-yl)methyl 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) as starting materials, the title compound (24.6 mg, 19%) was obtained as a light brown oily substance, similar to that in Reference Example 130.

[1067] 1 H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 8.0, 1.6Hz), 7.52 (1H, br t,J=8.0Hz),7.34(1H,d,J=5.6Hz),7.27-7.20(3H,m),7.16-7.10(3H,m),5.65(1H,dd,J=8.0,8.0Hz),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).

[1068] See Example 155

[1069] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 5-(2-methyl-1,3-dioxapentan-2-yl)furan-2-yl]propionate

[1070]

[1071] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (115 mg, 0.25 mmol), (E)-3-[5-(2-methyl-1,3-dioxapentane-2-yl)furan-2-yl]methyl 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) as starting materials, the procedure was performed in the same manner as in Reference Example 130, and the title compound (13.5 mg, 9%) was obtained as a pale yellow oil.

[1072] 1 H NMR (400MHz, CDCl3) δ7.89(1H,dd,J=8.0,1.6Hz),7.52(1H,t,J=8.0Hz),7.25(1H,t,J=8.0Hz),7.20(1H,d,J= 8.0Hz),7.13-7.12(2H,m),7.06(1H,s),6.17(1H,d,J=3.2Hz),5.85(1H,d,J=3.2Hz), 4.56(1H,d,J=14.0Hz), 4.48(1H,t,J=8.0Hz),4.04-3.93(5H,m),3.81-3.69(2H,m),3.60(3H,s),3.07(1H,d,J=15.2,7.2Hz),2.97(1 H,d,J=15.2Hz),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=7.2Hz).

[1073] See Example 156

[1074] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 4-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]propionate

[1075]

[1076] Using (R)-4-ethyl-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)benzyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (165 mg, 0.36 mmol), (E)-3-[4-(2-methyl-1,3-dioxapentane-2-yl)thiophen-2-yl]methyl 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) as starting materials, the procedure was performed in the same manner as in Reference Example 130, and the title compound (83.4 mg, 40%) was obtained as a colorless oil.

[1077] 1 H NMR (400MHz, CDCl3) δ7.89 (1H, dd, J = 8.0, 1.6Hz), 7.51 (1H, td, J = 8.0, 1.6Hz), 7.25 (1H, br t, J = 8.0Hz), 7.20 (1H, br d,J=8.0Hz),7.15-7.14(2H,m),7.07(2H,br s),6.77(1H,dt,J=4.8,1.2Hz),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,J=15.6,6.8Hz),3.00-2.93(2H,m),2.35(3H,br s),1.73-1.70(1H,m),1.62(3H,s),1.45-1.41(1H,m),1.09-1.07(3H,m).

[1078] See Example 157

[1079] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 5-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]propionate

[1080]

[1081] In 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Methyl methyl [2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxapentyl-2-yl)thiophen-2-yl]propionate (49.5 mg, 0.085 mmol) was added to a THF (0.6 mL) solution under argon atmosphere at -78 °C with 1 M LDA THF / hexane (150 μL, 0.15 mmol). The reaction mixture was stirred at -78 °C for 30 min and then at -40 °C for 20 min. Iodomethane (106 μL, 1.7 mmol) was added, and the mixture was heated to room temperature and stirred for 3 h. Water was added to the mixture to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, 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 was able to be separated into a mixture of two isomers, yielding isomer 1 with a short retention time and isomer 2 with a long retention time.

[1082] Isomer 1: 1 H NMR (400MHz, CDCl3) δ7.90 (1H, dd, J = 8.0, 1.6Hz), 7.53 (1H, td, J = 8.0, 1.6Hz), 7.26 (1H, br t, J = 8.0Hz), 7.22 (1H, dd, J = 8.0, 1.6Hz), 7.14 (2H, br s),7.06(1H,d,J=11.2Hz),6.77(1H,dd,J=3.6,0.8Hz),6.69(1H,br d,J=3.6Hz),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=15.2,2.0Hz),2.36-2.34(3H,m),1.73-1.62(4H,m),1.46-1.38(1H,m),1.11-1.04(6H,m).

[1083] Isomer 2: 1H NMR (400MHz, CDCl3) δ7.89 (1H, dd, J = 8.0, 1.6Hz), 7.53 (1H, td, J = 8.0, 1.6Hz), 7.26 (1H, br t,J=8.0Hz),7.22(1H,dd,J=8.0,1.6Hz),7.20-7.17(1H,m),7.11-7.07(2H,m),6.82(1H,d ,J=3.6Hz),6.73(1H,t,J=3.6Hz),4.57(1H,d,J=14.0Hz),4.21(1H,d,J=11.2Hz),4.07-3.8 9(5H,m),3.79-3.68(2H,m),3.43(3H,s),3.21-3.10(1H,m),2.94(1H,dd,J=15.2,8.8Hz),2 .33(3H,s),1.73-1.65(4H,m),1.51-1.42(1H,m),1.20(3H,d,J=6.8Hz),1.15-1.07(3H,m).

[1084] See Example 158

[1085] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl [-2-yl]methyl}-4-methylphenyl)-2-methyl-3-[4-methyl-5-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]propionate

[1086]

[1087] A solution of diisopropylamine (30 μL, 0.21 mmol) in THF (200 μL) was cooled to -78 °C and stirred for 10 minutes. A 1.6 M solution of n-butyllithium hexane (110 μL, 0.18 mmol) was added at -78 °C, and the temperature was raised to -40 °C and stirred for 30 minutes. The solution was then cooled again to -78 °C. 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] A solution of methyl [2-yl]methyl}-4-methylphenyl)-3-[4-methyl-5-(2-methyl-1,3-dioxapentyl-2-yl)thiophen-2-yl]propionate (41.5 mg, 0.069 mmol) in THF (400 μL) was added dropwise to the reaction solution. The mixture was stirred at -78 °C for 10 min, then heated to -40 °C and stirred for 10 min. Iodomethane (90 μL, 1.4 mmol) was added to the reaction solution, and the mixture was stirred at -40 °C for 15 min, then heated to room temperature and stirred for 2 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The 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 brownish oil.

[1088] 1 H NMR (400MHz, CDCl3) δ7.89 (1H, d, J = 7.6Hz), 7.53 (1H, t, J = 7.6Hz), 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).

[1089] See Example 159

[1090] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 5-(2-methyl-1,3-dioxapentan-2-yl)furan-2-yl]propionate

[1091]

[1092] Using 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Methyl methyl [-2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxapentan-2-yl)furan-2-yl]propionate (55.7 mg, 0.098 mmol), 1 M LDA THF / hexane solution (150 μL, 0.15 mmol), methyl iodoforme (106 μL, 1.7 mmol), and THF (0.6 mL) were used as starting materials, and the procedure was performed in the same manner as in Reference Example 157 to obtain the title compound (40.1 mg, 79%) as a colorless oil.

[1093] 1 H NMR (400MHz, CDCl3) δ7.89 (1H, br d, J = 8.0Hz), 7.52 (1H, br t,J=8.0Hz),7.28-7.23(1H,m),7.22-7.04(4H,m),6.18-6.14(1H,m),6.0 1-5.92(1H,m),4.58-4.51(1H,m),4.15-4.08(1H,m),4.04-3.94(5H,m),3. 85-3.71(2H,m),3.63-3.44(3H,m),3.23-3.16(1H,m),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).

[1094] See Example 160

[1095] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 4-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]propionate

[1096]

[1097] Using 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Methyl propionate (83 mg, 0.14 mmol), THF (0.9 mL), 2 M LDA THF / heptane / ethylbenzene solution (92 μL, 0.18 mmol), and iodomethane (133 μL, 2.1 mmol) were used as starting materials, and the procedure was the same as in Reference Example 157, yielding the title compound (58.0 mg, 81%) as a colorless oil. The title compound was purified by silica gel column chromatography to a mixture of two isomers, yielding 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.

[1098] Isomer 1: 1 H NMR (400MHz, CDCl3) δ7.89 (1H, dd, J = 7.6, 1.6Hz), 7.53 (1H, br t,J=8.0Hz),7.28-7.25(1H,m),7.24-7.18(2H,m),7.11-7.08(3H,m),6.86(1H,dd ,J=6.0,1.2Hz),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).

[1099] Isomer 2: 1H NMR (400MHz, CDCl3) δ7.89 (1H, br d,J=8.0Hz),7.53(1H,td,J=8.0,1.6Hz),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).

[1100] See Example 161

[1101] 3-[5-(dimethylcarbamoyl)furan-2-yl]-3-(3-{[(R)-4-ethyl-1,1-dioxy-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1102]

[1103] In 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Methyl methyl [-2-yl]methyl}-4-methylphenyl)-3-[5-(methylcarbamoyl)furan-2-yl]propionate (43 mg, 0.08 mmol) was added to a THF solution of 2.0 mL at -78 °C with 96 μL of 1 M LDA THF solution (0.096 mmol). The reaction mixture was stirred at -78 °C for 20 min and then at -40 °C for 15 min. Iodomethane (100 μL, 1.6 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction was stopped by water, 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) = 3 / 7 → 1 / 1) to give the title compound (26.4 mg, 60%) as a pale yellow solid.

[1104] 1H NMR (400MHz, CDCl3) δ7.89 (1H, dd, J = 7.6, 1.6Hz), 7.52 (1H, t, J = 7.6Hz), 7.26 (1H, t, J = 7.6H z),7.21(1H,d,J=7.6Hz),7.15-7.10(3H,m),6.90(1H,d,J=3.6Hz),6.10(1H,d,J=3.6Hz),4 .56-4.52(2H,m),4.04-3.99(1H,m),3.82(1H,d,J=14Hz),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=7.2Hz).

[1105] See Example 162

[1106] 3-(5-carbamoylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1107]

[1108] In 3-{5-[(2,4-dimethoxybenzyl)carbamoyl]thiophen-2-yl}-3-(3-{[(R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza TFA (750 μL, 9.8 mmol) was added to a solution of methyl methyl 2-[2-yl]methyl}-4-methylphenyl)propionate (83.4 mg, 0.12 mmol) in dichloromethane (1 mL) under argon atmosphere, and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, and the residue was neutralized with 1 N aqueous sodium hydroxide solution and extracted with methanol / dichloromethane (1 / 10). The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (99.4 mg, quant.) as a pale yellow solid.

[1109] 1H NMR (400MHz, CDCl3) δ7.87(1H,dd,J=8.0,1.6Hz),7.52(1H,br t,J=8.0Hz),7.35(1H,d,J=3.6Hz),7.25(1H,t,J=8.0Hz),7.20(1H,br d,J=8.0Hz),7.14(2H,br s),7.08(1H,d,J=8.4Hz),6.81-6.79(1H,m),6.01(2H,br s),4.70(1H,t,J=8.0Hz),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,d d,J=15.6,7.6Hz),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).

[1110] See Example 163

[1111] 3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2,2-dimethylpropionate (-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1112]

[1113] Methyl 3-(5-acetylthiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropionate (29.8 mg, 0.079 mmol), (R)-4-ethyl-3,4-2H-benzo[b][1,4,5]oxathiaza A solution of 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 brine. 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) = 73 / 27 → 52 / 48) to give the title compound (43.1 mg, 96%) as a white solid.

[1114] 1H NMR (400Mz, CDCl3) δ7.87 (1H, dt, J = 7.6, 1.2Hz), 7.55-7.50 (1H, m), 7.49 (1H, d, J=4.0Hz),7.27-7.11(5H,m),6.97-6.95(1H,m),4.69-4.67(1H,m),4.56-4.55(1 H,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).

[1115] See Example 164

[1116] 3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-9-fluoro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2,2-dimethylpropionate (-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1117]

[1118] Methyl 3-(5-acetylthiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropionate (23.4 mg, 0.062 mmol), and (R)-4-ethyl-9-fluoro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (18.3 mg, 0.075 mmol), potassium carbonate (27.2 mg, 0.20 mol), tetrabutylammonium iodide (5.3 mg, 0.014 mmol), and DMF (1.0 mL) as starting materials, the same procedure as in Reference Example 163 was followed to give the title compound (31.8 mg, 88%) as a white solid.

[1119] 1H NMR (400MHz, CDCl3) δ7.51(1H,dd,J=4.0,1.6Hz),7.44-7.39(1H,m),7.29 / 7.28(1H,m),7.25-7.22(1H,m),7.14(1H,br d,J=8.0Hz),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=14.4,4.0Hz),3.10(1H,d,J=14.4,1.2Hz),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).

[1120] See Example 165

[1121] 3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiaza] Manufacturing of methyl 2,2-dimethylpropionate (-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1122]

[1123] Methyl 3-(5-acetylthiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropionate (50 mg, 0.139 mmol), and (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiaza were used. Using 1,1-dioxide (38.1 mg, 0.167 mmol), triphenylphosphine (73 mg, 0.278 mmol), THF (0.4 mL), and 2.2 M DEAD toluene solution (126 μL, 0.278 mmol) as starting materials, the same procedure as in Reference Example 12 was followed to obtain the title compound (39.4 mg, 50%) as a pale yellow oil.

[1124] 1H NMR(400MHz, CDCl3)δ8.51-8.49(1H,m),8.26(1H,br d,J=8.0Hz),7.51(1H,d,J=4.0Hz),7.30-7.24(2H,m),7.21(1H,s),7.14(1H,d,J=8.0Hz),6.98(1H,t, J=4.0Hz),4.69(1H,d,J=5.6Hz),4.47-4.42(2H,m),4.11-4.05(1H,m),3.62-3.59(4H,m),3.16(1H,br d,J=15.2Hz),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=7.2Hz).

[1125] See Example 166

[1126] 3-(5-acetylthiophene-2-yl)-3-[3-({4-[2-(benzyloxy)ethyl]-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl [-2-yl]methyl]-4-methylphenyl]-2-methylpropionate

[1127]

[1128] Methyl 3-(5-acetylthiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropionate (22 mg, 0.064 mmol), and 4-[2-(benzyloxy)ethyl]-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (23 mg, 0.070 mmol), triphenylphosphine (20.1 mg, 0.077 mmol), THF (0.27 mL), and 2,2-MDEAD toluene solution (38 μL, 0.083 mmol) as starting materials, the same procedure as in Reference Example 12 was followed to obtain the title compound (29.6 mg, 70%) as a colorless oil.

[1129] 1H NMR (400MHz, CDCl3) δ7.88(1H,br d,J=8.0Hz),7.49(1H,br t,J=8.0Hz),7.43(1H,t,J=4.0Hz),7.35-7.24(6H,m),7.14-7.09(3H,m),7.00(1H,br t,J=8.0Hz),6.89(1H,br t,J=4.0Hz),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=7.2Hz).

[1130] See Example 167

[1131] 3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)-2-methylpropionate

[1132]

[1133] Methyl 3-(5-acetylthiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2-methylpropionate (50 mg, 0.14 mmol), and (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza Using 1,1-dioxide (38.1 mg, 0.17 mmol), triphenylphosphine (43.7 mg, 0.17 mmol), THF (3.7 mL), and 2.2 M DEAD toluene solution (100 μL, 0.22 mmol) as starting materials, the same procedure as in Reference Example 12 was followed to obtain the title compound (24.8 mg, 31%) as a colorless oil.

[1134] 1H NMR(400MHz, CDCl3)δ9.03(1H,s),8.66(1H,dd,J=5.6,2.0Hz),7.47(1H,dd,J=4.0,2.4Hz),7.17(2H,s),7.12-7.09(2H,m),6.93-6.9 2(1H,m),4.47-4.44(1H,m),4.38(2H,d,J=12.0Hz),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).

[1135] See Example 168

[1136] 3-(5-acetylthiophene-2-yl)-3-(3-{[4-(2-hydroxyethyl)-1,1-dioxo-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)-2-methylpropionate

[1137]

[1138] In 3-(5-acetylthiophene-2-yl)-3-[3-({4-[2-(benzyloxy)ethyl]-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza [-2-yl]methyl]-4-methylphenyl]-2-methylpropionate (126 mg, 0.19 mmol) was dissolved in methanol / dichloromethane (0.6 mL / 0.4 mL) and palladium on carbon (35.7 mg) was added. The mixture was stirred at room temperature for 32 hours. The mixture was filtered through diatomaceous earth, 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 give the title compound (44.4 mg, 41%) as a colorless oil.

[1139] 1H NMR (400MHz, CDCl3) δ7.89 (1H, dd, J = 8.0, 1.6Hz), 7.69-7.44 (3H, m), 7.29-7.22 (1H,m),7.17-7.10(3H,m),6.93(1H,d,J=4.0Hz),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).

[1140] See Example 169

[1141] Production of (5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)methanol

[1142]

[1143] A solution of 2 M n-butyllithium cyclohexane (354 μL, 0.71 mmol) was added to a solution of [1-(5-bromo-3-fluorothiophene-2-yl)ethoxy](tert-butyl)dimethylsilane (200 mg, 0.59 mmol) in THF (2.0 mL) at -78 °C. The mixture was stirred at -78 °C for 30 min, 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 h, and then heated to room temperature. After stirring the mixture for 1.5 h, a saturated aqueous solution of ammonium chloride was added to stop the reaction, 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. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 1 / 0 → 95 / 5) to give the title compound (168.3 mg, 63%) as a colorless oil.

[1144] 1H NMR (400MHz, CDCl3) δ7.31 (1H, br s), 7.22-7.16 (3H, m), 7.10 (1H, d, J = 7.6Hz), 6.82 (2H, br d, J = 8.8Hz), 6.40 (1H, d, J = 20.8Hz), 5.76 (1H, br s),5.09(1H,q,J=6.4Hz),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).

[1145] See Example 170

[1146] Manufacturing of methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1147]

[1148] To a solution of (5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophene-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 min, and a solution of dimethylketene methyltrimethylsilyl acetal (201 μL, 0.99 mmol) and bis(trifluoromethanesulfonyl)imide (11.1 mg, 0.040 mmol) in acetonitrile (111 μL) was added, and the mixture was stirred at room temperature for 3.5 h. A saturated aqueous solution of potassium carbonate was added to the mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, 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) = 1 / 0 → 85 / 15) to give the title compound (184.3 mg, 76%) as a colorless oil.

[1149] 1H NMR (400MHz, CDCl3) δ7.25-7.22(3H,m),7.13(1H,br t,J=8.0Hz),7.04(1H,dd,J=8.0,3.2Hz),6.84(2H,br d,J=8.8Hz),6.55(1H,d,J=19.6Hz),5.07(1H,q,J=6.4Hz),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).

[1150] See Example 171

[1151] Manufacturing of methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropionate

[1152]

[1153] Using methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophen-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionate (204 mg, 0.33 mmol), dichloromethane (2.9 mL), water (290 μL), and DDQ (82.6 mg, 0.36 mmol) as starting materials, the procedure was performed in the same manner as in Reference Example 25, and the title compound (109.3 mg, 66%) was obtained as a colorless oil.

[1154] 1 H NMR (400MHz, CDCl3) δ7.31(1H,s),7.18(1H,br t,J=8.0Hz),7.10(1H,dd,J=8.0,4.0Hz),6.60(1H,d,J=19.6Hz),5.12(1H,q,J=6.4Hz),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).

[1155] See Example 172

[1156] 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2,2-dimethylpropionate (-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1157]

[1158] Methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropionate (65 mg, 0.13 mmol), (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Using 1,1-dioxide (33 mg, 0.15 mmol), triphenylphosphine (38 mg, 0.15 mmol), THF (0.4 mL), and 2.2 M DEAD toluene solution (78 μL, 0.17 mmol) as starting materials, the same procedure as in Reference Example 12 was followed to give the title compound (66.2 mg, 71%) as a white solid.

[1159] 1 H NMR (400MHz, CDCl3) δ7.84 (1H, d, J = 8.0Hz), 7.47 (1H, br t,J=8.0Hz),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).

[1160] See Example 173

[1161] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of 2-[4-fluoro-5-(1-hydroxyethyl)thiophen-2-yl]-2,2-dimethylpropionic acid

[1162]

[1163] In 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Methyl methyl 2-(2-yl]methyl)-4-methylphenyl)-2,2-dimethylpropionate (87.2 mg, 0.12 mmol) was dissolved in methanol / 1,4-dioxane (0.5 mL / 0.5 mL) and 4N sodium hydroxide aqueous solution (310 μL, 1.2 mmol) was added. The mixture was stirred in a microwave at 100 °C for 1 hour. 1N hydrochloric acid was added to the mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (90.7 mg, quant.) as a pale yellow oil.

[1164] 1 H NMR (400MHz, CDCl3) δ7.88 (1H, br d, J = 8.0Hz), 7.52 (1H, br t,J=8.0Hz),7.27-7.20(4H,m),7.13-7.11(1H,m),6.69-6.64(1H,m), 5.13(1H,q,J=6.4Hz),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).

[1165] See Example 174

[1166] 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 2,2-dimethylpropionate (-2-yl]methyl}-4-methylphenyl)-3-[4-fluoro-5-(1-hydroxyethyl)thiophen-2-yl]-2,2-dimethylpropionate

[1167]

[1168] In 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza A solution of methyl methyl 2,2-dimethylpropionate (66 mg, 0.094 mmol) in THF (0.2 mL) was added to a solution of 1N tetrabutylammonium fluoride in THF (188 μL, 0.19 mmol), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture, 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 give the title compound (62.1 mg, quant.) as a white solid.

[1169] 1 H NMR (400MHz, CDCl3) δ7.88 (1H, dd, J = 8.0, 1.6Hz), 7.52 (1H, br t,J=8.0Hz),7.27-7.17(4H,m),7.12(1H,d,J=7.6Hz),6.63-6.61(1H,m),5.15(1H,q,J=6.4Hz),4.54-4.50(1H,m),4.48(1H,br s),4.05-4.01(1H,m),3.83(1H,d,J=14.0Hz),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 = 7.2Hz).

[1170] See Example 175

[1171] 3-(5-acetyl-4-fluorothiophene-2-yl)3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza Manufacturing of methyl 2,2-dimethylpropionate (-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1172]

[1173] In 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] [2-yl]methyl}-4-methylphenyl)-3-[4-fluoro-5-(1-hydroxyethyl)thiophen-2-yl]-2,2-dimethylpropionate (62.1 mg, 0.094 mmol) was dissolved in DMSO (0.4 mL) with TEA (47 μL, 0.34 mmol) and a pyridine-sulfur trioxide complex (32.9 mg, 0.21 mmol). 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 brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (48.1 mg, 87%) as a colorless oil.

[1174] 1 H NMR (400MHz, CDCl3) δ7.89 (1H, dt, J = 8.0, 1.6Hz), 7.53 (1H, br t, J = 8.0Hz), 7.29-7.14 (5H, m), 6.75 (1H, br d,J=6.8Hz),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).

[1175] See Example 176

[1176] 3-(4-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Manufacturing of methyl 5-(2-methyl-1,3-dioxapentan-2-yl)thiophene-2-yl)propionate

[1177]

[1178] Add (R)-4-ethyl-2-{[6-(4,4,5,5-tetramethyl-1,3,2-diaxoxocyclopentaborane-2-yl)-1-triphenylmethyl-1H-benzo[d]imidazol-4-yl]methyl}-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazaza Argon displacement was performed using 1,1-dioxide (126.9 mg, 0.17 mmol), (E)-3-[5-(2-methyl-1,3-dioxapentane-2-yl)thiophen-2-yl)]methyl acrylate (88.4 mg, 0.35 mmol), and [RhCl(cod)]2 (9.3 mg, 0.019 mmol). Then, 1,4-dioxane / water (1 / 1) (0.8 mL) and TEA (75 μL, 0.54 mmol) were added, and the mixture was heated in a microwave at 140 °C for 3 hours. The reaction solution was allowed to return to room temperature, diluted with ethyl acetate, washed with water and saturated brine, 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) = 7 1 / 29 → 1 / 1) to give the title compound (86.6 mg, 58%) as a pale yellow solid.

[1179] 1 H NMR(400MHz, CDCl3)δ7.88(1H,d,J=7.6Hz),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=2.0Hz),6.29-6.26(2H,m),4.77(1H,d,J=15.2Hz),4 .55-4.54(1H.m),4.48(1H,q,J=7.2Hz),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).

[1180] See Example 177

[1181] 3-(5-acetylthiophene-2-yl)-3-(4-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-1H-benzo[d]imidazol-6-yl)propionate

[1182]

[1183] In 3-(4-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza [2-yl]methyl}-1-triphenylmethyl-1H-benzo[d]imidazol-6-yl)-3-[5-(2-methyl-1,3-dioxapentyl-2-yl)thiophen-2-yl]propionate (49.8 mg, 0.058 mmol) was dissolved in dichloromethane (0.9 mL) and then mixed with triethylsilane (0.1 mL) and TFA (1.0 mL). The mixture was stirred at room temperature for 30 minutes. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 → 95 / 5) and preparative thin-layer chromatography (dichloromethane / methanol = 97 / 3) to give the title compound (23.2 mg, 70%) as a white solid.

[1184] 1 H NMR (400MHz, CDCl3) δ10.6 (1H, s), 8.11 (1H, s), 7.90 (1H, dd, J = 7.6, 1.2Hz), 7.74 (1H, s) ),7.56(1H,t,J=7.6Hz),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=7.6Hz),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).

[1185] See Example 178

[1186] 3-(5-acetyl-4-methylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)-2-methylpropionate

[1187]

[1188] In 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Methyl [-2-yl]methyl}-4-methylphenyl)-2-methyl-3-[4-methyl-5-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]propionate (31.2 mg, 0.05 mmol) was added to a THF (0.5 mL) solution and stirred at room temperature for 1 hour with 1 M hydrochloric acid (0.1 mL, 0.1 mmol). The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation to give the title compound (26.7 mg, 92%) as a clear, amber-colored oil.

[1189] 1 H NMR (400MHz, CDCl3) δ7.89 (1H, d, J = 7.6Hz), 7.53 (1H, t, J = 7.6Hz), 7.26 (1H, t, J = 7.6Hz), 7.22 (1H, d,J=8.0Hz),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).

[1190] See Example 179

[1191] 3-(5-acetylthiazolyl-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)-propionate

[1192]

[1193] In 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] A solution of methyl [2-yl]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxapentan-2-yl)thiazo-2-yl]propionate (23.7 mg, 0.040 mmol) in THF (0.5 mL) was added to 1 M hydrochloric acid (0.1 mL), and the mixture was stirred for 2 hours. Then, 6 M hydrochloric acid (0.1 mL) was added, and the mixture was 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 vacuum distillation to give the title compound (19.0 mg, 89%) as a white oil.

[1194] 1 H NMR(400MHz,CDCl3)δ8.17(1H,br s),7.89(1H,dd,J=7.6,1.6Hz),7.52(1H,td,J=7.6,1.6Hz),7.28-7.24(1H,m),7.22-7.14(4H,m),4.79(1H,t,J=7.6Hz),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).

[1195] See Example 180

[1196] 3-(5-acetyl-4-methylthiazolyl-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)-propionate

[1197]

[1198] In 3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxasulfurazine] Methyl [2-yl]methyl}-4-methylphenyl)-3-[4-methyl-5-(2-methyl-1,3-dioxapentyl-2-yl)thiazo-2-yl]propionate (32.8 mg, 0.06 mmol) was added to a THF (0.5 mL) solution with 0.1 mL of 3 M hydrochloric acid (0.3 mmol) 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 brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 1 → dichloromethane / methanol = 98 / 2) to give the title compound (24.8 mg, 82%) as a white solid.

[1199] 1 H NMR (400MHz, CDCl3) δ7.89 (1H, d, J = 7.6Hz), 7.52 (1H, t, J = 7.6Hz), 7.28-7.24 (1H, m), 7.22-7.15 (4H, m), 4.73 (1H, t, J = 7.6Hz), 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),3.4 3-3.42(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).

[1200] See Example 181

[1201] 3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza] Manufacturing of methyl 2,2-dimethylpropionate (-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1202]

[1203] methyl 3-(5-acetylthiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropionate (87.4 mg, 0.231 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza A DMF solution (6.9 mL) of 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) 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 brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 67 / 33 → 46 / 54) to give the title compound (181.0 mg, quant.) as a pale yellow oil.

[1204] 1 H NMR (400Mz, CDCl3) δ9.03 (1H, s), 8.66 (1H, dd, J = 5.6, 1.6Hz), 7.51 (1H, dd, J = 4.0, 1.6Hz), 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).

[1205] See Example 182

[1206] Preparation of methyl 3-(5-acetylthiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)propionate

[1207]

[1208] Methyl 3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-3-[5-(2-methyl-1,3-dioxapentyl-2-yl)thiophen-2-yl]propionate (297.6 mg, 0.60 mmol) in tetrahydrofuran (1.8 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated brine, dried with sodium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (230.4 mg, 85%) as a pale yellow oil.

[1209] 1 H NMR(400MHz, CDCl3)δ7.49(1H,d,J=4.0Hz),7.28-7.24(3H,m),7.11(2H,brs),6.90-6.86(3H,m),4.74(1H,t ,J=8.0Hz),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).

[1210] See Example 183

[1211] Manufacturing of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]propionate

[1212]

[1213] DDQ (231.1 mg, 1.02 mmol) was added to a solution of methyl 3-(5-acetylthiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)propionate (230.4 mg, 0.509 mmol) in dichloromethane / water (10 / 1) (5.28 mL) 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 brine, 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) = 57 / 43 → 36 / 64) to give the title compound (149.6 mg, 85%) as a colorless oil.

[1214] 1 H NMR (400MHz, CDCl3) δ7.49 (1H, d, J = 4.0Hz), 7.29 (1H, br s), 7.10 (2H, br s), 6.87 (1H, br d,J=4.0Hz),4.74(1H,t,J=8.0Hz),4.64(2H,s),3.60(3H,s),3.15-3.01(2H,m),2.46(3H,s),2.28(3H,s).

[1215] See Example 184

[1216] Manufacturing of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]propionate

[1217]

[1218] DIPEA (115.7 μL, 0.68 mmol) and methanesulfonyl chloride (41.8 μL, 0.54 mmol) were added to a suspension of methyl 3-(5-acetylthiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]propionate (150.0 mg, 0.45 mmol) and lithium chloride (38.4 mg, 0.91 mmol) in dichloromethane (3.5 mL), and the mixture was stirred at room temperature for 19 hours. Dichloromethane was added to the reaction solution, and the mixture was washed with saturated aqueous sodium bicarbonate solution and saturated brine. 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) = 67 / 33 → 46 / 54) to give the title compound (105.0 mg, 67%) as a colorless oil.

[1219] 1 H NMR (400MHz, CDCl3) δ7.51 (1H, d, J = 4.0Hz), 7.21 (1H, br s), 7.15 (2H, br s), 6.87 (1H, br d,J=4.0Hz),4.74(1H,t,J=8.0Hz),4.56(2H,s),3.62(3H,s),3.15-3.00(2H,m),2.48(3H,s),2.38(3H,s).

[1220] See Example 185

[1221] 3-(5-acetylthiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)propionate

[1222]

[1223] Methyl 3-(5-acetylthiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]propionate (35.0 mg, 0.10 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza A solution of 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 brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 55 / 45 → 36 / 64) to give the title compound (48.2 mg, 89%) as a colorless oil.

[1224] 1 H NMR (400Mz, CDCl3) δ9.02 (1H, s), 8.65 (1H, d, J = 5.6Hz), 7.50 (1H, br d, J = 4.0Hz), 7.17 (2H, br s), 7.11-7.08 (2H, m), 6.88 (1H, br d,J=4.0Hz),4.73(1H,t,J=7.6Hz),4.45-4.37(2H,m),4.16-4.09(1H,m),3.62(3H,s),3.51-3.43(1H,m),3.1 7-3.09(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=7.6Hz).

[1225] See Example 186

[1226] Preparation of methyl 3-[4-fluoro-5-(1-hydroxyethyl)thiophen-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1227]

[1228] A solution of methyl 3-(5-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-fluorothiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionate (131.8 mg, 0.21 mmol) in THF (2.0 mL) was added to a solution of 1N tetrabutylammonium fluoride in THF (550 μL, 0.55 mmol), and the mixture was stirred at room temperature for 1.5 h. The solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 76 / 24 → 55 / 45) to give the title compound (95.5 mg, 94%) as a colorless oil.

[1229] 1 H NMR (400MHz, CDCl3) δ7.29-7.27(3H,m),7.16(1H,d,J=8.0Hz),7.10(1H,d,J=8.0Hz),6.89(2H,d,J=8.4Hz),6.6 4,6.63(each0.5H,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=6.4Hz,thiopheneβ-CH3 regioisomers),1.30(3H,s),1.20(3H,s).

[1230] See Example 187

[1231] Preparation of methyl 3-[5-acetyl-4-fluorothiophene-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1232]

[1233] 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-dimethylpropionate (95.5 mg, 0.19 mmol) in dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 2.5 h. Further addition of manganese dioxide (317.7 mg, 3.65 mmol) followed by stirring at room temperature for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 86 / 14 → 65 / 35) to give the title compound (92.1 mg, 97%) as a colorless oil.

[1234] 1H NMR (400MHz, CDCl3) δ7.29-7.27(3H,m),7.15(1H,dd,J=7.6,1.2Hz),7.11(1H,d,J=7.6Hz),6.90(2H,d,J =8.4Hz),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).

[1235] See Example 188

[1236] Preparation of methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropionate

[1237]

[1238] Using methyl 3-[5-acetyl-4-fluorothiophene-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionate (92.1 mg, 0.18 mmol), dichloromethane (2.5 mL), water (250 μL), and DDQ (63.9 mg, 0.28 mmol) as starting materials, the procedure was the same as in Reference Example 25, and the title compound (65.7 mg, 94%) was obtained as a colorless oil.

[1239] 1 H NMR (400MHz, CDCl3) δ7.31(1H,d,J=1.6Hz),7.15(1H,dd,J=8.0,1.6Hz),7.11(1H,d,J=8.0Hz),6.75(1H,s),4.67(2 H,s),4.55(1H,s),3.63(3H,s),2.50,2.49(each1.5H,s,acetyl regioisomers),2.29(3H,s),1.32(3H,s),1.20(3H,s).

[1240] See Example 189

[1241] Preparation of methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropionate

[1242]

[1243] DIPEA (90 μL, 0.52 mmol) and methanesulfonyl chloride (27 μL, 0.35 mmol) were added to a suspension of methyl 3-(5-acetylthiophen-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]propionate (65.7 mg, 0.17 mmol) and lithium chloride (40.1 mg, 0.95 mmol) in dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation, yielding the title compound (71.8 mg, quant.) as a pale brown, transparent oily substance.

[1244] 1 H NMR(400MHz, CDCl3) δ7.23(1H,d,J=1.6Hz),7.21(1H,dd,J=8.0,1.6Hz),7.15(1H,d,J=8.0Hz),6.76(1H,s) ,4.57(2H,s),4.44(1H,s),3.64(3H,s),2.514,2.507(each1.5H,s),2.39(3H,s),1.32(3H,s),1.22(3H,s).

[1245] See Example 190

[1246] 3-(5-acetyl-4-fluorothiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza] Manufacturing of methyl 2,2-dimethylpropionate (-2-yl]methyl}-4-methylphenyl)-2,2-dimethylpropionate

[1247]

[1248] Methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropionate (0.17 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza A solution of 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 brine. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 57 / 43 → 36 / 64) to give the title compound (93.7 mg, 92%) as a colorless oil.

[1249] 1 H NMR(400Mz, CDCl3)δ9.02(1H,s),8.65(1H,dd,J=5.6,0.4Hz),7.21(1H,dd,J=7.6,1.6Hz),7.17-7.14(2H,m),7.09(1H,d,J=5.6,2.0Hz),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=14.4Hz),3.640,3.639(each 1.5H,s),3.51-3.43(1H,m),3.17(1H,dt,J=15.2,2.8Hz),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=7.2Hz).

[1250] See Example 191

[1251] Preparation of 3-(5-acetyl-4-methoxythiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionic acid

[1252]

[1253] Using methyl 3-[5-acetyl-4-fluorothiophene-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionate (609.6 mg, 1.2 mmol), methanol / 1,4-dioxane (1 / 1) (10.0 mL), and 4N sodium hydroxide aqueous solution (5.0 mL, 20 mmol) as starting materials, the same procedure as in Preparation Example 43 was followed to obtain the title compound (497.2 mg, 82%) as an orange solid.

[1254] 1 H NMR (400MHz, CDCl3) δ7.32 (1H, d, J = 2.0Hz), 7.27 (2H, d, J = 8.8Hz), 7.21 (1H, dd, J = 8.0, 2.0Hz), 7.10 (1H, d, J = 8.0Hz), 6.89 (2H, d ,J=8.8Hz),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(3Hs).

[1255] See Example 192

[1256] Preparation of 2-(trimethylsilyl)ethyl 3-(acetyl-4-methoxythiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionic acid (trimethylsilyl)ethyl ester)

[1257]

[1258] To a solution of 3-(5-acetyl-4-methoxythiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionic 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 the mixture was stirred at room temperature for 3 hours. Then, 2-(trimethylsilyl)ethanol (280 μL, 2.0 mmol) and DMAP (119.5 mg, 1.0 mmol) were added, and the mixture was 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 sodium bicarbonate aqueous solution, and saturated brine, and the organic layer was dried over sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 86 / 14 → 65 / 35) to give the title compound (409.4 mg, 69%) as a yellow, transparent oil.

[1259] 1 H NMR (400MHz, CDCl3) δ7.31-7.26(3H,m),7.18(1H,dd,J=7.6,1.6H),7.10(1H,d,J=7.6Hz),6.89(2H,d,J=8.8Hz),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).

[1260] See Example 193

[1261] Preparation of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropionic acid (trimethylsilyl)ethyl ester

[1262]

[1263] Using 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2,2-dimethylpropionic acid 2-(trimethylsilyl)ethyl ester (409.3 mg, 0.69 mmol), dichloromethane (6.0 mL), water (600 μL), and DDQ (188.4 mg, 0.83 mmol) as starting materials, the procedure was performed in the same manner as in Reference Example 25, and the title compound (316.9 mg, 97%) was obtained as a colorless oil.

[1264] 1 H NMR (400MHz, CDCl3) δ7.32(1H,d,J=2.0Hz),7.21(1H,dd,J=8.0,2.0Hz),7.11(1H,d,J=8.0Hz),6.73(1H,s),4.67(2H,d,J=5.6Hz),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=5.6Hz),1.32(3H,s),1.22(3H,s),0.90-0.86(2H,m),0.02(9H,s).

[1265] See Example 194

[1266] Preparation of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropionic acid (trimethylsilyl)ethyl ester

[1267]

[1268] DIPEA (115 μL, 0.66 mmol) and methanesulfonyl chloride (34 μL, 0.44 mmol) were added to a suspension of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2,2-dimethylpropionic acid 2-(trimethylsilyl)ethyl ester (101.8 mg, 0.22 mmol) and lithium chloride (49.6 mg, 1.2 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 15.5 h. Ethyl acetate was added to the reaction solution, and the mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, and saturated brine. The organic layer was dried with sodium sulfate, and the solvent was removed by vacuum distillation, yielding the title compound (110.3 mg, quant.) as a pale brown, transparent oily substance.

[1269] 1H NMR (400MHz, CDCl3) δ7.26-7.23(2H,m),7.12(1H,d,J=7.6Hz),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).

[1270] See Example 195

[1271] 3-(5-acetyl-4-methoxythiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza] Manufacturing of 2-(trimethylsilyl)ethyl 2,2-dimethylpropionic acid

[1272]

[1273] The total amount of the compound synthesized in Reference Example 194 was 3-(5-acetyl-4-methoxythiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2,2-dimethylpropionic acid 2-(trimethylsilyl)ethyl ester, (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza A DMF (1.0 mL) solution of 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) was stirred at 25 °C for 1 hour, followed by stirring at 40 °C for 1 hour. The reaction solution was cooled to room temperature, and hexane / ethyl acetate (1 / 1) was added. The mixture was washed with water and saturated brine, and the organic layer was dried over sodium sulfate. The solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 63 / 37 → 42 / 58) to give the title compound (154.1 mg, quant.) as a colorless, transparent oil.

[1274] 1H NMR (400Mz, CDCl3) δ9.01 (1H, s), 8.66, 8.65 (each 0.5H, d, J = 5.6Hz), 7.24-7.22 (2H, m), 7.14 (1H, d, J = 8.0Hz), 7.10, 7.09 (each 0.5H,d,J=5.6Hz),6.76,6.75(each0.5H,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=7.2Hz),0.90-0.86(2H,m),0.02,0.01(each 4.5H,s).

[1275] See Example 196

[1276] Preparation of 2-(5-bromo-3-fluorothiophene-2-yl)-2-methyl-1,3-dioxapentane

[1277]

[1278] Using 1-(5-bromo-3-fluorothiophene-2-yl)ethane-1-one (350.0 mg, 1.57 mmol), ethylene glycol (0.957 mL, 17.3 mmol), p-TsOH·H2O (15.0 mg, 0.08 mmol), and toluene (9.7 mL) as starting materials, the procedure was the same as in Reference Example 76, and the title compound (386.9 mg, 92%) was obtained as a light brown oily substance.

[1279] 1 H NMR (400MHz, CDCl3) δ6.78 (1H, br s), 4.07-4.03 (2H, m), 4.02-3.97 (2H, m), 1.77 (3H, s).

[1280] See Example 197

[1281] Manufacturing of (E)-3-[4-fluoro-5-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]methyl acrylate

[1282]

[1283] Using 2-(5-bromo-3-fluorothiophene-2-yl)-2-methyl-1,3-dioxapentane (150 mg, 0.56 mmol), tetrabutylammonium chloride (7.8 mg, 0.028 mmol), PdCl2(dppf)2-CH2Cl2 (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) as starting materials, the procedure was the same as in Reference Example 88, and the title compound (86.3 mg, 56%) was obtained as a pale yellow solid.

[1284] 1 H NMR (400MHz, CDCl3) δ7.58 (1H,d,J=16.0Hz), 6.93 (1H,s), 6.20 (1H,d,J=16.0Hz), 4.10-4.03 (2H,m), 4.02-3.99 (2H,m), 3.79 (3H,s), 1.80 (3H,s).

[1285] See Example 198

[1286] Preparation of methyl 3-[4-fluoro-5-(2-methyl-1,3-dioxapentane-2-yl)thiophen-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)propionate

[1287]

[1288] A solution of 2-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-diaxoxycyclopentaborane (46.7 mg, 0.13 mmol), (E)-3-[4-fluoro-5-(2-methyl-1,3-dioxapentan-2-yl)thiophen-2-yl]acrylate (86.3 mg, 0.32 mmol), and [RhCl(cod)]2 (6.3 mg, 0.013 mmol) in toluene (0.48 mL) was added under argon atmosphere with 32 μL of 2N potassium hydroxide solution (0.063 mmol), and the mixture was heated at 100 °C for 1.5 h. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with 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 give the title compound (43.7 mg, 67%) as a pale yellow oil.

[1289] 1H NMR (400MHz, CDCl3) δ7.27 (2H, br d, J = 6.8Hz), 7.21 (1H, br s), 7.13-7.07 (2H, m), 6.89 (2H, br d, J = 6.8Hz), 6.52 (1H, br s),4.55(1H,t,J=8.0Hz),4.48(4H,brs),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).

[1290] See Example 199

[1291] Preparation of methyl 3-[4-fluoro-5-(2-methyl-1,3-dioxapentane-2-yl)thiophen-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionate

[1292]

[1293] A 2M LDA THF / heptane / ethylbenzene solution (0.17 mL, 0.34 mmol) was added to a THF (2.0 mL) solution of methyl 3-[4-fluoro-5-(2-methyl-1,3-dioxapentyl-2-yl)thiophene-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl) at -78 °C under an argon atmosphere. The reaction mixture was stirred at -78 °C for 30 min, then at -40 °C for 20 min. Iodomethane (0.3 mL, 4.9 mmol) was added, and the mixture was heated to room temperature and stirred for 3 h. Water was added to stop the reaction, 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. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 8%) to give the title compound (141.1 mg, 81%) as a colorless oil.

[1294] 1H NMR (400MHz, CDCl3) δ7.27(2H,br d,J=8.8Hz),7.24-7.20(1H,m),7.13-7.06(2H,m),6.90(2H,br d,J=8.8Hz),6.61-6.52(1H,m),4.49(4H,br s),4.17-4.14(1H,m),3.98-3.89(4H,m),3.82(3H,s),3.63-3.43(3H,m),3 .19-2.92(1H,m),2.28-2.25(3H,m),1.74-1.72(3H,m),1.23-1.02(3H,m).

[1295] Reference Example 200

[1296] Preparation of methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionate

[1297]

[1298] Methyl 3-[4-fluoro-5-(2-methyl-1,3-dioxapentane-2-yl)thiophen-2-yl]3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionate (243.2 mg, 0.46 mmol) in tetrahydrofuran (3.5 mL) was added to 1.2 mL of 2 N hydrochloric acid and stirred at room temperature for 15 hours. The mixture was neutralized with 1 N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water, dried with sodium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (216.5 mg, 97%) as a pale yellow oil.

[1299] 1 H NMR (400MHz, CDCl3) δ7.28 (2H, d, J = 8.4Hz), 7.24-7.21 (1H, m), 7.14-7.06 (2H, m), 6.90 (2H, d, J = 8.4Hz), 6.71-6.63 (1H, m), 4.50-4. 46(4H,m),4.27-4.22(1H,m),3.82(3H,s),3.65(3H,s),3.23-3.14(1H,m),2.50-2.48(3H,m),2.27-2.25(3H,m),1.24-1.06(3H,m).

[1300] Refer to Example 201

[1301] Preparation of methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2-methylpropionate

[1302]

[1303] DDQ (38.1 mg, 0.17 mmol) was added to a solution of methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionate (68.5 mg, 0.14 mmol) in dichloromethane / water (10 / 1) (3.5 mL) at 0 °C. The mixture was stirred at room temperature for 3 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 brine, 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) = 87 / 13 → 66 / 34) to give the title compound (34.5 mg, 68%) as a pale yellow oil.

[1304] 1 H NMR(400MHz, CDCl3)δ7.28-7.26(1H,m),7.15-7.04(2H,m),6.73-6.65(1H,m),4.69-4.64(2H,m),4.28 -4.23(1H,m),3.65-3.48(3H,m),3.26-2.98(1H,m),2.50-2.47(3H,m),2.30-2.28(3H,m),1.80(1H,br s),1.25-1.07(3H,m).

[1305] See Example 202

[1306] Preparation of methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2-methylpropionate

[1307]

[1308] DIPEA (42.7 μL, 0.25 mmol) and methanesulfonyl chloride (78 μL, 0.17 mmol) were added to a suspension of methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2-methylpropionate (30.4 mg, 0.083 mmol) and lithium chloride (64.1 mg, 0.334 mmol) in dichloromethane (0.75 mL), and the mixture was stirred at room temperature for 16 hours. Water was added 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 vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 97 / 3 → 76 / 24) to give the title compound (23.0 mg, 72%) as a pale yellow oil.

[1309] 1 H NMR (400MHz, CDCl3) δ7.21-7.11(3H,m),6.73-6.70(1H,m),4.57-4.55(2H,m),4.28-4.21(1H,m) ,3.66-3.48(3H,m),3.23-3.14(1H,m),2.51-2.48(3H,m),2.39-2.36(3H,m),1.25-1.07(3H,m).

[1310] See Example 203

[1311] 3-(5-acetyl-4-fluorothiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza] Manufacturing of methyl 2-yl]methyl}-4-methylphenyl)-2-methylpropionate

[1312]

[1313] Methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2-methylpropionate (23.0 mg, 0.06 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza A solution of 1,1-dioxide (13.7 mg, 0.06 mmol), potassium carbonate (24.9 mg, 0.18 mmol), and tetrabutylammonium iodide (4.4 mg, 0.012 mmol) in DMF (1.3 mL) was stirred at room temperature for 3 hours. The reaction solution was cooled to room temperature, and hexane / ethyl acetate (4 / 6) was added. The mixture was washed with water and saturated brine, and the organic layer was dried over sodium sulfate. The solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 67 / 33 → 46 / 54) to give the title compound (29.6 mg, 86%) as a pale yellow oil.

[1314] 1 H NMR(400Mz,CDCl3)δ9.03(1H,s),8.66(1H,br d,J=5.6Hz),7.20-7.08(4H,m),6.73-6.70(1H,m),4.49-4.40(2H,m),4.30-4.13(2H,m),3.66-3.40(4H,m),3. 21-3.13(2H,m),2.51-2.48(3H,m),2.34-2.32(3H,m),1.75-1.65(1H,m),1.61-1.50(1H,m),1.24-1.03(6H,m).

[1315] See Example 204

[1316] Preparation of 3-(5-acetyl-4-methoxythiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionic acid

[1317]

[1318] Using methyl 3-(5-acetyl-4-fluorothiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionate (216 mg, 0.45 mmol), methanol / 1,4-dioxane (1 / 1) (3.2 mL), and 4N sodium hydroxide aqueous solution (1.1 mL, 4.5 mmol) as starting materials, the procedure was the same as in Reference Example 43, and the title compound (248.9 mg, quant.) was obtained as a brown oil.

[1319] 1H NMR (400MHz, CDCl3) δ7.28-7.06(5H,m),6.90-6.87(2H,m),6.70-6.68(1H,m),4.49-4.44(4H,m),4.25-4.21(1H,m),3.91-3.80(3H,m),3.81(3H,br s),3.25-3.15(1H,m),2.44-2.42(3H,m),2.26-2.23(3H,m),1.25-1.07(3H,m).

[1320] See Example 205

[1321] Preparation of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionic acid (trimethylsilyl)ethyl ester)

[1322]

[1323] To a solution of 3-(5-acetyl-4-methoxythiophene-2-yl)-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionic acid (248.9 mg, 0.52 mmol) and HATU (294.3 mg, 0.77 mmol) in dimethylformamide (4.7 mL), 2-(trimethylsilyl)ethanol (0.37 mL, 2.58 mmol), DIPEA (0.27 mL, 1.55 mmol), and 4-dimethylaminopyridine (126.1 mg, 1.03 mmol) were added. The reaction mixture was stirred at room temperature for 22 hours, then water was added, and the mixture was extracted with hexane / ethyl acetate (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) = 100 / 0 → 85 / 15) to give the title compound (74.7 mg, 25%) as a colorless oil.

[1324] 1H NMR (400MHz, CDCl3) δ7.26 (2H, br d, J = 8.8Hz), 7.21 (1H, s), 7.09 (2H, s), 6.88 (2H, br d,J=8.8Hz),6.67(1H,s),4.47(2H,s),4.43(2H,s),4.24(1H,d,J=11.2Hz),4.10-4.05(2H,m),3.86(3H,s),3. 80(3H,s),3.17-3.09(1H,m),2.41(3H,s),2.24(3H,s),1.04(3H,d,J=6.8Hz),0.89-0.85(2H,m),-0.00(9H,s).

[1325] See Example 206

[1326] Preparation of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2-methylpropionic acid (trimethylsilyl)ethyl ester

[1327]

[1328] Using methyl 3-[5-acetyl-4-fluorothiophene-2-yl]-3-(3-{[(4-methoxybenzyl)oxy]methyl}-4-methylphenyl)-2-methylpropionate (74.7 mg, 0.13 mmol), dichloromethane (3 mL), water (0.17 mL), and DDQ (34.9 mg, 0.15 mmol) as starting materials, the procedure was performed in the same manner as in Reference Example 25, and the title compound (57.9 mg, 98%) was obtained as a colorless oil.

[1329] 1 H NMR(400MHz,CDCl3)δ7.28(1H,s),7.12(2H,br s),6.70(1H,s),4.68-4.67(2H,m),4.27(1H,d,J=11.2Hz),4.15-4.04(2H,m),3.90(3H,s),3.19-3.12(1 H,m),2.43(3H,s),2.30(3H,s),1.74-1.71(1H,m),1.06(3H,d,J=7.2Hz),0.91-0.87(2H,m),0.02(9H,s).

[1330] See Example 207

[1331] Preparation of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2-methylpropionic acid (trimethylsilyl)ethyl ester

[1332]

[1333] DIPEA (85.7 μL, 0.50 mmol) and methanesulfonyl chloride (29.0 μL, 0.38 mmol) were added to a suspension of 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophene-2-yl)-3-[3-(hydroxymethyl)-4-methylphenyl]-2-methylpropionic acid (57.9 mg, 0.13 mmol) and lithium chloride (26.5 mg, 0.63 mmol) in dichloromethane (1.1 mL), and the mixture was stirred at room temperature for 2.5 h. Water was added 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 vacuum distillation to give the title compound (77.1 mg, quant.) as a pale yellow oil.

[1334] 1 H NMR(400MHz,CDCl3)δ7.18(1H,s),7.13(2H,br s),6.68(1H,s),4.55(2H,s),4.25(1H,d,J=11.2Hz),4.10-4.05(2H,m),3.88(3H,s),3.16-3 .08(1H,m),2.42(3H,s),2.36(3H,s),1.04(3H,d,J=7.2Hz),0.89-0.85(2H,m),-0.00(9H,s).

[1335] See Example 208

[1336] 3-(5-acetyl-4-methoxythiophene-2-yl)-3-(3-{[(R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza] Manufacturing of 2-(trimethylsilyl)ethyl ester of 2-[2-yl]methyl}-4-methylphenyl)-2-methylpropionic acid

[1337]

[1338] 2-(trimethylsilyl)ethyl 3-(5-acetyl-4-methoxythiophene-2-yl)-3-[3-(chloromethyl)-4-methylphenyl]-2-methylpropionic acid (75.0 mg, 0.16 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiaza A solution of 1,1-dioxide (35.6 mg, 0.16 mmol), potassium carbonate (64.7 mg, 0.47 mmol), and tetrabutylammonium iodide (11.5 mg, 0.031 mmol) in DMF (3.4 mL) was stirred at room temperature for 7 hours. Water was added to the reaction solution, and the mixture was extracted with hexane / ethyl acetate (1 / 1). The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate (v / v) = 67 / 33 → 46 / 54) to give the title compound (54.2 mg, 52%) as a pale yellow oil.

[1339] 1 H NMR(400Mz, CDCl3)δ9.02(1H,s),8.67-...

Claims

1. The compound represented by general formula (I) or its salt: In formula (I): R 1 R represents an alkyl group having 1 to 4 carbon atoms. 2 Indicates that it was selected from -CO-R 24 -R 21 -NR 22 R 23 At least one substituted thiophene group selected from alkoxy groups having 1 to 8 carbon atoms, halogen atoms, and alkyl groups having 1 to 4 carbon atoms, wherein... R 24 R represents an alkyl group having 1 to 8 carbon atoms. 21 R represents a carbonyl group. 22 and R 23 For hydrogen atoms, R 4 and R 5 Same or different, indicating a hydrogen atom or an alkyl group with 1 to 4 carbon atoms that can be replaced by a halogen atom, R 6 R represents an alkyl group having 1 to 8 carbon atoms that can be substituted by a hydroxyl group or an alkoxy group having 1 to 8 carbon atoms. 7 Indicates hydroxyl or -NR 71 R 72 , where R 71 and R 72 A represents a hydrogen atom. 1 A 2 A 3 and A 4 Same or different, represented by CH or N, where N is less than 1, and Z represents a hydrogen atom or a halogen atom.

2. Compounds or salts thereof with lower polarity among the two diastereomers of general formula (II) in which the carbon atom represented by * is a chiral carbon atom: In formula (II): R 1a and R 1b R represents an alkyl group having 1 to 4 carbon atoms. 2 Indicates that it was selected from -CO-R 24 -R 21 -NR 22 R 23 At least one substituted thiophene group selected from alkoxy groups having 1 to 8 carbon atoms, halogen atoms, and alkyl groups having 1 to 4 carbon atoms, wherein... R 24 R represents an alkyl group having 1 to 8 carbon atoms. 21 R represents a carbonyl group. 22 and R 23 For hydrogen atoms, R 4 and R 5 Same or different, indicating a hydrogen atom or an alkyl group with 1 to 4 carbon atoms that can be replaced by a halogen atom, R 6 R represents an alkyl group having 1 to 8 carbon atoms that can be substituted by a hydroxyl group or an alkoxy group having 1 to 8 carbon atoms. 7 Indicates hydroxyl or -NR 71 R 72 , where R 71 and R 72 A represents a hydrogen atom. 1 A 2 A 3 and A 4 The same or different indicates CH or N, where N is less than one, and Z indicates a hydrogen atom or a halogen atom. The compound is a compound containing chiral carbon atoms represented by * in the formula, and wherein R... 6 The compound initially eluted during column separation of a mixture of two diastereomers with a fixed stereoconfiguration, wherein the column type is CHIRAL ART Cellulose-SC, and the elution solvent is a 40 / 60 / 0.1 mixture of n-hexane / ethanol / trifluoroacetic acid.

3. The compound or its salt as described in claim 1 or 2, characterized in that: The thiophene group has substituents including acetyl groups.

4. The compound or its salt as described in claim 1 or 2, characterized in that: The R 2 It is a group represented by the general formula (R2Aa) or (R2Ab). or In the formula: R 3 The symbol represents an acetyl group, and Y represents a hydrogen atom, alkyl group, halogen atom, or alkoxy group.

5. The compound or its salt as described in claim 4, characterized in that: The R 4 and the R 5 Whether the same or different, they are alkyl groups having 1 to 4 hydrogen atoms or carbon atoms.

6. The compound or its salt as described in claim 1 or 2, characterized in that: The R 2 The general formula is (R2Aa): In the formula: R 3 The group represents acetyl, and Y represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, a halogen atom, or an alkoxy group with 1 to 8 carbon atoms. The R 4 It is a hydrogen atom. The R 5 It is an alkyl group having 1 to 4 carbon atoms. The R 6 It is an ethyl group that can be substituted with a hydroxyl group or an alkoxy group having 1 to 8 carbon atoms. The R 7 It is a hydroxyl group. The A 1 The A mentioned 2 and the A 4 All are CH, the A mentioned 3 It is CH or N, and Z represents a hydrogen atom.

7. A pharmaceutical product, characterized in that: It contains at least one of the compounds selected from those described in claim 1 or 2 and their salts.

8. Use of at least one substance selected from the compounds of claim 1 or 2 and their salts in the manufacture of a preventive or therapeutic agent for a disease involving Nrf2.

9. The pharmaceutical product as described in claim 7, characterized in that: It is a topical medication.

10. The pharmaceutical product as described in claim 7, characterized in that: It is an ophthalmic preparation.

11. The pharmaceutical product as described in claim 7, characterized in that: It is a non-oral administration preparation.

12. The pharmaceutical product as described in claim 7, characterized in that: It is an intravenously administered preparation.

13. The use as described in claim 8, characterized in that: The diseases mentioned are brain diseases, lung diseases, skin diseases, ear, nose and throat diseases, kidney diseases, or eye diseases.

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