Abamectin derivative

Abstract

A compound represented by general formula (I) (wherein n represents an integer of 0-2) or a pharmaceutically acceptable salt thereof; x represents CH, CF, CCl, N, CHCH = N, CHCH = CH or CHCH = CF; y represents O, NH or a single bond; z represents a hydroxyl group or an oxo group; r1 represents a hydrogen atom, a C1-C6 alkyl group, a 3-to 6-membered cycloalkyl group, a 4-to 8-membered heterocycloalkyl group, a 6-to 10-membered aryl group, a 5-to 10-membered heteroaryl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a group represented by-CO-R2, a group represented by-COO-R2, a group represented by-CONH-R2, or a group represented by-B (OR4) OR5, and these groups may be substituted; r2, R4, and R5 each represent a hydrogen atom, an alkyl group, or the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an avermectin derivative and a composition containing the same, and more particularly, to a novel avermectin derivative having antiviral activity against coronaviruses and a composition containing the same as an active ingredient. Background Art

[0002] Coronaviruses (CoV) are enveloped viruses with the largest single-stranded positive-sense RNA genome of 26 to 32 kb among RNA viruses. They are classified as the Orthocoronavirinae subfamily of the Coronaviridae family of the order Nidovirales. The Orthocoronavirinae subfamily is further divided into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Coronaviruses are characterized by a high frequency of genetic recombination and mutation, resulting in their diversity and ability to adapt to and infect a wide range of hosts, from birds to whales.

[0003] Seven types of coronaviruses have been confirmed to infect humans. For example, human coronaviruses (HCoV) 229E, OC43, NL63, and HKU1 account for 10-30% of upper respiratory tract infections annually, and are characterized by causing mild respiratory illnesses such as colds. Meanwhile, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (novel coronavirus, SARS-CoV-2), and Middle East respiratory syndrome coronavirus (MERS-CoV) are known causes of respiratory illness, potentially leading to high mortality rates due to the spread of infection (Non-Patent Documents 1 and 2). In particular, the novel coronavirus disease (COVID-19) is caused by SARS-CoV-2. Due to its high infectivity, SARS-CoV-2 has spread globally, causing a pandemic that has infected 600 million people and killed 6.46 million people as of September 7, 2022 (Non-Patent Document 3). The epidemic continues to expand, posing a significant threat to the world.

[0004] So far, a variety of studies are underway on compounds that are agents with antiviral activity against coronaviruses, especially SARS-CoV-2. Most of these compounds are substances that have been found to have antiviral effects through drug repositioning of existing drugs. As novel compounds that have been licensed in Japan, for example, Molnupiravir (Molnupiravir) (product name: LAGEVRIO) (patent documents 1 and 2) and the combination of Nirmatrelvir and Ritonavir (product name: Paxlovid) (patent document 3) and other low-molecular compounds can be cited. However, these compounds were specially licensed as therapeutic drugs for COVID-19 in December 2021 and February 2022, and there is limited information on the effectiveness and safety of the license. Furthermore, since these compounds have not yet confirmed their effectiveness for patients with severe COVID-19, further development of compounds with antiviral activity against SARS-CoV-2 is urgently needed.

[0005] Chemical 1

[0006]

[0007] Furthermore, several other compounds having antiviral activity against SARS-CoV-2 are known, and examples thereof include Ensitrelvir (Patent Document 4) and the compounds described in Patent Documents 5 and 6.

[0008] Chemical 2

[0009]

[0010] Furthermore, in addition to the above-mentioned compounds, it was reported in 2020 that ivermectin, a compound obtained by reducing the double bonds at positions 22 and 23 of avermectin, has antiviral activity against SARS-CoV-2 (Patent Document 7, Non-Patent Document 4).

[0011] Abamectin and its derivatives are a group of compounds characterized by a 16-membered macrolide structure, a hexahydrobenzofuran skeleton, and a bipyran structure containing a spiro ring. Ivermectin, an abamectin derivative, is well known as a therapeutic drug for river blindness and scabies. Abamectin derivatives, including ivermectin, include emamectin, eprinomectin, milbemycin oxime, lepimectin, nemadectin, and moxidectin, which are widely used as human anthelmintics, pesticides, and animal medicines.

[0012] Therefore, extensive research has been conducted on the synthesis and pharmacological effects of avermectin derivatives and analogs. For example, Patent Documents 8 to 13 describe compounds described in these documents as exhibiting anthelmintic effects, and Patent Document 14 describes compounds represented by general formula (I) in this document as exhibiting FXR regulation. Furthermore, Non-Patent Document 5 describes that ivermectin binds to TELO2 and exhibits inhibitory effects on the Wnt / β-catenin pathway.

[0013] Prior art literature

[0014] Patent Literature

[0015] Patent Document 1: International Publication No. 2019 / 113462

[0016] Patent Document 2: International Publication No. 2019 / 173602

[0017] Patent Document 3: International Publication No. 2021 / 250648

[0018] Patent Document 4: International Publication No. 2022 / 138988

[0019] Patent Document 5: International Publication No. 2021 / 176010

[0020] Patent Document 6: International Publication No. 2022 / 010948

[0021] Patent Document 7: International Publication No. 2021 / 179050

[0022] Patent Document 8: International Publication No. 94 / 15944

[0023] Patent Document 9: International Publication No. 95 / 22552

[0024] Patent Document 10: International Publication No. 95 / 04746

[0025] Patent Document 11: Japanese Patent Application Laid-Open No. 63-045281

[0026] Patent Document 12: International Publication No. 2000 / 47597

[0027] Patent Document 13: International Publication No. 2002 / 12248

[0028] Patent Document 14: International Publication No. 2018 / 185684

[0029] Non-patent literature

[0030] Non-patent literature 1: H. Yang and Z. Rao, Nature Reviews Microbiology, 2021, 19, pp. 685-700

[0031] Non-patent literature 2: Journal of the Japanese Society of Virology, Vol. 70, No. 1, pp. 29-36, 2020

[0032] Non-patent literature 3: Weekly epidemiological update on COVID-19 - September 7, 2022, https: / / www.who.int / publications / m / item /

[0033] weekly-epidemiological-update-on-covid-19---7-september-2022

[0034] Non-patent literature 4: Kylie M. Wagstaff et al., Antiviral Research, 2020, 178, 104787

[0035] Non-patent literature 5: Naoyuki Nishiya et al., iScience, 2021, 25, 3, 103912 Summary of the Invention

[0036] Problems to be solved by the invention

[0037] The present invention is made in view of the problems of the above-mentioned prior art, and its purpose is to provide a novel compound having antiviral activity against coronaviruses and useful for treating or preventing diseases or conditions involving coronaviruses, as well as a composition for treating or preventing diseases or conditions involving coronaviruses containing the compound as an active ingredient.

[0038] Means for solving problems

[0039] The present inventors have diligently researched to achieve the above-mentioned objectives and have discovered that avermectin derivatives represented by the following general formula (I) have excellent antiviral activity against coronaviruses, thereby completing the present invention. The embodiments of the present invention obtained from this discovery are as follows. [1]

[0041] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof,

[0042] [Chemistry 3]

[0043]

[0044] [In the above formula (I),

[0045] n represents an integer 0, 1 or 2,

[0046] X represents CH, CF, CCl, N, CHCH=N, CHCH=CH or CHCH=CF,

[0047] Y represents O, NH or a single bond,

[0048] Z represents a hydroxyl group or an oxo group,

[0049] R 1 represents a hydrogen atom; a halogen atom; a C1-C6 alkyl group; a 3-membered to 6-membered cycloalkyl group; a 4-membered to 8-membered heterocycloalkyl group; a 6-membered to 10-membered aryl group; a 5-membered to 10-membered heteroaryl group; a C2-C6 alkenyl group; a C2-C6 alkynyl group; -CO-R 2 The group shown; -COO-R 2 The group shown; -CONH-R 2 The group shown; or -B(OR 4 )OR 5 The basis shown, where

[0050] R 1 When it is not a hydrogen atom or a C1-C6 alkyl group, the above R 1 It can also be selected from halogen atoms, hydroxyl, amino, cyano, nitro, formyl, sulfanyl, oxo, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C6 alkoxy, C1-C3 aminoalkyl, C1-C3 haloalkyl, -NR 2 R 3 The group shown, -COO-R 2 The group shown, -CONH-R 2 The group shown, -NHCO-R 2 The group shown, -NHSO2-R 2The group shown and -NHSO2NH-R 2 The group shown is substituted with one or more substituents,

[0051] R 1 In the case of a C1-C6 alkyl group, the C1-C6 alkyl group may be substituted by one or more substituents selected from the following atoms or groups: a halogen atom; a hydroxyl group; an amino group; a nitro group; a cyano group; an oxo group; or a hydroxyl group, an amino group, -CONH-R 2 The group shown, -NHCO-R 2 The group shown or -NHSO2-R 2 3- to 6-membered cycloalkyl substituted by the group shown; 4- to 8-membered heterocycloalkyl which may be substituted by an oxo group; 6- to 10-membered aryl which may be substituted by a halogen atom or a C1-C3 alkyl group; 5- to 10-membered heteroaryl; -OR 2 The group shown; -O-CO-R 2 The group shown; -O-CONH-R 2 The group shown; -NR 2 R 3 The base shown; -SR 2 The group shown; -CONH-R 2 The group shown; -NHCO-R 2 The group shown; -COO-R 2 The group shown; -NHCOO-R 2 The group shown; -NHCONH-R 2 The group shown; -NHSO2-R 2 The group shown; -CO-R 2 The group shown; -SO2-R 2 The group shown; and -NHSO2NH-R 2 The base shown,

[0052] R 2 represents a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C3 haloalkyl group, a hydroxyl group, a C1-C3 hydroxyalkyl group, a C1-C6 alkoxy group, a C1-C3 haloalkoxy group, a 3-membered to 6-membered cycloalkyl group, a 3-membered to 6-membered cycloalkyl C1-C3 alkyl group, a 4-membered to 8-membered heterocycloalkyl group, a 6-membered to 10-membered aryl group, a 6-membered to 10-membered aryl C1-C3 alkyl group, a 5-membered to 10-membered heteroaryl group, a 5-membered to 10-membered heteroaryl C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkyl group, an amino group, a C1-C6 alkylamino group, a C1-C6 dialkylamino group, a mercapto group or a C1-C6 trialkylsilyl group, wherein R 2The 5- to 10-membered heteroaryl group shown may be further selected from halogen atoms, hydroxyl groups, amino groups, cyano groups, C1-C3 alkyl groups, C1-C3 hydroxyalkyl groups, C1-C6 alkoxy groups, C1-C3 aminoalkyl groups, C1-C3 haloalkyl groups, -NR 2 R 3 The group shown and -CONH-R 2 The group shown is substituted by one or more substituents, R 2 The heteroaryl group of the 5-membered to 10-membered heteroaryl C1-C3 alkyl group shown may be further substituted by an amino group or a C1-C3 alkyl group.

[0053] R 3 represents a hydrogen atom or a C1-C6 alkyl group,

[0054] R 4 and R 5 are all hydrogen atoms, or R 4 and R 5 Each independently represents a C1-C10 alkyl group which may be bonded to each other to form a ring structure,

[0055] The numbers 3, 4, 22, and 23 each represent the position number of a carbon atom, and the bond between the 3rd and 4th positions and between the 22nd and 23rd positions may be a single bond or a double bond, respectively.] [2]

[0057] The compound as described in [1] or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), X is N, Y is O, and there is a single bond between the 3-position and the 4-position. [3]

[0059] The compound as described in [1] or [2] or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R 1 It is a C1-C6 alkyl group which may be substituted. [4]

[0061] The compound as described in any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R 1 is a 5- to 10-membered heteroaryl group, -CONH-R 2 The group shown or -CO-R 2 C1-C6 alkyl substituted with the group shown. [5]

[0063] The compound as described in [1] or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), X is N, Y is O, and there is a double bond between the 3-position and the 4-position. [6]

[0065] The compound as described in [1], [2], [3] or [5] or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), X is N, Y is O, and R 1 is a hydrogen atom; a C2-C6 alkenyl group; a C2-C6 alkynyl group; a halogen atom; a 3- to 6-membered cycloalkyl group which may be substituted with a hydroxyl group; a 4- to 8-membered heterocycloalkyl group; or a group selected from -OR 2 The group shown, -O-CONH-R 2 The group shown, -COO-R 2 The group shown, -CONH-R 2 The group shown, -NHCONH-R 2 The group shown, -CO-R 2 The group shown and -NHSO2-R 2 A C1-C6 alkyl group substituted with one or more substituents in the group shown. [7]

[0067] The compound described in any one of [1] to [6] or a pharmaceutically acceptable salt thereof, wherein the compound represented by the above formula (I) is selected from the compounds represented by the following formulas (1) to (94).

[0068] [Chemistry 4]

[0069]

[0070] [Chemistry 5]

[0071]

[0072] Chemical 6]

[0073]

[0074] [Chemification 7]

[0075]

[0076] [Chemistry 8]

[0077]

[0078] Chemical 9]

[0079]

[0080] [Chemistry 10]

[0081]

[0082] [Chemistry 11]

[0083]

[0084] [Chemistry 12]

[0085]

[0086] [Chemistry 13]

[0087]

[0088] [Chemistry 14]

[0089]

[0090] [Chemistry 15]

[0091]

[0092] [Chemistry 16]

[0093]

[0094] [Chemistry 17]

[0095]

[0096] [Chemistry 18]

[0097]

[0098] [Chemistry 19]

[0099] [8]

[0101] The compound or pharmaceutically acceptable salt thereof as described in [1], wherein in the above formula (I), X is CH, CF or CHCH=CH, and there is a single bond between the 3-position and the 4-position. [9]

[0103] The compound or pharmaceutically acceptable salt thereof as described in [1], wherein in the above formula (I), X is CH, CF or CHCH=CH, and there is a double bond between the 3-position and the 4-position.

[10]

[0105] The compound as described in [1], [7] or [8] or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), X is CH, CF or CHCH=CH, and Y is a single bond,

[0106] R 1 -COO-R is a 4- to 8-membered heterocycloalkyl group which may be substituted by an oxo group; 2 can also be selected from halogen atoms, hydroxyl, amino, cyano, formyl, oxo, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C6 alkoxy, C1-C3 haloalkyl, -NR 2 R3 The group shown, -NHCO-R 2 The group shown and -CONH-R 2 A 5- to 10-membered heteroaryl group substituted with one or more substituents (preferably one substituent) in the group shown; or a 5- to 10-membered heteroaryl group selected from hydroxyl, amino, nitro, oxo, -CONH-R 2 The groups shown and -COO-R 2 A C1-C6 alkyl group substituted with one or more substituents in the group shown.

[11]

[0108] The compound described in [1] or [8] or a pharmaceutically acceptable salt thereof, wherein the compound represented by the above formula (I) is selected from the compounds represented by the following formulas (201) to (271).

[0109] [Chemistry 20]

[0110]

[0111] [Chemistry 21]

[0112]

[0113] [Chemistry 22]

[0114]

[0115] [Chemistry 23]

[0116]

[0117] [Chemistry 24]

[0118]

[0119] [Chemistry 25]

[0120]

[0121] [Chemistry 26]

[0122]

[0123] [Chemistry 27]

[0124]

[0125] [Chemistry 28]

[0126]

[0127] [Chemistry 29]

[0128]

[0129] [Chemistry 30]

[0130]

[0131] [Chemistry 31]

[0132]

[12]

[0134] The compound as described in [1] or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), X is N, Y is NH, R 1 -CO-R 2 The base shown.

[13]

[0136] The compound described in any one of [1] to

[12] or a pharmaceutically acceptable salt thereof has antiviral activity against coronavirus.

[14]

[0138] The compound or pharmaceutically acceptable salt thereof as described in

[13] , wherein the coronavirus is a coronavirus classified into the genus Betacoronavirus.

[15]

[0140] The compound or pharmaceutically acceptable salt thereof as described in

[13] or

[14] , wherein the coronavirus is at least one selected from human coronavirus (HCoV), severe acute respiratory syndrome coronavirus (SARS-CoV), new coronavirus (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV).

[16]

[0142] A composition for treating or preventing a disease or condition involving coronavirus, comprising a compound described in any one of [1] to

[12] or a pharmaceutically acceptable salt thereof as an active ingredient.

[17]

[0144] As described in

[16] , the above-mentioned coronavirus is a coronavirus classified into the genus Betacoronavirus.

[18]

[0146] The composition as described in

[16] or

[17] , wherein the above-mentioned coronavirus is at least one selected from human coronavirus (HCoV), severe acute respiratory syndrome coronavirus (SARS-CoV), new coronavirus (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV).

[19]

[0148] A method for treating or preventing a disease or condition involving coronavirus, comprising administering a compound according to any one of [1] to

[12] or a pharmaceutically acceptable salt thereof to a subject.

[20]

[0150] Use of a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[12] , wherein the compound or a pharmaceutically acceptable salt thereof is used to manufacture a composition for treating or preventing a disease or condition involving coronavirus.

[0151] Effects of the Invention

[0152] According to the present invention, there can be provided novel compounds having antiviral activity against coronaviruses and useful for treating or preventing diseases or conditions involving coronaviruses, as well as compositions for treating or preventing diseases or conditions involving coronaviruses containing the compounds as active ingredients. DETAILED DESCRIPTION

[0153] Hereinafter, the present invention will be described in detail based on its preferred embodiments. In the following description, the same or corresponding elements are given the same reference numerals, and repeated descriptions are omitted.

[0154] <Avermectin derivatives>

[0155] The present invention provides compounds represented by the following general formula (I) and pharmaceutically acceptable salts thereof (collectively referred to as "compounds of the present invention" as appropriate in this specification):

[0156] [Chemistry 32]

[0157]

[0158] As described above, the compound represented by formula (I) is an avermectin derivative having a 16-membered macrolide structure, a hexahydrobenzofuran skeleton, and a bipyran structure containing a spiro ring. In formula (I), the numbers 3, 4, 22, and 23 represent the positions of carbon atoms, respectively. The bond between positions 3 and 4 and between positions 22 and 23 can each independently be a single bond or a double bond. Furthermore, in formula (I), Me represents a methyl group.

[0159] In the above formula (I), n represents an integer of 0, 1 or 2.

[0160] In the above formula (I), X represents CH, CF, CCl, N, CHCH=N, CHCH=CH, or CHCH=CF. When X represents CHCH=N, CHCH=CH, or CHCH=CF, that is, the structure represented by "=X~" represents the structure represented by "=CHCH=N~," "=CHCH=CH~," or "=CHCH=CF~," respectively.

[0161] Furthermore, in this specification, a wavy line representing a single bond between atoms in a structural formula, for example, a wavy line (-) representing a single bond between X and Y in formula (I), represents any of the isomer structures ((E) isomer, (Z) isomer) shown below, when geometric isomers exist. In this case, the compound represented by the above formula (I) may be any of these isomers or a mixture. Furthermore, in this specification, a single bond represented by a straight line (-) in a structural formula represents either a "wedge-shaped bond" or a "dashed bond" when stereoisomers exist. In this case, the compound represented by the above formula (I) may be any of these isomers or a mixture.

[0162] [Chemistry 33]

[0163]

[0164] In the above formula (I), Y represents O, NH or a single bond.

[0165] In the above formula (I), Z represents a hydroxyl group or an oxo group. When Z is a hydroxyl group, a single bond is formed between OH and the carbon atom to which it is bonded, and when Z is an oxo group, a double bond is formed between O and the carbon atom to which it is bonded.

[0166] In the above formula (I), R 1 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a 3-membered to 6-membered cycloalkyl group, a 4-membered to 8-membered heterocycloalkyl group, a 6-membered to 10-membered aryl group, a 5-membered to 10-membered heteroaryl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, -CO-R 2 The groups shown (C is bonded to O via a double bond and to R via a single bond) 2 Bond. Same below), -COO-R 2 The group shown, -CONH-R 2 The group shown or -B(OR 4 )OR 5 The base shown.

[0167] Here, R 1 When it is not a hydrogen atom or a C1-C6 alkyl group, the above R 1 It can also be selected from halogen atoms, hydroxyl, amino, cyano, nitro, formyl, mercapto, oxo, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C6 alkoxy, C1-C3 aminoalkyl, C1-C3 haloalkyl, -NR 2 R 3 The group shown, -COO-R 2 The group shown, -CONH-R 2 The group shown, -NHCO-R2 The group shown, -NHSO2-R 2 The group shown and -NHSO2NH-R 2 In the present specification, "each group is substituted with an oxo group" means that two hydrogen atoms bonded to carbon atoms contained in the group are replaced with one oxygen atom.

[0168] Furthermore, R 1 In the case of a C1-C6 alkyl group, the C1-C6 alkyl group may be substituted by one or more substituents selected from the following atoms or groups: a halogen atom; a hydroxyl group; an amino group; a nitro group; a cyano group; an oxo group; or a hydroxyl group, an amino group, -CONH-R 2 The group shown, -NHCO-R 2 The group shown or -NHSO2-R 2 3- to 6-membered cycloalkyl substituted by the group shown; 4- to 8-membered heterocycloalkyl which may be substituted by an oxo group; 6- to 10-membered aryl which may be substituted by a halogen atom or a C1-C3 alkyl group; 5- to 10-membered heteroaryl; -OR 2 The group shown; -O-CO-R 2 The group shown; -O-CONH-R 2 The group shown; -NR 2 R 3 The base shown; -SR 2 The group shown; -CONH-R 2 The group shown; -NHCO-R 2 The group shown; -COO-R 2 The group shown; -NHCOO-R 2 The group shown; -NHCONH-R 2 The group shown; -NHSO2-R 2 The group shown; -CO-R 2 The group shown; -SO2-R 2 The group shown; and -NHSO2NH-R 2 The base shown.

[0169] In the above formula (I), R 1 R in 2represents a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C3 haloalkyl group, a hydroxyl group, a C1-C3 hydroxyalkyl group, a C1-C6 alkoxy group, a C1-C3 haloalkoxy group, a 3-membered to 6-membered cycloalkyl group, a 3-membered to 6-membered cycloalkyl C1-C3 alkyl group, a 4-membered to 8-membered heterocycloalkyl group, a 6-membered to 10-membered aryl group, a 6-membered to 10-membered aryl C1-C3 alkyl group, a 5-membered to 10-membered heteroaryl group, a 5-membered to 10-membered heteroaryl C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkyl group, an amino group, a C1-C6 alkylamino group, a C1-C6 dialkylamino group, a mercapto group, or a C1-C6 trialkylsilyl group. In this case, R 2 The 5- to 10-membered heteroaryl group shown can also be selected from halogen atoms, hydroxyl groups, amino groups, cyano groups, C1-C3 alkyl groups, C1-C3 hydroxyalkyl groups, C1-C6 alkoxy groups, C1-C3 aminoalkyl groups, C1-C3 haloalkyl groups, -NR 2 R 3 The group shown and -CONH-R 2 The group shown is substituted by one or more substituents, R 2 The heteroaryl group of the 5-membered to 10-membered heteroaryl C1-C3 alkyl group may be further substituted by an amino group or a C1-C3 alkyl group.

[0170] Furthermore, in the above formula (I), R 1 R in 3 represents a hydrogen atom or a C1-C6 alkyl group. 1 R in 4 and R 5 are all hydrogen atoms, or R 4 and R 5 Each independently represents a C1-C10 alkyl group which may be bonded to each other to form a ring structure.

[0171] In this specification, "C1-C6 alkyl" means an alkyl group having 1 to 6 carbon atoms, which may be linear or branched. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, tert-pentyl, 3-methylbutyl (isopentyl), neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. In the present specification, "C1-C3 alkyl" means an alkyl group having 1 to 3 carbon atoms, which may be linear or branched. Specific examples include methyl, ethyl, n-propyl, and isopropyl.

[0172] In this specification, "3- to 6-membered cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Furthermore, in this specification, when used to represent the number of ring members, for example, "3- to 6-membered" refers to any range between 3 and 6 members (e.g., "3- to 4-membered," "4- to 5-membered," etc.). The same applies to other ring structures.

[0173] In this specification, "4- to 8-membered heterocycloalkyl" refers to a 4- to 8-membered monocyclic or bicyclic ring structure formed by carbon atoms and one or more heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. Specific examples include oxetane, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dihydropyranyl, and 1,4-dihydropyranyl groups, which can have a bonding position at any carbon atom or nitrogen atom. Alkyl, pyrrolidinyl, piperidinyl, piperazinyl, Oxazolidinyl (1,2,4- Oxazolidinyl, 1,3,4- oxadiazolidinyl, ...

[0174] In the present specification, the "6- to 10-membered aryl group" refers to a 6- to 10-membered monocyclic or bicyclic aromatic hydrocarbon group composed of carbon atoms, and specific examples thereof include phenyl, 1-naphthyl, 2-naphthyl, and azulenyl.

[0175] In this specification, "5-membered to 10-membered heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic aromatic hydrocarbon group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms as the constituent atoms of the ring. Specific examples include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, Azolyl, iso Azolyl, thiazolyl, isothiazolyl, triazolyl (1,2,3-triazolyl, 1,2,4-triazolyl, etc.), Oxazolyl (1,2,4- oxadiazole, 1,3,4- oxadiazole, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, purinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, indazolyl, benzo oxazolyl, benzothiazolyl, benzopyrazolyl, benzotriazolyl, isobenzofuranyl, isoindolyl, indolizinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, triazolopyridinyl, benzofuranyl, benzothiophenyl, benzoisothiophene, oxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrazolyl and the like.

[0176] In this specification, "C2-C6 alkenyl" means an alkenyl group having 2 to 6 carbon atoms and containing at least one double bond, and may be straight-chain or branched. Specific examples include vinyl, allyl, 2-propenyl, isopropenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 3-methyl-1-butenyl, 1,2-dimethyl-2-propenyl, 1,1-dimethyl-2-propenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1,2-dimethyl-1-propenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,3-pentadienyl, 1-vinyl-2-propenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl.

[0177] In this specification, "C2-C6 alkynyl" means an alkynyl group having 2 to 6 carbon atoms and containing at least one triple bond, and may be straight-chain or branched. Specific examples include ethynyl, propargyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-1-butyn-3-yl, prop-1-yn-1-yl, and 4-methyl-2-pentynyl.

[0178] In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0179] In this specification, "may also be hydroxyl, amino, -CONH-R 2 The group shown, -NHCO-R 2 The group shown or -NHSO2-R 2 "3-membered to 6-membered cycloalkyl substituted with a group shown in the figure" means the above-mentioned 3-membered to 6-membered cycloalkyl, or one or more (preferably one) hydrogen atoms of the above-mentioned 3-membered to 6-membered cycloalkyl are selected from hydroxyl, amino, -CONH-R 2The group shown, -NHCO-R 2 The group shown and -NHSO2-R 2 A group obtained by replacing the group shown in the figure with a substituent. When there are multiple substituents, they may be the same or different. The 3- to 6-membered cycloalkyl group substituted with a substituent may have the substituent bonded to a carbon atom at a bonding point in the ring structure.

[0180] In this specification, the "6- to 10-membered aryl group which may be substituted with a halogen atom or a C1-C3 alkyl group" means the above-mentioned 6- to 10-membered aryl group, or a group in which one or more hydrogen atoms of the above-mentioned 6- to 10-membered aryl group are substituted with the above-mentioned halogen atom and / or the above-mentioned C1-C3 alkyl group.

[0181] In this specification, "C1-C3 aminoalkyl" refers to a group in which one hydrogen atom of the above-mentioned C1-C3 alkyl group is substituted with an amino group. Specific examples include aminomethyl, aminoethyl, and aminopropyl.

[0182] In this specification, the term "C1-C3 haloalkyl" refers to a group in which 1 to 6, preferably 1 to 3, of the hydrogen atoms of the above-mentioned C1-C3 alkyl group are substituted with the above-mentioned halogen atoms. Specific examples include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, tribromomethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, and 1,1,1,3,3,3-hexafluoro-2-propyl.

[0183] In this specification, "C1-C3 hydroxyalkyl" means a group in which one hydrogen atom of the above-mentioned C1-C3 alkyl group is substituted with a hydroxyl group. Specific examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxyisopropyl.

[0184] In this specification, "C1-C6 alkoxy" refers to a group represented by -O-Alk, where Alk is the above-mentioned C1-C6 alkyl group. Specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, 2-pentoxy, 3-pentoxy, 2-methylbutoxy, hexoxy, isohexoxy, 3-methylpentoxy, and 4-methylpentoxy. Furthermore, in this specification, "C1-C3 alkoxy" refers to a group represented by -O-Alk, where Alk is the above-mentioned C1-C3 alkyl group. Specific examples include methoxy, ethoxy, propoxy, and isopropoxy.

[0185] In this specification, "C1-C3 haloalkoxy" means a group represented by -O-Alk', where Alk' is the above-mentioned C1-C3 haloalkyl group. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, 2-chloroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2,2 -trichloroethoxy, 2,2,2-tribromoethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 3,3-trifluoropropoxy, heptafluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 3,3,3-trichloropropoxy, heptachloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 3,3,3-tribromopropoxy, heptabromopropoxy.

[0186] In the present specification, the "3-membered to 6-membered cycloalkyl C1-C3 alkyl group" means a group in which one hydrogen atom of the above-mentioned C1-C3 alkyl group is substituted by the above-mentioned 3-membered to 6-membered cycloalkyl group.

[0187] In the present specification, the "6- to 10-membered aryl C1-C3 alkyl group" refers to a group in which one hydrogen atom of the above-mentioned C1-C3 alkyl group is substituted with the above-mentioned 6- to 10-membered aryl group.

[0188] In this specification, a "5- to 10-membered heteroaryl C1-C3 alkyl group" refers to a group in which one hydrogen atom of the aforementioned C1-C3 alkyl group is substituted with a 5- to 10-membered heteroaryl group. Furthermore, in this specification, when a 6- to 10-membered aryl C1-C3 alkyl group is substituted with a substituent, it is preferred that one or two hydrogen atoms bonded to a carbon atom constituting the ring structure of the aryl group be substituted with the substituent.

[0189] In the present specification, a "C1-C3 alkoxy C1-C3 alkyl group" refers to a group in which one hydrogen atom of the above-mentioned C1-C3 alkyl group is substituted by the above-mentioned C1-C3 alkoxy group.

[0190] In this specification, "C1-C6 alkylamino" means a group in which one hydrogen atom of an amino group is substituted with the above-mentioned C1-C6 alkyl group. Specific examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, sec-butylamino, n-pentylamino, 1-methylbutylamino, 2-methylbutylamino, 1,2-dimethylpropylamino, tert-pentylamino, 3-methylbutylamino (isopentyl), neopentylamino, 1-ethylpropylamino, n-hexylamino, isohexylamino, 2-methylpentylamino, 3-methylpentylamino, 2,3-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,2-dimethylbutylamino, 2,3-dimethylbutylamino, 3,3-dimethylbutylamino, and 2-ethylbutylamino.

[0191] In the present specification, a "C1-C6 dialkylamino group" means a group in which two hydrogen atoms of an amino group are substituted with the above-mentioned C1-C6 alkyl group which may be the same as or different from each other. Specific examples include dimethylamino, diethylamino, N-ethyl-N-methylamino, di(n-propyl)amino, N-methyl-N-(n-propyl)amino, N-ethyl-N-n-propylamino, diisopropylamino, N-ethyl-N-isopropylamino, di(n-butyl)amino, N-methyl-N-sec-butylamino, di(n-heptyl)amino, N-(n-heptyl)-N-methylamino, N-ethyl-N-(n-heptyl)amino, diisoheptylamino, N-isoheptyl-N-methylamino, N-ethyl-N-isoheptylamino, di(n-hexyl)amino, N-hexyl-N-methylamino, N-ethyl-N-hexylamino, diisohexylamino, N-isohexyl-N-methylamino, and N-ethyl-N-isohexylamino.

[0192] In this specification, a "C1-C6 trialkylsilyl group" refers to a group in which three hydrogen atoms of a silyl group are replaced by the aforementioned C1-C6 alkyl group, which may be the same or different. Specific examples include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, and tri(tert-butyl)silyl.

[0193] In this specification, "-B(OR 4 )OR 5 The radical shown in the figure represents -OR 4 AND-OR 5 are respectively bonded to -B. 4 and R 5 The "C1-C10 alkyl groups which may be bonded to each other to form a ring structure" shown in the figure represents R 4 and R 5Each independently represents an alkyl group having 1 to 10 carbon atoms, which may be linear or branched. 4 and R 5 They can also be bonded to each other to form ring structures such as pinacol ester (pin) and neopentyl glycol ester (neo) of boric acid.

[0194] In this specification, the phrase "optionally substituted" in each group refers to an unsubstituted group or a group in which one or more hydrogen atoms of the group are replaced by atoms or substituents. When there are multiple substituting atoms or substituents, they may be the same or different. Furthermore, the number of substituting atoms or substituents is preferably 1 to 3, for example.

[0195] When an asymmetric carbon is present in the compound represented by the above formula (I), the compound may be in the form of a racemate, a mixture of diastereomers, or any of the optically active forms, or a mixture thereof. Furthermore, when geometric isomers are present in the compound represented by the above formula (I), the compound may be in the form of an (E) form, a (Z) form, or a mixture thereof. Furthermore, in the compound represented by the above formula (I), any one or more hydrogen atoms present in a substituent such as an alkyl group or an alkoxy group may be substituted with a deuterium atom.

[0196] As the pharmaceutically acceptable salt of the compound represented by the above formula (I), there is no particular limitation as long as it is pharmaceutically acceptable, and examples thereof include salts with organic acids, salts with inorganic acids, and salts with amino acids. Examples of the above-mentioned salts with organic acids include formate, acetate, propionate, tartrate, fumaric acid, maleate, succinate, lactate, citric acid, malate, ascorbate, oxalate, glycolate, phenylacetate, benzoate, mandelate, butyrate, malate, methanesulfonate, and benzenesulfonate. Examples of the above-mentioned salts with inorganic acids include hydrochloride, hydrobromide, phosphate, sulfamate, nitrate, and sulfate. Furthermore, examples of the above-mentioned salts with amino acids include aspartic acid and glutamic acid.

[0197] Next, preferred embodiments of the compound of the present invention will be described, but the compound of the present invention is not limited to these examples.

[0198] In the compound of the present invention, it is particularly preferred that n is 2 in the above formula (I).

[0199] The compound of the present invention is preferably one wherein X in the above formula (I) is CH, CF, N or CHCH=CH, more preferably CH, CF or N.

[0200] In the compound of the present invention, preferably, in the above formula (I), Y is O or a single bond. Furthermore, in the above formula (I), preferably, Z is either a hydroxyl group or an oxo group.

[0201] The compound of the present invention, in the above formula (I), R 1 Preferably a hydrogen atom; a 4- to 8-membered heterocycloalkyl group which may be substituted by an oxo group; or a halogen atom, a hydroxyl group, an amino group, a cyano group, a formyl group, an oxo group, a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C6 alkoxy group, a C1-C3 haloalkyl group, -NR 2 R 3 The group shown, -COO-R 2 The group shown, -NHCO-R 2 The group shown and -CONH-R 2 5- to 10-membered heteroaryl substituted with one or more substituents (preferably one substituent) in the group shown; C2-C6 alkenyl; C2-C6 alkynyl; -CO-R 2 The group shown; -COO-R 2 The group shown; or -CONH-R 2 The base shown, or

[0202] It may also be selected from halogen atoms, hydroxyl groups, amino groups, nitro groups, cyano groups, oxo groups, 3- to 6-membered cycloalkyl groups (which may also be substituted by hydroxyl groups), 4- to 8-membered heterocycloalkyl groups (which may also be substituted by oxo groups), 6- to 10-membered aryl groups (which may also be substituted by halogen atoms or C1-C3 alkyl groups), 5- to 10-membered heteroaryl groups, -OR 2 The group shown, -O-CONH-R 2 The group shown, -NR 2 R 3 The group shown, -CONH-R 2 The group shown, -NHCO-R 2 The group shown, -COO-R 2 The group shown, -NHSO2-R 2 The group shown, -NHCONH-R 2 The group shown, -CO-R 2 The group shown and -SO2-R 2 A C1-C6 alkyl group (preferably a C1-C3 alkyl group) substituted with one or more substituents (preferably one substituent) in the group shown.

[0203] In the above formula (I), R 1 More preferably, it is a hydrogen atom; a 4- to 8-membered heterocycloalkyl group which may be substituted with an oxo group; a C2-C6 alkenyl group; a C2-C6 alkynyl group; or -COO-R 2 The base shown, or

[0204] is selected from halogen atoms, hydroxyl, amino, cyano, formyl, oxo, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C6 alkoxy, C1-C3 haloalkyl, -NR 2 R 3 The group shown, -COO-R 2 The group shown, -NHCO-R 2 The group shown and -CONH-R 2 A 5- to 10-membered heteroaryl group substituted with one or more substituents (preferably one substituent) in the group shown in

[0205] is selected from halogen atoms, hydroxyl groups, nitro groups, oxo groups, 3- to 6-membered cycloalkyl groups (which may also be substituted with hydroxyl groups), 5- to 10-membered heteroaryl groups, 4- to 8-membered heterocycloalkyl groups, -OR 2 The group shown, -CONH-R 2 The group shown, -NHCO-R 2 The group shown, -NHSO2-R 2 The group shown, -NHCONH-R 2 The group shown, -CO-R 2 The group shown and -SO2-R 2 A C1-C6 alkyl group (preferably a C1-C3 alkyl group) substituted with one or more substituents (preferably one substituent) in the group shown.

[0206] R 1 More preferably, it is a hydrogen atom, or a member selected from a halogen atom, a hydroxyl group, an amino group, a cyano group, an oxo group, a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C6 alkoxy group, -NR 2 R 3 substituted with one or more substituents (preferably one substituent) in the group shown in the figure and C1-C3 haloalkyl, or a 5- to 10-membered heteroaryl group selected from 4- to 8-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -OR 2 The group shown, -CONH-R 2 The group shown and -NHSO2-R 2 A C1-C6 alkyl group (preferably a C1-C3 alkyl group) substituted with one or more substituents (preferably one substituent) in the group shown.

[0207] In the above formula (I), R 2Preferred are hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, 3-membered to 6-membered cycloalkyl, 3-membered to 6-membered cycloalkylC1-C3 alkyl, 4-membered to 8-membered heterocycloalkyl, 6-membered to 10-membered aryl, 6-membered to 10-membered arylC1-C3 alkyl, 5-membered to 10-membered heteroaryl, 5-membered to 10-membered heteroarylC1-C3 alkyl (which may also be substituted with an amino group or a C1-C3 alkyl), C1-C3 alkylamino or C1-C6 dialkylamino.

[0208] R 2 More preferably, it is a hydrogen atom, a C1-C6 alkyl group, a C1-C3 haloalkyl group, a C1-C3 hydroxyalkyl group, a 3-membered to 6-membered cycloalkyl group, a 4-membered to 8-membered heterocycloalkyl group, a 3-membered to 6-membered cycloalkyl C1-C3 alkyl group, a 5-membered to 10-membered heteroaryl group, a 5-membered to 10-membered heteroaryl C1-C3 alkyl group (which may be substituted with an amino group or a C1-C3 alkyl group), or a C1-C6 dialkylamino group; further preferably, it is a C1-C6 alkyl group, a 3-membered to 6-membered cycloalkyl group, a C1-C3 haloalkyl group, a 5-membered to 10-membered heteroaryl group, or a 5-membered to 10-membered heteroaryl C1-C3 alkyl group (which may be substituted with an amino group or a C1-C3 alkyl group).

[0209] Furthermore, in the compound of the present invention, preferably, in the above formula (I), there is a single bond between positions 22 and 23.

[0210] n, X, Y, and R in the above formula (I) 1 、R 2 and R 3 There are no particular restrictions on the preferred embodiment of the combination, and examples thereof include the following embodiments.

[0211] (Method 1)

[0212] A preferred embodiment of the compound of the present invention is Embodiment 1 in which, in the above-mentioned formula (I), n is 2, X is N, and Y is O.

[0213] In method 1, R 1 Preferably a hydrogen atom; a 4- to 8-membered heterocycloalkyl group which may be substituted by an oxo group; a C2-C6 alkenyl group; or a C2-C6 alkynyl group; or

[0214] is selected from halogen atoms, hydroxyl groups, amino groups, 3- to 6-membered cycloalkyl groups (which may be substituted by hydroxyl groups), 4- to 8-membered heterocycloalkyl groups (which may be substituted by oxo groups), 5- to 10-membered heteroaryl groups, -OR 2 The group shown, -O-CONH-R 2 The group shown, -NR 2 R 3 The group shown, -CONH-R 2 The group shown, -NHCO-R 2The group shown, -COO-R 2 The group shown, -NHSO2-R 2 The group shown, -NHCONH-R 2 The groups shown and -CO-R 2 The group shown is a C1-C6 alkyl group substituted with one or more substituents.

[0215] R 1 More preferably, it is a hydrogen atom; a C2-C6 alkenyl group; or a C2-C6 alkynyl group; or it may be selected from a halogen atom, a hydroxyl group, a 3-membered to 6-membered cycloalkyl group (which may also be substituted with a hydroxyl group), a 4-membered to 6-membered heterocycloalkyl group, a 5-membered to 10-membered heteroaryl group, -OR 2 The group shown, -CONH-R 2 The group shown, -NHCO-R 2 The group shown, -NHSO2-R 2 The group shown is -NHCONH-R 2 The group shown is a C1-C6 alkyl group substituted with one or more substituents.

[0216] In method 1, R 2 Preferably, it is a hydrogen atom, a C1-C6 alkyl group, a C1-C3 haloalkyl group, a C1-C3 hydroxyalkyl group, a 3-membered to 6-membered cycloalkyl group, a 3-membered to 6-membered cycloalkyl C1-C3 alkyl group, a 4-membered to 8-membered heterocycloalkyl group, a 5-membered to 10-membered heteroaryl group, a 5-membered to 10-membered heteroaryl C1-C3 alkyl group (which may also be substituted by an amino group or a C1-C3 alkyl group) or a C1-C6 dialkylamino group.

[0217] R 2 More preferably, it is a hydrogen atom, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 hydroxyalkyl group, a 4-membered to 6-membered cycloalkyl group, a 3-membered to 6-membered cycloalkyl C1-C3 alkyl group, a 4-membered to 6-membered heterocycloalkyl group, a 5-membered to 8-membered heteroaryl group, a 5-membered to 8-membered heteroaryl C1-C3 alkyl group (which may also be substituted by an amino group or a C1-C3 alkyl group) or a C1-C6 dialkylamino group.

[0218] In method 1, R 3 It can be either a hydrogen atom or a C1-C6 alkyl group. Furthermore, in Embodiment 1, Z can be either a hydroxyl group or an oxo group. Furthermore, in Embodiment 1, a single bond or a double bond can be formed between positions 3 and 4, and a single bond is preferably formed between positions 22 and 23.

[0219] (Method 2)

[0220] Another preferred embodiment of the compound of the present invention is embodiment 2 in which, in the above formula (I), n is 2, X is CH, CF, CHCH=N, or CHCH=CH, and Y is a single bond. In this case, X is preferably CH, CF, or CHCH=CH, and more preferably CH or CF.

[0221] In method 2, R 1 Preferably, it is a 4- to 8-membered heterocycloalkyl group which may be substituted with an oxo group; -COO-R 2 The group shown; can also be selected from halogen atoms, hydroxyl, amino, cyano, formyl, oxo, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C6 alkoxy, C1-C3 haloalkyl, -COO-R 2 The group shown, -NR 2 R 3 The group shown, -NHCO-R 2 The group shown and -CONH-R 2 5- to 10-membered heteroaryl group substituted with one or more substituents (preferably one substituent) in the group shown; C2-C6 alkenyl group; -CO-R 2 The group shown; or -CONH-R 2 The base shown, or

[0222] It may also be selected from hydroxyl, amino, nitro, cyano, oxo, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl (which may also be substituted with a halogen atom or a C1-C3 alkyl), -NR 2 R 3 The group shown, -CONH-R 2 The group shown, -COO-R 2 The group shown, -CO-R 2 The group shown and -SO2-R 2 A C1-C6 alkyl group substituted with one or more substituents in the group shown.

[0223] R 1 More preferably, it is a 4- to 6-membered heterocycloalkyl group which may be substituted with an oxo group; or -COO-R 2 or may be selected from halogen atoms, hydroxyl, amino, cyano, formyl, oxo, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C6 alkoxy, C1-C3 haloalkyl, -COO-R 2 The group shown, -NR 2 R 3 The group shown, -NHCO-R 2 The group shown and -CONH-R 2A 5- to 10-membered heteroaryl group substituted with one or more substituents (preferably one substituent) in the group shown; or a 5- to 10-membered heteroaryl group selected from hydroxyl, nitro, oxo, -CONH-R 2 The group shown, -COO-R 2 The group shown, -CO-R 2 The group shown and -SO2-R 2 A C1-C6 alkyl group substituted with one or more substituents in the group shown.

[0224] In method 2, R 2 It is preferably a C1-C6 alkyl, a C2-C6 alkenyl, a C1-C3 haloalkyl, a C1-C3 hydroxyalkyl, a 3-membered to 6-membered cycloalkyl, a 6-membered to 10-membered aryl, a 6-membered to 10-membered aryl C1-C3 alkyl, a 5-membered to 10-membered heteroaryl C1-C3 alkyl or a C1-C3 alkylamino, and more preferably a C1-C6 alkyl, a C1-C3 haloalkyl or a C1-C3 hydroxyalkyl.

[0225] In method 2, R 3 Preferably, it is a hydrogen atom. In Embodiment 2, Z may be either a hydroxyl group or an oxo group. Furthermore, in Embodiment 2, a single bond or a double bond may be present between positions 3 and 4, and a single bond is preferably present between positions 22 and 23.

[0226] As a preferred embodiment of the compound of the present invention, more specifically, for example, a compound represented by any one of the above formulae (1) to (94) and a compound represented by any one of the formulae (201) to (271) can be cited. The compound represented by formula (1) to the compound represented by formula (94) correspond to compounds I-1 to 5, 10, 11, 18, 19, 28, 49 to 55, 57, 59, 60, 62 to 64, 66, 68, 70, 72, 74, 79 to 82, 92 to 98, 101 to 106, 109 to 115, 120 to 127, 129 to 136, 139 to 148, 150 to 152, 155, 156, 159 to 162, 165, 166, 169 / 170, 172, 175, 176; the compound represented by formula (201) to the compound represented by formula (271) correspond to compounds II-2~5, 11, 15, 22, 23, 25 / 26, 28, 38~41, 43, 47, 48, 50, 54, 55, 57, 59~63, 65, 68, 69, 71~74, 76~80, 84~92, 94~96, 98, 99, 102, 104~107, 109, 110, 112, 113, 115~117, and 119~124 described in the following examples, respectively.

[0227] The method for producing the compound of the present invention is not particularly limited and can be produced by using starting materials, precursors, reagents, and solvents that are commercially available or synthesized by methods known to those skilled in the art, by combining a wide variety of synthetic methods known to those skilled in the art and by modifying such synthetic methods as needed. For example, the compound can be produced by the representative methods shown in the following steps 1 to 5, but is not limited thereto.

[0228] Chemical 34

[0229]

[0230] By the method shown in step 1 above, for example, through an oxidation reaction and a reduction reaction, a compound represented by formula (III) and a compound represented by formula (IV) can be synthesized as intermediates for synthesizing the compound represented by formula (I) above. In formulas (III) and (IV), n has the same meaning as n in formula (I) above.

[0231] [Process 1-1]

[0232] The compound represented by the above formula (III) can be synthesized by subjecting the compound represented by the above formula (II) to an oxidation reaction in a solvent.

[0233] The oxidation reaction in step 1-1 can be carried out by a known method or a method based thereon, for example, a Swern oxidation reaction; a Parikh-Doering oxidation reaction; an oxidation reaction using a reagent such as 2-iodoxybenzoic acid, a Dess-Martin periodinane reagent, manganese dioxide, or tetrapropylammonium perruthenate. The amount of the reagent is preferably in the range of 2 to 100 equivalents based on the compound represented by formula (II).

[0234] The solvent in step 1-1 is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include tetrahydrofuran (THF), 1,4-dihydrofuran (DHT), and Alkane, acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, etc. may be used alone or in combination of two or more.

[0235] The reaction temperature of step 1-1 is, for example, selected from the range of 0 to 100° C., preferably 0 to 50° C. The reaction time is, for example, 1 to 72 hours, preferably 12 to 48 hours.

[0236] [Process 1-2]

[0237] The compound represented by the above formula (IV) can be synthesized by reacting the compound represented by the above formula (III) with a reducing agent in a solvent (performing a reduction reaction).

[0238] Examples of the reducing agent in step 1-2 include sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride (DIBAL), lithium borohydride, lithium tri(sec-butyl)borohydride (L-Selectride), potassium tri(sec-butyl)borohydride (K-Selectride), and sodium triethylborohydride. The amount of the reducing agent is preferably in the range of 1 to 10 equivalents based on the compound represented by formula (III).

[0239] The solvent in step 1-2 is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dihydrofuran, and the like. Alkane, acetonitrile, methanol, ethanol, n-hexane, heptane, toluene, etc. may be used alone or in combination of two or more.

[0240] The reaction temperature in step 1-2 is, for example, selected from the range of -100 to 50° C., preferably -78 to 0° C. The reaction time is, for example, 15 minutes to 24 hours, preferably 30 minutes to 3 hours.

[0241] Chemical 35

[0242]

[0243] By the method shown in the above step 2, for example, the compound represented by formula (Ia) and the compound represented by formula (Ib) among the compounds represented by formula (I) can be synthesized. In step 2, the compound represented by formula (V) is the compound represented by formula (III) or the compound represented by formula (IV) obtained in the above step 1. In the above formulas (V), (Ia) and (Ib), n, R 1 、R 2 、R 3 Respectively with n, R in the above formula (I) 1 、R 2 、R 3 Synonymous.

[0244] [Process 2-1]

[0245] The compound represented by the above formula (Ia) can be prepared by reacting the compound represented by the above formula (V) with an appropriate hydroxylamine (the compound represented by the formula (i): R 1 and R in the above formula (Ia) 1 Synonymous) is synthesized by reaction in a solvent in the presence of a base.

[0246] The hydroxylamine may be in the form of a hydrochloride. The amount of hydroxylamine and / or its hydrochloride is preferably in the range of 1 to 20 equivalents (preferably 2 to 20 equivalents) based on the compound represented by the above formula (V).

[0247] Examples of the base in step 2-1 include sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, potassium fluoride, etc. The amount of the base is preferably in the range of 1 to 30 equivalents (preferably 2 to 30 equivalents) based on the compound represented by formula (V).

[0248] The solvent in step 2-1 is not particularly limited as long as it does not significantly inhibit the reaction. Examples thereof include dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, ethyl acetate, tetrahydrofuran, diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, dimethyl sulfoxide, and toluene. These may be used alone or in combination of two or more.

[0249] In the reaction of step 2-1, a reaction reagent such as cerium chloride anhydrate, cerium chloride heptahydrate, lanthanum chloride anhydrate, or lanthanum chloride heptahydrate may be further added as needed. In this case, the amount of the reaction reagent is preferably in the range of 1 to 5 equivalents based on the compound represented by formula (V).

[0250] The reaction temperature in step 2-1 is not particularly limited, and is, for example, -20 to 80° C., preferably 0 to 50° C. The reaction time is also not particularly limited, and is, for example, 10 minutes to 24 hours, preferably 30 minutes to 5 hours.

[0251] [Process 2-2]

[0252] The compound represented by the above formula (Ib) can be prepared by reacting the compound represented by the above formula (Ia) with an appropriate amine (the compound represented by the formula (ii): R 2 、R 3 Respectively with R in the above formula (Ib) 2 、R 3 Synonymous) It is synthesized by carrying out a condensation reaction using a condensing agent in a solvent in the presence of a base.

[0253] The above-mentioned amine may be in the form of a hydrochloride. The amount of the amine and / or its hydrochloride is preferably in the range of 1 to 10 equivalents (preferably 2 to 10 equivalents) based on the compound represented by the above formula (Ia).

[0254] Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 1,1-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridine Iodine, 1-propylphosphoric acid cyclic anhydride (PPA), N,N'-dicyclohexylcarbodiimide, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU). The amount of the condensing agent is preferably in the range of 1 to 8 equivalents based on the compound represented by formula (Ia).

[0255] Examples of the base in step 2-2 include organic amines such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, N,N-dimethylpyridin-4-amine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). The amount of the base is preferably in the range of 1 to 30 equivalents (preferably 5 to 30 equivalents) based on the compound represented by formula (Ia).

[0256] The solvent in step 2-2 is not particularly limited as long as it does not significantly inhibit the reaction. Examples thereof include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, dimethyl sulfoxide, and toluene. These may be used alone or in combination of two or more.

[0257] In the reaction of step 2-2, a reaction reagent such as 1-hydroxybenzotriazole (HOBt) or N,N-dimethylpyridin-4-amine (DMAP) may be further added as needed.

[0258] The reaction temperature in step 2-2 is not particularly limited, and is, for example, -20 to 80° C., preferably 0 to 50° C. The reaction time is not particularly limited, and is, for example, 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0259] Chemical 36

[0260]

[0261] By the method shown in the above step 3, for example, the compound represented by formula (Ic), the compound represented by formula (Id), and the compound represented by formula (Ie) among the compounds represented by formula (I) can be synthesized. In step 3, the compound represented by formula (V) is the compound represented by formula (III) or the compound represented by formula (IV) obtained in the above step 1. In the above formulas (V), (Ic), (Id), and (Ie), X is CH or CF, n, R 2 Respectively with n, R in the above formula (I) 2 Synonymous.

[0262] [Process 3-1]

[0263] The compound represented by the above formula (1c) can be prepared by combining the compound represented by the above formula (V) with the compound represented by the above formula (iii) (X, R 2 Respectively with X, R in the above formula (Ic) 2 Synonymically, Et represents ethyl. ) is synthesized by reaction in a solvent in the presence of a base.

[0264] The compound represented by formula (iii) can be prepared using various Horner-Wadsworth-Emmons reagents well known to those skilled in the art, such as ethyl 2-(diethoxyphosphoryl)acetate, ethyl 2-(diphenoxyphosphoryl)acetate, and methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate. The amount of the compound represented by formula (iii) is preferably in the range of 1 to 10 equivalents based on the compound represented by formula (V).

[0265] Examples of the base in step 3-1 include sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamide, and n-butyllithium. The amount of the base is preferably in the range of 1 to 10 equivalents based on the compound represented by formula (V).

[0266] The solvent in step 3-1 is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include tetrahydrofuran, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dihydrofuran, and the like. Alkane, acetonitrile, n-hexane, heptane, toluene, etc. may be used alone or in combination of two or more.

[0267] The reaction temperature of step 3-1 is not particularly limited, and is, for example, -100 to 60° C., preferably -78 to 20° C. The reaction time is also not particularly limited, and is, for example, 10 minutes to 10 hours, preferably 30 minutes to 3 hours.

[0268] [Process 3-2]

[0269] The compound represented by the above formula (Id) can be synthesized by reacting the compound represented by the above formula (Ic) with a reducing agent in a solvent.

[0270] Examples of the reducing agent in step 3-2 include sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride (DIBAL), lithium borohydride, lithium tri(sec-butyl)borohydride (L-Selectride), potassium tri(sec-butyl)borohydride (K-Selectride), and sodium triethylborohydride. The amount of the reducing agent is preferably in the range of 1 to 10 equivalents based on the compound represented by formula (Ic).

[0271] The solvent in step 3-2 is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dihydrofuran, and the like. Alkane, acetonitrile, methanol, ethanol, n-hexane, heptane, dichloromethane, 1,2-dichloroethane, toluene, etc. may be used alone or in combination of two or more.

[0272] The reaction temperature in step 3-2 is, for example, selected from the range of -100 to 50° C., preferably -78 to 0° C. The reaction time is, for example, 15 minutes to 24 hours, preferably 30 minutes to 3 hours.

[0273] [Process 3-3]

[0274] The compound represented by the above formula (Ie) can be synthesized by subjecting the compound represented by the above formula (Id) to an oxidation reaction in a solvent.

[0275] The oxidation reaction in step 3-3 can be carried out by a suitable known method or a method based thereon, and can be selected from, for example, the Swern oxidation reaction; the Parikh-Doering oxidation reaction; an oxidation reaction using a reagent such as 2-iodoxybenzoic acid, a Dess-Martin periodinane reagent, manganese dioxide, tetrapropylammonium perruthenate (TPAP), or TEMPO. The amount of the above reagents is preferably in the range of 2 to 100 equivalents based on the compound represented by formula (Id).

[0276] The solvent in step 3-3 is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include tetrahydrofuran, 1,4-dihydrofuran, Alkane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, and chloroform may be used alone or in combination of two or more.

[0277] The reaction temperature of step 3-3 is, for example, selected from the range of 0 to 100° C., preferably 0 to 50° C. The reaction time is, for example, 1 to 24 hours, preferably 1 to 6 hours.

[0278] Chemical 37

[0279]

[0280] By the method shown in the above step 4, for example, the compound represented by formula (If) and the compound represented by formula (Ig) among the compounds represented by formula (I) can be synthesized. In step 4, the compound represented by formula (V) is the compound represented by formula (III) or the compound represented by formula (IV) obtained in the above step 1. In the above formulas (V), (If) and (Ig), X is CH, n, R 1 Respectively with n, R in the above formula (I) 1 Furthermore, L1, L2, and L3 in formula (If), formula (iv), and formula (v) each independently represent a functional group such as Cl, Br, I, alkylstannyl, dihydroxyboryl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl, trifluoromethylsulfoxide, triarylphosphinyl, or trialkylphosphinyl.

[0281] [Process 4-1]

[0282] The compound represented by the above formula (1f) can be synthesized by reacting the compound represented by the above formula (V) with the compound represented by the above formula (iv) (X and L1 are the same as X and L1 in the above formula (If), respectively) in a solvent in the presence of a base.

[0283] The compound represented by the above formula (iv) can be, for example, (methoxymethyl)triphenyl chloride , (bromomethyl)triphenylphosphine bromide , tributyl(cyanomethyl) chloride Various Wittig reagents and bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane well known to those skilled in the art are also included. The amount of the compound represented by formula (iv) is preferably in the range of 1 to 10 equivalents based on the compound represented by formula (V).

[0284] Examples of the base in step 4-1 include sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamide, n-butyllithium, sec-butyllithium, and lithium 2,2,6,6-tetramethylpiperidide. The amount of the base is preferably in the range of 1 to 10 equivalents based on the compound represented by formula (V).

[0285] The solvent in step 4-1 is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include tetrahydrofuran, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dihydrofuran, and the like. Alkane, n-hexane, heptane, toluene, etc. may be used alone or in combination of two or more.

[0286] The reaction temperature of step 4-1 is not particularly limited, and is, for example, -100 to 80° C., preferably -78 to 40° C. The reaction time is also not particularly limited, and is, for example, 10 minutes to 24 hours, preferably 30 minutes to 6 hours.

[0287] [Process 4-2]

[0288] The compound represented by the above formula (Ig) can be prepared by reacting the compound represented by the above formula (If), a metal catalyst, and the compound represented by the above formula (v) (R 1 and R in the above formula (Ig) 1 Synonymous.) Synthesized by reaction in a solvent in the presence of a base.

[0289] The amount of the compound represented by the above formula (v) is preferably in the range of 1 to 20 equivalents based on the compound represented by the above formula (If).

[0290] Examples of the metal catalyst in step 4-2 include palladium compounds such as tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, and palladium(II) acetate; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. The amount of the metal catalyst is preferably in the range of 0.01 to 2 equivalents based on the compound represented by formula (If).

[0291] Examples of the base in step 4-2 include sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium tert-butoxide, and potassium tert-butoxide. The amount of the base is preferably in the range of 1 to 30 equivalents based on the compound represented by the above formula (If).

[0292] The solvent in step 4-2 is not particularly limited as long as it does not significantly inhibit the reaction, and examples thereof include tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dihydrofuran, and the like. Alkane, acetonitrile, ethanol, isopropanol, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, n-hexane, heptane, toluene, etc., may be used alone or in combination of two or more.

[0293] In the reaction of step 4-2, reaction reagents such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 1,2-bis(diphenylphosphino)ethane, dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine, and dicyclohexyl(2',6'-diisopropyl-[1,1'-biphenyl]-2-yl)phosphine may be further added as needed. In this case, the amount of the reaction reagent is preferably in the range of 0.01 to 4 equivalents based on the compound represented by the above formula (If).

[0294] The reaction temperature of step 4-2 is, for example, selected from the range of -78 to 200° C., preferably 25 to 150° C. The reaction time is, for example, 15 minutes to 24 hours, preferably 30 minutes to 3 hours.

[0295] Chemical 38

[0296]

[0297] By the method shown in the above step 5, for example, a compound represented by formula (Ih) among the compounds represented by formula (I) can be synthesized. In step 5, the compound represented by formula (V) is the compound represented by formula (III) or the compound represented by formula (IV) obtained in the above step 1. In the above formulas (V) and (Ih), n, R 1 Respectively with n, R in the above formula (I) 1 Synonymous.

[0298] [Process 5-1]

[0299] The compound represented by the above formula (1h) can be prepared by reacting the compound represented by the above formula (V) with an appropriate hydrazine (the compound represented by the formula (vi): R 1 and R in the above formula (Ih) 1 Synonymous) is synthesized by reaction in a solvent in the presence of a base.

[0300] The hydrazine may be in the form of a hydrochloride. The amount of hydrazine and / or its hydrochloride is preferably in the range of 2 to 20 equivalents based on the compound represented by the above formula (V).

[0301] Examples of the base in step 5-1 include sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, and potassium fluoride. The amount of the base is preferably in the range of 5 to 30 equivalents (preferably 2 to 30 equivalents) based on the compound represented by formula (V).

[0302] The solvent in step 5-1 is not particularly limited as long as it does not significantly inhibit the reaction. Examples thereof include dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, ethyl acetate, tetrahydrofuran, diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, dimethyl sulfoxide, and toluene. These may be used alone or in combination of two or more.

[0303] The reaction temperature in step 5-1 is not particularly limited, and is, for example, -20 to 80° C., preferably 0 to 50° C. The reaction time is also not particularly limited, and is, for example, 10 minutes to 24 hours, preferably 30 minutes to 5 hours.

[0304] Those skilled in the art will appreciate that it is necessary or preferred to protect one or more unstable groups in the molecule with a protecting group to prevent undesirable side reactions at any stage in the synthesis of the compound represented by formula (I). In particular, protecting the hydroxyl group is necessary or preferred. Examples of protecting groups used in the synthesis of the compound represented by formula (I) include those described in, for example, Greene Wuts, Protective Groups in Organic Synthesis Third Dedition, John Wiley & Sons, Inc. (which also describes methods for removing such groups).

[0305] The compounds of the present invention have antiviral activity against coronaviruses. The fact that the compounds have the above-mentioned antiviral activity can be confirmed by, for example, infecting cultured cells (e.g., VeroE6 cells) with coronaviruses (e.g., SARS-CoV-2), adding the compound diluted in appropriate stages to the culture medium for culturing, and measuring the amount of virus in the culture supernatant. More specifically, it can be confirmed by the method described in the following Test Example 1. In this case, for example, the compound concentration that reduces the replication of coronavirus by 50% is set as IC 50 The value is less than 20 μM (for example, less than 19.9 μM), preferably less than 5 μM (for example, less than 4.9 μM), and more preferably less than 1 μM (for example, less than 0.9 μM), which can be judged to have excellent antiviral activity against coronavirus.

[0306] <Compositions and Treatment Methods>

[0307] Since the compounds of the present invention have antiviral activity against coronaviruses as described above, compositions, preferably pharmaceutical compositions, containing them as active ingredients can be used as antiviral agents or therapeutic agents for treating or preventing diseases or conditions involving coronaviruses. Therefore, the present invention also provides compositions containing the compounds of the present invention as active ingredients, as well as uses of the compounds of the present invention for preparing compositions for treating or preventing diseases or conditions involving coronaviruses.

[0308] Furthermore, the present invention also provides a method for treating or preventing a disease or condition involving coronavirus (hereinafter referred to as "the method of the present invention" as appropriate), comprising administering the compound of the present invention directly or the composition containing the compound as an active ingredient to a subject. The subject may be a human or an animal other than a human (preferably a mammal).

[0309] The coronavirus is preferably a virus classified as, for example, the subfamily Orthocoronavirinae of the family Coronaviridae of the order Nidovirales, and more preferably a virus classified as the genus Beta (β) coronavirus. The coronavirus is preferably at least one selected from the group consisting of human coronavirus (HCoV), severe acute respiratory syndrome coronavirus (SARS-CoV), novel coronavirus (SARS-CoV-2), and Middle East respiratory syndrome coronavirus (MERS-CoV), and more preferably the novel coronavirus.

[0310] Examples of diseases and conditions involving coronaviruses include, but are not limited to, novel coronavirus infection (also referred to as coronavirus disease 2019 or COVID-19), severe acute respiratory syndrome, and Middle East respiratory syndrome.

[0311] The compound and composition of the present invention can be administered to the above-mentioned subject via either oral or parenteral administration routes. Therefore, the composition of the present invention can be formulated into a suitable dosage form depending on the administration route.

[0312] Examples of the above-mentioned preparations include, specifically, oral preparations such as tablets, pills, capsules, granules, powders, elixirs, suspensions, emulsions, and syrups; and parenteral preparations such as injections, inhalants, rectal administrations, suppositories, emulsions, sprays, ointments, creams, patches, and sustained-release preparations.

[0313] These various preparations can be prepared by conventional methods using pharmaceutically acceptable additives and carriers such as excipients, disintegrants, binders, lubricants, and colorants, depending on the type of preparation used. Therefore, the composition of the present invention may further contain these pharmaceutically acceptable additives and / or carriers.

[0314] In the composition of the present invention, the content of the compound of the present invention (the content of the compound represented by formula (I) or the content of its pharmaceutically acceptable salt, or the total content thereof, converted to the free form in the case of a mixture thereof) cannot be generalized because it is appropriately adjusted according to the purpose of administration, the dosage form of the preparation, etc., but is usually 0.01 to 70% by mass, preferably 0.05 to 50% by mass, based on the total mass of the composition, when converted to the free form of the compound represented by formula (I).

[0315] In the method of the present invention, the dosage of the compound of the present invention (the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt, or the total dosage in the case of a mixture thereof) is appropriately determined on a case-by-case basis, taking into account the type, age, weight, sex, differences in the disease, the severity of the symptoms, etc. of the subject, and cannot be generalized. For example, for human adults, 0.01 to 3000 mg, preferably 0.1 to 800 mg, of the compound represented by formula (I) above, as a free form, is administered per day. This can be administered once a day or in divided doses.

[0316] Example

[0317] Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to the following examples.

[0318] <Production of Compounds>

[0319] As examples, the methods for producing the compounds of the present invention (Compounds I-1 to III-5) and ... 1 The H-NMR spectra are shown below. 1 H-NMR spectra are also shown below. However, the compounds of the present invention are not limited to these examples, and each reference example is also used to specifically illustrate the implementation of the present invention. These examples are not intended to limit the scope of the present invention. It goes without saying that various applications, modifications, and corrections can be made without departing from the scope of the present invention.

[0320] 1H-NMR spectra were measured using deuterated chloroform (CDCl3), deuterated dimethyl sulfoxide (DMSO-d6), deuterated water (D2O), or deuterated methanol (CD3OD) as solvents, with tetramethylsilane (TMS) as the internal standard. Chemical shifts are expressed as δ in ppm, and the binding constant (J) in Hz. The abbreviations s denote singlet, d doublet, t triplet, q quartet, m multiplet, and br broad. Mass spectra (ESI-MS) were measured using electrospray ionization.

[0321] The abbreviations in the following Examples and Reference Examples have the following meanings.

[0322] M:mol / L

[0323] L-Selectride: lithium tri(sec-butyl)borohydride

[0324] THF: Tetrahydrofuran

[0325] DMF: N,N-dimethylformamide

[0326] DIPEA: N,N-diisopropylethylamine

[0327] DMAP: N,N-dimethylpyridin-4-amine

[0328] HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0329] tert:tertiary(uncle)

[0330] n: normal.

[0331] Production of 5-oxo-ivermectin B1a

[0332] Ivermectin B1a (5.00 g, 5.71 mmol) was dissolved in dichloromethane (114 mL), and manganese dioxide (24.9 g, 0.286 mol) was added. The reaction solution was stirred at room temperature overnight. The reaction solution was filtered through cerium silicate, and the solvent was distilled off from the obtained filtrate under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 5-oxo-ivermectin B1a (yield 3.87 g, yield 78%).

[0333] 1H-NMR (500MHz, CDCl3, δ): 6.58-6.55 (m, 1H), 5.92 (td, J = 10.9, 2.3Hz, 1H), 5.82-5.68 (m, 2H), 5.39 ( d,J=3.4Hz,1H),5.44-5.36(m,2H),5.01-4.96(m,1H),4.79-4.76(m,1H),4.75-4.69(m,2H),3.94(br s,1H),3.85(s,1H),3.84-3.79(m,1H),3.78-3.72(m,1H),3.71-3.65(m,1H),3.64-3.59(m,1H),3.58-3.55(m,1H), 3.50-3.43(m,2H),3.42(s,3H),3.41(s,3H),3.26-3.20(m,2H),3.16(t,J=9.2Hz,1H),2.56-2.48(m,1H),2.37-2.24 (m,4H),2.23-2.18(m,1H),1.88(d,J=1.7Hz,3H),1.90-1.85(m,1H),1.79-1.75(m,1H),1.67-1.64(m,1H),1.60-1.3 4(m,10H),1.29-1.23(m,8H),1.16(d,J=6.9Hz,3H),0.93(t,J=7.4Hz,3H),0.86(d,J=6.3Hz,3H),0.81-0.74(m,4H).

[0334] Production of 3,4α-dihydro-5-oxo-ivermectin B1a and 3,4β-dihydro-5-oxo-ivermectin B1a

[0335] 5-Oxo-ivermectin B1a (4.00 g, 4.58 mmol) was dissolved in THF (46 mL). Under an argon atmosphere, 1 M L-Selectride THF solution (5.95 mL, 5.95 mmol) was added at -78°C and stirred at the same temperature for 1 hour. An aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and the mixture was then warmed to room temperature. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 3,4β-dihydro-5-oxo-ivermectin B1a (yield 1.33 g, yield 33%) and 3,4α-dihydro-5-oxo-ivermectin B1a (yield 1.81 g, yield 45%).

[0336] (3,4β-dihydro-5-oxo-ivermectin B1a)

[0337] 1H-NMR (500MHz, CDCl3, δ):5.95-5.88(m,1H),5.81-5.71(m,1H),5.71-5.62(m,1H),5.43-5.35(m,2H) ,4.97-4.90(m,1H),4.76(d,J=2.9Hz,1H),4.67-4.56(m,2H),4.56-4.51(m,1H),4.01(s,1H),3.93(br s,1H),3.85-3.80(m,1H),3.79-3.74(m,1H),3.70-3.59(m,2H),3.51-3.46(m,1H),3.44(s,3H),3.43-3. 41(s,3H),3.26-3.14(m,3H),3.11-3.02(m,1H),2.66-2.46(m,3H),2.36-2.19(m,5H),1.86-1.81(m,1H) ,1.76-1.72(m,1H),1.70-1.62(m,3H),1.59-1.36(m,10H),1.29-1.22(m,8H),1.15(d,J=6.9Hz,3H),1.1 1(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.83(d,J=6.9Hz,3H),0.80-0.75(m,4H); MSm / z897.4962[M+Na] + .

[0338] (3,4α-dihydro-5-oxo-ivermectin B1a)

[0339] 1H-NMR (500MHz, CDCl3, δ):5.85-5.81(m,1H),5.79-5.72(m,1H),5.70-5.63(m,1H),5.45-5.35( m,2H),4.98-4.91(m,1H),4.78-4.71(m,2H),4.68-4.59(m,2H),4.11(d,J=7.4Hz,1H),3.93(br s,1H),3.86-3.79(m,1H),3.76(s,1H),3.79-3.72(m,1H),3.71-3.65(m,1H),3.64-3.59(m,1H),3.51-3.45(m,1H),3.43(s,3 H),3.42(s,3H),3.27-3.20(m,2H),3.16(t,J=9.2Hz,1H),3.05-3.00(m,1H),2.84-2.75(m,1H),2.53-2.46(m,1H),2.38-2.18 (m,5H),2.07-2.01(m,2H),1.94-1.88(m,1H),1.77-1.72(m,1H),1.69-1.64(m,1H),1.60-1.36(m,10H),1.28-1.23(m,8H),1. 15(d,J=6.9Hz,3H),1.10(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.85-0.82(m,3H),0.80-0.75(m,4H); MSm / z897.4957[M+Na] + .

[0340] Preparation of Compound I-1

[0341] After dissolving 3,4β-dihydro-5-oxo-ivermectin B1a (200 mg, 0.229 mmol) in methanol (4.6 mL), sodium acetate (112 mg, 1.37 mmol) and hydroxylamine hydrochloride (95 mg, 1.37 mmol) were added in sequence and stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-1 (yield 177 mg, yield 87%) as a mixture of isomers that are difficult to separate. The following 1 The H-NMR spectrum is the analytical data of the main isomer.

[0342] 1H-NMR (500MHz, CDCl3, δ): 5.88-5.83 (m, 1H), 5.76-5.65 (m, 2H), 5.45-5.38 (m, 2H), 4.95 (d, J= 10.9Hz,1H),4.91-4.86(m,1H),4.77(d,J=4.0Hz,1H),4.68-4.57(m,3H),3.98(s,1H),3.93(br s,1H),3.86-3.74(m,2H),3.71-3.57(m,3H),3.52-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.20(m,2H ),3.17(t,J=9.2Hz,1H),2.95-2.81(m,1H),2.52-2.45(m,1H),2.36-2.20(m,5H),1.99-1.93(m,1H),1.90(d d,J=12.0,5.2Hz,1H),1.79-1.73(m,1H),1.67(d,J=13.2Hz,1H),1.59-1.36(m,13H),1.30-1.21(m,10H),1 .15(d,J=6.9Hz,3H),0.92(t,J=7.5Hz,3H),0.86-0.80(m,4H),0.78(d,J=6.3Hz,3H); MSm / z912.5092[M+Na] + .

[0343] Preparation of Compound I-2

[0344] After dissolving 3,4α-dihydro-5-oxo-ivermectin B1a (30.0 mg, 0.034 mmol) in methanol (0.69 mL), sodium acetate (16.9 mg, 0.206 mmol) and hydroxylamine hydrochloride (14.9 mg, 0.206 mmol) were added sequentially and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-2 (yield 22.5 mg, yield 73%).

[0345] 1H-NMR(500MHz,CDCl3,δ):8.47(br s,1H),5.84(dt,J=10.6,2.4Hz,1H),5.77-5.65(m,2H),5.43-5.36(m,2H),5.02(s,1H) ,4.95(d,J=10.9Hz,1H),4.77(d,J=3.4Hz,1H),4.72-4.63(m,2H),4.61(s,1H),3.93(br s,1H),3.86-3.74(m,2H),3.70-3.60(m,2H),3.53-3.46(m,1H),3.44(s,3H),3.43(s ,4H),3.26-3.19(m,2H),3.17(t,J=9.2Hz,1H),2.80(dd,J=12.9,3.2Hz,1H),2.75(br s,1H),2.68-2.58(m,1H),2.54-2.45(m,1H),2.36-2.30(m,2H),2.30-2 .19(m,2H),1.95-1.81(m,3H),1.77-1.70(m,1H),1.70-1.62(m,2H),1.5 9-1.37(m,10H),1.30-1.22(m,7H),1.16(t,J=6.3Hz,6H),0.92(t,J=7.5 Hz,3H),0.83(d,J=6.3Hz,3H),0.82-0.75(m,4H); MSm / z912.5093[M+Na] + .

[0346] Preparation of Compound I-3 and Compound I-4

[0347] 3,4β-dihydro-5-oxo-ivermectin B1a (250 mg, 0.286 mmol) was dissolved in methanol (5.7 mL). Sodium acetate (70.3 mg, 0.857 mmol) and O-(prop-2-yn-1-yl)hydroxylamine hydrochloride (92.0 mg, 0.857 mmol) were added sequentially, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) and high-performance liquid chromatography (acetonitrile / water = 85:15) to obtain Compound I-3 (yield 8.4 mg, yield 3.2%) and Compound I-4 (yield 2.8 mg, yield 1.1%), respectively.

[0348] (Compound I-3)

[0349] 11H-NMR (500 MHz, CDCl3, δ): 5.86 (dt, J = 10.3, 2.3 Hz, 1H), 5.78 - 5.65 (m, 2H), 5.46 - 5.35 (m, 2H), 4.95 (d, J = 11.5 Hz, 1H), 4.83 (s, 1H), 4.77 (d, J = 3.4 Hz, 1H), 4.71 - 4.58 (m, 5H), 3.93 (br s, 1H), 3.87 - 3.72 (m, 2H), 3.71 - 3.57 (m, 2H), 3.52 - 3.45 (m, 1H), 3.45 (s, 3H), 3.43 (s, 3H), 3.28 - 3.20 (m, 2H), 3.17 (t, J = 9.2 Hz, 1H), 2.94 - 2.86 (m, 2H), 2.58 - 2.46 (m, 2H), 2.43 (t, J = 2.6 Hz, 1H), 2.39 - 2.19 (m, 5H), 1.93 - 1.86 (m, 1H), 1.79 - 1.71 (m, 1H), 1.70 - 1.35 (m, 16H), 1.32 - 直译为“1H核磁共振(500兆赫兹,氘代氯仿,δ):5.86(双二重峰,J = 10.3,2.3赫兹,1个氢原子),5.78 - 5.65(多重峰,2个氢原子),5.46 - 5.35(多重峰,2个氢原子),4.95(双峰,J = 11.5赫兹,1个氢原子),4.83(单峰,1个氢原子),4.77(双峰,J = 3.4赫兹,1个氢原子),4.71 - 4.58(多重峰,5个氢原子),3.93(宽单峰,1个氢原子),3.87 - 3.72(多重峰,2个氢原子),3.71 - 3.57(多重峰,2个氢原子),3.52 - 3.45(多重峰,1个氢原子),3.45(单峰,3个氢原子),3.43(单峰,3个氢原子),3.28 - 3.20(多重峰,2个氢原子),3.17(三重峰,J = 9.2赫兹,1个氢原子),2.94 - 2.86(多重峰,2个氢原子),2.58 - 2.46(多重峰,2个氢原子),2.43(三重峰,J = 2.6赫兹,1个氢原子),2.39 - 2.19(多重峰,5个氢原子),1.93 - 1.86(多重峰,1个氢原子),1.79 - 1.71(多重峰,1个氢原子),1.70 - 1.35(多重峰,16个氢原子),1.32 - 1.23(多重峰,8个氢原子),1.16(双峰,J = 6.9赫兹,3个氢原子),0.92(三重峰,J = 7.5赫兹,3个氢原子),0.89 - 0.76(多重峰,7个氢原子)。

[0350] (Compound I-4)

[0351] 1H-NMR (500MHz, CDCl3, δ): 5.86 (dt, J=10.4, 2.5Hz, 1H), 5.78-5.63 (m, 2H), 5.46-5.37 (m, 2H), 4.95 (d, J= 12.6Hz,1H),4.77(d,J=3.4Hz,1H),4.71(dd,J=2.3,1.2Hz,2H),4.69-4.56(m,3H),4.00(s,1H),3.94(br s,1H),3.87-3.73(m,2H),3.72-3.60(m,2H),3.56-3.46(m,2H),3.45(s,3H),3.43(s,3H),3.29-3. 20(m,2H),3.17(t,J=9.2Hz,1H),2.90(dd,J=13.8,2.9Hz,1H),2.53-2.47(m,2H),2.46-2.45(m,1H) ,2.38-2.31(m,2H),2.31-2.20(m,3H),1.93-1.87(m,1H),1.80-1.73(m,1H),1.69-1.64(m,1H),1.6 1-1.35(m,15H),1.31-1.21(m,8H),1.16(d,J=6.9Hz,3H),0.95-0.81(m,7H),0.78(d,J=5.7Hz,3H).

[0352] Preparation of Compound I-5

[0353] Compound I-5 (yield 41.9 mg, 83%) was obtained by the same method using O-(prop-2-yn-1-yl)hydroxylamine hydrochloride instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0354] 1H-NMR (500MHz, CDCl3, δ):5.88-5.78(m,1H),5.77-5.63(m,2H),5.47-5.32(m,2H),5.00-4.87(m,2H),4.76(br d,J=3.44Hz,1H),4.73-4.56(m,5H),3.93(br s,1H),3.87-3.71(m,2H),3.70-3.56(m,2H),3.43(d,J=9.4Hz,6H),3.30 -3.12(m,3H),2.79(dd,J=12.60,2.86Hz,1H),2.68-2.58(m,1H),2.55(br s,1H),2.53-2.44(m,1H),2.43-2.38(m,1H),2.37-2.16(m,5H),1.96-1.78(m,4H),1.77-1.70(m,1H), 1.68-1.63(m,2H),1.58-1.36(m,15H),1.30-1.11(m,15H),0.94-0.74(m,13H); MSm / z950.6138[M+Na] + .

[0355] Preparation of Compound I-6

[0356] Compound I-6 was obtained as a mixture of isomers that was difficult to separate (yield 22.8 mg, 68%) by the same method using O-benzylhydroxylamine hydrochloride instead of hydroxylamine hydrochloride in [Production of Compound I-1].

[0357] 1H-NMR (500MHz, CDCl3, δ): 7.36-7.27(m,5H),5.89-5.82(m,1H),5.78-5.63(m,2H),5.45-5.38(m,2H),5.20-5. 07(m,2H),4.95(d,J=9.2Hz,1H),4.90(s,0.5H),4.78-4.75(m,1H),4.71-4.54(m,3H),4.00(s,0.5H),3.93(br s,1H),3.86-3.74(m,2H),3.71-3.59(m,2H),3.60-3.45(m,2H),3.45-3.43(m,3H) ,3.42(s,3H),3.26-3.19(m,2H),3.17(t,J=9.2Hz,1H),2.92-2.83(m,1H),2.56(br s,1H),2.53-2.46(m,1H),2.37-2.19(m,5H),1.93-1.85(m,1H),1.78-1.71(m,1H),1.68-1.60(m,2H),1.59-1.38(m,12H),1.3 1-1.21(m,10H),1.15(t,J=7.2Hz,3H),0.92(t,J=7.2Hz,3H),0.85-0.80(m,4H),0.78(d,J=5.7Hz,3H); MSm / z1002.6900[M+Na] + .

[0358] Preparation of Compound I-7

[0359] Compound I-7 (yield 25.2 mg, 75%) was obtained by the same method using O-benzylhydroxylamine hydrochloride instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0360] 1H-NMR (500MHz, CDCl3, δ): 7.37-7.24 (m, 5H), 5.83 (dt, J=10.6, 2.4Hz, 1H), 5.76-5.62 (m, 2H), 5.44-5.35 (m, 2H), 5.13(s,2H),4.99(s,1H),4.94(d,J=10.9Hz,1H),4.76(d,J=3.4Hz,1H),4.68-4.60(m,2H),4.58(s,1H),3.93(br s,1H),3.86-3.74(m,2H),3.70-3.60(m,2H),3.52-3.45(m,1H),3.44(s,3H),3.43(s,3H),3.26-3.19(m, 2H),3.17(t,J=9.2Hz,1H),2.79(dd,J=12.6,3.4Hz,1H),2.64-2.56(m,1H),2.55-2.45(m,2H),2.36-2.19 (m,4H),1.94-1.80(m,3H),1.78-1.70(m,1H),1.69-1.61(m,1H),1.59-1.37(m,12H),1.29-1.24(m,7H),1 .18-1.13(m,6H),0.92(t,J=7.5Hz,3H),0.84(d,J=6.9Hz,3H),0.82-0.74(m,4H); MSm / z1002.5565[M+Na] + .

[0361] Reference Example 1

[0362] (1) Production of 2-phenoxyisoindoline-1,3-dione

[0363] 2-Phenoxyisoindoline-1,3-dione was obtained with reference to the synthesis method described in Journal of Medicinal Chemistry (2005), 48(5), 1576-1587 (yield 1.47 g, yield 61%).

[0364] (2) Production of O-phenylhydroxylamine hydrochloride

[0365] 2-Phenoxyisoindoline-1,3-dione (1.47 g, 6.14 mmol) obtained in Reference Example 1-(1) was dissolved in a mixed solvent of chloroform (27 mL) and methanol (3 mL), and then hydrazine monohydrate (1.14 mL, 18.4 mmol) was added and stirred at room temperature for 14 hours. The suspension was filtered and 4 M 1,4-dihydrochloric acid was added to the filtrate. The mixture was stirred at room temperature for 30 minutes in an oxane solution (1.84 mL, 7.37 mmol). The solvent was distilled off under reduced pressure, ether was added, and the suspension was filtered to obtain O-phenylhydroxylamine hydrochloride (yield 0.819 g, yield 92%).

[0366] 1 H-NMR (500MHz, DMSO-d6, δ): 7.41-7.28 (m, 2H), 7.16-7.11 (m, 2H), 7.02 (t, J = 7.5Hz, 1H).

[0367] Compound I-8

[0368] Using O-phenylhydroxylamine hydrochloride obtained in Reference Example 1-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-8 (yield 30.0 mg, yield 91%) was obtained as a mixture of isomers that was difficult to separate by the same method. 1 The H-NMR spectrum is the analytical data of the main isomer.

[0369] 1 H-NMR (500MHz, CDCl3, δ): 7.31-7.27 (m, 2H), 7.21-7.14 (m, 2H), 7.02 (t, J = 7.5Hz, 1H), 5.89 (dt, J = 10.2, 2.4Hz, 1H), 5.7 9-5.67(m,2H),5.47-5.39(m,2H),4.96(d,J=10.9Hz,1H),4.77(d,J=4.0Hz,1H),4.76-4.61(m,3H),4.15(s,1H),3.94(br s,1H),3.87-3.74(m,3H),3.72-3.61(m,2H),3.53-3.46(m,1H),3.45(s,3H),3.43-3.40(m,3H),3.28 -3.19(m,2H),3.17(t,J=9.2Hz,1H),2.98-2.93(m,1H),2.61-2.47(m,2H),2.44-2.19(m,5H),1.92(dd ,J=12.0,3.4Hz,1H),1.80-1.74(m,1H),1.71-1.61(m,4H),1.59-1.31(m,14H),1.30-1.24(m,7H),1.1 9-1.14(m,3H),0.93(t,J=7.5Hz,3H),0.88-0.80(m,4H),0.79(d,J=5.7Hz,3H); MSm / z988.5402[M+Na] + .

[0370] Preparation of Compound I-9

[0371] Compound I-9 (yield 22.6 mg, 68%) was obtained by the same method using O-phenylhydroxylamine hydrochloride obtained in Reference Example 1-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0372] 1 H-NMR (500MHz, CDCl3, δ):7.29-7.25(m,2H),7.20-7.14(m,2H),7.02-6.97(m,1H),5.93-5.83(m,1H),5.80-5.66(m,2H), 5.46-5.36(m,2H),5.15(s,1H),4.95(d,J=9.7Hz,1H),4.77(d,J=3.4Hz,1H),4.72(d,J=2.3Hz,1H),4.65(s,1H),3.94(br s,1H),3.87-3.74(m,2H),3.71-3.60(m,2H),3.53-3.41(m,6H),3.30-3.20(m,2H),3.17(t,J=9.2Hz,1H),2.86(dd,J=12.6,3.4H z,1H),2.82-2.73(m,1H),2.57-2.46(m,2H),2.37-2.19(m,4H),2.03-1.87(m,3H),1.82-1.71(m,1H),1.69-1.64(m,1H),1.62(br s,1H),1.59-1.38(m,13H),1.31(d,J=6.3Hz,3H),1.29-1.23(m,7H),1.16(d,J=6.9Hz,3H ),0.93(t,J=7.2Hz,3H),0.84(d,J=6.9Hz,3H),0.82-0.74(m,4H); MSm / z988.5415[M+Na] + .

[0373] Preparation of Compound I-10

[0374] Compound I-10 (yield 27.8 mg, 87%) was obtained by the same method using 2-(aminooxy)ethan-1-ol instead of hydroxylamine hydrochloride in [Production of Compound I-1].

[0375] 1H-NMR (500MHz, CDCl3, δ): 5.88-5.82 (m, 1H), 5.78-5.64 (m, 2H), 5.39 (m, 2H), 4.94 (d, J = 10.9Hz, 1H), 4.85 (s, 0. 5H),4.76(d,J=3.4Hz,1H),4.73-4.54(m,3H),4.22(t,J=4.6Hz,1H),4.20-4.16(m,1H),3.96(s,0.5H),3.93(br s,1H),3.89-3.73(m,4H),3.65(d,J=4.6Hz,2H),3.48(d,J=1.7Hz,2H),3.44(s,3H),3.42(s,3H ),3.28-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.91-2.74(m,2H),2.49(d,J=2.3Hz,1H),2.38-2.1 6(m,6H),1.93-1.87(m,1H),1.79-1.71(m,1H),1.70-1.62(m,2H),1.59-1.45(m,12H),1.30-1. 20(m,10H),1.15(d,J=6.9Hz,3H),0.95-0.89(m,3H),0.86-0.73(m,7H); MSm / z956.6654[M+Na] + .

[0376] Preparation of Compound I-11

[0377] Compound I-11 (yield 177 mg, 87%) was obtained by the same method using 2-(aminooxy)ethan-1-ol instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0378] 1H-NMR (500MHz, CDCl3, δ): 5.83 (dt, J = 10.7, 2.1Hz, 1H), 5.78-5.64 (m, 2H), 5.44-5.35 (m, 2H), 4.97 (s, 1H),4.95(d,J=11.5Hz,1H),4.76(d,J=3.44Hz,1H),4.72-4.61(m,2H),4.20(t,J=4.3Hz,2H),3.93(br s,1H),3.88-3.74(m,4H),3.70-3.60(m,2H),3.51-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H), 3.16(t,J=9.2Hz,1H),2.79(dd,J=12.3,3.7Hz,1H),2.63(dt,J=11.9,5.8Hz,1H),2.54-2.45(m,1H),2.38-2.1 7(m,7H),1.95-1.82(m,3H),1.78-1.70(m,1H),1.66(d,J=12.6Hz,1H),1.59-1.36(m,12H),1.29-1.23(m,7H) ,1.16(t,J=6.6Hz,6H),0.92(t,J=7.2Hz,3H),0.84(d,J=6.3Hz,3H),0.81-0.74(m,4H);MSm / z956.5364[M+Na] + .

[0379] Reference Example 2

[0380] (1) Production of 2,2,2-trichloroethyl (2-hydroxyethyl) carbamate

[0381] 2-Aminoethane-1-ol (0.611 g, 10.0 mmol) and triethylamine (2.09 mL, 15.0 mmol) were dissolved in dichloromethane (50 mL) and ice-cooled to 0°C. 2,2,2-trichloroethyl chloroformate (1.48 mL, 11.0 mmol) was then added dropwise and stirred at the same temperature for 1 hour. The mixture was warmed to room temperature and stirred for an additional 17 hours. Water was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 2,2,2-trichloroethyl (2-hydroxyethyl)carbamate (yield 1.85 g, yield 78%).

[0382] 1 H-NMR (500MHz, CDCl3, δ): 4.74 (s, 2H), 3.78 (q, J = 5.2Hz, 2H), 3.42 (q, J = 4.6Hz, 2H), 1.81 (t, J = 5.2Hz, 1H).

[0383] (2) Production of 2,2,2-trichloroethyl (2-((1,3-dioxoindolin-2-yl)oxy)ethyl)carbamate

[0384] 2-Hydroxyisoindoline-1,3-dione (1.25 g, 7.67 mmol), 2,2,2-trichloroethyl (2-hydroxyethyl)carbamate (1.85 g, 7.82 mmol) obtained in Reference Example 2-(1), and triphenylphosphine (4.10 g, 15.7 mmol) were dissolved in THF (39 mL) and ice-cooled to 0°C. A 2.2 M toluene solution of diethyl (E)-diazene-1,2-dicarboxylate (7.1 mL, 15.7 mmol) was then added dropwise, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 2,2,2-trichloroethyl (2-((1,3-dioxoindolin-2-yl)oxy)ethyl)carbamate (yield 1.32 g, yield 44%).

[0385] 1 H-NMR (500MHz, CDCl3, δ): 7.89-7.84 (m, 2H), 7.81-7.77 (m, 2H), 6.20 (br s, 1H), 4.77 (s, 2H), 4.30 (t, J = 4.6Hz, 2H), 3.56 (q, J = 4.0Hz, 2H).

[0386] (3) Production of 2,2,2-trichloroethyl (2-(aminooxy)ethyl)carbamate

[0387] 2,2,2-trichloroethyl (2-((1,3-dioxoindolin-2-yl)oxy)ethyl)carbamate (1.32 g, 3.46 mmol) obtained in Reference Example 2-(2) was dissolved in dichloromethane (34.6 mL), and hydrazine monohydrate (0.202 mL, 4.15 mmol) was added, followed by stirring at room temperature for 13 hours. The suspension was filtered, and the solvent was distilled off under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 2,2,2-trichloroethyl (2-(aminooxy)ethyl)carbamate (yield 1.02 g, quantitative).

[0388] 1 H-NMR (500MHz, CDCl3, δ): 4.73 (s, 2H), 3.76 (t, J = 4.6 Hz, 2H), 3.48 (q, J = 4.6 Hz, 2H).

[0389] Preparation of Compound I-12

[0390] Using 2,2,2-trichloroethyl (2-(aminooxy)ethyl)carbamate obtained in Reference Example 2-(3) instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-12 was obtained as a mixture of isomers that were difficult to separate by the same method (yield 37.3 mg, yield 74%).

[0391] 1 H-NMR (500MHz, CDCl3, δ):5.90-5.80(m,1H),5.80-5.64(m,2H),5.48-5.31(m ,2H),4.98-4.91(m,1H),4.82(s,0.6H),4.78-4.59(m,6H),4.42-4.26(m,1H), 4.26-4.14(m,4H),3.96(s,0.4H),3.94-3.89(m,1H),3.86-3.72(m,2H),3.70 -3.58(m,2H),3.56-3.45(m,3H),3.44(s,3H),3.43-3.39(m,3H),3.30-3.19(m ,2H),3.16(t,J=9.2Hz,1H),2.91-2.83(m,1H),2.60(s,1H),2.53-2.45(m,1H ),2.38-2.19(m,4H),1.90(dd,J=12.0,5.2Hz,1H),1.78-1.71(m,3H),1.70-1. 61(m,2H),1.59-1.37(m,12H),1.35-1.21(m,8H),1.18-1.14(m,3H),0.92(t,J =7.5Hz,3H),0.83(d,J=6.9Hz,3H),0.81-0.74(m,4H); MSm / z1129.4558[M+Na] + .

[0392] Preparation of Compound I-13

[0393] Compound I-13 (yield 35.3 mg, 93%) was obtained by the same method using 2,2,2-trichloroethyl (2-(aminooxy)ethyl)carbamate obtained in Reference Example 2-(3) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0394] 1 H-NMR (500MHz, CDCl3, δ): 5.87-5.62 (m, 3H), 5.48-5.30 (m, 2H), 4.97-4.91 (m, 1. 5H),4.80-4.65(m,5.5H),4.31-4.15(m,3H),3.96-3.88(m,1H),3.86-3.72(m,2H) ,3.70-3.55(m,2H),3.54-3.44(m,4H),3.44(s,3H),3.42(s,3H),3.29-3.19(m,2H ),3.16(t,J=9.2Hz,1H),2.79(dd,J=12.0,4.0Hz,1H),2.68-2.59(m,1H),2.57(br s,1H),2.54-2.42(m,1H),2.38-2.18(m,4H),1.94-1.82(m,3H),1.77-1.62(m,4H),1.59-1.37(m,12H), 1.34-1.20(m,6H),1.20-1.07(m,6H),0.92(t,J=7.5Hz,3H),0.89-0.74(m,7H); MSm / z1129.4570[M+Na] + .

[0395] Reference Example 3

[0396] (1) Production of 2-(3,3,3-trifluoropropoxy)isoindoline-1,3-dione

[0397] 2-Hydroxyisoindoline-1,3-dione (0.500 g, 3.07 mmol), 3,3,3-trifluoropropan-1-ol (0.269 mL, 3.07 mmol), and triphenylphosphine (0.965 g, 3.68 mmol) were dissolved in THF (15.4 mL) and ice-cooled to 0°C. A 2.2 M solution of diethyl (E)-diazene-1,2-dicarboxylate in toluene (1.67 mL, 3.68 mmol) was then added dropwise, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 2-(3,3,3-trifluoropropoxy)isoindoline-1,3-dione (yield 0.630 g, 79%).

[0398] 1H-NMR (500MHz, CDCl3, δ): 7.88-7.83 (m, 2H), 7.80-7.76 (m, 2H), 4.43 (t, J = 6.9Hz, 2H), 2.76-2.66 (m, 2H).

[0399] (2) Production of O-(3,3,3-trifluoropropyl)hydroxylamine hydrochloride

[0400] 2-(3,3,3-trifluoropropoxy)isoindoline-1,3-dione (0.630 g, 2.43 mmol) obtained in Reference Example 3-(1) was dissolved in ethanol (24.3 mL), and hydrazine monohydrate (0.163 mL, 2.67 mmol) was added, and stirred at 65°C for 1 hour. The suspension was filtered and 1,4-dione in 4 M hydrogen chloride was added to the filtrate. The mixture was stirred at room temperature for 15 minutes in an oxane solution (1.22 mL, 4.86 mmol). The solvent was distilled off under reduced pressure to obtain O-(3,3,3-trifluoropropyl)hydroxylamine hydrochloride (yield 0.339 g, yield 84%).

[0401] 1 H-NMR (500MHz, DMSO-d6, δ): 4.14 (t, J = 5.7Hz, 2H), 2.82-2.66 (m, 2H).

[0402] Preparation of Compound I-14

[0403] Using O-(3,3,3-trifluoropropyl)hydroxylamine hydrochloride obtained in Reference Example 3-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-14 was obtained as a mixture of isomers that were difficult to separate by the same method (yield 16.1 mg, yield 48%).

[0404] 1H-NMR (500MHz, CDCl3, δ): 5.85 (dt, J=10.4, 2.8Hz, 1H), 5.77-5.66 (m, 2H), 5.45-5.37 (m, 2H), 4.95 ( d,J=10.9Hz,1H),4.78-4.75(m,1.6H),4.71-4.55(m,3H),4.33-4.23(m,2H),3.96(s,0.4H),3.93(br s,1H),3.86-3.74(m,2H),3.71-3.60(m,2H),3.52-3.47(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2 H),3.16(t,J=9.2Hz,1H),2.92-2.81(m,2H),2.56-2.44(m,4H),2.37-2.20(m,5H),1.90(dd,J=11.7,4.9Hz ,1H),1.78-1.72(m,1H),1.69-1.60(m,3H),1.59-1.38(m,12H),1.32-1.22(m,8H),1.20(d,J=7.5Hz,1H), 1.19-1.14(m,3H),0.92(t,J=7.2Hz,3H),0.84(d,J=6.9Hz,3H),0.82-0.76(m,4H); MSm / z1008.5277[M+Na] + .

[0405] Preparation of Compound I-15

[0406] Compound I-15 (yield 21.4 mg, 63%) was obtained by the same method using O-(3,3,3-trifluoropropyl)hydroxylamine hydrochloride obtained in Reference Example 3-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0407] 1H-NMR (500MHz, CDCl3, δ): 5.85-5.80 (m, 1H), 5.77-5.63 (m, 2H), 5.44-5.34 (m, 2H), 4.94 (d, J=10.9Hz, 1H ),4.88(s,1H),4.76(d,J=2.9Hz,1H),4.65(t,J=2.0Hz,2H),4.60(s,1H),4.29(t,J=6.9Hz,2H),3.93(br s,1H),3.85-3.74(m,2H),3.70-3.60(m,2H),3.51-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H),3.16(t,J=9.2Hz,1H), 2.78(dd,J=12.6,3.4Hz,1H),2.65-2.56(m,1H),2.54-2.45(m,4H),2.36-2.30(m,2H),2.29-2.20(m,2H),1.94-1.81(m,3H),1.73(br s,1H),1.69-1.63(m,1H),1.60(br s,1H),1.59-1.38(m,12H),1.30-1.22(m,7H),1.16(t,J=6.9Hz,5H),0.92(t,J =7.5Hz,3H),0.84(d,J=6.9Hz,3H),0.82-0.75(m,4H); MSm / z1008.5268[M+Na] + .

[0408] Reference Example 4

[0409] (1) Production of 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione

[0410] 2-Hydroxyisoindoline-1,3-dione (1.63 g, 10.0 mmol) was dissolved in dichloromethane (33.3 mL). DIPEA (1.91 mL, 11.0 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.58 mL, 11.0 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by short pad silica gel column chromatography to obtain 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (yield 1.88 g, yield 77%).

[0411] 1H-NMR (500MHz, CDCl3, δ): 7.91-7.85 (m, 2H), 7.82-7.77 (m, 2H), 4.56 (q, J = 8.0Hz, 2H).

[0412] (2) Production of O-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride

[0413] 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (1.88 g, 7.67 mmol) obtained in Reference Example 4-(1) was dissolved in ethanol (76.7 mL), and hydrazine monohydrate (0.513 mL, 8.44 mmol) was added, and stirred at 65°C for 30 minutes. The suspension was filtered and 4 M 1,4-difluorohydrogen chloride was added to the filtrate. The mixture was stirred at room temperature for 15 minutes in an oxane solution (3.84 mL, 15.3 mmol). The solvent was distilled off under reduced pressure to obtain O-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride (yield 1.16 g, yield 99%).

[0414] 1 H-NMR (500MHz, DMSO-d6, δ): 4.37 (q, J=9.2Hz, 2H).

[0415] Preparation of Compound I-16

[0416] Using O-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride obtained in Reference Example 4-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-16 was obtained as a mixture of isomers that were difficult to separate by the same method (yield 11.3 mg, yield 34%).

[0417] 1H-NMR (500MHz, CDCl3, δ): 5.91-5.82 (m, 1H), 5.79-5.64 (m, 2H), 5.46-5.37 (m, 2H), 4.95 (d, J = 10.9Hz, 1 H),4.81(s,0.6H),4.77(d,J=3.4Hz,1H),4.73-4.56(m,3H),4.51-4.39(m,2H),3.97(s,0.4H),3.94(br s,1H),3.87-3.73(m,2H),3.71-3.57(m,2H),3.52-3.45(m,1H),3.45(s,3H),3.43(s,3H),3.27-3 .20(m,2H),3.17(t,J=9.2Hz,1H),2.92-2.83(m,1H),2.54-2.46(m,2H),2.38-2.17(m,5H),1.95-1 .85(m,1H),1.79-1.71(m,1H),1.70-1.61(m,1H),1.61-1.38(m,14H),1.31-1.23(m,10H),1.20-1 .12(m,3H),0.92(t,J=7.5Hz,3H),0.84(d,J=6.9Hz,3H),0.82-0.76(m,4H); MSm / z994.5120[M+Na] + .

[0418] Preparation of Compound I-17

[0419] Compound I-17 (yield 14.9 mg, 45%) was obtained by the same method using O-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride obtained in Reference Example 4-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0420] 1H-NMR (500MHz, CDCl3, δ): 5.91-5.82 (m, 1H), 5.80-5.63 (m, 2H), 5.44-5.35 (m, 2H), 4.94 (d, J = 10.9Hz, 1H ),4.92(s,1H),4.77(d,J=3.4Hz,1H),4.67(d,J=1.7Hz,2H),4.62(s,1H),4.44(q,J=8.6Hz,2H),3.93(br s,1H),3.86-3.73(m,3H),3.71-3.58(m,2H),3.52-3.45(m,1H),3.44(s,3H),3.43-3.39(m,4H),3.2 6-3.19(m,2H),3.17(t,J=9.2Hz,1H),2.79(dd,J=12.3,3.2Hz,1H),2.67-2.58(m,1H),2.55-2.45(m, 2H),2.38-2.19(m,4H),1.98-1.81(m,3H),1.77-1.70(m,1H),1.69-1.62(m,1H),1.60-1.37(m,8H),1 .31-1.21(m,9H),1.20-1.11(m,6H),0.92(t,J=7.5Hz,3H),0.90-0.74(m,7H); MSm / z994.5115[M+Na] + .

[0421] Reference Example 5

[0422] (1) Production of 2-(2-methoxyethoxy)isoindoline-1,3-dione

[0423] 2-Hydroxyisoindoline-1,3-dione (1.63 g, 10.0 mmol) was dissolved in DMF (4.35 mL). 1-Bromo-2-methoxyethane (4.76 mL, 50.0 mmol) and triethylamine (5.12 mL, 36.8 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours and then at 50°C for 2 hours. Water was added to the reaction mixture, and the mixture was filtered. The filtrate was then dissolved in ethyl acetate and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 2-(2-methoxyethoxy)isoindoline-1,3-dione (yield 1.20 g, 54%).

[0424] 1H-NMR (500MHz, CDCl3, δ): 7.88-7.82(m,2H), 7.78-7.71(m,2H), 4.40-4.33(m,2H), 3.79-3.73(m,2H), 3.40-3.38(m,3H).

[0425] (2) Production of O-(2-methoxyethyl)hydroxylamine hydrochloride

[0426] 2-(2-methoxyethoxy)isoindoline-1,3-dione (1.00 g, 4.52 mmol) obtained in Reference Example 5-(1) was dissolved in ethanol (45.2 mL), and hydrazine monohydrate (0.302 mL, 4.97 mmol) was added, followed by stirring at 65°C for 1 hour. The suspension was filtered and 4 M 1,4-dihydrochloric acid was added to the filtrate. The mixture was added to an oxane solution (2.26 mL, 9.04 mmol) and stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure to obtain O-(2-methoxyethyl)hydroxylamine hydrochloride (yield 0.338 g, yield 59%).

[0427] 1 H-NMR (500MHz, DMSO-d6, δ): 10.7 (br s, 3H), 4.12-4.07 (m, 2H), 3.57-3.53 (m, 2H), 3.26 (s, 3H).

[0428] Preparation of Compound I-18

[0429] Using O-(2-methoxyethyl)hydroxylamine hydrochloride obtained in Reference Example 5-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-18 was obtained as a mixture of isomers that were difficult to separate by the same method (yield 14.8 mg, yield 46%).

[0430] 1H-NMR (500MHz, CDCl3, δ): 5.89-5.81 (m, 1H), 5.77-5.63 (m, 2H), 5.45-5.38 (m, 2H), 4.95 (d, J = 9.2Hz, 1H), 4.85 (s, 0.4H),4.77(d,J=4.0Hz,1H),4.70-4.55(m,3H),4.26(t,J=4.9Hz,1H),4.24-4.17(m,1H),3.98(s,0.6H),3.93(br s,1H),3.86-3.74(m,2H),3.71-3.54(m,5H),3.52-3.52(m,1H),3.45(s,3H),3.43(s,3H),3.39-3.35(m ,3H),3.26-3.19(m,2H),3.17(t,J=9.2Hz,1H),2.92-2.82(m,1H),2.52-2.46(m,2H),2.37-2.20(m,5H) ,1.93-1.87(m,1H),1.78-1.73(m,1H),1.70-1.64(m,1H),1.40(d,J=7.5Hz,1H),1.62-1.35(m,12H),1. 31-1.19(m,10H),1.16(d,J=6.9Hz,3H),0.92(t,J=7.5Hz,3H),0.90-0.76(m,7H); MSm / z970.5511[M+Na] + .

[0431] Preparation of Compound I-19

[0432] Compound I-19 (yield 20.0 mg, 62%) was obtained by the same method using O-(2-methoxyethyl)hydroxylamine hydrochloride obtained in Reference Example 5-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0433] 1H-NMR (500MHz, CDCl3, δ):5.86-5.79(m,1H),5.75-5.65(m,2H),5.43-5.34(m,2H),4.96-4.92 (m,2H),4.76(d,J=3.4Hz,1H),4.69-4.60(m,2H),4.56(s,1H),4.23(t,J=5.2Hz,2H),3.93(br s,1H),3.86-3.74(m,2H),3.71-3.58(m,4H),3.52-3.45(m,1H),3.44(s,3H),3.43(s,3H),3.36(s,3H), 3.26-3.19(m,2H),3.17(t,J=9.2Hz,1H),2.79(dd,J=12.6,3.4Hz,1H),2.64-2.56(m,1H),2.52-2.46(m ,2H),2.38-2.19(m,4H),1.95-1.79(m,3H),1.77-1.71(m,1H),1.68-1.62(m,2H),1.59-1.36(m,12H),1 .29-1.24(m,6H),1.16(t,J=7.2Hz,6H),0.92(t,J=7.5Hz,3H),0.86-0.76(m,7H); MSm / z970.5495[M+Na] + .

[0434] Reference Example 6

[0435] (1) Production of 2-(2-hydroxyethoxy)isoindoline-1,3-dione

[0436] 2-Hydroxyisoindoline-1,3-dione (1.63 g, 10.0 mmol) was dissolved in acetonitrile (33.3 mL). 2-Bromoethane-1-ol (1.43 mL, 20.0 mmol) and triethylamine (2.78 mL, 20 mmol) were added sequentially, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain 2-(2-hydroxyethoxy)isoindoline-1,3-dione (yield 1.80 g, 87%).

[0437] 1 H-NMR (500MHz, CDCl3, δ): 7.90-7.85 (m, 2H), 7.81-7.77 (m, 2H), 4.32-4.29 (m, 2H), 3.83-3.78 (m, 2H), 3.46 (t, J = 7.2Hz, 1H).

[0438] (2) Production of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)isoindoline-1,3-dione

[0439] 2-(2-Hydroxyethoxy)isoindoline-1,3-dione (0.449 g, 2.17 mmol) obtained in Reference Example 6-(1) was dissolved in DMF (21.7 mL). Imidazole (0.885 g, 13.0 mmol), DMAP (26.5 mg, 0.217 mmol), and tert-butylchlorodimethylsilane (0.981 g, 6.51 mmol) were added sequentially, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)isoindoline-1,3-dione (yield 0.704 g, yield 100%).

[0440] 1 H-NMR (500MHz, CDCl3, δ):7.85-7.80(m,2H),7.75-7.71(m,2H),4.32-4.29 (m,2H),4.01-3.98(m,2H),3.46(t,J=7.2Hz,1H),0.81(s,9H),0.01(s,3H).

[0441] (3) Production of O-(2-((tert-butyldimethylsilyl)oxy)ethyl)hydroxylamine hydrochloride

[0442] 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)isoindoline-1,3-dione (1.00 g, 3.11 mmol) obtained in Reference Example 6-(2) was dissolved in ethanol (31.1 mL), and hydrazine monohydrate (0.189 mL, 3.11 mmol) was added, followed by stirring at 67°C for 30 minutes. The suspension was filtered, and the filtrate was washed with ether. The solvent was distilled off under reduced pressure to obtain O-(2-((tert-butyldimethylsilyl)oxy)ethyl)hydroxylamine hydrochloride (yield 0.577 g, yield 97%).

[0443] 1 H-NMR (500MHz, DMSO-d6, δ): 5.95 (br s, 2H), 3.73-3.67 (m, 2H), 3.57-3.53 (m, 2H), 0.86 (s, 9H), 0.01 (s, 3H).

[0444] Preparation of Compound I-20

[0445] Using O-(2-((tert-butyldimethylsilyl)oxy)ethyl)hydroxylamine hydrochloride obtained in Reference Example 6-(3) instead of hydroxylamine hydrochloride in [Manufacture of Compound I-1], Compound I-20 (yield 38.5 mg, yield 64%) was obtained as a mixture of isomers that were difficult to separate by the same method.

[0446] 1 H-NMR (500MHz, CDCl3, δ): 5.88-5.79 (m, 1H), 5.78-5.63 (m, 2H), 5.45-5.36 (m, 2H), 4.99-4.93 (m, 1H), 4.82 (s, 0. 4H),4.76(d,J=2.9Hz,1H),4.70-4.54(m,2.6H),4.54-4.51(m,0.4H),4.20-4.09(m,2H),3.97(s,0.6H),3.93(br s,1H),3.87-3.74(m,4H),3.71-3.59(m,2H),3.56-3.45(m,2H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H),3.16(t,J= 9.2Hz,1H),2.91-2.81(m,1H),2.58-2.45(m,2H),2.36-2.27(m,3H),2.27-2.19(m,2H),1.92-1.85(m,1H),1.79-1.72(m ,1H),1.66(d,J=13.2Hz,1H),1.63-1.37(m,12H),1.31-1.23(m,8H),1.21(d,J=6.9Hz,2H),1.15(d,J=7.5Hz,3H),0.92( t,J=7.2Hz,3H),0.89-0.86(m,10H),0.86-0.80(m,4H),0.78(d,J=6.3Hz,3H),0.06-0.02(m,6H); MSm / z1070.6219[M+Na] + .

[0447] Preparation of Compound I-21

[0448] Using O-(2-((tert-butyldimethylsilyl)oxy)ethyl)hydroxylamine hydrochloride obtained in Reference Example 6-(3) instead of hydroxylamine hydrochloride in [Production of Compound I-2], Compound I-21 was obtained by the same method (yield 51.3 mg, yield 86%).

[0449] 1H-NMR (500MHz, CDCl3, δ):5.85-5.79(m,1H),5.76-5.63(m,2H),5.44-5.34(m ,2H),4.98-4.90(m,2H),4.79-4.73(m,1H),4.67-4.58(m,2H),4.53(s,1H),4 .18-4.09(m,2H),3.95-3.90(m,1H),3.86-3.74(m,4H),3.70-3.59(m,2H),3. 52-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H),3.16(t,9.2Hz,1 H),2.81-2.73(m,1H),2.65-2.54(m,1H),2.55-2.45(m,3H),2.36-2.18(m,4H ),1.95-1.78(m,3H),1.77-1.71(m,1H),1.69-1.63(m,1H),1.62-1.36(m,12H) ,1.31-1.23(m,7H),1.18-1.14(m,5H),0.95-0.89(m,3H),0.89-0.86(m,9H), 0.84(d,J=6.9Hz,3H),0.81-0.74(m,4H),0.05(s,6H); MSm / z1070.6221[M+Na] + .

[0450] Preparation of Compound I-22

[0451] After dissolving 3,4β-dihydro-5-oxo-ivermectin B1a (30.0 mg, 0.034 mmol) in methanol (0.69 mL), sodium acetate (16.9 mg, 0.206 mmol) and 2-(aminooxy)ethane-1-amine dihydrochloride (10.2 mg, 0.069 mmol) were added sequentially and stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol system) to obtain compound I-22 (yield 21.3 mg, yield 67%) as a mixture of isomers that were difficult to separate.

[0452] 1H-NMR (500MHz, CD3OD, δ): 5.92-5.84 (m, 2H), 5.78-5.68 (m, 1H), 5.34 (d, J = 3.4Hz, 1H), 5.28-5.18 (m, 1H), 5.13(t,J=7.5Hz,1H),4.80(d,J=2.9Hz,1H),4.76(s,0.6H),4.71-4.58(m,2H),4.31-4.18(m,2H),3.99(br s,1H),3.91-3.85(m,1H),3.84(s,0.4H),3.76-3.62(m,3H),3.42(s,3H),3.41(s,3H),3.27(d,J= 8.0Hz,1H),3.22-3.13(m,3H),3.03(t,J=9.2Hz,1H),2.95-2.87(m,1H),2.86-2.78(m,1H),2.68- 2.61(m,1H),2.38-2.24(m,5H),2.04-1.96(m,1H),1.89-1.82(m,1H),1.66-1.36(m,15H),1.34-1 .19(m,12H),1.17(d,J=6.9Hz,3H),0.97(t,J=7.5Hz,3H),0.91-0.78(m,7H);MSm / z933.5685[M+H] + .

[0453] Preparation of Compound I-23

[0454] After dissolving 3,4α-dihydro-5-oxo-ivermectin B1a (30.0 mg, 0.034 mmol) in methanol (0.69 mL), sodium acetate (16.9 mg, 0.206 mmol) and 2-(aminooxy)ethane-1-amine dihydrochloride (10.2 mg, 0.069 mmol) were added sequentially and stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol system) to obtain compound I-23 (yield 19.8 mg, yield 74%).

[0455] 1H-NMR (500MHz, CDCl3, δ): 5.89-5.81 (m, 1H), 5.77-5.64 (m, 2H), 5.39 (d, J = 3 .4Hz,1H),5.36-5.27(m,1H),5.02-4.92(m,2H),4.77(d,J=3.4Hz,1H),4.66 (s,2H),4.24-4.14(m,2H),3.98-3.74(m,5H),3.69-3.60(m,2H),3.52-3.45 (m,1H),3.43(s,3H),3.42(s,3H),3.26-3.19(m,2H),3.16(t,J=9.2Hz,1H),3 .11-2.99(m,2H),2.77(dd,J=12.6,3.4Hz,1H),2.66-2.58(m,1H),2.54-2.4 6(m,1H),2.36-2.20(m,4H),1.99-1.81(m,5H),1.79-1.72(m,1H),1.68-1.6 1(m,1H),1.60-1.32(m,12H),1.29-1.23(m,7H),1.19-1.12(m,6H),0.92(t, J=7.2Hz,3H),0.83(d,J=6.9Hz,3H),0.81-0.75(m,4H); MSm / z933.5692[M+H] + .

[0456] Preparation of Compound I-24 and Compound I-25

[0457] Compound I-20 (33.0 mg, 0.031 mmol) was added to a 3% sulfuric acid methanol solution (0.63 mL) and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (n-hexane / acetone = 2:1) to obtain compound I-24 (yield 16.2 mg, yield 65%) and compound I-25 (yield 4.5 mg, yield 22%), respectively.

[0458] (Compound I-24)

[0459] 1H-NMR(500 MHz, CDCl3, δ): 5.85 - 5.79 (m, 1H), 5.77 - 5.66 (m, 2H), 5.44 - 5.35 (m, 1H), 5.35 - 5.28 (m, 1H), 4.70 - 4.55 (m, 3H), 4.23 (t, J = 4.3 Hz, 2H), 4.00 (br s, 1H), 3.96 (s, 1H), 3.91 - 3.83 (m, 2H), 3.73 - 3.65 (m, 1H), 3.56 - 3.49 (m, 1H), 3.19 (dd, J = 9.2, 1.7 Hz, 1H), 2.88 (dd, J = 13.8, 2.9 Hz, 1H), 2.51 (br s, 1H), 2.35 - 2.16 (m, 4H), 1.94 - 1.84 (m, 1H), 1.77 - 1.70 (m, 1H), 1.70 - 1.63 (m, 1H), 1.63 - 1.39 (m, 12H), 1.30 - 1.19 (m, 4H), 1.17 (d, J = 6.9 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 0.85 - 0.77 (m, 7H); MS m / z 646.3950 [M + H] + .

[0460] (Compound I-25)

[0461] 1H-NMR (500MHz, CDCl3, δ): 5.86 (dt, J=10.5, 2.5Hz, 1H), 5.78-5.64 (m, 2H), 5.48-5.38 (m, 1H), 4.99 -4.92(m,1H),4.81(d,J=3.4Hz,1H),4.68-4.55(m,3H),4.23(t,J=4.0Hz,2H),3.96(s,1H),3.95(br s,1H),3.90-3.81(m,3H),3.71-3.65(m,1H),3.60-3.52(m,2H),3.49(s,3H),3.22( dd,J=9.2,1.7Hz,1H),3.16(t,J=9.2Hz,1H),2.90(dd,J=13.8,2.9Hz,1H),2.55(br s,1H),2.51-2.45(m,1H),2.37-2.17(m,5H),1.92-1.85(m,1H),1.79-1.73(m,1H),1.70-1.64(m,1H),1.637-1.38(m,12H), 1.30-1.20(m,7H),1.15(d,J=6.9Hz,3H),0.95-0.90(m,3H),0.86-0.80(m,4H),0.79(d,J=5.7Hz,3H); MSm / z790.4744[M+H] + .

[0462] Preparation of compounds I-26 and I-27

[0463] Using compound I-21 instead of compound I-20 in [Production of compound I-24 and compound I-25], compound I-26 (yield 22.5 mg, yield 62%) and compound I-27 (yield 6.2 mg, yield 21%) were obtained by the same method.

[0464] (Compound I-26)

[0465] 1H-NMR(500 MHz, CDCl3, δ): 5.83 - 5.77 (m, 1H), 5.76 - 5.65 (m, 2H), 5.43 - 5.33 (m, 1H), 5.33 - 5.28 (m, 1H), 4.96 (s, 1H), 4.75 - 4.61 (m, 3H), 4.20 (t, J = 4.3 Hz, 2H), 4.00 (br s, 1H), 3.91 - 3.79 (m, 2H), 3.75 - 3.61 (m, 1H), 3.18 (dd, J = 9.2, 1.7 Hz, 1H), 2.77 (dd, J = 12.0, 3.4 Hz, 1H), 2.67 - 2.57 (m, 1H), 2.55 - 2.46 (m, 1H), 2.36 - 2.24 (m, 2H), 1.94 - 1.80 (m, 3H), 1.75 - 1.69 (m, 1H), 1.68 - 1.45 (m, 12H), 1.44 - 1.37 (m, 2H), 1.20 - 1.13 (m, 6H), 0.95 (t, J = 7.5 Hz, 3H), 0.86 - 0.77 (m, 7H); MS m / z 646.3956 [M + H] + .

[0466] (Compound I-27)

[0467] 1 H-NMR(500 MHz, CDCl3, δ): 5.84 (dt, J = 10.3, 2.3 Hz, 1H), 5.78 - 5.63 (m, 2H), 5.46 - 5.35 (m, 1H), 4.97 (s, 1H), 4.94 (d, J = 9.7 Hz, 1H), 4.81 (d, J =+ .

[0468] Preparation of Compound I-28

[0469] After dissolving compound I-1 (30 mg, 0.034 mmol) in DMF (0.67 mL), potassium carbonate (9.32 mg, 0.067 mmol) and iodoethane (10.8 μL, 0.135 mmol) were added in sequence at room temperature, and the mixture was stirred at 70°C for 4 hours. Potassium carbonate (9.32 mg, 0.067 mmol) and iodoethane (10.8 μL, 0.135 mmol) were added to the reaction solution at room temperature, and the mixture was stirred at 70°C for 48 hours. An aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-28 (yield 10.7 mg, yield 35%) as a mixture of isomers that are difficult to separate. The following 1 The H-NMR spectrum is the analytical data of the main isomer.

[0470] 1 H-NMR (500MHz, CDCl3, δ): 5.86 (dt, J=10.2, 2.4Hz, 1H), 5.78-5.65 (m, 2H), 5.46-5.38 (m, 2H), 4.95 ( d,J=10.9Hz,1H),4.77(d,J=3.4Hz,1H),4.69-4.55(m,3H),4.19-4.12(m,2H),3.98(s,1H),3.93(br s,1H),3.86-3.74(m,2H),3.72-3.59(m,2H),3.54-3.45(m,2H),3.44(s,3H),3.43(s,3H),3.2 7-3.19(m,2H),3.17(t,J=9.2Hz,1H),2.93-2.87(m,1H),2.53-2.45(m,2H),2.38-2.19(m,5H), 1.93-1.87(m,1H),1.80-1.72(m,1H),1.67(d,J=12.6Hz,1H),1.61-1.38(m,12H),1.33-1.18(m ,14H),1.16(d,J=6.9Hz,3H),0.92(t,J=7.5Hz,3H),0.85-0.76(m,7H); MSm / z935.5800[M+NH4] + .

[0471] Preparation of Compound I-29

[0472] Compound I-2 was used instead of Compound I-1 in [Production of Compound I-28] to obtain Compound I-29 (yield 12.2 mg, yield 39%) by the same method.

[0473] 1 H-NMR (500MHz, CDCl3, δ): 5.84 (dt, J = 10.3, 2.3Hz, 1H), 5.77-5.65 (m, 2H), 5.45-5.36 (m, 2H), 4.98 -4.92(m,2H),4.77(d,J=3.4Hz,1H),4.66(d,J=2.9Hz,2H),4.62(s,1H),4.18-4.09(m,2H),3.93(br s,1H),3.87-3.72(m,2H),3.72-3.60(m,2H),3.53-3.45(m,2H),3.44(s,3H),3.44-3.41(m,3H),3.27-3.19 (m,2H),3.17(t,J=9.2Hz,1H),2.79(dd,J=12,6,2.9Hz,1H),2.65-2.55(m,1H),2.55-2.45(m,2H),2.37-2. 18(m,4H),1.95-1.79(m,2H),1.78-1.71(m,1H),1.69-1.64(m,1H),1.62-1.37(m,12H),1.30-1.22(m,10H) ,1.20-1.14(m,6H),0.92(t,J=7.2Hz,3H),0.84(d,J=6.9Hz,3H),0.82-0.74(m,4H); MSm / z935.5800[M+NH4] + .

[0474] Preparation of Compound I-30

[0475] Using 1-bromopropane instead of ethyl iodide in [Production of Compound I-28], Compound I-30 was obtained as a mixture of isomers that was difficult to separate (yield 7.9 mg, yield 25%) by the same method. 1 The H-NMR spectrum is the analytical data of the main isomer.

[0476] 1H-NMR (500MHz, CDCl3, δ): 5.86 (dt, J=10.3, 2.3Hz, 1H), 5.77-5.64 (m, 2H), 5.46-5.37 (m, 2H), 4.95 ( d,J=10.9Hz,1H),4.77(d,J=3.4Hz,1H),4.68-4.54(m,3H),4.10-4.00(m,2H),3.98(s,1H),3.93(br s,1H),3.87-3.73(m,2H),3.72-3.60(m,2H),3.53-3.45(m,1H),3.45(s,3H),3.43(s,3H),3.27-3.20(m,2 H),3.17(t,J=9.2Hz,1H),2.93-2.87(m,1H),2.53-2.46(m,2H),2.37-2.30(m,2H),2.30-2.17(m,3H),1.93 -1.87(m,1H),1.79-1.73(m,1H),1.71-1.63(m,3H),1.61-1.35(m,12H),1.32-1.23(m,7H),1.23-1.18(m,5 H),1.18-1.14(m,3H),0.96-0.89(m,6H),0.87-0.80(m,4H),0.78(d,J=6.3Hz,3H); MSm / z949.5981[M+NH4] + .

[0477] Preparation of Compound I-31

[0478] Compound I-2 was used instead of Compound I-1 in [Production of Compound I-28], and 1-bromopropane was used instead of iodoethane. Compound I-31 was obtained by the same method (yield 9.6 mg, yield 31%).

[0479] 1H-NMR (500MHz, CDCl3, δ):5.86-5.80(m,1H),5.76-5.64(m,2H),5.44-5.36(m,2H),4.98-4.93( m,2H),4.77(d,J=3.4Hz,1H),4.66(d,J=2.3Hz,2H),4.60(s,1H),4.03(t,J=6.9Hz,2H),3.93(br s,1H),3.86-3.73(m,2H),3.71-3.60(m,2H),3.52-3.45(m,1H),3.44(s,3H),3.43(s,3H),3.2 6-3.19(m,2H),3.17(t,J=9.2Hz,1H),2.79(dd,J=12.6,2.9Hz,1H),2.63-2.55(m,1H),2.54-2. 45(m,2H),2.38-2.18(m,4H),1.94-1.80(m,3H),1.78-1.70(m,1H),1.70-1.61(m,3H),1.59-1 .38(m,12H),1.29-1.24(m,6H),1.19-1.13(m,6H),0.94-0.76(m,14H); MSm / z949.5981[M+NH4] + .

[0480] Preparation of Compound I-32

[0481] Compound I-32 was obtained as a mixture of isomers that was difficult to separate (yield 14.5 mg, 50%) by the same method using O-(3-methylphenethyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-1].

[0482] 1H-NMR (500MHz, CDCl3, δ): 7.16 (t, J = 7.1Hz, 1H), 7.04-6.99 (m, 3H) 5.89-5 .82(m,1H)5.78-5.64(m,2H)5.40(d,J=3.4Hz,2H)4.99-4.92(m,1H)4.83(s ,1H)4.77(d,J=3.4Hz,1H)4.70-4.59(m,2H)4.57(s,1H)4.24(t,J=7.5Hz, 2H)4.14-4.09(m,1H)3.93(brs,1H)3.88-3.72(m,2H)3.71-3.61(m,2H)3.5 1-3.40(m,1H)3.45(s,3H)3.43(s,3H)3.27-3.19(m,2H)3.17(t,J=9.2Hz, 1H)2.96-2.84(m,4H)2.49(m,2H)2.39-2.18(m,5H)2.31(s,3H),1.94-1.83 (m,1H)1.79-1.72(m,1H)1.69-1.35(m,16H)1.33-1.22(m,9H)1.16(d,J=6 .9Hz,3H)0.92(t,J=7.2Hz,3H)0.88-0.73(m,7H); MSm / z1025.6306[M+NH4] + .

[0483] Preparation of Compound I-33

[0484] Compound I-33 was obtained as a mixture of isomers that was difficult to separate (yield 21.5 mg, 56%) by the same method using O-(2-ethylbenzyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-1].

[0485] 1H-NMR (500MHz, CDCl3, δ):7.35-7.30(m,1H)7.24-7.13(m,3H)5.89-5.81(m,1H)5.7 6-5.63(m,2H)5.46-5.38(m,2H)5.24-5.11(m,2H)4.98-4.93(m,1H)4.88-4.86(m,1 H)4.79-4.73(m,1H)4.69-4.52(m,3H)4.01(s,1H)3.95-3.91(m,1H)3.86-3.73(m,2 H)3.71-3.59(m,2H)3.57-3.45(m,2H)3.45-3.43(m,3H)3.43-3.41(m,3H)3.37-3.19 (m,2H)3.16(t,J=8.9Hz,1H)2.93-2.82(m,1H)2.73-2.63(m,2H)2.54-2.45(m,2H)2 .38-2.19(m,5H)1.93-1.86(m,1H)1.78-1.73(m,1H)1.69-1.66(m,1H),1.62-1.35(m ,8H),1.30-1.24(m,11H),1.23-1.18(m,5H),1.15(dd,J=10.3,6.9Hz,3H),0.92(t, J=7.5Hz,3H)0.83(dd,J=6.9,1.7Hz,3H)0.75-0.82(m,4H); MSm / z1025.6304[M+NH4] + .

[0486] Preparation of Compound I-34

[0487] Compound I-34 (yield 27.6 mg, 68%) was obtained by the same method using O-(3-fluorophenethyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0488] 1H-NMR (500MHz, CDCl3, δ): 7.21 (dt, J=7.9, 6.0Hz, 1H), 6.96 (d, J=7.4Hz, 1H), 6.9 3-6.85(m,2H),5.83(dt,J=10.3,2.3Hz,1H),5.76-5.65(m,2H),5.43-5.36(m,2H ),4.95(d,J=9.7Hz,1H),4.91(s,1H),4.76(d,J=3.4Hz,1H),4.69-4.61(m,2H),4 .58(s,1H),4.27(t,J=6.9Hz,2H),4.14-4.11(m,1H),4.11-4.09(m,1H),3.93(br s,1H),3.86-3.80(m,1H),3.80-3.73(m,1H),3.70-3.60(m,2H),3.51-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.45-3.41( m,1H),3.26-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.97-2.92(m,2H),2.78(dd,J=12.6,3.4Hz,1H),2.64-2.56(m,1H),2.54- 2.45(m,2H),2.37-2.19(m,5H),1.91-1.79(m,1H),1.77-1.72(m,1H),1.68-1.59(m,1H),1.58-1.36(m,9H),1.29-1.23(m, 8H),1.16(dd,J=6.6,1.4Hz,6H),0.92(t,J=7.4Hz,3H),0.83(d,J=6.3Hz,3H),0.82-0.74(m,4H); MSm / z1029.6066[M+NH4] + .

[0489] Preparation of Compound I-35

[0490] Compound I-35 was obtained as a mixture of isomers that was difficult to separate (yield 26.1 mg, 66%) by the same method using O-(3-methylbenzyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-1].

[0491] 1H-NMR (500MHz, CDCl3, δ):7.25-7.18(m,1H)7.16-7.05(m,3H)5.88-5.82(m,1H )5.77-5.64(m,2H)5.46-5.37(m,2H)5.15-5.04(m,2H)4.98-4.93(m,1H)4.90(s ,0.5H)4.78-4.75(m,1H)4.70-462(m,1H)4.61-4.56(m,1H)4.00(s,0.5H)3.94 -3.91(m,1H)3.86-3.79(m,1H)3.79-3.73(m,1H),3.72-3.52(m,2H),3.52-3.45 (m,1H),3.44(s,3H)3.42(s,3H)3.26-3.19(m,2H)3.16(t,J=9.2Hz,1H)2.93-2 .84(m,1H)2.53-2.45(m,1H)2.34(m,5H)2.30-2.19(m,3H)1.93-1.87(m,1H)1.8 0-1.72(m,1H)1.70-1.64(m,1H)1.64-1.35(m,12H)1.33-1.20(m,12H)1.15(t, J=7.4Hz,3H),0.92(t,J=7.2Hz,3H)0.90-0.75(m,9H); MSm / z1011.6149[M+NH4] + .

[0492] Preparation of Compound I-36

[0493] Compound I-36 (yield 14.0 mg, 35%) was obtained by the same method using O-(3-methylbenzyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0494] 1H-NMR (500MHz, CDCl3, δ): 7.20 (t, J=7.2Hz, 1H), 7.16-7.11 (m, 2H), 7.08 (d, J=7.4Hz, 1H), 5.84-5.79 (m, 1H), 5. 75-5.63(m,2H),5.40(d,J=4.0Hz,2H),5.09(s,2H),4.99(s,1H),4.97-4.91(m,1H),4.78-4.73(m,1H),4.64(br s,2H),4.58(s,1H),3.92(br s,1H),3.87-3.73(m,2H),3.71-3.58(m,2H),3.51-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.27-3.19(m,2H),3 .16(t,J=9.2Hz,1H),2.79(dd,J=12.9,3.2Hz,1H),2.66-2.56(m,1H),2.55-2.43(m,2H),2.36-2.33(m,2H),2. 33(s,3H),2.27-2.23(m,2H),1.94-1.79(m,3H),1.77-1.70(m,1H),1.68-1.62(m,1H),1.61-1.34(m,7H),1.32 -1.20(m,9H),1.16(dd,J=14.6,6.6Hz,6H),0.92(t,J=7.4Hz,3H),0.89-0.75(m,8H); MSm / z1011.6145[M+NH4] + .

[0495] Preparation of Compound I-37

[0496] Compound I-37 was obtained as a mixture of isomers that was difficult to separate (yield 20.5 mg, 60%) by the same method using O-(3-fluorobenzyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-1].

[0497] 1H-NMR (500MHz, CDCl3, δ):7.32-7.26(m,1H),7.13-7.01(m,2H),7.00-6.91(m,1H),5 .85(s,1H),5.71(m,2H),5.40(m,2H),5.13(d,J=5.7Hz,1H),5.10(d,J=8.0Hz,1H),4. 99-4.92(m,1H),4.89(s,0.5H),4.79-4.74(m,1H),4.71-4.63(m,1H),4.62-4.55(m,1 H),3.99(s,0.5H),3.94-3.92(m,1H),3.87-3.73(m,2H),3.71-3.53(m,2H),3.51-3.4 5(m,1H),3.44(s,3H),3.42(s,3H),3.27-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.93-2 .88(m,1H),2.87-2.75(m,1H),2.53-2.45(m,2H),2.37-2.19(m,5H),1.93-1.79(m,2H ),1.79-1.71(m,1H),1.70-1.34(m,15H),1.32-1.17(m,11H),1.17-1.13(m,3H),0.92 (t,J=7.2Hz,3H),0.88(d,J=14.3Hz,1H),0.85-0.74(m,8H); MSm / z1015.5895[M+NH4] + .

[0498] Preparation of Compound I-38

[0499] Compound I-38 (yield 17.5 mg, 51%) was obtained by the same method using O-(3-fluorobenzyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0500] 1H-NMR (500MHz, CDCl3, δ): 7.30-7.23 (m, 1H), 7.09 (d, J = 8.0Hz, 1H), 7.07-7.03 (m, 1H), 6.95 (dt, J = 8.3, 2.3Hz, 1H), 5.83 (td, J = 10.2, 2.4Hz, 1H), 5. 70(dd,J=13.7,9.7Hz,2H),5.40(d,J=2.9Hz,2H),5.11(s,2H),4.98(s,1H ),4.97-4.91(m,1H),4.78-4.75(m,1H),4.65(s,2H),4.59(s,1H),3.93(br s,1H),3.86-3.73(m,2H),3.71-3.60(m,2H),3.51-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.23( d,J=9.2Hz,2H),3.16(t,J=9.5Hz,1H),2.79(dd,J=12.6,3.4Hz,1H),2.65-2.57(m,1H),2.48(br s,2H),2.32(br s,2H),2.29-2.19(m,2H),1.89(d,J=12.6Hz,3H),1.77-1.72(m,1H),1.69-1.63(m,1H),1.60-1.34(m,11H),1.30-1.23 (m,7H),1.15(dd,J=6.9,4.0Hz,6H),0.92(t,J=7.4Hz,3H),0.84(m,4H),0.78(d,J=5.7Hz,4H); MSm / z1015.5908[M+NH4] + .

[0501] Preparation of Compound I-39

[0502] Compound I-39 (yield 20.0 mg, 53%) was obtained by the same method using O-(2-ethylbenzyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0503] 1H-NMR (500MHz, CDCl3, δ): 7.32 (dd, J=1.1, 7.4Hz, 1H), 7.23 (dd, J=7.2, 1.4Hz, 1H ),7.20-7.17(m,1H),7.17-7.13(m,1H),5.81(td,J=10.3,2.3Hz,1H),5.75-5.63( m,J=13.2,9.7Hz,2H),5.39(d,J=4.0Hz,2H),5.21-5.12(m,2H),4.96(s,1H),4.9 5(d,J=4.0Hz,1H),4.76(d,J=3.4Hz,1H),4.67-4.57(m,2H),4.52(s,1H),3.92(br s,1H),3.86-3.73(m,2H),3.70-3.59(m,2H),3.52-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H),3.16(t,J=9.2Hz ,1H),2.78(dd,J=12.6,2.6Hz,1H),2.69(q,J=7.4Hz,2H),2.64-2.57(m,1H),2.52-2.43(m,2H),2.37-2.30(m,2H),2.29-2.18 (m,2H),1.94-1.85(m,2H),1.84-1.78(m,1H),1.77-1.72(m,1H),1.68-1.62(m,1H),1.58-1.37(m,15H),1.22-1.22(m,1H),1. 31-1.12(m,19H),0.92(t,J=7.4Hz,3H),0.90-0.86(m,3H),0.83(d,J=6.3Hz,3H),0.82-0.74(m,4H); MSm / z1025.6302[M+NH4] + .

[0504] Preparation of Compound I-40

[0505] Compound I-40 (yield 23.2 mg, 75%) was obtained by the same method using O-(3-methylphenethyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0506] 1H-NMR (500MHz, CDCl3, δ): 7.15 (t, J = 7.4Hz, 1H), 7.05-6.95 (m, 3H), 5.83 (td, J = 10.3, 2.3Hz, 1H), 4.94 (s, 2H), 5.40 (d, J = 2.9Hz, 2H), 4.9 5(d,J=10.8Hz,1H),4.94(s,1H),4.77(d,J=3.4Hz,1H),4.69-4.62(m,2H),4.56(s,1H),4.28-4.24(m,2H),4.11(q,J=6.9Hz,1H),3.93(br s,1H),3.87-3.73(m,2H),3.71-3.60(m,2H),3.52-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.27-3. 19(m,2H),3.16(t,J=9.2Hz,1H),2.96-2.90(m,3H),2.82-2.77(m,1H),2.65-2.57(m,1H),2.49(br s,2H),2.37-2.19(m,5H),2.31(s,3H),1.95-1.87(m,2H),1.87-1.80(m,2H),1.77-1.72(m,1H),1.69-1.64(m,1H),1.60-1.3 5(m,15H),1.30-1.24(m,9H),1.17(dd,J=9.6,6.9Hz,6H),0.92(t,J=7.4Hz,3H),0.89-0.74(m,8H); MSm / z1025.6306[M+NH4] + .

[0507] Preparation of compounds I-41 and I-42

[0508] Using O-(3-fluorophenethyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-41 (yield 8.7 mg, yield 23%) and Compound I-42 (yield 8.2 mg, yield 22%) were obtained by the same method.

[0509] (Compound I-41)

[0510] 11H-NMR (500 MHz, CDCl3, δ): 7.24 - 7.18 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.94 - 6.90 (m, 1H), 6.90 - 6.85 (m, 1H), 5.88 - 5.83 (m, 1H), 5.78 - 5.65 (m, 2H), 5.40 (m, 2H), 4.98 - 4.93 (m, 1H), 4.80 (s, 1H), 4.77 (d, J = 4.0 Hz, 1H), 4.71 - 4.59 (m, 2H), 4.57 (s, 1H), 4.25 (t, J = 7.2 Hz, 2H), 3.93 (br s, 1H), 3.87 - 3.74 (m, 2H), 3.72 - 3.60 (m, 2H), 3.51 - 3.45 (m, 1H), 3.45 (s, 3H), 3.42 (s, 4H), 3.26 - 3.20 (m, 2H), 3.16 (t, J = 9.2 Hz, 1H), 2.95 (t, J = 7.2 Hz, 2H), 2.90 (dd, J = 13.2, 2.9 Hz, 1H), 2.87 - 2.82 (m, 1H), 2.53 - 2.45 (m, 2H), 2.38 - 2.19 (m, 5H), 1.93 - 1.87 (m, 1H), 1.79 - 1.73 (m, 1H), 1.69 - 1.60 (m, 2H), 1.49 (s, 8H), 1.30 - 1.23 (m, 11H), 1.16 (d, J = 6.9 Hz, 4H), 0.92 (t, J = 7.4 Hz, 3H), 0.85 - 0.75 (m, 8H); MS m / z 1029.6057 [M + NH4] + .

[0511] (Compound I-42)<000H-NMR (500MHz, CDCl3, δ): 7.23 (dt, J = 7.7, 6.3Hz, 1H), 6.97 (d, J = 7.4Hz, 1H), 6.93-6.86 (m, 2H), 5.86 (td, J = 10.3, 2.6Hz, 1H), 5.77-5.65 (m, 2 H),5.46-5.38(m,2H),4.95(d,J=10.9Hz,1H),4.77(d,J=2.9Hz,1H),4.68-4.55(m,2H),4.61(s,1H),4.34-4.23(m,2H),3.99(s,1H),3.93(br s,1H),3.87-3.72(m,2H),3.71-3.60(m,2H),3.52-3.45(m,1H),3.45-3.40(m,2H),3.44(s,3H),3.43(s,3H),3. 27-3.20(m,2H),3.16(t,J=9.2Hz,1H),2.97(t,J=6.9Hz,2H),2.89(dd,J=13.7,2.9Hz,1H),2.52-2.45(m,2H),2. 37-2.18(m,5H),1.92-1.86(m,1H),1.79-1.73(m,1H),1.70-1.64(m,1H),1.60-1.35(m,10H),1.30-1.23(m,8H) ,1.16(d,J=7.4Hz,6H),0.92(t,J=7.4Hz,3H),0.84(d,J=6.3Hz,3H),0.82-0.75(m,5H); MSm / z1029.6050[M+NH4] + .

[0513] Preparation of compounds I-43 and I-44

[0514] Using O-(3-bromophenethyl)hydroxylamine (28.5 mg, 0.132 mmol) instead of hydroxylamine hydrochloride in [Production of Compound I-1], compound I-43 (yield 10.7 mg, yield 26%) and compound I-44 (yield 10.2 mg, yield 25%) were obtained by the same method.

[0515] (Compound I-43)

[0516] 1H-NMR(500 MHz, CDCl3, δ): 7.36 (m, 1H), 7.34 - 7.30 (m, 1H), 7.14 - 7.10 (m, 2H), 5.86 (td, J = 10.3, 2.6 Hz, 1H), 5.79 - 5.65 (m, 2H), 5.46 - 5.37 (m, 2H), 4.99 - 4.92 (m, 1H), 4.79 (s, 1H), 4.77 (d, J = 3.4 Hz, 1H), 4.71 - 4.61 (m, 2H), 4.55 (s, 1H), 4.29 - 4.21 (m, 2H), 3.94 (br s, 1H), 3.87 - 3.73 (m, 2H), 3.71 - 3.60 (m, 2H), 3.52 - 3.46 (m, 1H), 3.45 (s, 3H), 3.43 (s, 3H), 3.27 - 3.19 (m, 2H), 3.16 (t, J = 9.2 Hz, 1H), 2.96 - 2.81 (m, 4H), 2.53 - 2.45 (m, 2H), 2.39 - 2.19 (m, 5H), 1.94 - 1.87 (m, 1H), 1.79 - 1.73 (m, 1H), 1.69 - 1.61 (m, 2H), 1.60 - 1.36 (m, 10H), 1.33 - 1.23 (m, 11H), 1.16 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.89 - 0.86 (m, 1H), 0.84 (d, J = 6.9 Hz, 3H), 0.82 - 0.75 (m, 4H); MS m / z 1089.5251 [M + NH4] + .

[0517] (Compound I-44)

[0518] 1H-NMR (500MHz, CDCl3, δ): 7.37-7.35 (m, 1H), 7.33 (td, J=7.0, 2.2Hz, 1H), 7.13 (s, 2H), 5.88-5.84 (m, 1H), 5.78-5.66 (m, 2H), 5 .40(m,2H),4.99-4.91(m,1H),4.77(d,J=3.4Hz,1H),4.68-4.54(m,2H),4.61(s,1H),4.33-4.23(m,2H),3.99(s,1H),3.93(br s,1H),3.86-3.74(m,2H),3.72-3.59(m,2H),3.52-3.41(m,2H),3.44(s,3H),3.42(s,3H),3.27-3.19(m,2H),3.16 (t,J=9.5Hz,1H),2.94(dt,J=6.7,2.0Hz,2H),2.89(dd,J=13.5,2.6Hz,1H),2.52-2.44(m,2H),2.37-2.19(m,6H),1 .93-1.86(m,1H),1.79-1.73(m,1H),1.69-1.63(m,1H),1.59-1.35(m,9H),1.29-1.23(m,9H),1.16(dd,J=6.9,2.9H z,6H),0.92(t,J=7.4Hz,3H),0.90-0.85(m,1H),0.84(d,J=6.3Hz,3H),0.82-0.75(m,4H); MSm / z1089.5254[M+NH4] + .

[0519] Preparation of Compound I-45

[0520] Compound I-45 (yield 28.8 mg, 71%) was obtained by the same method using O-(3-bromophenethyl)hydroxylamine instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0521] 1H-NMR (500MHz, CDCl3, δ):7.38-7.35(m,1H),7.34-7.29(m,1H),7.15-7.1 1(m,2H),5.83(td,J=10.3,2.6Hz,1H),5.76-5.65(m,2H),5.44-5.37(m,2 H),4.97-4.92(m,1H),4.91(s,1H),4.77(d,J=3.4Hz,1H),4.66(d,J=2.3H z,2H),4.56(s,1H),4.26(t,J=6.9Hz,2H),4.19(t,J=6.9Hz,1H),3.93(br s,1H),3.87-3.74(m,2H),3.71-3.60(m,2H),3.52-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.43-3.39(m,1H),3.26-3.19 (m,2H),3.16(t,J=9.2Hz,1H),2.94-2.90(m,3H),2.79(dd,J=12.6,3.4Hz,1H),2.65-2.57(m,1H),2.48(m,2H),2.37-2.1 9(m,5H),1.92-1.80(m,1H),1.77-1.72(m,1H),1.68-1.64(m,1H),1.59-1.36(m,7H),1.30-1.24(m,9H),1.15(dd,J=6.9 ,1.7Hz,6H),0.92(t,J=7.2Hz,3H),0.89-0.86(m,1H),0.84(d,J=6.9Hz,3H),0.82-0.74(m,4H); MSm / z1089.5244[M+NH4] + .

[0522] Preparation of Compound I-46 and Compound I-47

[0523] Using 2-(aminooxy)acetic acid 1 / 2 hydrochloride instead of hydroxylamine hydrochloride in [Production of Compound I-1], compound I-46 (yield 11.5 mg, yield 30%) and compound I-47 (yield 15.5 mg, yield 41%) were obtained by the same method.

[0524] (Compound I-46)

[0525] 1H-NMR(500 MHz, CDCl3, δ): 5.89 - 5.82 (m, 1H), 5.77 - 5.62 (m, 2H), 5.41 - 5.33 (m, 2H), 4.99 - 4.91 (m, 1H), 4.79 - 4.75 (m, 1H), 4.68 - 4.52 (m, 4H), 3.94 (d, J = 9.7 Hz, 2H), 3.86 - 3.72 (m, 3H), 3.71 - 3.60 (m, 3H), 3.56 (m, 1H), 3.51 - 3.46 (m, 1H), 3.44 (s, 3H), 3.42 (s, 3H), 3.43 - 3.37 (m, 1H), 3.26 - 3.19 (m, 2H), 3.16 (t, J = 8.9 Hz, 1H), 2.89 - 2.84 (m, 1H), 2.54 - 2.45 (m, 1H), 2.38 - 2.19 (m, 5H), 1.95 - 1.87 (m, 1H), 1.79 - 1.71 (m, 1H), 1.69 - 1.63 (m, 1H), 1.60 - 1.35 (m, 9H), 1.30 - 1.19 (m, 11H), 1.15 (d, J = 6.9 Hz, 4H), 0.92 (t, J = 7.2 Hz, 3H), 0.89 - 0.86 (m, 1H), 0.83 (d, J = 6.9 Hz, 3H), 0.82 - 0.74 (m, 4H); MS m / z 965.5586 [M + NH4] + .

[0526] (Compound I-47)

[0527] 1H-NMR (500MHz, CDCl3, δ): 5.89-5.80 (m, 1H), 5.78-5.64 (m, 2H), 5.42-5.3 0(m,2H),5.01-4.93(m,1H),4.85-4.74(m,2H),4.68-4.42(m,4H),3.93(br s,1H),3.86-3.72(m,2H),3.69-3.60(m,2H),3.58-3.46(m,2H),3.44(s,3H),3.41(s,3H),3.27-3.19(m,2H),3 .16(t,J=8.9Hz,1H),2.90-2.75(m,1H),2.54-2.46(m,1H),2.37-2.19(m,5H),2.00(brs,1H),1.95-1.89(m,1H) ,1.79-1.73(m,1H),1.68-1.61(m,1H),1.60-1.34(m,12H),1.30-1.24(m,8H),1.22-1.18(m,3H),1.17-1.12(m, 3H),0.92(t,J=7.2Hz,3H),0.89-0.85(m,1H),0.83(d,J=6.3Hz,3H),0.80-0.74(m,4H); MSm / z965.5583[M+NH4] + .

[0528] Preparation of Compound I-48

[0529] Compound I-48 (yield 24.7 mg, 65%) was obtained by the same method using 2-(aminooxy)acetic acid 1 / 2 hydrochloride instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0530] 1H-NMR (500MHz, CDCl3, δ): 5.88-5.81 (m, 1H), 5.79-5.64 (m, 2H), 5.38 (d, J = 3. 4Hz,1H),5.35-5.27(m,1H),5.00-4.92(m,2H),4.77(d,J=3.4Hz,1H),4.64(br s,2H),4.51(br s,2H),3.93(br s,1H),3.86-3.72(m,2H),3.70-3.59(m,2H),3.52-3.45(m,1H),3.43(s,3H),3.41(s,1H),3.40-3.35(m,1H ),3.26-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.73-2.66(m,1H),2.63-2.47(m,2H),2.37-2.19(m,4H),1.95- 1.86(m,2H),1.82-1.71(m,2H),1.67-1.61(m,1H),1.59-1.37(m,12H),1.30-1.23(m,8H),1.15(d,J=6.9Hz ,6H),0.93(t,J=7.2Hz,3H),0.88(s,1H),0.84(d,J=6.9Hz,3H),0.82-0.71(m,5H); MSm / z965.5586[M+NH4] + .

[0531] Reference Example 7

[0532] Production of 2-(aminooxy)-2-methylpropane-1-ol hydrochloride

[0533] With reference to US20120238599A1, 2-(aminooxy)-2-methylpropan-1-ol hydrochloride (yield 898 mg, quantitative) was obtained by changing the three steps using tert-butylhydroxycarbamate and ethyl 2-bromo-2-methylpropionate as raw materials.

[0534] 1 H-NMR (500MHz, CDCl3, δ): 3.39 (s, 1H), 3.38 (s, 1H), 1.71-1.66 (m, 1H), 1.19 (s, 6H).

[0535] Preparation of Compound I-49

[0536] Using 2-(aminooxy)-2-methylpropane-1-ol hydrochloride obtained in Reference Example 7 instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-49 was obtained as a mixture of isomers that were difficult to separate by the same method (yield 27.4 mg, yield 71%).

[0537] 1 H-NMR(500MHz, CDCl3, δ):5.87-5.84(m,1H),5.77-5.64(m,2H),5.46-5.37 (m,2H),4.97-4.91(m,1H),4.85(s,1H),4.76(d,J=3.4Hz,1H),4.70-4.55(m ,3H),3.94-3.91(m,1H),3.87-3.72(m,2H),3.71-3.58(m,4H),3.45(s,2H), 3.44(s,3H),3.42(s,3H),3.27-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.89(dd ,J=3.2,13.5Hz,1H),2.87-2.81(m,1H),2.53-2.45(m,2H),2.37-2.18(m,5 H),1.93-1.87(m,1H),1.79-1.73(m,1H),1.69-1.35(m,10H),1.31-1.22(m, 17H),1.20(d,J=7.4Hz,1H),1.17-1.11(m,3H),0.92(t,J=7.2Hz,3H),0.89- 0.85(m,2H),0.84(d,J=6.3Hz,3H),0.82-0.75(m,4H); MSm / z962.5841[M+H] + .

[0538] Preparation of Compound I-50

[0539] Compound I-50 (yield 24.7 mg, 64%) was obtained by the same method using 2-(aminooxy)-2-methylpropan-1-ol hydrochloride obtained in Reference Example 7 instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0540] 1H-NMR (500MHz, CDCl3, δ): 5.83 (td, J=10.5, 2.5Hz, 1H), 5.76-5.64 (m, 2H), 5.43-5.35 ( m,2H),4.96(s,1H),4.94(d,J=9.7Hz,1H),4.76(d,J=3.4Hz,1H),4.66(s,2H),3.93(br s,1H),3.86-3.73(m,2H),3.70-3.57(m,4H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H),3.16( t,J=9.2Hz,1H),2.79(dd,J=11.7,4.3Hz,1H),2.67-2.58(m,1H),2.54-2.45(m,2H),2.37-2.30(m,2H),2.29-2.19( m,2H),1.92-1.82(m,3H),1.78-1.71(m,1H),1.69-1.63(m,1H),1.59-1.32(m,11H),1.29-1.22(m,14H),1.15(t,J= 7.2Hz, 6H), 0.92 (t, J=7.4Hz, 3H), 0.89-0.85 (m, 1H), 0.83 (d, J=6.9Hz, 3H), 0.81-0.73 (m, 4H); MSm / z962.5833[M+H] + .

[0541] Preparation of Compound I-51

[0542] Potassium carbonate (13 mg, 0.094 mmol) and 2-bromoacetamide (7.1 μL, 0.094 mmol) were added to a DMF (0.24 mL) solution of compound I-1 (21 mg, 0.024 mmol) obtained in [Manufacture of compound I-1], and the mixture was stirred at 50°C overnight. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin-layer silica gel column chromatography (ethyl acetate) to obtain compound I-51 (yield 14.5 mg, yield 65%) as a mixture of isomers that are difficult to separate. The following 1 The H-NMR spectrum is the analytical data of the main isomer.

[0543] 1H-NMR(500MHz,CDCl3,δ):6.08(br s,1H),5.86(td,J=10.5,2.5Hz,1H),5.78-5.63(m,3H),5.46-5.40(m,1H),5.39(d,J=4.0Hz,1H),4.98-4.92(m ,1H),4.76(d,J=3.4Hz,1H),4.68-4.63(m,1H),4.60(d,J=2.3Hz,1H),4.60-4.55(m,2H),3.97(s,1H),3.93(br s,1H),3.85-3.79(m,1H),3.78-3.72(m,1H),3.70-3.59(m,2H),3.58-3.52(m,1H),3.50-3.45(m,1H),3.44(s, 3H),3.41(s,3H),3.27-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.90(dd,J=13.7,2.9Hz,1H),2.53-2.45(m,1H),2.3 7-2.19(m,5H),1.93-1.88(m,1H),1.79-1.72(m,1H),1.69-1.63(m,1H),1.61-1.35(m,15H),1.29-1.23(m,10H) ,1.15(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.83(d,J=6.9Hz,3H),0.82-0.74(m,4H);MSm / z964.5757[M+NH4] + .

[0544] Preparation of Compound I-52

[0545] Compound I-52 was obtained by the same method using Compound I-2 instead of Compound I-1 in [Production of Compound I-51] (yield 14.6 mg, yield 68%).

[0546] 1H-NMR(500MHz,CDCl3,δ):6.40(br s,1H),5.86-5.80(m,1H),5.78-5.71(m,1H),5.70-5.60(m,2H),5.43-5.35(m,2H),4.97(s,1H), 4.95(d,J=10.9Hz,1H),4.76(d,J=3.4Hz,1H),4.71-4.63(m,2H),4.58(d,J=1.7Hz,2H),3.93(br s,1H),3.86-3.79(m,1H),3.78-3.71(m,1H),3.70-3.58(m,2H),3.51-3.46(m,1H),3.43(s,3H),3.41(s,3H),3.27-3.1 9(m,2H),3.16(t,J=9.2Hz,1H),2.80-2.73(m,1H),2.68-2.60(m,1H),2.52-2.46(m,1H),2.37-2.30(m,2H),2.29-2.17( m,2H),1.93-1.83(m,3H),1.75-1.69(m,1H),1.68-1.62(m,1H),1.59-1.36(m,13H),1.27(d,J=6.3Hz,3H),1.26-1.23(m ,4H),1.15(d,J=6.9Hz,6H),0.92(t,J=7.4Hz,3H),0.83(d,J=6.9Hz,3H),0.78(d,J=5.7Hz,4H); MSm / z964.5746[M+NH4] + .

[0547] Reference Example 8

[0548] Preparation of 3-(aminooxy)propan-1-ol hydrochloride

[0549] With reference to European Journal of Organic Chemistry (2018), 2018(29), 3920-3927, 2-hydroxyisoindoline-1,3-dione (891 mg, 4.03 mmol) was used as a raw material to obtain the target 3-(aminooxy)propan-1-ol hydrochloride (yield 447 mg, yield 87%).

[0550] 1 H-NMR (500MHz, D2O, δ): 4.06 (t, J = 6.0 Hz, 2H), 3.59 (t, J = 6.3 Hz, 2H), 3.48 (t, J = 6.6 Hz, 2H), 1.83-1.79 (m, 2H).

[0551] Preparation of Compound I-53

[0552] Compound I-53 (yield 9.5 mg, 25%) was obtained by the same method using 3-(aminooxy)propan-1-ol hydrochloride obtained in Reference Example 8 instead of hydroxylamine hydrochloride in [Production of Compound I-1].

[0553] 1 H-NMR (500MHz, CDCl3, δ): 5.87-5.84 (dt, J=10.7, 2.4Hz, 1H), 5.76-5.65 (m, 2H), 5.45-5.40 (m ,2H),4.95(d,J=10.9Hz,1H),4.77-4.76(m,2H),4.69-4.60(m,3H),4.27-4.19(m,2H),3.93(br s,1H),3.86-3.61(m,6H),3.51-3.42(m,7H),3.26-3.15(m,3H),2.88-2.85(m,2H),2.50-2.49(m,2H),2.36-2.20(m,4H),1.94-1.8 4(m,3H),1.76-1.73(m,1H),1.68-1.36(m,17H),1.28-1.25(m,9H),1.16-1.14(m,2H),0.935-0.756(m,10H); MSm / z970.5552[M+Na] + .

[0554] Preparation of Compound I-54

[0555] Compound I-54 (yield 19.4 mg, 51%) was obtained by the same method using 3-(aminooxy)propan-1-ol hydrochloride obtained in Reference Example 8 instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0556] 1H-NMR (500MHz, CDCl3, δ): 5.84-5.81 (dt, J=10.3, 2.3Hz, 1H), 5.75-5.64 (m, 2H), 5.43-5.36 (m, 2H), 4.95 (d, J=10.9 Hz,1H),4.91(s,1H),4.76(d,J=2.9Hz,1H),4.68-4.61(m,3H),4.25(t,J=5.7Hz,2H),4.18(t,J=5.7Hz,1H),3.93(br s,1H),3.85-3.60(m,7H),3.50-3.42(m,7H),3.25-3.14(m,3H),2.79(dd,J=1 2.6,3.4Hz,1H),2.63-2.57(m,1H),2.51-2.47(m,2H),2.35-2.20(m,4H),1.93 -1.81(m,9H),1.74-1.73(m,1H),1.67-1.65(m,1H),1.58-1.36(m,12H),1.28 -1.24(m,6H),1.18-1.14(m,6H),0.931-0.739(m,10H); MSm / z970.5623[M+Na] + .

[0557] Reference Example 9

[0558] (1) Production of 2-(2,2-difluoroethoxy)isoindoline-1,3-dione

[0559] 2-(2,2-difluoroethoxy)isoindoline-1,3-dione (yield 1.94 g, 85%) was obtained in the same manner as in Reference Example 1-(2) using 2,2-difluoroethane-1-ol instead of cyclopropylmethanol.

[0560] 1 H-NMR (500MHz, CDCl3, δ): 7.89-7.85 (m, 2H), 7.82-7.76 (m, 2H), 6.23 (tt, J = 55.0, 4.3Hz, 1H), 4.38 (td, J = 12.7, 4.3Hz, 2H).

[0561] (2) Production of O-(2,2-difluoroethyl)hydroxylamine hydrochloride

[0562] 2-(2,2-difluoroethoxy)isoindoline-1,3-dione (1.94 g, 8.54 mmol) obtained in Reference Example 9-(1) was dissolved in dichloromethane (34.2 mL), and hydrazine monohydrate (0.415 mL, 8.54 mmol) was added, and stirred at room temperature for 14 hours. The suspension was filtered and 4 M 1,4-difluorohydrochloride was added to the filtrate. The solution was stirred at room temperature for 15 minutes in an oxane solution (2.24 mL, 8.97 mmol). The solvent was distilled off under reduced pressure, ether was added, and the suspension was filtered to obtain O-(2,2-difluoroethyl)hydroxylamine hydrochloride (yield 1.55 g, yield 95%).

[0563] 1 H-NMR (500MHz, DMSO-d6, δ): 6.51-6.19 (m, 1H), 4.33-4.16 (m, 2H).

[0564] Preparation of Compound I-55

[0565] Using O-(2,2-difluoroethyl)hydroxylamine hydrochloride obtained in Reference Example 9-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-55 was obtained as a mixture of isomers that was difficult to separate (yield 20.4 mg, yield 62%) by the same method. 1 The H-NMR spectrum is the analytical data of the main isomer.

[0566] 1H-NMR (500MHz, CDCl3, δ): 6.10-5.94(m,1H),5.89-5.82(m,1H),5.79-5.63(m,2H),5.46-5.38(m,2H),4 .95(d,J=10.9Hz,1H),4.81(s,1H),4.77(d,J=3.4Hz,1H),4.71-4.56(m,3H),4.30-4.19(m,2H),3.93(br s,1H),3.86-3.74(m,2H),3.71-3.60(m,2H),3.52-3.45(m,1H),3.44(s,3H),3.43(s,3H),3.26- 3.19(m,2H),3.17(t,J=9.2Hz,1H),2.92-2.81(m,2H),2.54-2.46(m,2H),2.37-2.20(m,5H),1.9 0(dd,J=12.0,4.6Hz,1H),1.79-1.71(m,1H),1.69-1.63(m,1H),1.63-1.38(m,12H),1.32-1.21( m,11H),1.16(d,J=6.9Hz,3H),0.92(t,J=7.2Hz,3H),0.86-0.76(m,7H); MSm / z971.5892[M+NH4] + .

[0567] Preparation of Compound I-56

[0568] Compound I-56 (yield 30.9 mg, 94%) was obtained by the same method using O-(2,2-difluoroethyl)hydroxylamine hydrochloride obtained in Reference Example 9-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0569] 1H-NMR (500MHz, CDCl3, δ): 6.12-5.85 (tt, J=55.0, 4.3Hz, 1H), 5.83 (dt, J=10.5, 2 .5Hz,1H),5.77-5.65(m,2H),5.44-5.36(m,2H),4.94(d,J=11.5Hz,1H),4.91(s,1 H),4.76(d,J=2.9Hz,1H),4.66(s,2H),4.62(s,1H),4.24(td,J=13.3,4.3Hz,2H) ,3.93(brs,1H),3.87-3.73(m,2H),3.71-3.59(m,2H),3.52-3.45(m,1H),3.44(s, 3H),3.42(s,3H),3.28-3.19(m,2H),3.16(t,J=8.9Hz,1H),2.79(dd,J=12.6,2.9 Hz,1H),2.65-2.56(m,1H),2.56-2.45(m,2H),2.37-2.19(m,4H),1.95-1.81(m,3H ),1.78-1.70(m,1H),1.68-1.64(m,1H),1.59-1.37(m,12H),1.29-1.24(m,7H),1. 19-1.12(m,6H),0.92(t,J=7.5Hz,3H),0.85-0.76(m,7H); MSm / z971.5892[M+NH4] + .

[0570] Reference Example 10

[0571] (1) Production of 2-(3,3-difluoropropyl)isoindoline-1,3-dione

[0572] 2-(3,3-difluoropropyl)isoindoline-1,3-dione (yield 418 mg, 94%) was obtained by the same method as in Reference Example 1-(2) using 3,3-difluoropropane-1-ol instead of cyclopropylmethanol.

[0573] 1 H-NMR (500MHz, CDCl3, δ): 7.88-7.82 (m, 2H), 7.78-7.73 (m, 2H), 6.27 (tt, J = 55.0, 4.9Hz1H), 4.38 (t, J = 6.3Hz, 2H), 2.39-2.27 (m, 2H).

[0574] (2) Production of O-(3,3-difluoropropyl)hydroxylamine hydrochloride

[0575] Using 2-(3,3-difluoropropyl)isoindoline-1,3-dione obtained in Reference Example 5-(1) instead of 2-(2,2-difluoroethoxy)isoindoline-1,3-dione in the preparation of Reference Example 10-(2), O-(3,3-difluoropropyl)hydroxylamine hydrochloride was obtained in the same manner as in the preparation of Reference Example 4-(2) (yield 254 mg, yield 69%).

[0576] 1 H-NMR (500MHz, DMSO-d6, δ): 6.16 (tt, J = 55.0, 4.6Hz1H), 4.17-4.04 (m, 2H), 2.31-2.14 (m, 2H).

[0577] Preparation of Compound I-57

[0578] Using O-(3,3-difluoropropyl)hydroxylamine hydrochloride obtained in Reference Example 10-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-1], a mixture of isomers difficult to separate, Compound I-57 (yield 23.1 mg, yield 70%), was obtained by the same method. 1 The H-NMR spectrum is the analytical data of the main isomer.

[0579] 1H-NMR (500MHz, CDCl3, δ): 5.93 (t, J=55.0, 4.9Hz, 1H), 5.89-5.83 (m, 1H), 5.78-5.64 (m, 2H), 5.47-5.37 (m, 2 H),4.96(d,J=11.5Hz,1H),4.78(s,1H),4.77(d,J=3.4Hz,1H),4.71-4.55(m,3H),4.30-4.17(m,2H),3.94(br s,1H),3.87-3.73(m,2H),3.71-3.58(m,2H),3.52-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.27-3.20(m,2H),3.16(t,J=9.2Hz,1H) ,2.92-2.77(m,2H),2.55-2.44(m,2H),2.38-2.13(m,7H),1.90(dd,J=12.0,4.6Hz,1H),1.80-1.71(m,1H),1.71-1.38(m,16H),1.31 -1.24(m,7H),1.21(d,J=7.5Hz,1H),1.19-1.14(m,3H),0.93(t,J=7.2Hz,3H),0.84(d,J=6.9Hz,3H),0.82-0.75(m,4H); MSm / z985.6105[M+NH4] + .

[0580] Preparation of Compound I-58

[0581] Compound I-58 (yield 31.0 mg, 93%) was obtained by the same method using O-(3,3-difluoropropyl)hydroxylamine hydrochloride obtained in Reference Example 10-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0582] 1H-NMR (500MHz, CDCl3, δ): 5.95 (tt, J=55.0, 4.9Hz, 1H), 5.86-5.80 (m, 1H), 5.77-5.63 (m, 2H), 5.45-5.34 (m, 2H), 4.95 (d,J=10.9Hz,1H),4.89(s,1H),4.77(d,J=3.4Hz,1H),4.70-4.62(m,2H),4.61(s,1H),4.23(t,J=6.3Hz,2H),3.93(br s,1H),3.87-3.72(m,2H),3.71-3.59(m,2H),3.52-3.44(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2 H),3.16(t,J=9.2Hz,1H),2.79(dd,J=12.3,3.7Hz,1H),2.65-2.56(m,1H),2.54-2.46(m,2H),2.37-2.13(m ,6H),1.93-1.81(m,3H),1.77-1.71(m,1H),1.69-1.63(m,1H),1.61-1.36(m,12H),1.30-1.23(m,7H),1.1 6(t,J=6.3Hz,6H),0.92(t,J=7.5Hz,3H),0.84(d,J=6.3Hz,3H),0.80-0.74(m,4H); MSm / z985.6105[M+NH4] + .

[0583] Preparation of Compound I-59

[0584] To a dichloromethane (0.32 mL) solution of a mixture of compound I-46 and compound I-47 (30 mg, 0.0352 mmol) obtained in [Manufacturing of compound I-46 and compound I-47], DIPEA (0.022 mL, 0.141 mmol), 2M dimethylamine THF solution (63 μL, 0.141 mmol) and HATU (24.0 mg, 0.070 mmol) were added, and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-59 (yield 24.0 mg, yield 78%). The following 1 The H-NMR spectrum is the analytical data of the main isomer.

[0585] 1H-NMR (500MHz, CDCl3, δ): 5.88-5.82 (m, 1H), 5.77-5.64 (m, 2H), 5.46-5.31 (m, 2H), 4. 95(d,J=10.3Hz,1H),4.82-4.72(m,3H),4.67-4.57(m,2H),3.97-3.95(m,1H),3.93(br s,1H),3.86-3.73(m,2H),3.71-3.58(m,3H),3.52-3.46(m,1H),3.44(s,3H),3 .42(s,3H),3.27-3.13(m,3H),2.97(dd,J=17.2,3.2Hz,6H),2.53-2.44(m,2H), 2.37-2.18(m,5H),1.96-1.80(m,2H),1.78-1.72(m,1H),1.70-1.33(m,16H),1. 32-1.21(m,9H),1.18-1.11(m,3H),0.96-0.72(m,11H); MSm / z992.6049[M+NH4] + .

[0586] Preparation of Compound I-60

[0587] To a dichloromethane (0.32 mL) solution of compound I-48 (30 mg, 0.0352 mmol) obtained in [Manufacture of Compound I-48], DIPEA (0.016 mL, 0.106 mmol), 2M dimethylamine THF solution (0.048 mL, 0.106 mmol) and HATU (15.6 mg, 0.0458 mmol) were added and stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin-layer silica gel column chromatography (ethyl acetate) to obtain compound I-60 (yield 26.0 mg, yield 84%).

[0588] 1H-NMR (500MHz, CDCl3, δ):5.87-5.82(m,1H),5.75-5.64(m,2H),5.41-5.30( m,2H),5.03(d,J=1.7Hz,1H),4.98-4.92(m,1H),4.79-4.71(m,3H),4.65(br s,2H),3.92(brs,1H),3.86-3.79(m,1H),3.78-3.72(m,1H),3.70-3.59(m,2H),3.51-3.45(m,1H),3.43(s,3H),3. 42(s,3H),3.41-3.38(m,1H),3.26-3.13(m,3H),2.98(d,J=2.3Hz,3H),2.92(d,J=1.7Hz,3H),2.80-2.73(m,1H),2 .65-2.57(m,1H),2.55-2.45(m,2H),2.37-2.18(m,5H),1.96-1.79(m,2H),1.77-1.71(m,1H),1.68-1.60(m,1H),1 .59-1.33(m,9H),1.30-1.21(m,8H),1.18-1.10(m,6H),0.94-0.86(m,4H),0.85-0.71(m,8H); MSm / z975.5793[M+H] + .

[0589] Preparation of Compound I-61

[0590] Compound I-61 was obtained as a mixture of isomers that was difficult to separate (yield 28.1 mg, 87%) by the same method using morpholine instead of dimethylamine in [Production of Compound I-59].

[0591] 1H-NMR (500MHz, CDCl3, δ): 5.88-5.82 (m, 1H), 5.78-5.63 (m, 2H), 5.46-5.33 (m, 2H), 4. 98-4.90(m,0.5H),4.78-4.75(m,2H),4.84-4.52(m,5H),3.97-3.94(m,0.5H),3.92(br s,1H),3.86-3.80(m,1H),3.79-3.73(m,1H),3.71-3.54(m,9H),3.53-3.46(m,3H),3.45-3.43 (m,3H),3.43-3.41(m,3H),3.27-3.14(m,3H),2.92-2.86(m,1H),2.81-2.75(m,1H),2.54-2.4 4(m,2H),2.37-2.20(m,5H),1.94-1.80(m,2H),1.78-1.73(m,1H),1.68-1.64(m,1H),1.62-1. 35(m,10H),1.30-1.22(m,11H),1.18-1.12(m,4H),0.96-0.74(m,8H); MSm / z1034.6150[M+NH4] + .

[0592] Preparation of Compound I-62

[0593] Compound I-62 (yield 26.9 mg, 84%) was obtained by the same method using morpholine instead of dimethylamine in [Production of Compound I-60].

[0594] 1H-NMR (500MHz, CDCl3, δ):5.86-5.81(m,1H),5.77-5.63(m,2H),5.42-5.3 3(m,2H),4.98-4.91(m,2H),4.79-4.71(m,3H),4.71-4.59(m,3H),3.93(br s,1H),3.86-3.80(m,1H),3.79-3.72(m,1H),3.70-3.56(m,9H),3.54-3.45(m,3H),3.43(s,3H),3.4 2(s,3H),3.27-3.12(m,3H),2.81-2.74(m,1H),2.66-2.58(m,1H),2.56-2.43(m,2H),2.37-2.30(m,2 H),2.29-2.18(m,2H),1.95-1.81(m,3H),1.78-1.68(m,2H),1.68-1.62(m,1H),1.60-1.34(m,9H),1 .30-1.22(m,7H),1.18-1.11(m,6H),0.91(t,J=7.2Hz,3H),0.89-0.73(m,8H); MSm / z1017.5884[M+H] + .

[0595] Preparation of Compound I-63

[0596] Compound I-63 was obtained as a mixture of isomers that was difficult to separate (yield 13.2 mg, 43%) by the same method using 2 M methylamine THF solution instead of dimethylamine in [Production of Compound I-59].

[0597] 1H-NMR (500MHz, CDCl3, δ): 6.12-6.07(m,1H),5.89-5.83(m,1H),5.79-5.64(m,2H),5.46-5.37 (m,2H),4.97-4.91(m,0.5H),4.76(d,J=3.4Hz,1H),4.74-4.54(m,4H),3.97(s,0.5H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.72(m,1H),3.71-3.59(m,2H),3.58-3.51(m,1H),3.44(s,3H),3.42(s,3H),3.27 -3.19(m,2H),3.16(t,J=9.2Hz,1H),2.93-2.88(m,1H),2.86(d,J=5.2Hz,2H),2.81(d,J=4.6Hz,1H),2.55-2.45(m ,2H),2.37-2.18(m,4H),1.93-1.85(m,1H),1.78-1.71(m,1H),1.69-1.35(m,16H),1.32-1.22(m,10H),1.17-1.14 (m,3H),0.92(t,J=7.2Hz,3H),0.89-0.85(m,1H),0.83(d,J=6.3Hz,3H),0.82-0.74(m,4H); MSm / z978.5889[M+NH4] + .

[0598] Preparation of Compound I-64

[0599] Compound I-64 (yield 23.1 mg, 76%) was obtained by the same method using 2M methylamine THF solution instead of dimethylamine in [Production of Compound I-60].

[0600] 1H-NMR (500MHz, CDCl3, δ): 6.44-6.38(m,1H),5.87-5.81(m,1H),5.79-5.64(m,2H),5.45-5.36(m,2H),4.99(s, 1H),4.95(d,J=10.3Hz,1H),4.82(s,1H),4.76(d,J=3.4Hz,1H),4.73-4.65(m,2H),4.64-4.54(m,2H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.72(m,1H),3.71-3.59(m,2H),3.51-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.23(m, 2H),3.16(t,J=8.9Hz,1H),2.81(d,J=4.6Hz,3H),2.80-2.76(m,1H),2.69-2.61(m,1H),2.54-2.46(m,2H),2.37-2.31( m,2H),2.30-2.18(m,2H),1.92-1.82(m,3H),1.77-1.70(m,1H),1.69-1.35(m,11H),1.30-1.24(m,8H),1.15(t,J=6.6 Hz,6H),0.92(t,J=7.4Hz,3H),0.87(t,J=6.6Hz,1H),0.84(d,J=6.9Hz,3H),0.81-0.74(m,4H); MSm / z978.5902[M+NH4] + .

[0601] Preparation of Compound I-65

[0602] Compound I-65 (yield 28.0 mg, yield 86%) was obtained by the same method using cyclohexylamine instead of dimethylamine in [Production of Compound I-59]. 1 The H-NMR spectrum is the analytical data of the main isomer.

[0603] 1H-NMR (500MHz, CDCl3, δ): 5.95 (d, J = 8.0Hz, 1H), 5.89-5.83 (m, 1H), 5.79-5.6 4(m,2H),5.48-5.37(m,2H),4.97-4.92(m,1H),4.79-4.71(m,1H),4.70-4.63( m,1H),4.61-4.51(m,3H),3.97(s,1H),3.95-3.91(m,1H),3.87-3.73(m,3H), 3.72-3.59(m,2H),3.58-3.52(m,1H),3.51-3.46(m,1H),3.44(s,3H),3.42(s, 3H),3.27-3.20(m,2H),3.16(t,J=9.2Hz,1H),2.94-2.88(m,1H),2.53-2.44( m,2H),2.38-2.17(m,4H),1.93-1.81(m,3H),1.74(d,J=4.6Hz,1H),1.79-1.32 (m,19H),1.30-1.21(m,10H),1.21-1.11(m,7H),0.92(t,J=7.2Hz,3H),0.89-0 .86(m,1H),0.84(d,J=6.3Hz,3H),0.81-0.74(m,4H); MSm / z1046.6510[M+NH4] + .

[0604] Preparation of Compound I-66

[0605] Compound I-66 (yield 25.5 mg, 78%) was obtained by the same method using cyclohexylamine instead of dimethylamine in [Production of Compound I-60].

[0606] 1H-NMR (500MHz, CDCl3, δ): 6.28 (d, J = 8.0Hz, 1H), 5.88-5.83 (m, 1H), 5.80-5.65 (m, 2H), 5.46-5.37 (m, 2H), 4.9 9(s,1H),4.96-4.92(m,1H),4.76(d,J=3.4Hz,1H),4.74(s,1H),4.73-4.64(m,2H),4.60-4.51(m,2H),3.93(br s,1H),3.86-3.79(m,2H),3.78-3.73(m,1H),3.71-3.60(m,2H),3.52-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.2 8-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.79(dd,J=11.5,4.6Hz,1H),2.68-2.60(m,1H),2.53-2.45(m,2H),2.36-2. 30(m,2H),2.30-2.19(m,2H),1.92-1.81(m,5H),1.68(m,5H),1.63-1.30(m,10H),1.29-1.23(m,9H),1.21-1.09( m,10H),0.92(t,J=7.2Hz,3H),0.87(t,J=6.9Hz,1H),0.85-0.81(m,3H),0.82-0.74(m,4H); MSm / z1029.6263[M+H] + .

[0607] Reference Example 11

[0608] Using 4-bromobutane-1-ol instead of 2-bromoethane-1-ol in Reference Example 6-(1), O-(4-((tert-butyldimethylsilyl)oxy)butyl)hydroxylamine (yield 966 mg, 3-step yield 41%) was obtained by the same method as in the 3 steps of Reference Examples 6-(1), (2) and (3).

[0609] 1 H-NMR (500MHz, DMSO-d6, δ): 5.84 (br s, 1H), 3.55 (t, J = 6.0Hz, 2H), 3.48 (t, J = 6.6Hz, 2H), 1.50-1.38 (m, 4H), 0.823 (s, 9H), 0.823 (s, 6H).

[0610] Preparation of Compound I-67

[0611] Using O-(4-((tert-butyldimethylsilyl)oxy)butyl)hydroxylamine obtained in Reference Example 11-(3) instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-67 (yield 30.6 mg, yield 71%) was obtained by the same method.

[0612] 1 H-NMR (500MHz, CDCl3, δ): 5.86-5.84 (m, 1H), 5.75-5.65 (m, 2H), 5.44-5.38 (m, 2H), 4.95 (d, J = 10.9Hz, 1H), 4. 76(d,J=3.4Hz,1H),4.69-4.55(m,3H),4.13-3.93(m,4H),3.85-3.73(m,2H),3.69-3.58(m,5H),3.52-3.42(m ,8H),3.25-3.14(m,3H),2.91(dt,J=13.6,3.0Hz,1H),2.53-2.47(m,2H),2.35-2.20(m,5H),1.91-1.88(m,1H ),1.76-1.36(m,24H),1.28-1.14(m,13H),0.930-0.742(m,25H),0.034-0.022(m,8H); MSm / z1076.6895[M+H] + .

[0613] Preparation of Compound I-68

[0614] After dissolving the compound I-67 (30.6 mg, 0.028 mmol) obtained in [Manufacturing of Compound I-67] in THF (1.12 mL), a hydrogen fluoride pyridine solution (0.378 mL) was added and stirred at room temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer chromatography (n-hexane / ethyl acetate = 1: 2) to obtain compound I-68 (yield 13.1 mg, yield 49%).

[0615] 1H-NMR (500MHz, CDCl3, δ): 5.86-5.84 (m, 1H), 5.75-5.65 (m, 2H), 5.44-5.39 (m, 2H), 4.95 (d, J= 10.9Hz,1H),4.76(d,J=3.4Hz,1H),4.66-4.56(m,3H),4.16-4.09(m,2H),3.97(s,1H),3.93(br s,1H),3.85-3.73(m,2H),3.69-3.60(m,4H),3.50-3.42(m,8H),3.25-3.14(m,3H),2.90(dd,J=13.5,2.6Hz,1H),2.53-2.47(m,2H), 2.35-2.20(m,4H),1.91(dd,J=12.3,4.9Hz,1H),1.77-1.36(m,24H),1.28-1.14(m,13H),0.931-0.771(m,11H); MSm / z962.5991[M+H] + .

[0616] Preparation of Compound I-69

[0617] Using O-(4-((tert-butyldimethylsilyl)oxy)butyl)hydroxylamine obtained in Reference Example 11-(3) instead of hydroxylamine hydrochloride in [Production of Compound I-2], Compound I-69 was obtained by the same method (yield 25.2 mg, yield 59%).

[0618] 1H-NMR (500MHz, CDCl3, δ):5.84-5.81(m,1H),5.74-5.65(m,2H),5.42-5.36(m,2H),4.94-4.93( m,2H),4.76(d,J=3.4Hz,1H),4.65(d,J=1.1Hz,1H),4.59(s,1H),4.09(t,J=6.6Hz,2H),3.92(br s,1H),3.85-3.74(m,2H),3.68-3.59(m,4H),3.50-3.42(m,7H),3.25-3. 14(m,3H),2.80(dd,J=12.6,3.4Hz,1H),2.62-2.55(m,1H),2.51-2.47(m ,2H),2.36-2.20(m,4H),1.92-1.79(m,3H),1.75-1.34(m,21H),1.28-1. 14(m,12H),0.929-0.769(m,21H),0.026(s,6H); MSm / z1093.7158[M+NH4] + .

[0619] Preparation of Compound I-70

[0620] After dissolving the compound I-69 (25.2 mg, 0.023 mmol) obtained in [Manufacturing of Compound I-69] in THF (0.920 mL), a hydrogen fluoride pyridine solution (0.311 mL) was added and stirred at room temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer chromatography (n-hexane / ethyl acetate = 1: 2) to obtain compound I-70 (yield 15.8 mg, yield 71%).

[0621] 1H-NMR (500MHz, CDCl3, δ): 5.84 (dd, J=8.0, 2.3Hz, 1H), 5.76-5.65 (m, 2H), 5.43-5.36 (m, 2H ),4.95-4.93(m,2H),4.77(d,J=3.4Hz,1H),4.66-4.62(m,3H),4.17-4.10(m,2H),3.93(br s,1H),3.86-3.75(m,2H),3.69-3.61(m,4H),3.51-3.43(m,7H),3.28-3.15(m,3H),2.80(dd,J=12.3,3.2Hz,1H),2.62-2.57(m,1H),2.51 -2.48(m,2H),2.36-2.20(m,4H),1.93-1.80(m,3H),1.77-1.36(m,22H),1.28-1.15(m,12H),0.935-0.776(m,10H); MSm / z984.5617[M+Na] + .

[0622] Reference Example 12

[0623] (1) Production of 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethoxy)isoindoline-1,3-dione

[0624] According to the method described in International Publication No. 2013 / 186632, 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethoxy)isoindoline-1,3-dione (yield 340 mg, yield 36%) was obtained by modifying the three steps using 2,2'-oxybis(ethane-1-ol) (1.73 mL, 18.3 mmol) as the starting material.

[0625] 1 H-NMR (500MHz, CDCl3, δ):7.85-7.82(m,2H),7.76-7.73(m,2H),4.37-4.36(m,2H),3.8 8-3.86(m,2H),3.68(t,J=5.2Hz,2H),3.56(t,J=5.2Hz,2H),0.85(s,9H),0.01(s,6H).

[0626] (2) Production of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethan-1-ol

[0627] 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethoxy)isoindoline-1,3-dione (292 mg, 1.16 mmol) obtained in Reference Example 12-(1) was dissolved in ethanol (11.6 mL, 11.6 mmol). Hydrazine monohydrate (0.062 mL, 1.28 mmol) was added to this solution, and the mixture was heated under reflux and stirred for 0.5 hours. After completion of the reaction, the mixture was filtered, and the solvent was distilled off under reduced pressure to obtain 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethan-1-ol (yield 185 mg, yield 68%).

[0628] 1 H-NMR (500MHz, DMSO-d6, δ): 5.97 (s, 2H), 3.69 (t, J = 5.2Hz, 2H), 3.63-3.61 (m,2H),3.54-3.53(m,2H),3.45(t,J=5.2Hz,2H),0.86(s,9H),0.04(s,6H).

[0629] Preparation of Compound I-71

[0630] Using 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethane-1-ol obtained in Reference Example 12-(2), instead of O-(4-((tert-butyldimethylsilyl)oxy)butyl)hydroxylamine in [Manufacture of Compound I-67], Compound I-71 (yield 4.1 mg, yield 14%) was obtained by the same method as [Manufacture of Compound I-67] and [Manufacture of Compound I-68].

[0631] 1H-NMR (500MHz, CDCl3, δ): 5.87-5.85 (m, 1H), 5.76-5.66 (m, 2H), 5.45-5.39 (m, 2H), 4.96 (d, J= 9.2Hz,1H),4.77(d,J=4.0Hz,1H),4.68-4.57(m,3H),4.31-4.24(m,2H),3.98(s,1H),3.93(br s,1H),3.86-3.58(m,19H),3.26-3.15(m,3H),2.91(dd,J=13.2,2.9Hz, 1H),2.51-2.49(m,2H),2.36-2.18(m,5H),1.92(dd,J=11.7,3.7Hz,1H) ,1.77-1.74(m,1H),1.68-1.66(m,1H),1.58-1.37(m,21H),1.29-1.15( m,12H),0.94(t,J=7.2Hz,3H),0.85-0.80(m,7H); MSm / z978.5771[M+H] + .

[0632] Preparation of Compound I-72

[0633] Using 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethane-1-ol obtained in Reference Example 12-(2), instead of O-(4-((tert-butyldimethylsilyl)oxy)butyl)hydroxylamine in [Manufacture of Compound I-69], Compound I-72 (yield 12.0 mg, yield 42%) was obtained by the same method as [Manufacture of Compound I-69] and [Manufacture of Compound I-70].

[0634] 1H-NMR (500MHz, CDCl3, δ): 5.84 (dd, J=8.0, 2.3Hz, 1H), 5.76-5.65 (m, 2H), 5.41-5.34 (m, 2H ),4.97-4.93(m,2H),4.77(d,J=3.4Hz,1H),4.68-4.65(m,3H),4.26-4.24(m,2H),3.93(br s,1H),3.86-3.54(m,11H),3.51-3.43(m,8H),3.26-3.15(m,3H),2.80(dd,J=12.6,3.4Hz,1H),2.64-2.47(m,4H),2.36-2.20(m,4H),1 .94-1.82(m,3H),1.75-1.73(m,1H),1.66(s,3H),1.58-1.34(m,13H),1.28-1.15(m,13H),0.93-0.78(m,11H); MSm / z995.6039[M+NH4] + .

[0635] Preparation of Compound I-73

[0636] Compound I-73 was obtained by the same method using 2-aminoethane-1-ol instead of dimethylamine in [Production of Compound I-59] (yield 11.7 mg, yield 37%).

[0637] 1H-NMR (500MHz, CDCl3, δ): 6.52 (t, J=5.7Hz, 1H), 5.90 -5.81(m,1H),5.79-5.62(m,2H),5.45-5.35(m,2H),4.99-4.90(m,1H),4.8 6-4.74(m,2H),4.71-4.62(m,2H),4.62-4.56(m,2H),3.97(s,1H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.73(m,1H),3.72-3.59(m,4H),3.59-3.54(m,1H),3.52-3.45(m,2H),3.44(s,3H),3. 42(s,3H),3.27-3.19(m,2H),3.16(t,J=8.9Hz,1H),2.92-2.84(m,2H),2.57-2.46(m,1H),2.37-2.30(m,2H),2.30-2.1 7(m,2H),1.93-1.87(m,1H),1.78-1.69(m,1H),1.68-1.64(m,1H),1.63-1.34(m,14H),1.33-1.21(m,11H),1.15(d,J=6 .9Hz,3H),0.92(t,J=7.2Hz,3H),0.89-0.85(m,1H),0.83(d,J=6.9Hz,3H),0.82-0.74(m,3H); MSm / z1008.6011[M+NH4] + .

[0638] Preparation of Compound I-74

[0639] Compound I-74 (yield 13.5 mg, 43%) was obtained by the same method using 2-aminoethane-1-ol instead of dimethylamine in [Production of Compound I-60].

[0640] 1H-NMR (500MHz, CDCl3, δ): 6.82 (t, J = 5.4Hz, 1H), 5.85 (d, J = 9.7Hz, 1H), 5.79-5.64 (m, 2H), 5.43 -5.34(m,2H),5.00(s,1H),4.99-4.90(m,2H),4.76(d,J=4.0Hz,1H),4.73-4.54(m,4H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.74(m,1H),3.72-3.60(m,4H),3.52-3.34(m,3H),3.43(s,3H),3.41(s,3H),3.26-3.19( m,2H),3.16(t,J=8.9Hz,1H),2.87-2.85(m,1H),2.82-2.75(m,3H),2.70-2.63(m,1H),2.54-2.45(m,1H),2.37-2.30(m,2H) ),2.29-2.18(m,2H),1.93-1.82(m,3H),1.76-1.69(m,1H),1.68-1.62(m,1H),1.59-1.35(m,5H),1.33-1.21(m,10H),1.18 -1.11(m,6H),0.92(t,J=7.2Hz,3H),0.87(t,J=6.3Hz,2H),0.83(d,J=6.3Hz,3H),0.80-0.74(m,4H); MSm / z991.5743[M+H] + .

[0641] Preparation of Compound I-75

[0642] To a solution of compound I-22 (30 mg, 0.0321 mmol) obtained in [Manufacture of compound I-22] in dichloromethane (0.32 mL), 37% formalin (23.8 μL, 0.32 mmol) and sodium cyanoborohydride (16.2 mg, 0.252 mmol) were added in sequence and stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (chloroform: methanol = 10: 1) to obtain compound I-75 (yield 6.5 mg, yield 21%) as a mixture of isomers that are difficult to separate.

[0643] 1H-NMR (500MHz, CDCl3, δ):5.88-5.82(m,1H),5.76-5.64(m,2H),5.44-5.36(m,2H),4.97-4.92(m,1H ),4.83(s,0.67H),4.78-4.75(m,1H),4.70-4.54(m,2H),4.26-4.15(m,2H),3.97(s,0.33H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.73(m,1H),3.70-3.60(m,2H),3.53-3.46(m,1H),3.45(s,3H),3.42(s,3H),3.26-3.19(m,2H) ,3.16(t,J=8.9Hz,1H),2.91-2.81(m,2H),2.71-2.59(m,2H),2.52-2.45(m,1H),2.30(s,6H),2.38-2.18(m,6H),1.94-1.87(m,1 H),1.78-1.73(m,1H),1.69-1.60(m,2H),1.59-1.35(m,12H),1.27(d,J=6.9Hz,5H),1.25(d,J=6.3Hz,4H),1.20(d,J=6.9Hz,1H) ,1.15(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.89-0.85(m,1H),0.83(d,J=6.3Hz,3H),0.81-0.75(m,4H);MSm / z961.6001[M+H] + .

[0644] Preparation of Compound I-76

[0645] Compound I-76 (yield 101 mg, yield 33%) was obtained by the same method using compound I-23 instead of compound I-22 in [Production of compound I-75].

[0646] 1H-NMR (500MHz, CDCl3, δ): 5.86-5.81 (m, 1H), 5.76-5.64 (m, 2H), 5.40 (d, J = 2.9Hz, 1H), 5.39-5.32 (m, 1H) ,4.98-4.93(m,1H),4.93(s,1H),4.76(d,J=3.4Hz,1H),4.68-4.60(m,2H),4.21(t,J=6.0Hz,2H),3.92(br s,1H),3.86-3.80(m,1H),3.80-3.72(m,1H),3.70-3.59(m,2H),3.52-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.18(m, 2H),3.16(t,J=9.2Hz,1H),2.77(dd,J=3.4,12.6Hz,1H),2.69-2.56(m,3H),2.52-2.45(m,1H),2.37-2.18(m,4H),2.28(s,6H ),1.94-1.85(m,2H),1.85-1.79(m,1H),1.77-1.70(m,1H),1.68-1.61(m,1H),1.59-1.35(m,13H),1.30-1.23(m,7H),1.15( t,J=6.9Hz,6H),0.91(t,J=7.4Hz,3H),0.87(t,J=6.9Hz,1H),0.83(d,J=6.3Hz,3H),0.80-0.73(m,4H); MSm / z961.6001[M+H] + .

[0647] Preparation of Compound I-77

[0648] To a solution of compound I-22 (25 mg, 0.0267 mmol) obtained in [Manufacture of compound I-22] in dichloromethane (0.27 mL) was added triethylamine (11.1 μL, 0.0803 mmol), and then phenylsulfonyl chloride (4.11 μL, 0.0321 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-77 (yield 18.9 mg, yield 66%). The following 1 The H-NMR spectrum is the analytical data of the main isomer.

[0649] 1H-NMR (500MHz, CDCl3, δ):7.87-7.82(m,2H),7.58-7.52(m,1H),7.52-7.44(m,2H),5.9 0-5.83(m,1H),5.79-5.66(m,2H),5.53(t,J=6.0Hz,1H),5.46-5.36(m,2H),4.99-4.92( m,1H),4.76(d,J=3.4Hz,1H),4.72(s,1H),4.70-4.65(m,1H),4.64-4.54(m,1H),4.14- 4.02(m,2H),3.95-3.91(m,1H),3.87-3.80(m,1H),3.80-3.73(m,1H),3.71-3.59(m,2H) ,3.52-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.29-3.13(m,5H),2.84-2.76(m,1H),2. 56-2.45(m,2H),2.38-2.17(m,5H),1.94-1.86(m,1H),1.79-1.72(m,1H),1.70-1.62(m, 3H),1.61-1.35(m,12H),1.29-1.24(m,8H),1.20-1.13(m,6H),0.92(t,J=7.4Hz,3H),0 .87(t,J=6.9Hz,2H),0.84(d,J=6.9Hz,3H),0.82-0.74(m,4H); MSm / z1090.5881[M+NH4] + .

[0650] Preparation of Compound I-78

[0651] Compound I-78 (yield 19.2 mg, 67%) was obtained by the same method using compound I-23 instead of compound I-22 in [Production of compound I-77].

[0652] 1H-NMR (500MHz, CDCl3, δ): 7.86-7.83 (m, 2H), 7.57-7.53 (m, 1H), 7.51-7.46 (m, 2H), 5.84 (td, J = 2.4, 10.7Hz, 1H), 5.79-5.64 (m, 2H), 5.46-5.36(m,3H),4.97-4.92(m,1H),4.85(s,1H),4.76(d,J=3.4Hz,1H),4.72(s,1H),4.71-4.62(m,2H),4.12-4.04(m,2H),3.93(br s,1H),3.86-3.80(m,1H),3.79-3.73(m,1H),3.71-3.60(m,2H),3.51-3.46(m,1H),3.44(s,3H),3.41(s,3H),3.22(s,4H),3. 16(t,J=9.2Hz,1H),2.76(dd,J=4.0,12.0Hz,1H),2.61-2.46(m,3H),2.37-2.30(m,2H),2.30-2.18(m,2H),1.93-1.87(m,1H) ,1.86-1.78(m,2H),1.76-1.71(m,1H),1.70-1.64(m,3H),1.59-1.35(m,7H),1.30-1.22(m,9H),1.16(d,J=6.9Hz,3H),1.08( d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.89-0.85(m,2H),0.84(d,J=6.9Hz,3H),0.80-0.75(m,4H); MSm / z1090.5879[M+NH4] + .

[0653] Reference Example 13

[0654] (1) Production of O-(oxetane-3-ylmethyl)hydroxylamine

[0655] After dissolving oxetan-3-ylmethanol (0.75 mL, 9.28 mmol) in THF (93 mL), a toluene solution of bis(2-methoxyethyl)(E)-diazene-1,2-dicarboxylate (2.28 mL, 10.6 mmol), 2-hydroxyisoindoline-1,3-dione (1.44 g, 8.84 mmol), and triphenylphosphine (2.78 g, 10.6 mmol) were added sequentially, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain 2-(oxetan-3-ylmethoxy)isoindoline-1,3-dione (yield 1.96 g, 95%).

[0656] 1 H-NMR (500MHz, CDCl3, δ):7.86-7.81(m,2H),7.78-7.73(m,2H),4.89-4.84(m,2 H), 4.59 (dt, J = 4.0, 6.0 Hz, 2H), 4.47 (dd, J = 3.7, 7.2 Hz, 2H), 3.49-3.38 (m, 1H).

[0657] (2) O-(Oxetane-3-ylmethyl)hydroxylamine

[0658] 2-(Oxetane-3-ylmethoxy)isoindoline-1,3-dione (400 mg, 1.71 mmol) obtained in Reference Example 13-(1) was dissolved in ethanol (17 mL). Hydrazine monohydrate (91.7 μL, 1.89 mmol) was added to this solution and stirred at 60°C for 30 minutes. The reaction solution was cooled to 0°C, and the resulting precipitate was removed by filtration. The solvent was distilled off the filtrate under reduced pressure to obtain O-(oxetane-3-ylmethyl)hydroxylamine (yield 166 mg, yield 93%).

[0659] MSm / z104.0706[M+H] + C4H10NO2(FAB)

[0660] 1 H-NMR (500MHz, DMSO-d6, δ): 4.58 (d, J = 6.3Hz, 1H), 4.57 (d, J = 6.3Hz, 1H), 4.25 (t, J = 6.3Hz, 2H), 3.71 (d, J = 6.3Hz, 2H), 3.18-3.09 (m, 1H).

[0661] Preparation of Compound I-79

[0662] Using O-(oxetane-3-ylmethyl)hydroxylamine (14.1 mg, 0.141 mmol) obtained in Reference Example 13-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-79 (yield 255 mg, yield 77%) was obtained as a mixture of isomers that were difficult to separate by the same method.

[0663] 1 H-NMR (500MHz, CDCl3, δ): 5.88-5.83 (m, 1H), 5.78-5.64 (m, 2H), 5.46-5.37 (m, 2H), 4.94 (d, J = 10.9Hz, 1H), 4.80 -4.75(m,3H),4.70-4.56(m,3H),4.53-4.46(m,2H),4.35-4.27(m,2H),4.02-4.00(m,1H),3.95(s,1H),3.93(br s,1H),3.86-3.80(m,1H),3.79-3.73(m,1H),3.71-3.60(m,2H),3.52-3.45(m,2H),3.44(s,3H),3.42(s,3H),3.38-3.29(m,1 H),3.27-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.88(dd,J=2.9,13.7Hz,1H),2.85-2.78(m,1H),2.53-2.45(m,2H),2.37-2.28( m,3H),2.28-2.18(m,2H),1.93-1.87(m,1H),1.78-1.72(m,1H),1.69-1.35(m,22H),1.29-1.23(m,10H),1.20(d,J=7.4Hz,1H ),1.17-1.12(m,4H),0.92(t,J=7.4Hz,3H),0.89-0.85(m,1H),0.83(d,J=6.3Hz,3H),0.81-0.75(m,5H); MSm / z960.5689[M+H] + .

[0664] Preparation of Compound I-80

[0665] Compound I-80 (yield 25.5 mg, 77%) was obtained by the same method using O-(oxetan-3-ylmethyl)hydroxylamine obtained in Reference Example 13-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0666] 1H-NMR (500MHz, CDCl3, δ): 5.83 (td, J = 2.3, 10.3Hz, 1H), 5.76-5.63 (m, 2H), 5.43-5.35 (m, 2H), 4.93 (d, J = 11.5Hz, 1 H),4.88(s,1H),4.81-4.74(m,3H),4.70-4.60(m,3H),4.50(dt,J=1.4,6.2Hz,2H),4.32(d,J=6.9Hz,2H),3.92(br s,1H),3.86-3.79(m,1H),3.79-3.73(m,1H),3.70-3.59(m,2H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.37-3.29( m,1H),3.26-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.77(dd,J=3.4,12.0Hz,1H),2.62-2.54(m,1H),2.53-2.44(m,2H),2.37- 2.30(m,2H),2.29-2.18(m,2H),1.93-1.80(m,3H),1.77-1.70(m,1H),1.68-1.60(m,3H),1.59-1.34(m,10H),1.31-1.23(m ,7H),1.14(dd,J=2.6,6.6Hz,6H),0.91(t,J=7.4Hz,3H),0.83(d,J=6.9Hz,3H),0.81-0.71(m,4H); MSm / z977.5950[M+NH4] + .

[0667] Preparation of Compound I-81

[0668] Using isopropyl sulfonium chloride instead of phenylsulfonyl chloride in [Production of Compound I-77], Compound I-81 was obtained as a mixture of isomers that was difficult to separate (yield 3.1 mg, yield 11%) by the same method. 1 The H-NMR spectrum is the analytical data of the main isomer.

[0669] 1H-NMR (500MHz, CDCl3, δ): 5.86 (td, J=10.5, 2.5Hz, 1H), 5.78-5.65 (m, 2H), 5.45-5.37 (m, 2H), 5.01-4.97 (m, 1 H),4.94(d,J=10.3Hz,1H),4.79(s,1H),4.76(d,J=3.4Hz,1H),4.71-4.55(m,3H),4.24-4.16(m,2H),3.93(br s,1H),3.86-3.80(m,1H),3.80-3.73(m,1H),3.71-3.60(m,2H),3.52-3.45(m,2H),3.44(s,3H),3.42(s,3H),3.4 1-3.35(m,2H),3.27-3.19(m,2H),3.19-3.11(m,2H),2.91-2.83(m,2H),2.54-2.45(m,1H),2.37-2.28(m,3H),2. 28-2.18(m,2H),1.93-1.88(m,1H),1.78-1.72(m,1H),1.70-1.33(m,12H),1.31-1.23(m,11H),1.16(d,J=6.9Hz, 3H),0.92(t,J=7.2Hz,3H),0.89-0.86(m,2H),0.84(d,J=6.9Hz,3H),0.82-0.74(m,4H); MSm / z1056.6042[M+NH4] + .

[0670] Preparation of Compound I-82

[0671] Compound I-82 (yield 6.3 mg, 23%) was obtained by the same method using isopropylsulfonium chloride instead of phenylsulfonyl chloride in [Production of Compound I-78].

[0672] 1H-NMR (500MHz, CDCl3, δ): 5.83 (td, J=2.5, 10.5Hz, 1H), 5.78-5.63 (m, 2H), 5.44-5.35 (m, 2 H),4.98-4.91(m,3H),4.76(d,J=3.4Hz,1H),4.72-4.59(m,3H),4.24-4.16(m,2H),3.93(br s,1H),3.87-3.80(m,1H),3.80-3.73(m,1H),3.71-3.59(m,2H),3.51-3.45(m,1H),3. 44(s,3H),3.42(s,3H),3.41-3.37(m,2H),3.27-3.19(m,2H),3.19-3.10(m,2H),2.81 -2.75(m,1H),2.66-2.59(m,1H),2.53-2.45(m,2H),2.37-2.31(m,2H),2.3 0-2.18(m,2H),1.93-1.83(m,3H),1.76-1.70(m,1H),1.69-1.38(m,8H),1. 35(d,J=6.9Hz,6H),1.29-1.23(m,7H),1.18-1.14(m,6H),0.92(t,J=7.4Hz ,3H),0.83(d,J=6.3Hz,3H),0.78(d,J=5.7Hz,4H); MSm / z1056.6042[M+NH4] + .

[0673] Reference Example 14

[0674] (1) Production of 2-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methoxy)isoindoline-1,3-dione

[0675] According to the method described in International Publication No. 2020 / 260857, 1-hydroxycyclopropane-1-carboxylic acid methyl ester (3 g, 25.8 mmol) was used as a starting material to obtain 2-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methoxy)isoindoline-1,3-dione (yield 1.17 g, yield 42%).

[0676] 1 H-NMR (500MHz, CDCl3, δ): 7.81 (dd, J=5.5, 3.0Hz, 2H), 7.73 (dd, J=5.5, 3.0Hz, 2 H),4.18(s,2H),0.90-0.87(m,2H),0.83(s,9H),0.85-0.82(m,2H),0.17(s,6H).

[0677] (2) Production of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethan-1-ol

[0678] 2-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methoxy)isoindoline-1,3-dione (500 mg, 1.43 mmol) obtained in Reference Example 14-(1) was dissolved in ethanol (14 mL). Hydrazine monohydrate (76.9 μL, 1.52 mmol) was added to this solution, and the mixture was stirred at 60°C for 30 minutes. After the reaction was completed, the reaction solution was cooled to 0°C, and the resulting precipitate was removed by filtration. The solvent was distilled off the filtrate under reduced pressure to obtain 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethan-1-ol (yield 261 mg, yield 83%).

[0679] 1 H-NMR (500MHz, DMSO-d6, δ): 3.52 (s, 2H), 0.77 (d, J = 1.1 Hz, 9H), 0.55 (s, 4H), 0.05 (d, J = 1.1 Hz, 6H).

[0680] Preparation of Compound I-83 and Compound I-84

[0681] O-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)hydroxylamine obtained in Reference Example 14-(2) was used instead of hydroxylamine hydrochloride in [Manufacture of Compound I-1], and preparative thin-layer silica gel column chromatography (n-hexane / ethyl acetate system) was used instead of silica gel chromatography for purification. Thus, Compound I-83 (yield 12.7 mg, yield 34%) and Compound I-84 (yield 16.7 mg, yield 45%) were obtained by the same method as [Manufacture of Compound I-1].

[0682] (Compound I-83)

[0683] 1H-NMR (500 MHz, CDCl3, δ): 5.87 - 5.81 (m, 1H), 5.77 - 5.66 (m, 2H), 5.45 - 5.37 (m, 2H), 4.98 - 4.93 (m, 1H), 4.83 (s, 1H), 4.77 (d, J = 3.4 Hz, 1H), 4.69 - 4.49 (m, 3H), 4.25 - 4.18 (m, 1H), 4.14 - 4.00 (m, 1H), 3.93 (br s, 1H), 3.86 - 3.80 (m, 1H), 3.79 - 3.73 (m, 1H), 3.71 - 3.60 (m, 2H), 3.52 - 3.45 (m, 1H), 3.44 (s, 3H), 3.42 (s, 3H), 3.26 - 3.20 (m, 2H), 3.16 (t, J = 9.2 Hz, 1H), 2.93 - 2.86 (m, 1H), 2.86 - 2.75 (m, 1H), 2.53 - 2.45 (m, 2H), 2.37 - 2.30 (m, 3H), 2.30 - 2.19 (m, 2H), 1.93 - 1.87 (m, 1H), 1.79 - 1.73 (m, 1H), 1.69 - 1.64 (m, 1H), 1.63 - 1.36 (m, 12H), 1.30 - 1.23 (m, 10H), 1.18 - 1.13 (m, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.86 - 0.80 (m, 14H), 0.78 (d, J = 6.3 Hz, 3H), 0.74 - 0.61 (m, 4H), 0.10 (s, 3H), 0.10 (s, 3H); MS m / z 1091.6815 [M+NH4] + 。

[0684] (Compound I-84)

[0685] 1H-NMR(500MHz,CDCl3,δ):5.85(td,J=2.3,10.3Hz,1H),5.76-5.64(m,2H),5.46-5.38(m,2H),4.95(d,J=9.7Hz,1H),4.76(d,J=3.4Hz,1H),4.60(s,1H),4.67-4.55(m,2H),4.23(d,J=11.5Hz,1H),4.06(d,J=11.5Hz,1H),3.96(s,1H),3.93(br s,1H),3.86-3.80(m,1H),3.79-3.73(m,1H),3.71-3.60(m,2H),3.60-3.53(m,1H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.27-3.20(m,2H),3.16(t,J=9.2Hz,1H),2.90(dd,J=2.9,13.7Hz,1H),2.49(d,J=2.3Hz,2H),2.34(dd,J=4.3,12.3Hz,2H),2.23(d,J=5.7Hz,3H),1.93-1.87(m,1H),1.79-1.72(m,1H),1.69-1.64(m,1H),1.61-1.36(m,10H),1.26(dd,J=6.3,12.0Hz,8H),1.22(d,J=6.9Hz,3H),1.15(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.89-0.85(m,1H),0.85-0.81(m,13H),0.80-0.77(m,4H),0.74-0.62(m,3H),0.10(s,3H),0.10(s,3H);MSm / z1091.6815[M+NH4] + 。

[0686] Preparation of Compound I-85 and Compound I-86

[0687] After dissolving the compound I-83 (12.7 mg, 0.0118 mmol) obtained in [Manufacturing of Compound I-83 and Compound I-84] in THF (0.24 mL), the mixture was cooled to 0°C. A hydrogen fluoride pyridine solution (0.108 mL, 1.18 mmol) was added thereto and stirred at room temperature for 20 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin-layer silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-85 (yield 4.4 mg, yield 55%) and compound I-86 (yield 1.8 mg, yield 19%).

[0688] (Compound I-85)

[0689] 1 H-NMR (500MHz, CDCl3, δ): 5.85-5.79 (m, 1H), 5.77-5.67 (m, 2H), 5.43-5.35 (m, 1H), 5.33-5.27 (m, 1H), 4.69-4.54 (m, 3H), 4.21-4 .18(m,1H),4.17-4.04(m,2H),3.99(brs,1H),3.96(s,1H),3.72-3.64(m,1H),3.59-3.52(m,1H),3.20-3.16(m,1H),2.88(dd,J= 2.9,13.7Hz,1H),2.55-2.46(m,1H),2.36-2.21(m,3H),1.92-1.83(m,1H),1.76-1.71(m,1H),1.69-1.46(m,15H),1.46-1.37(m, 4H),1.28-1.21(m,5H),1.17(d,J=6.9Hz,4H),0.95(t,J=7.4Hz,3H),0.85-0.77(m,10H),0.67-0.60(m,2H); MSm / z672.4112[M+H] + .

[0690] (Compound I-86)

[0691] 1H-NMR (500MHz, CDCl3, δ):5.89-5.84(m,1H),5.77-5.64(m,2H),5.47-5.3 7(m,1H),4.97-4.92(m,1H),4.82-4.79(m,1H),4.69-4.54(m,3H),4.21-4. 17(m,1H),4.13-4.09(m,1H),3.97(s,1H),3.96-3.93(m,1H),3.89-3.83(m ,1H),3.73-3.64(m,1H),3.60-3.53(m,2H),3.49(s,3H),3.42-3.32(m,1H) ,3.24-3.19(m,1H),3.18-3.14(m,1H),2.93-2.88(m,1H),2.53-2.45(m,2H ),2.37-2.22(m,5H),1.93-1.86(m,2H),1.80-1.74(m,2H),1.71-1.34(m,9 H),1.32-1.22(m,8H),1.14(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.86-0 .83(m,5H),0.78(d,J=6.3Hz,4H),0.67-0.59(m,2H); MSm / z816.4898[M+H] + .

[0692] Preparation of Compound I-87 and Compound I-88

[0693] Using compound I-84 instead of compound I-83 in [Production of compound I-85 and compound I-86], compound I-87 (yield 5.9 mg, yield 56%) and compound I-88 (yield 3.3 mg, yield 26%) were obtained by the same method.

[0694] (Compound I-87)

[0695] 1H-NMR(500 MHz, CDCl3, δ): 5.85 - 5.80 (m, 1H), 5.76 - 5.67 (m, 2H), 5.43 - 5.35 (m, 1H), 5.32 - 5.27 (m, 1H), 4.68 - 4.56 (m, 3H), 4.22 - 4.17 (m, 1H), 4.16 - 4.04 (m, 2H), 4.00 (brs, 1H), 3.96 (s, 1H), 3.72 - 3.64 (m, 1H), 3.59 - 3.51 (m, 1H), 3.21 - 3.17 (m, 1H), 2.88 (dd, J = 2.9, 13.7 Hz, 1H), 2.54 - 2.45 (m, 1H), 2.37 - 2.21 (m, 3H), 1.91 - 1.86 (m, 1H), 1.77 - 1.70 (m, 1H), 1.69 - 1.63 (m, 2H), 1.61 - 1.44 (m, 9H), 1.44 - 1.37 (m, 3H), 1.30 - 1.21 (m, 7H), 1.17 (d, J = 6.9 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 0.87 (s, 1H), 0.85 - 0.74 (m, 10H), 0.67 - 0.58 (m, 2H); MS m / z 672.4112 [M + H] + .

[0696] (Compound I - 88)

[0697] 1H-NMR (500MHz, CDCl3, δ): 5.86 (td, J = 2.4, 10.2Hz, 1H), 5.77-5.64 (m, 2H), 5.47-5.38 (m, 1H), 4.96-4.91 (m, 1H), 4.8 1(d,J=3.4Hz,1H),4.68-4.61(m,2H),4.60-4.55(m,1H),4.21-4.17(m,1H),4.15-4.08(m,1H),3.97(s,1H),3.95(br s,1H),3.90-3.83(m,1H),3.72-3.65(m,1H),3.60-3.54(m,2H),3.49(s,3H),3.42-3.30(m,1H),3.24-3.19 (m,1H),3.16(t,J=9.2Hz,1H),2.90(dd,J=2.9,13.2Hz,1H),2.56-2.44(m,2H),2.38-2.22(m,4H),1.93-1.8 7(m,1H),1.79-1.73(m,1H),1.70-1.64(m,1H),1.62-1.35(m,10H),1.27(d,J=6.3Hz,4H),1.26-1.22(m,4H ),1.14(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.87-0.76(m,10H),0.68-0.58(m,2H); MSm / z816.4898[M+H] + .

[0698] Preparation of Compound I-89

[0699] Using O-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)hydroxylamine obtained in Reference Example 14-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2], Compound I-89 was obtained by the same method (yield 17.5 mg, yield 48%).

[0700] 1H-NMR (500MHz, CDCl3, δ):5.85-5.79(m,1H),5.76-5.64(m,2H),5.43-5.35(m,2H),4.97-4.92(m,1H),4.94(s,1H ),4.76(d,J=3.4Hz,1H),4.68-4.56(m,2H),4.51(s,1H),4.20(d,J=11.5Hz,1H),4.07(d,J=11.5Hz,1H),3.93(br s,1H),3.86-3.80(m,1H),3.80-3.73(m,1H),3.70-3.60(m,2H),3.51-3 .45(m,1H),3.51-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m, 2H),3.16(t,J=9.2Hz,1H),2.78(dd,J=2.9,12.6Hz,1H),2.64-2.55(m, 1H),2.53-2.45(m,2H),2.37-2.19(m,4H),1.93-1.86(m,2H),1.85-1.7 8(m,1H),1.77-1.72(m,1H),1.68-1.63(m,1H),1.57-1.35(m,6H),1.27 (d,J=6.3Hz,4H),1.25(d,J=6.3Hz,4H),1.16(d,J=3.4Hz,3H),1.15(d, J=2.9Hz,3H),0.92(t,J=7.2Hz,3H),0.88-0.82(m,8H),0.82-0.76(m,12H),0.73-0.64(m,4H),0.09(d,J=5.2Hz,6H); MSm / z1091.6815[M+NH4] + .

[0701] Preparation of Compound I-90 and Compound I-91

[0702] Using compound I-89 instead of compound I-83 in [Production of compound I-85 and compound I-86], compound I-90 (yield 6.5 mg, yield 59%) and compound I-91 (yield 2.6 mg, yield 20%) were obtained by the same method.

[0703] (Compound I-90)

[0704] 1H-NMR(500 MHz, CDCl3, δ): 5.82 - 5.77 (m, 1H), 5.73 - 5.69 (m, 2H), 5.40 - 5.33 (m, 1H), 5.32 - 5.27 (m, 1H), 5.03 (s, 1H), 4.76 (s, 1H), 4.72 - 4.63 (m, 2H), 4.18 - 4.14 (m, 1H), 4.08 - 4.04 (m, 1H), 3.99 (br s, 1H), 3.71 - 3.64 (m, 1H), 3.20 - 3.16 (m, 1H), 2.77 (dd, J = 4.0, 12.0 Hz, 1H), 2.68 - 2.61 (m, 1H), 2.54 - 2.47 (m, 1H), 2.36 - 2.23 (m, 2H), 2.17 (s, 1H), 1.91 - 1.83 (m, 3H), 1.74 - 1.69 (m, 1H), 1.69 - 1.46 (m, 7H), 1.44 - 1.36 (m, 4H), 1.27 - 1.23 (m, 2H), 1.17 (dd, J = 1.7, 6.9 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H), 0.83 (d, J = 6.9 Hz, 4H), 0.80 - 0.76 (m, 6H), 0.66 - 0.56 (m, 2H); MS m / z 672.4112 [M + H] + .

[0705] (Compound I-91)

[0706] 1H-NMR (500MHz, CDCl3, δ): 5.84 (td, J = 2.4, 10.6Hz, 1H), 5.77-5.64 (m, 2H), 5.44-5.36 (m, 1H), 5.04 (s, 1 H),4.96-4.91(m,1H),4.81(d,J=4.0Hz,1H),4.67(s,2H),4.18-4.14(m,1H),4.10-4.05(m,1H),3.95(br s,1H),3.90-3.83(m,1H),3.72-3.65(m,1H),3.60-3.54(m,1H),3.49(s,3H),3.23-3.19(m,1H),3.16(t, J=9.2Hz,1H),2.80(dd,J=4.6,11.5Hz,1H),2.69-2.62(m,1H),2.54-2.47(m,2H),2.37-2.31(m,2H),2.2 9-2.22(m,2H),1.92-1.86(m,4H),1.77-1.72(m,2H),1.68-1.65(m,3H),1.59-1.36(m,10H),1.29-1.24( m,5H),1.19-1.11(m,3H),0.94-0.91(m,3H),0.86-0.76(m,6H),0.67-0.54(m,2H); MSm / z816.4907[M+H] + .

[0707] Preparation of Compound I-92

[0708] After dissolving compound I-83 (15.0 mg, 0.0140 mmol) obtained in [Manufacturing of Compound I-83 and Compound I-84] in THF (0.23 mL), the reaction solution was cooled to -10°C. Pyridine (0.75 mL) and hydrogen fluoride pyridine solution (0.125 mL) were added and stirred at the same temperature for 30 minutes. Hydrogen fluoride pyridine solution (62.5 μL) was added and stirred at the same temperature for 30 minutes. After that, hydrogen fluoride pyridine solution (0.11 mL) was added again, the temperature was raised to 0°C, and stirred for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin-layer silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-92 (yield 10.8 mg, yield 81%).

[0709] 1H-NMR (500MHz, CDCl3, δ):5.88-5.83(m,1H),5.78-5.65(m,2H),5.44-5.37(m,2H),4.97-4.92(m,1H),4.91(s,1H ),4.76(d,J=3.4Hz,1H),4.71-4.62(m,3H),4.16-4.13(m,1H),4.11(d,J=6.9Hz,1H),4.08-4.04(m,1H),3.93(br s,1H),3.86-3.80(m,1H),3.79-3.73(m,1H),3.71-3.59(m,2H),3.51-3.46(m,1H),3.44(s,3H),3.42(s, 3H),3.26-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.91-2.85(m,2H),2.57-2.46(m,2H),2.39-2.19(m,5H),2. 13(s,2H),1.92-1.85(m,2H),1.79-1.71(m,2H),1.71-1.35(m,9H),1.30-1.23(m,12H),1.20-1.13(m,4H) ,0.92(t,J=7.4Hz,3H),0.84(d,J=6.9Hz,2H),0.82-0.75(m,6H),0.65-0.57(m,2H);MSm / z960.5684[M+H] + .

[0710] Preparation of Compound I-93

[0711] Compound I-93 (yield 14.1 mg, 95%) was obtained by the same method using compound I-84 instead of compound I-83 in [Production of compound I-92].

[0712] 1H-NMR (500MHz, CDCl3, δ): 5.88-5.83 (m, 1H), 5.77-5.65 (m, 2H), 5.47-5.38 (m, 2H), 4.97-4.92 (m, 1H), 4.76 (d, J = 3.4H z,1H),4.64(s,1H),4.68-4.62(m,1H),4.61-4.56(m,1H),4.21-4.17(m,1H),4.13-4.09(m,1H),3.97(s,1H),3.93(br s,1H),3.87-3.80(m,1H),3.80-3.73(m,1H),3.71-3.54(m,3H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3. 26-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.90(dd,J=13.7,2.9Hz,1H),2.58-2.45(m,2H),2.36-2.19(m,5H),2.13 (s,1H),1.93-1.86(m,1H),1.79-1.72(m,1H),1.70-1.35(m,13H),1.27(d,J=6.3Hz,4H),1.24(dd,J=6.9,4.6Hz ,6H),1.16(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.88-0.76(m,10H),0.67-0.59(m,2H); MSm / z960.5684[M+H] + .

[0713] Preparation of Compound I-94

[0714] Compound I-94 (yield 14.8 mg, 85%) was obtained by the same method using compound I-89 instead of compound I-83 in [Production of compound I-92].

[0715] 1H-NMR (500MHz, CDCl3, δ): 5.83 (td, J = 10.6, 2.4Hz, 1H), 5.77-5.64 (m, 2H), 5.44-5.36 (m, 2H), 5.04 (s, 1H), 4.97- 4.92(m,1H),4.76(d,J=3.4Hz,1H),4.75(s,1H),4.69-4.66(m,2H),4.18-4.13(m,1H),4.09-4.04(m,1H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.73(m,1H),3.70-3.59(m,3H),3.44(s,3H),3.42(s,3H),3.51-3.38(m,2H),3.27-3.19( m,2H),3.16(t,J=9.2Hz,1H),2.80(dd,J=11.7,4.3Hz,1H),2.69-2.61(m,1H),2.54-2.45(m,2H),2.37-2.18(m,5H),2.13( s,1H),1.92-1.84(m,3H),1.76-1.71(m,1H),1.68-1.35(m,10H),1.27(d,J=5.7Hz,4H),1.25(d,J=6.3Hz,4H),1.16(dd,J= 10.0,7.2Hz,3H),0.92(t,J=7.4Hz,4H),0.83(d,J=6.9Hz,4H),0.85-0.76(m,6H),0.67-0.56(m,2H); MSm / z960.5684[M+H] + .

[0716] Preparation of Compound I-95

[0717] To a solution of compound I-23 (20 mg, 0.0214 mmol) obtained in [Manufacture of compound I-23] in DMF (0.21 mL), DIPEA (22.4 μL, 0.129 mmol), isobutyric acid (11.9 μL, 0.129 mmol) and HATU (16.3 mg, 0.0428 mmol) were added and stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin-layer silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-95 (yield 17.7 mg, yield 82%).

[0718] 1H-NMR (500MHz, CDCl3, δ): 6.14-6.09 (m, 1H), 5.84 (td, J = 10.7, 2.4Hz, 1H), 5.77-5.65 (m, 2H), 5.44-5.35 (m ,2H),4.95(s,1H),4.95-4.91(m,1H),4.76(d,J=2.9Hz,1H),4.71-4.62(m,2H),4.20-4.11(m,2H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.73(m,1H),3.70-3.60(m,2H),3.56-3.44(m,4H),3.44(s,3H),3.42(s,3H),3.26-3.19( m,2H),3.16(t,J=9.2Hz,1H),2.82-2.77(m,1H),2.67-2.59(m,1H),2.53-2.45(m,1H),2.36-2.19(m,6H),1.92-1.84(m,4 H),1.76-1.71(m,1H),1.59-1.34(m,7H),1.27(d,J=6.3Hz,5H),1.25(d,J=6.3Hz,5H),1.16(t,J=6.9Hz,7H),1.13(dd,J= 6.9,1.1Hz,7H),0.92(t,J=7.4Hz,3H),0.89-0.85(m,1H),0.83(d,J=6.9Hz,3H),0.82-0.76(m,4H); MSm / z1003.6106[M+H] + .

[0719] Preparation of Compound I-96

[0720] Compound I-96 (yield 17.1 mg, 80%) was obtained by the same method using glycolic acid instead of isobutyric acid in [Production of Compound I-95].

[0721] 1H-NMR (500MHz, CDCl3, δ): 5.83 (td, J = 10.9, 2.3Hz, 1H), 5.78-5.63 (m, 2H), 5.44-5.36 (m, 2H), 4.94 (s, 1 H),4.97-4.91(m,1H),4.76(d,J=3.4Hz,1H),4.70-4.62(m,2H),4.28-4.15(m,2H),4.04(s,2H),3.93(br s,1H),3.87-3.79(m,1H),3.79-3.72(m,1H),3.71-3.59(m,2H),3.56(q,J=4.8Hz,2H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3. 27-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.79(dd,J=4.9,11.2Hz,1H),2.66-2.58(m,1H),2.53-2.45(m,1H),2.36-2.31(m,2H),2.30-2. 19(m,3H),1.93-1.81(m,3H),1.75-1.69(m,1H),1.69-1.63(m,1H),1.59-1.34(m,12H),1.27(d,J=6.3Hz,4H),1.25(d,J=6.3Hz,4H),1 .16(dd,J=3.7,6.6Hz,6H),0.92(t,J=7.2Hz,3H),0.87(t,J=6.9Hz,1H),0.83(d,J=6.9Hz,3H),0.82-0.74(m,4H); MSm / z991.5743[M+H] + .

[0722] Preparation of Compound I-97

[0723] Compound I-97 (yield 16.3 mg, 75%) was obtained by the same method using cyclopropylacetic acid instead of isobutyric acid in [Production of Compound I-95].

[0724] 1H-NMR (500MHz, CDCl3, δ): 5.83 (td, J=10.7, 2.4Hz, 1H), 5.77-5.65 (m, 2H), 5.43-5.35 (m, 2H), 4.9 4(s,1H),4.98-4.91(m,1H),4.76(d,J=3.4Hz,1H),4.70-4.61(m,2H),4.23-4.14(m,2H),3.93(br s,1H),3.87-3.79(m,1H),3.79-3.73(m,1H),3.70-3.45(m,6H),3.44(s,3 H),3.42(s,3H),3.27-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.81-2.76(m,1H ),2.67-2.57(m,1H),2.53-2.45(m,1H),2.36-2.33(m,1H),2.32(d,J=3.4 Hz,1H),2.29-2.18(m,2H),2.12(d,J=6.9Hz,2H),1.92-1.83(m,3H),1.76- 1.71(m,1H),1.66(d,J=12.6Hz,1H),1.60-1.33(m,10H),1.27(d,J=5.7Hz ,4H),1.25(d,J=6.3Hz,4H),1.16(dd,J=3.7,6.6Hz,6H),0.99-0.94(m,1H) ,0.92(t,J=7.2Hz,3H),0.89-0.85(m,2H),0.83(d,J=6.9Hz,3H),0.81-0. 73(m,5H),0.60-0.53(m,2H),0.16(q,J=5.2Hz,2H); MSm / z1015.6102[M+H] + .

[0725] Preparation of Compound I-98

[0726] Compound I-98 (yield 36.3 mg, 67%) was obtained by the same method using 2,2,2-trifluoroethylamine hydrochloride instead of dimethylamine in [Production of Compound I-60].

[0727] 1H-NMR (500MHz, CDCl3, δ): 7.04 (t, J=6.3Hz, 1H), 5.86 (dt, J=10.9, 2.6Hz, 1H), 5.78-5.65 (m, 2H), 5.44-5.37 (m,2H),5.00(s,1H),4.95-4.84(m,2H),4.76(d,J=3.4Hz,1H),4.72-4.60(m,4H),4.13-4.02(m,1H),3.93(br s,1H),3.85-3.60(m,5H),3.50-3.40(m,7H),3.25-3.14(m,3H),2.78(dd ,J=12.3,3.7Hz,1H),2.70-2.63(m,1H),2.52-2.47(m,1H),2.34-2.19(m, 4H),1.91-1.80(m,3H),1.74-1.71(m,1H),1.67-1.64(m,1H),1.58-1.35( m,12H),1.27-1.13(m,12H),0.93-0.74(m,10H); MSm / z1046.5906[M+NH4] + .

[0728] Reference Example 15

[0729] Preparation of O-(azetidin-3-yl)hydroxylamine dihydrochloride

[0730] With reference to Journal of Medicinal Chemistry (2008), 51(15), 4601-4608, tert-butyl 3-hydroxyazetidine-1-carboxylate (1.34 g, 7.72 mmol) was used as a starting material to obtain a crude product of O-(azetidin-3-yl)hydroxylamine dihydrochloride (yield 648 mg).

[0731] 1 H-NMR(500MHz,DMSO-d6,δ):9.68-9.16(m,2H),4.66(br s,1H),4.22-3.82(m,4H); MSm / z89.0723[M+H] + .

[0732] Preparation of Compound I-99

[0733] Using the crude product of O-(azetidin-3-yl)hydroxylamine dihydrochloride obtained in Reference Example 15 instead of hydroxylamine hydrochloride in [Production of Compound I-1], Compound I-99 (yield 4.2 mg, yield 13%), a mixture of isomers that was difficult to separate, was obtained by the same method.

[0734] 1 H-NMR (500MHz, CDCl3, δ): 5.89-5.83 (m, 1H), 5.78-5.65 (m, 2H), 5.43-5.36 (m, 2H), 5.12-5.06 (m, 1H), 5.12-5.00 (m, 1H), 4.98-4. 92(m,1H),4.81(s,0.5H),4.76(d,J=3.4Hz,1H),4.70-4.56(m,2H),4.33-4.23(m,2H),4.21-4.13(m,2H),3.98(s,0.5H),3.93(br s,1H),3.86-3.72(m,3H),3.70-3.59(m,3H),3.44(s,3H),3.42(s,3H),3.53-3.40(m,1H), 3.27-3.19(m,2H),3.16(t,J=9.2Hz,2H),2.94-2.86(m,2H),2.53-2.46(m,2H),2.37-2.19 (m,5H),1.95-1.87(m,2H),1.78-1.73(m,1H),1.69-1.63(m,2H),1.60-1.33(m,9H),1.30- 1.21(m,10H),1.16(d,J=6.9Hz,4H),0.92(s,3H),0.89-0.76(m,8H);MSm / z945.5688[M+H] + .

[0735] Preparation of Compound I-100

[0736] Using the crude product of O-(azetidin-3-yl)hydroxylamine dihydrochloride obtained in Reference Example 15 instead of hydroxylamine hydrochloride in [Production of Compound I-2], Compound I-100 was obtained as a mixture of isomers that were difficult to separate by the same method (yield 10.7 mg, yield 33%).

[0737] 1H-NMR (500MHz, CDCl3, δ): 5.84 (td, J=10.7, 2.4Hz, 1H), 5.78-5.64 (m, 2H), 5.39 (br s,1H),5.38-5.30(m,1H),5.10-5.03(m,1H),4.98-4.93(m,1H),4.92(s,1H),4.78-4.75(m,1H),4.66(s,2H),4.28-4.13(m,4H),3.93(br s,1H),3.86-3.73(m,3H),3.69-3.61(m,2H),3.43(s,3H),3.41(s,3H),3.51-3.38(m,2H),3.26-3.18(m,2H),3.1 8-3.13(m,1H),2.80-2.75(m,1H),2.67-2.60(m,1H),2.53-2.45(m,1H),2.36-2.30(m,2H),2.28-2.19(m,2H),1.9 7-1.83(m,3H),1.77-1.71(m,1H),1.67-1.62(m,1H),1.58-1.34(m,12H),1.28-1.23(m,8H),1.16(dd,J=6.6,10. 0Hz, 6H), 0.91 (t, J=7.4Hz, 3H), 0.89-0.85 (m, 1H), 0.82 (d, J=6.9Hz, 3H), 0.80-0.75 (m, 4H); MSm / z945.5688[M+H] + .

[0738] Preparation of Compound I-101

[0739] Compound I-101 (yield 21.8 mg, 70%) was obtained by the same method using ethylamine hydrochloride instead of dimethylamine in [Production of Compound I-60].

[0740] 1H-NMR (500MHz, CDCl3, δ): 6.45 (t, J=5.7Hz, 1H), 5.85 (dd, J=8.6, 2.3Hz, 1H), 5. 44-5.33(m,2H),4.99(s,1H),4.95(d,J=10.9Hz,1H),4.76-4.53(m,6H),3.93(br s,1H),3.85-3.72(m,2H),3.69-3.60(m,2H),3.50-3.41(m,8H),3.38-3.14(m ,3H),2.80(dd,J=11.7,3.7Hz,1H),2.68-2.61(m,1H),2.51-2.47(m,1H),2.34 -2.19(m,4H),1.90-1.81(m,3H),1.74-1.72(m,1H),1.67-1.65(m,1H),1.58- 1.35(m,13H),1.27-1.10(m,17H),0.93-0.75(m,11H); MSm / z992.6066[M+NH4] + .

[0741] Preparation of Compound I-102

[0742] Compound I-102 (yield 23.1 mg, 73%) was obtained by the same method using 2-fluoroethylamine hydrochloride instead of dimethylamine in [Production of Compound I-60].

[0743] 1 H-NMR (500MHz, CDCl3, δ): 6.98 (t, J = 6.0 Hz, 1H), 5.86 (dt, J = 10.9, 2.3 Hz, 1H), 5.78-5.65 (m, 2H), 5. 44-5.36(m,2H),5.00(s,1H),4.95(d,J=10.9Hz,1H),4.76-4.50(m,6H),4.46-4.40(m,1H),3.93(br s,1H),3.85-3.60(m,5H),3.54-3.42(m,8H),3.25-3.14(m,3H),2.81-2.77(m,1H),2.70-2.63(m,1H),2.51-2.46 (m,1H),2.35-2.19(m,4H),1.92-1.34(m,19H),1.28-1.13(m,12H),0.93-0.742(m,10H); MSm / z1010.6110[M+NH4] + .

[0744] Preparation of Compound I-103

[0745] Compound I-103 (yield 24.2 mg, 76%) was obtained by the same method using isopropylamine instead of dimethylamine in [Production of Compound I-60].

[0746] 1 H-NMR (500MHz, CDCl3, δ): 6.29 (d, J=8.6Hz, 1H), 5.85 (dd, J=8.6, 2.3Hz, 1H), 5.78-5.65 (m, 2H), 5.44-5.38 (m, 2H) ,4.99(s,1H),4.95(d,J=10.9Hz,1H),4.76-4.65(m,4H),4.58(dd,J=25.8,16.0Hz,2H),4.17-4.09(m,1H),3.93(br s,1H),3.85-3.72(m,2H),3.69-3.61(m,2H),3.50-3.41(m,7H),3.25-3.14(m,3H),2.80(dd,J=12.0,4.0Hz,1H),2.68-2.61(m,1H),2.51 -2.46(m,1H),2.34-2.19(m,4H),1.99-1.65(m,6H),1.58-1.34(m,13H),1.27-1.10(m,19H),0.93-0.75(m,10H); MSm / z1006.6337[M+NH4] + .

[0747] Reference Example 16

[0748] Production of 2-((5-hydroxypentyl)oxy)isoindoline-1,3-dione (MM10-18)

[0749] 5-(Aminooxy)pentan-1-ol hydrochloride (yield 368 mg, yield 88%) was obtained by the same method as Reference Examples 5-(1) and (2) using 5-bromopentan-1-ol instead of 1-bromo-2-methoxyethane in Reference Example 5-(1).

[0750] 1 H-NMR (500MHz, DMSO-d6, δ): 5.84 (br s, 1H), 3.55 (t, J = 6.0Hz, 2H), 3.48 (t, J = 6.6Hz, 2H), 1.50-1.38 (m, 4H), 0.823 (s, 9H), 0.823 (s, 6H).

[0751] Preparation of Compound I-104

[0752] Compound I-104 (yield 9.3 mg, 28%) was obtained by the same method using 5-(aminooxy)pentan-1-ol hydrochloride obtained in Reference Example 16 instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0753] 1 H-NMR (500MHz, CDCl3, δ):5.84-5.82(m,1H),5.75-5.64(m,2H),5.42-5.36(m,2H),4.9 4-4.93(m,2H),4.76(d,J=6.9Hz,1H),4.654-4.650(m,2H),4.12-4.06(m,2H),3.93(br s,1H),3.86-3.74(m,2H),3.68-3.60(m,4H),3.52-3.41(m,8H),3.26-3.15(m,3H),2.80(dd,J=12.6,3.4Hz,1H),2.6 2-2.57(m,1H),2.50-2.47(m,1H),2.36-2.20(m,4H),1.92-1.14(m,51H),0.93-0.77(m,10H); MSm / z998.5876[M+Na] + .

[0754] Preparation of Compound I-105

[0755] Compound I-105 (yield 17.4 mg, 62%) was obtained by the same method as in [Production of Compound I-1] using 1-(aminooxy)-2-methylpropane-2-ol instead of hydroxylamine hydrochloride.

[0756] 1H-NMR (500MHz, CDCl3, δ):5.87-5.84(m,1H),5.77-5.65(m,2H),5.45-5.39(m,2H),4.97-4.93(m,1H),4 .76(d,J=3.4Hz,1H),4.70-4.56(m,2H),4.03-3.93(m,4H),3.85-3.74(m,2H),3.69-3.60(m,2H),3.50-3 .41(m,7H),3.25-3.14(m,3H),2.91-2.84(m,1H),2.51-2.47(m,1H),2.35-2.20(m,5H),1.93-1.89(m,1 H),1.76-1.74(m,1H),1.68-1.34(m,15H),1.28-1.14(m,20H),0.93-0.77(m,10H); MSm / z962.5615[M+H] + .

[0757] Preparation of Compound I-106

[0758] Compound I-106 (yield 19.2 mg, 69%) was obtained by the same method using 1-(aminooxy)-2-methylpropane-2-ol instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0759] 1 H-NMR (500MHz, CDCl3, δ):5.85-5.83(m,1H),5.76-5.65(m,2H),5.43-5.36(m,2H),4. 97-4.93(m,2H),4.76(d,J=3.4Hz,1H),4.69-4.63(m,2H),4.01-3.95(m,2H),3.92(br s,1H),3.85-3.73(m,2H),3.69-3.60(m,2H),3.50-3.41(m,7H),3.25-3.14(m, 3H),2.80-2.77(dd,J=12.6,3.4Hz,1H),2.65-2.60(m,1H),2.50-2.47(m,1H),2 .35-2.20(m,5H),1.93-1.82(m,3H),1.74-1.73(m,1H),1.67-1.65(m,1H),1.58 -1.36(m,13H),1.28-1.14(m,20H),0.93-0.77(m,10H); MSm / z979.5811[M+NH4] + .

[0760] Preparation of Compound I-107

[0761] Compound I-107 (yield 94.6 mg, 86%) was obtained as a mixture of isomers that was difficult to separate by the same method using 3-(aminooxy)propionic acid hydrochloride instead of hydroxylamine hydrochloride in [Production of Compound I-1].

[0762] 1 H-NMR (500MHz, CDCl3, δ): 5.88-5.83 (m, 1H), 5.77-5.65 (m, 2H), 5.40 (d, J= 3.4Hz,1H),5.45-5.38(m,1H),4.95(d,J=10.9Hz,1H),4.77(s,1H),4.76(br s,0.6H),4.70-4.56(m,3H),4.30(t,J=5.7Hz,2H),3.96(s,0.4H),3.94-3.92(br s,1H),3.87-3.80(m,1H),3.80-3.73(m,1H),3.71-3.65(m,1H),3.65-3.60(m,1H),3.52-3.46(m,2H),3.44(s,3H),3.4 2(s,3H),3.26-3.20(m,2H),3.17(t,J=9.2Hz,1H),2.91-2.82(m,2H),2.77-2.73(m,2H),2.52-2.46(m,1H),2.37-2.20( m,5H),1.92-1.87(m,3H),1.78-1.72(m,1H),1.69-1.65(m,1H),1.59-1.36(m,14H),1.29-1.24(m,6H),1.20-1.18(m,1 H),1.15(dd,J=1.4,7.2Hz,3H),0.92(t,J=7.4Hz,3H),0.84(d,J=6.9Hz,3H),0.82-0.75(m,5H); MSm / z979.5597[M+NH4] + .

[0763] Preparation of Compound I-108

[0764] Compound I-108 (yield 85.5 mg, 78%) was obtained by the same method using 3-(aminooxy)propionic acid hydrochloride instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0765] 1H-NMR(500MHz,CDCl3,δ):6.14(br s,1H),5.84-5.81(m,1H),5.78-5.64(m,2H),5.44-5.36(m,2H),4.94(brd,J=9.7Hz,1 H),4.89(s,1H),4.78-4.74(m,1H),4.70-4.60(m,1H),4.35(t,J=5.7Hz,2H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.73(m,1H),3.70-3.59(m,2H),3.51-3.45(m,1H),3.45 -3.43(m,3H),3.42-3.41(m,3H),3.27-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.80-2.74(m,4 H),2.62(d,J=8.6Hz,1H),2.55-2.45(m,3H),2.36-2.18(m,5H),1.92-1.83(m,3H),1.76-1 .70(m,1H),1.68-1.64(m,1H),1.60-1.34(m,10H),1.28-1.23(m,6H),1.16(t,J=5.7Hz,6H ),0.92(t,J=7.2Hz,3H),0.83(d,J=6.3Hz,3H),0.80-0.74(m,4H); MSm / z979.5597[M+NH4] + .

[0766] Preparation of Compound I-109

[0767] To a solution of compound I-107 (25 mg, 0.026 mmol) obtained in [Manufacture of compound I-107] in DMF (0.26 mL), DIPEA (45 μL, 0.260 mmol), 2M methylamine THF solution (0.065 mL, 0.065 mmol) and HATU (29.7 mg, 0.078 mmol) were added and stirred at room temperature for 1 hour. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin-layer silica gel column chromatography (ethyl acetate) to obtain compound I-109 (yield 16.2 mg, yield 64%) as a mixture of isomers that were difficult to separate.

[0768] 1H-NMR (500MHz, CDCl3, δ): 6.16 (br s, 0.4H), 5.88-5.83 (m, 1H), 5.82 (br s,0.6H),5.78-5.64(m,2H),5.45-5.37(m,2H),4.94(brd,J=10.9Hz,1H),4.77(s, 0.6H),4.76(s,1H),4.71-4.55(m,2H),4.39-4.29(m,2H),3.96(s,0.4H),3.93(br s,1H),3.86-3.80(m,1H),3.79-3.73(m,1H),3.71-3.59(m,2H),3.50-3.46(m,1H),3.44(s,3H),3.42-3.41(m,3H),3.26-3.19 (m,2H),3.16(t,J=9.2Hz,1H),2.91-2.81(m,2H),2.78(d,J=5.2Hz,1.2H),2.76(d,J=5.2Hz,1.8H),2.57(t,J=6.0Hz,1H),2.53 -2.47(m,2H),2.37-2.16(m,6H),1.92-1.88(m,1H),1.77-1.72(m,1H),1.68-1.64(m,1H),1.59-1.34(m,15H),1.28-1.23(m,8 H),1.19-1.17(m,1H),1.16(d,J=6.9Hz,3H),0.92(t,J=7.2Hz,3H),0.85-0.82(m,3H),0.80-0.75(m,4H); MSm / z975.5660[M+H] + .

[0769] Preparation of Compound I-110

[0770] To a solution of compound I-108 (25 mg, 0.026 mmol) obtained in [Manufacture of compound I-108] in DMF (0.26 mL), DIPEA (45 μL, 0.260 mmol), 2M methylamine THF solution (0.065 mL, 0.065 mmol) and HATU (29.7 mg, 0.078 mmol) were added and stirred at room temperature for 1 hour. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin layer silica gel column chromatography (ethyl acetate) to obtain compound I-110 (yield 16.2 mg, yield 64%).

[0771] 1H-NMR(500MHz,CDCl3,δ):6.14(br s,1H),5.85-5.81(m,1H),5.77-5.63(m,2H),5.44-5.35(m,2H),4.94(brd,J=9.7Hz,1 H),4.90(s,1H),4.78-4.75(m,1H),4.70-4.59(m,2H),4.35(t,J=5.7Hz,2H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.72(m,1H),3.70-3.59(m,2H),3.50-3.45(m,1H),3.45 -3.43(m,3H),3.42-3.41(m,3H),3.26-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.80-2.77(m,1H), 2.76-2.74(m,3H),2.65-2.59(m,1H),2.55-2.47(m,3H),2.36-2.18(m,5H),1.92-1.84(m,3H), 1.76-1.70(m,1H),1.68-1.63(m,1H),1.59-1.36(m,13H),1.28-1.23(m,7H),1.16(t,J=5.7Hz ,6H),0.92(t,J=7.2Hz,3H),0.83(d,J=6.3Hz,3H),0.80-0.76(m,4H); MSm / z1046.5776[M+NH4] + .

[0772] Preparation of Compound I-111

[0773] Compound I-111 was obtained by the same method using 2,2,2-trifluoroethylamine hydrochloride instead of methylamine in [Production of Compound I-110] (yield 22.5 mg, yield 83%).

[0774] 1H-NMR (500MHz, CDCl3, δ): 6.47 (t, J = 6.3Hz, 1H), 5.82 (td, J = 2.6, 10.9Hz, 1H), 5.78-5.63 (m, 2H), 5.44-5.37 (m, 1H), 5.40 (d, J = 4.6Hz, 1H), 4 .94(brd,J=11.5Hz,1H),4.88(s,1H),4.76(d,J=3.4Hz,1H),4.64(dq,J=2.3,14.1Hz,2H),4.38(t,J=5.4Hz,2H),4.04-3.96(m,1H),3.93(br s,1H),3.87-3.80(m,1H),3.80-3.71(m,2H),3.70-3.60(m,2H),3.50-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.27-3.2 0(m,2H),3.16(t,J=8.9Hz,1H),2.80-2.75(m,1H),2.68-2.62(m,1H),2.60-2.56(m,2H),2.53-2.47(m,1H),2.36-2.31( m,2H),2.29-2.20(m,2H),1.93-1.84(m,4H),1.76-1.71(m,2H),1.68-1.64(m,1H),1.60-1.36(m,12H),1.28-1.24(m,7H ),1.17(dd,J=4.9,6.6Hz,6H),0.92(t,J=7.4Hz,3H),0.83(d,J=6.3Hz,3H),0.80-0.76(m,4H); MSm / z1010.6110[M+NH4] + .

[0775] Preparation of Compound I-112

[0776] Compound I-112 was obtained as a mixture of isomers that was difficult to separate (yield 14.0 mg, 67%) by the same method using dimethylamine instead of methylamine in [Production of Compound I-109].

[0777] 1H-NMR (500MHz, CDCl3, δ): 5.87-5.83 (m, 1H), 5.77-5.65 (m, 2H), 5.40 (d, J = 4.0Hz, 1H), 5.46-5.37 (m, 1H), 4.94 (brd ,J=1.7Hz,1H),4.78(s,0.6H),4.76(d,J=3.4Hz,1H),4.69-4.55(m,2H),4.44-4.36(m,2H),3.96(s,0.4H),3.93(br s,1H),3.85-3.80(m,1H),3.79-3.73(m,1H),3.71-3.60(m,2H),3.51-3.45(m,2H),3.44(s,3H),3.42(s,3H),3.27-3. 20(m,2H),3.16(t,J=9.2Hz,1H),3.01-2.92(m,6H),2.91-2.86(m,1H),2.75-2.70(m,2H),2.52-2.46(m,1H),2.36-2.1 9(m,6H),1.93-1.87(m,1H),1.78-1.74(m,1H),1.68-1.60(m,2H),1.59-1.35(m,12H),1.29-1.23(m,10H),1.19(d,J=7 .4Hz,2H),1.15(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H),0.83(d,J=6.3Hz,3H),0.82-0.75(m,4H); MSm / z989.6359[M+H] + .

[0778] Preparation of Compound I-113

[0779] Compound I-113 (yield 17.5 mg, 85%) was obtained by the same method using dimethylamine hydrochloride instead of methylamine hydrochloride in [Production of Compound I-110].

[0780] 1H-NMR (500MHz, CDCl3, δ): 5.85-5.80 (m, 1H), 5.76-5.64 (m, 2H), 5.43-5.35 (m, 2H), 4.94 (brd, J =10.9Hz,1H),4.89(s,1H),4.78-4.74(m,1H),4.68-4.59(m,2H),4.40(t,J=7.2Hz,2H),3.93(br s,1H),3.86-3.80(m,1H),3.79-3.73(m,1H),3.70-3.59(m,2H),3.51-3.45(m,1 H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.99(br s,3H),2.93(br s,3H),2.80-2.75(m,1H),2.72(q,J=6.9Hz,2H),2.63-2.54(m,1H),2.52-2.45(m,1H),2.3 6-2.18(m,5H),1.93-1.86(m,2H),1.85-1.79(m,1H),1.76-1.72(m,1H),1.68-1.63(m,1H) ,1.59-1.36(m,13H),1.27(d,J=6.3Hz,3H),1.25(d,J=6.3Hz,4H),1.15(dd,J=2.6,7.2Hz, 6H),0.92(t,J=7.4Hz,3H),0.83(d,J=6.9Hz,3H),0.79-0.75(m,4H); MSm / z989.6359[M+H] + .

[0781] Preparation of Compound I-114

[0782] After dissolving 5-oxo-ivermectin B1a (50.0 mg, 0.057 mmol) in methanol (0.57 mL), sodium acetate (28.2 mg, 0.344 mmol) and O-(prop-2-yn-1-yl)hydroxylamine hydrochloride (37.0 mg, 0.344 mmol) were added sequentially and stirred at room temperature for 24 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-114 (yield 45.4 mg, yield 86%).

[0783] 1H-NMR (500MHz, CDCl3, δ): 5.94-5.90 (m, 1H), 5.83-5.81 (m, 1H), 5.79-5.70 (m, 2H), 5.42-5.36 (m, 2H), 4.96(d,J=10.9Hz,1H),4.78(d,J=2.9Hz,2H),4.77-4.64(m,3H),4.58(s,1H),4.00-3.90(m,2H),3.85 -3.73(m,2H),3.69-3.59(m,2H),3.50-3.46(m,1H),3.43(s,3H),3.42(s,3H),3.38(t,J=2.3Hz,1H),3 .26-3.19(m,2H),3.16(t,J=9.17Hz,1H),2.55-2.47(m,1H),2.45-2.40(m,1H),2.35-2.18(m,4H),1.99 -1.91(m,4H),1.79-1.73(m,1H),1.68-1.62(m,1H),1.59-1.34(m,13H),1.29-1.22(m,7H),1.16(d, J=6.9Hz,3H),0.92(t,J=7.5Hz,3H),0.86-0.81(m,4H),0.78(d,J=5.2Hz,3H); MSm / z948.5490[M+Na] + .

[0784] Preparation of Compound I-115

[0785] After dissolving 5-oxo-ivermectin B1a (50.0 mg, 0.057 mmol) in methanol (1.14 mL), sodium acetate (28.2 mg, 0.344 mmol), cesium chloride heptahydrate (25.6 mg, 0.069 mmol) and O-allylhydroxylamine hydrochloride (37.0 mg, 0.344 mmol) were added sequentially at 0°C and stirred at the same temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-115 (yield 34.0 mg, yield 64%).

[0786] 1H-NMR(500MHz,CD3OD,δ):6.04-5.96(m,1H),5.96-5.87(m,3H),5.80-5.69( m,1H),5.34(d,J=2.9Hz,1H),5.32-5.27(m,1H),5.21-5.08(m,3H),4.81(d,J =2.9Hz,1H),4.71-4.59(m,4H),4.51(s,1H),4.01-3.96(m,1H),3.91-3.85(m ,1H),3.75-3.60(m,3H),3.44-3.41(m,4H),3.40(s,3H),3.34(t,J=2.3Hz,1H ),3.27(d,J=8.0Hz,1H),3.19(t,J=8.9Hz,1H),3.03(t,J=9.2Hz,1H),2.70- 2.61(m,1H),2.34-2.26(m,4H),2.15(dd,J=12.6Hz,2.9Hz,1H),1.94-1.84(m ,4H),1.69-1.37(m,14H),1.30-1.20(m,8H),1.17(d,J=6.9Hz,3H),0.97(t,J =7.5Hz,3H),0.89(d,J=6.9Hz,3H),0.87-0.78(m,4H); MSm / z950.5767[M+Na] + .

[0787] Reference Example 17

[0788] (1) Production of 2-(cyclopropylmethoxy)isoindoline-1,3-dione

[0789] 2-Hydroxyisoindoline-1,3-dione (3.26 g, 20.0 mmol), cyclopropylmethanol (1.44 g, 20.0 mmol), and triphenylphosphine (6.30 g, 24.0 mmol) were dissolved in THF (100 mL) and ice-cooled to 0°C. A 2.2 M solution of diethyl (E)-diazene-1,2-dicarboxylate in toluene (10.9 mL, 24.0 mmol) was then added dropwise, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain 2-(cyclopropylmethoxy)isoindoline-1,3-dione (yield 3.82 g, 88%).

[0790] 1H-NMR (500MHz, CDCl3, δ): 7.86-7.82 (m, 2H), 7.77-7.73 (m, 2H), 4.04 (d, J = 7.5Hz, 2H), 1.33-1.24 (m, 1H), 0.65-0.61 (m, 2H), 0.34-0.31 (m, 2H).

[0791] (2) Production of O-(cyclopropylmethyl)hydroxylamine hydrochloride

[0792] 2-(Cyclopropylmethoxy)isoindoline-1,3-dione (3.82 g, 17.6 mmol) obtained in Reference Example 17-(1) was dissolved in dichloromethane (35.2 mL), and methylhydrazine (1.11 mL, 21.1 mmol) was added and stirred at room temperature for 2 hours. After filtering the suspension, the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, ether and 4M hydrogen chloride in 1,4-dione were added. The suspension was filtered and the obtained solid was washed with ether to obtain O-(cyclopropylmethyl)hydroxylamine hydrochloride (yield 0.992 g, yield 46%).

[0793] 1 H-NMR(500MHz,DMSO-d6,δ):10.9-10.6(m,3H),3.81-3.78(m,2H),1.10-1.02(m,1H),0.58-0.55(m,2H),0.31-0.27(m,2H).

[0794] Preparation of Compound I-116

[0795] Compound I-116 (yield 45.0 mg, 83%) was obtained by the same method using O-(cyclopropylmethyl)hydroxylamine hydrochloride obtained in Reference Example 17-(2) instead of O-allylhydroxylamine hydrochloride in [Production of Compound I-115].

[0796] 1H-NMR (500MHz, CD3OD, δ): 5.97-5.86 (m, 3H), 5.78-5.70 (m, 1H), 5.34 (d, J = 2. 86Hz,1H),5.21-5.06(m,2H),4.81(d,J=3.4Hz,1H),4.74-4.58(m,2H),4.52( s,1H),4.01-3.98(m,1H),3.98-3.94(m,2H),3.93-3.85(m,1H),3.75-3.63(m ,3H),3.45-3.41(m,4H),3.40(s,3H),3.35-3.32(m,1H),3.27(d,J=8.6Hz,1H) ,3.19(t,J=8.9Hz,1H),3.03(t,J=9.2Hz,1H),2.70-2.63(m,1H),2.34-2.23( m,4H),2.18-2.11(m,1H),1.94-1.88(m,4H),1.96-1.86(m,1H),1.68-1.38(m ,14H),1.31-1.13(m,11H),0.97(t,J=7.5Hz,3H),0.89(d,J=6.9Hz,3H),0.87 -0.79(m,4H),0.56-0.49(m,2H),0.30(q,J=5.5Hz,2H); MSm / z964.5845[M+Na] + .

[0797] Preparation of Compound I-117

[0798] After dissolving 5-oxo-ivermectin B1a (50.0 mg, 0.057 mmol) in methanol (1.14 mL), sodium acetate (28.2 mg, 0.344 mmol), lanthanum chloride heptahydrate (25.5 mg, 0.069 mmol) and O-isobutylhydroxylamine hydrochloride (43.2 mg, 0.344 mmol) were added sequentially at 0°C and stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) and preparative thin layer chromatography (n-hexane / acetone = 2:1) to obtain compound I-117 (yield 45.0 mg, yield 83%).

[0799] 1H-NMR (500MHz, CD3OD, δ): 5.95-5.88 (m, 3H), 5.78-5.69 (m, 1H), 5.35 (d, J = 3.44Hz, 1H) ,5.19-5.07(m,2H),4.81(d,J=2.9Hz,1H),4.66(q,J=13.9Hz,2H),4.50(s,1H),4.00(br s,1H),3.91(d,J=6.9Hz,2H),3.90-3.84(m,1H),3.75-3.62(m,3H),3.46-3.41(m,4H),3.41-3.37(m,3H) ,3.33(t,J=2.3Hz,1H),3.27(d,J=8.0Hz,1H),3.19(t,J=8.9Hz,1H),3.03(t,J=9.2Hz,1H),2.71-2.61(m ,1H),2.34-2.25(m,4H),2.18-2.11(m,1H),2.05-1.96(m,1H),1.94-1.87(m,4H),1.68-1.38(m,14H),1. 30-1.20(m,7H),1.17(d,J=6.9Hz,3H),0.99-0.83(m,13H),0.81(d,J=5.7Hz,4H); MSm / z966.6112[M+Na] + .

[0800] Preparation of Compound I-118 and Compound I-119

[0801] Compound I-114 (80.0 mg, 0.086 mmol) was added to a 3% aqueous solution of sulfuric acid in methanol (1.7 mL) and stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) and preparative thin layer chromatography (chloroform / ethyl acetate = 2:1) to obtain compound I-118 (yield 17.0 mg, yield 31%) and compound I-119 (yield 33.4 mg, yield 49%), respectively.

[0802] (Compound I-118)

[0803] 1H-NMR (500 MHz, CDCl3, δ): 5.90 - 5.85 (m, 1H), 5.82 - 5.81 (m, 1H), 5.77 - 5.68 (m, 2H), 5.39 - 5.29 (m, 2H), 4.78 (d, J = 2.3 Hz, 2H), 4.75 - 4.70 (m, 1H), 4.68 (d, J = 2.3 Hz, 1H), 4.58 (s, 1H), 4.01 (br s, 1H), 3.91 (s, 1H), 3.70 - 3.64 (m, 1H), 3.36 (q, J = 2.4 Hz, 1H), 3.19 (dd, J = 9.2, 1.7 Hz, 1H), 2.52 (ddd, J = 9.3, 7.0, 2.6 Hz, 1H), 2.45 - 2.44 (m, 1H), 2.34 - 2.26 (m, 2H), 1.99 - 1.93 (m, 4H), 1.77 - 1.73 (m, 1H), 1.67 - 1.59 (m, 4H), 1.57 - 1.40 (m, 8H), 1.34 (t, J = 11.7 Hz, 1H), 1.17 (d, J = 6.9 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H), 0.87 - 0.78 (m, 7H); MS m / z 660.4483 [M + Na] + .

[0804] (Compound I-119)

[0805] 1H-NMR (500MHz, CDCl3, δ): 5.93-5.89 (m, 1H), 5.82 (dd, J = 2.3, 1.2Hz, 1H), 5.79-5.68 (m, 2H), 5.38 (t, J = 4.9Hz, 1H), 4.96(dt,J=10.9,1.7Hz,1H),4.81(d,J=3.4Hz,1H),4.78(d,J=2.3Hz,2H),4.76-4.63(m,2H),4.58(s,1H),3.95(br s,1H),3.92(s,1H),3.86(dd,J=9.2,6.3Hz,1H),3.70-3.63(m,1H),3.59-3.51(m,1H),3 .48(s,3H),3.38(t,J=2.3Hz,1H),3.22(d,J=7.5Hz,1H),3.16(t,J=9.2Hz,1H),2.60(br s,1H),2.56-2.48(m,1H),2.45-2.43(m,1H),2.36-2.20(m,3H),2.12(s ,1H),2.03-1.92(m,4H),1.80-1.74(m,1H),1.70-1.61(m,1H),1.57-1. 36(m,12H),1.27(d,J=6.3Hz,3H),1.15(d,J=6.9Hz,3H),0.93(t,J=7.2Hz,3H),0.87-0.80(m,4H),0.78(d,J=5.7Hz,3H); MSm / z804.5444[M+Na] + .

[0806] Preparation of Compound I-120

[0807] Compound I-120 (yield 11.7 mg, 20%) was obtained by the same method using O-ethylhydroxylamine instead of O-isobutylhydroxylamine hydrochloride in [Production of Compound I-117].

[0808] 1H-NMR (500MHz, CDCl3, δ): 5.93-5.91 (dd, J=8.0, 2.3Hz, 1H), 5.831-5.827 (m, 1H), 5.79-5.69 (m, 2H), 5.42-5. 36(m,2H),4.98(d,J=11.5Hz,1H),4.77-4.65(m,3H),4.64(s,1H),4.31(t,J=2.3Hz,2H),3.99(s,1H),3.94(br s,1H),3.87-3.74(m,4H),3.69-3.59(m,2H),3.50-3.42(m,7H),3.67- 3.36(m,1H),3.26-3.14(m,3H),2.53-2.94(m,2H),2.35-2.20(m,4H), 1.98-1.94(m,4H),1.77-1.75(m,1H),1.67-1.35(m,16H),1.27-1.25( m,7H),1.17-1.15(m,2H),0.94-0.78(m,11H); MSm / z949.5826[M+NH4] + .

[0809] Preparation of Compound I-121

[0810] Compound I-121 (yield 21.9 mg, 58%) was obtained by the same method using O-(2-hydroxyethyl)hydroxylamine hydrochloride obtained in Reference Example 5-(2) instead of O-isobutylhydroxylamine hydrochloride in [Production of Compound I-117].

[0811] 1H-NMR (500MHz, CDCl3, δ):5.93-5.88(m,1H),5.79-5.77(m,1H),5.76-5.70(m,2H),5.42-5.35(m,2H) ,5.00-4.94(m,1H),4.77(d,J=3.4Hz,1H),4.74-4.63(m,2H),4.60(s,1H),4.39-4.29(m,2H),3.94(br s,1H),3.91(s,1H),3.86-3.79(m,1H),3.79-3.73(m,1H),3.70-3.59(m,4H),3.51-3.45(m,1H),3.43(s,3H),3.42(s,3 H),3.39-3.37(m,1H),3.36(s,3H),3.26-3.20(m,2H),3.16(t,J=9.2Hz,1H),2.55-2.46(m,2H),2.36-2.30(m,2H),2.3 0-2.18(m,2H),2.00-1.95(m,1H),1.93(d,J=2.3Hz,3H),1.80-1.73(m,1H),1.67-1.63(m,1H),1.68-1.33(m,7H),1.32 -1.23(m,9H),1.16(d,J=6.9Hz,3H),0.93(t,J=7.2Hz,3H),0.90-0.83(m,6H),0.82-0.75(m,4H); MSm / z946.5528[M+H] + .

[0812] Preparation of Compound I-122

[0813] Compound I-122 (yield 21.9 mg, 58%) was obtained by the same method using O-(2-methoxyethyl)hydroxylamine hydrochloride obtained in Reference Example 5-(2) instead of O-isobutylhydroxylamine hydrochloride in [Production of Compound I-117].

[0814] 1H-NMR (500MHz, CDCl3, δ):5.93-5.88(m,1H),5.79-5.77(m,1H),5.76-5.70(m,2H),5.42-5.35(m,2H) ,5.00-4.94(m,1H),4.77(d,J=3.4Hz,1H),4.74-4.63(m,2H),4.60(s,1H),4.39-4.29(m,2H),3.94(br s,1H),3.91(s,1H),3.86-3.79(m,1H),3.79-3.73(m,1H),3.70-3.59(m,4H),3.51-3.45(m,1H),3.43(s,3H),3.42(s,3 H),3.39-3.37(m,1H),3.36(s,3H),3.26-3.20(m,2H),3.16(t,J=9.2Hz,1H),2.55-2.46(m,2H),2.36-2.30(m,2H),2.3 0-2.18(m,2H),2.00-1.95(m,1H),1.93(d,J=2.3Hz,3H),1.80-1.73(m,1H),1.67-1.63(m,1H),1.68-1.33(m,7H),1.32 -1.23(m,9H),1.16(d,J=6.9Hz,3H),0.93(t,J=7.2Hz,3H),0.90-0.83(m,6H),0.82-0.75(m,4H); MSm / z946.5528[M+H] + .

[0815] Preparation of Compound I-123

[0816] Compound I-123 (yield 15.9 mg, 49%) was obtained by the same method using 3-(aminooxy)propan-1-ol hydrochloride obtained in Reference Example 8 instead of O-isobutylhydroxylamine hydrochloride in [Production of Compound I-117].

[0817] 1H-NMR (500MHz, CDCl3, δ):5.93-5.88(m,1H),5.81-5.78(m,1H),5.77-5.66(m,2H),5.42-5.34(m,2H),4.99 -4.92(m,1H),4.76(d,J=2.9Hz,1H),4.73-4.68(m,1H),4.66-4.61(m,1H),4.54(s,1H),4.36(t,J=5.7Hz,2H ),3.98-3.94(m,1H),3.94-3.91(m,1H),3.86-3.79(m,1H),3.78-3.72(m,3H),3.70-3.59(m,2H),3.51-3.4 4(m,1H),3.42(s,3H),3.41(s,3H),3.34(t,J=2.3Hz,1H),3.26-3.19(m,2H),3.15(t,J=9.2Hz,1H),2.59(br s,1H),2.54-2.47(m,1H),2.36-2.18(m,4H),2.00-1.91(m,6H),1.77-1.72(m,2H),1.67-1.62(m,1H),1.58-1.33(m,11H),1.29-1.23( m,7H),1.15(d,J=6.9Hz,3H),0.92(t,J=7.2Hz,3H),0.86-0.83(m,1H),0.84(d,J=6.9Hz,3H),0.81-0.75(m,4H); MSm / z968.5347[M+Na] + .

[0818] Production of 5-[(carboxymethoxy)imino]-ivermectin B1a

[0819] 5-[(carboxymethoxy)imino]-ivermectin B1a (yield 108 mg, yield 83%) was obtained in the same manner using 2-(aminooxy)acetic acid 1 / 2 hydrochloride instead of O-isobutylhydroxylamine hydrochloride in [Production of Compound I-117].

[0820] 1H-NMR (500MHz, CD3OD, δ): 6.27-6.22 (m, 1H), 6.23-6.16 (m, 1H), 6.01-5.85 (m, 2H), 5.78-5.66 (m, 1H), 5.33 (d, J = 3.4Hz, 1H), 5.29- 5.21(m,1H),5.20-4.98(m,2H),4.81-4.74(m,1H),4.71-4.54(m,4H),4.00-3.96(m,1H),3.95-3.92(m,1H),3.92-3.82(m,1H),3.7 5-3.60(m,3H),3.43-3.41(m,1H),3.40(s,3H),3.38(s,3H),3.34-3.31(m,1H),3.30-3.27(m,2H),3.26-3.21(m,1H),3.17(t,J=8. 9Hz,1H),3.01(t,J=8.9Hz,1H),2.69-2.62(m,1H),2.60-2.50(m,1H),2.33-2.23(m,4H),2.16-2.09(m,1H),1.92-1.87(m,3H),1.85 -1.80(m,1H),1.68-1.36(m,9H),1.35-1.26(m,1H),1.26-1.22(m,4H),1.21( d, J=6.3Hz, 4H), 1.16 (d, J=6.9Hz, 3H), 0.98-0.91 (m, 3H), 0.91-0.76 (m, 7H).

[0821] Preparation of Compound I-124

[0822] 5-[(Carboxymethoxy)imino]-ivermectin B1a (24 mg, 0.025 mmol) was dissolved in dichloromethane (0.25 mL), and DIPEA (22 μL, 0.127 mmol) and HATU (14.5 mg, 0.038 mmol) were added and stirred at room temperature for 15 minutes. After that, 2M methylamine THF solution (38 μL, 0.076 mmol) was added and stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer silica gel column chromatography (chloroform / methanol system) to obtain compound I-124 (yield 6.2 mg, yield 25%).

[0823] 1H-NMR(500MHz,CDCl3,δ):7.05(br s,1H),5.89-5.83(m,1H),5.82-5.66(m,2H),5.46-5.35(m,2H),5.00-4.9 3(m,1H),4.80-4.70(m,4H),4.68-4.59(m,2H),4.16-4.02(m,1H),3.94(br s,1H),3.88-3.79(m,1H),3.79-3.72(m,1H),3.70-3.58(m,2H),3.50-3.45(m,1H),3.44-3.42(m,3H),3.42-3.41(m,3H),3.38-3.32( m,1H),3.28-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.83-2.76(m,3H),2.59-2.48(m,2H),2.38-2.18(m,4H),2.01-1.95(m,1H),1.92(br s,3H),1.80-1.72(m,2H),1.71-1.34(m,8H),1.29-1.21(m,9H),1.16(d,J =5.7Hz,4H),0.95-0.91(m,3H),0.87-0.76(m,9H); MSm / z976.5746[M+NH4] + .

[0824] Preparation of Compound I-125

[0825] Compound I-125 (yield 3.3 mg, 12%) was obtained by the same method using ammonium chloride instead of methylamine in [Production of Compound I-124].

[0826] 1H-NMR (500MHz, CDCl3, δ): 7.04 (q, J = 4.6Hz, 1H), 5.97-5.92 (m, 1H), 5.87-5.84 (m, 1H), 5.81-5.68 (m, 2H), 5.43-5.34(m,2H),5.00-4.93(m,1H),4.79-4.60(m,6H),4.13-4.06(m,1H),4.10(d,J=6.9Hz,1H),3.93(br s,1H),3.85-3.78(m,1H),3.77-3.71(m,1H),3.70-3.57(m,2H),3.49-3.43(m,1H),3.42-3.41(m,3H),3.41-3.39 (m,3H),3.35-3.32(m,1H),3.25-3.18(m,2H),3.17-3.11(m,1H),2.55-2.47(m,1H),2.36-2.17(m,5H),2.03-2.0 1(m,2H),2.00-1.94(m,1H),1.91(s,3H),1.79-1.73(m,1H),1.67-1.62(m,1H),1.59-1.31(m,12H),1.28-1.21(m ,9H),1.15(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,2H),0.84(d,J=6.9Hz,3H),0.82-0.76(m,4H); MSm / z962.5589[M+H] + .

[0827] Preparation of Compound I-126

[0828] Compound I-126 (yield 5.5 mg, 13%) was obtained by the same method using O-(oxetan-3-ylmethyl)hydroxylamine obtained in Reference Example 13-(2) instead of O-isobutylhydroxylamine hydrochloride in [Production of Compound I-117].

[0829] 1H-NMR (500MHz, CDCl3, δ): 5.95-5.86 (m, 1H), 5.81-5.77 (m, 1H), 5.77-5.69 (m, 2H), 5.43-5.34 (m, 2H), 5.00-4. 93(m,1H),4.80-4.75(m,3H),4.74-4.63(m,2H),4.57-4.49(m,3H),4.43(d,J=6.9Hz,2H),4.01(s,1H),3.94(br s,1H),3.86-3.79(m,1H),3.78-3.73(m,1H),3.69-3.59(m,2H),3.51-3.46(m,1H),3.43(s,3H),3.42(s,3H),3.40-3 .34(m,2H),3.27-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.55-2.47(m,2H),2.37-2.31(m,2H),2.29-2.18(m,2H),1.99- 1.94(m,1H),1.90(s,3H),1.79-1.74(m,1H),1.68-1.40(m,7H),1.40-1.33(m,2H),1.27(d,J=6.3Hz,4H),1.26-1.24 (m,5H),1.16(d,J=6.9Hz,3H),0.93(t,J=7.4Hz,3H),0.85(d,J=6.9Hz,4H),0.83-0.76(m,5H); MSm / z958.5528[M+H] + .

[0830] Preparation of Compound I-127

[0831] Compound I-127 (yield 4.0 mg, 15%) was obtained by the same method as in [Production of Compound I-89] and [Production of Compound I-92] using 5-oxo-ivermectin B1a instead of 3,4α-dihydro-5-oxo-ivermectin B1a in [Production of Compound I-89].

[0832] 1H-NMR (500MHz, CDCl3, δ): 5.93 (td, J = 2.4, 10.6Hz, 1H), 5.84-5.82 (m, 1H), 5.80-5.68 (m, 2H), 5.44-5.36 (m, 2H), 4.97 (b rd,J=9.7Hz,1H),4.79-4.73(m,2H),4.69(s,1H),4.68-4.64(m,1H),4.37-4.33(m,1H),4.10(d,J=12.0Hz,1H),3.94(br s,1H),3.86-3.80(m,1H),3.80-3.74(m,1H),3.71-3.59(m,2H),3.51-3.44(m,2H),3.43(s,3H),3.42(s,3H),3.40- 3.36(m,1H),3.27-3.20(m,2H),3.16(t,J=8.9Hz,1H),2.56-2.49(m,1H),2.37-2.19(m,5H),2.00-1.93(m,5H),1.79 -1.74(m,1H),1.68-1.64(m,1H),1.60-1.34(m,9H),1.27(d,J=6.3Hz,4H),1.25(d,J=6.3Hz,5H),1.16(d,J=6.9Hz,3H),1 .19-1.14(m,1H),0.93(t,J=7.4Hz,3H),0.88-0.84(m,4H),0.84-0.75(m,7H),0.63-0.60(m,2H); MSm / z1089.6658[M+NH4] + .

[0833] Preparation of Compound I-128

[0834] Compound I-128 (yield 9.7 mg, 34%) was obtained by the same method as in [Production of Compound I-78] using trifluoromethanesulfonic anhydride instead of phenylsulfonyl chloride.

[0835] 1H-NMR (500MHz, CDCl3, δ): 6.61 (t, J = 5.4Hz, 1H), 5.86 (d, J = 10.9Hz, 1H), 5. 81-5.74(m,1H),5.72-5.65(m,1H),5.46-5.38(m,2H),5.00(s,1H),4.96(br d,J=11.5Hz,1H),4.78(d,J=3.4Hz,1H),4.74-4.65(m,2H),4.32-4.19(m,2H),3.95(br s,1H),3.88-3.81(m,1H),3.81-3.75(m,1H),3.72-3.61(m,2H),3.56-3.47(m,3H),3.46(s,3H),3.44(s,3H),3.28-3.20(m,2 H),3.18(t,J=9.2Hz,1H),2.80(dd,J=12.0,3.4Hz,1H),2.73-2.64(m,1H),2.55-2.47(m,1H),2.35(dd,J=12.3,4.3Hz,2H),2. 32-2.20(m,2H),1.96-1.82(m,4H),1.77-1.71(m,1H),1.68(d,J=11.5Hz,1H),1.60-1.39(m,13H),1.29(d,J=5.7Hz,3H),1.28 -1.25(m,4H),1.18(t,J=6.0Hz,6H),0.94(t,J=7.2Hz,3H),0.85(d,J=6.9Hz,3H),0.82-0.77(m,4H); MSm / z1082.5459[M+NH4] + .

[0836] Preparation of Compound I-129

[0837] After dissolving the compound I-64 (0.180 g, 0.187 mmol) obtained in [Manufacture of Compound I-64] in dichloromethane (3.7 mL), dimethyl sulfoxide (1.33 mL, 18.7 mmol) and triethylamine (0.470 mL, 3.37 mmol) were added in sequence. Subsequently, sulfur trioxide pyridine coordination compound (0.268 g, 1.69 mmol) was added and stirred at room temperature for 19 hours. Water was added to the reaction solution and extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-129 (yield 0.167 g, yield 93%).

[0838] 1H-NMR (500MHz, CDCl3, δ): 6.49-6.39(m,1H),5.97-5.83(m,1H),5.82-5.67(m,2H),5.54(s,1H),5.48-5.37(m,1H),5.00(s,1H),4.97(d ,J=9.7Hz,1H),4.80(d,J=3.4Hz,1H),4.76-4.66(m,2H),4.68-4.57(m,2H),4.43(q,J=6.3Hz,1H),4.21(dd,J=11.5,6.3Hz,1H),3.96(br s,1H),3.94-3.86(m,1H),3.78-3.64(m,2H),3.53(s,3H),3.47(s,3H),3.35(t,J=9.2Hz,1H),3.23(d,J=7.5Hz,1 H),2.88-2.77(m,4H),2.74-2.64(m,1H),2.64-2.55(m,1H),2.52(m,1H),2.40-2.32(m,1H),2.32-2.22(m,2H),2 .19-2.10(m,1H),1.98-1.81(m,3H),1.80-1.72(m,1H),1.68(d,J=12.6Hz,1H),1.62-1.39(m,13H),1.34-1.23(m ,6H),1.20-1.14(m,6H),0.94(t,J=7.5Hz,3H),0.85(d,J=6.9Hz,3H),0.83-0.77(m,4H); MSm / z976.5746[M+NH4] + .

[0839] Preparation of Compound I-130

[0840] Compound I-2 (50.0 mg, 0.056 mmol) obtained in [Production of Compound I-2] was dissolved in DMF (1.12 mL). Potassium carbonate (93.0 mg, 0.674 mmol), (S)-3-chloropropane-1,2-diol (0.0375 mL, 0.449 mmol), and sodium iodide (0.842 mg, 5.62 μmol) were added sequentially at room temperature, and the mixture was stirred at 100°C for 12 days. Aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin-layer chromatography (chloroform:acetone = 2:1) to obtain Compound I-130 (yield 4.60 mg, 5%).

[0841] 1H-NMR (500MHz, CDCl3, δ):5.87-5.83(m,1H),5.79-5.66(m,2H),5.46-5.38(m,2H),4.99-4.92( m,2H),4.78(d,J=3.4Hz,1H),4.72-4.63(m,2H),4.24-4.14(m,2H),4.04-3.92(m,1H),3.95(br s,1H),3.88-3.81(m,1H),3.78(dq,J=9.5,6.2Hz,1H),3.73-3.60(m,4H),3.53-3.47(m,1H),3.46(s,3H),3.4 4(s,3H),3.28-3.21(m,2H),3.18(t,J=9.2Hz,1H),2.83-2.77(m,1H),2.69-2.61(m,1H),2.55-2.45(m,2H),2 .38-2.20(m,5H),2.15-2.10(m,1H),1.94-1.84(m,3H),1.77-1.73(m,1H),1.70-1.37(m,15H),1.31-1.25(m, 6H),1.21-1.14(m,6H),0.94(t,J=7.4Hz,3H),0.85(d,J=6.9Hz,3H),0.81-0.78(m,4H); MSm / z986.5457[M+Na] + .

[0842] Preparation of Compound I-131

[0843] Compound I-129 (0.500 g, 0.521 mmol) obtained in [Production of Compound I-129] was dissolved in methanol (10 mL), and sodium borohydride (0.0592 g, 1.56 mmol) was added, followed by stirring at room temperature for 30 minutes. An aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-131 (yield 0.435 g, yield 89%).

[0844] 1H-NMR (500MHz, CDCl3, δ): 6.42 (q, J = 4.6Hz, 1H), 5.90-5.82 (m, 1H), 5.79-5.66 (m, 2 H),5.46-5.37(m,2H),4.99(s,1H),4.96(d,J=10.9Hz,1H),4.77(d,J=3.4Hz,1H),4. 73-4.65(m,2H),4.65-4.56(m,2H),3.99-3.90(m,2H),3.87-3.79(m,2H),3.72-3.64 (m,1H),3.65-3.56(m,2H),3.44(s,3H),3.42(s,3H),3.25(t,J=9.2Hz,1H),3.22(d, J=9.2Hz,1H),2.89-2.77(m,4H),2.70-2.62(m,1H),2.54-2.46(m,1H),2.38-2.31( m,1H),2.30-2.16(m,2H),2.01-1.94(m,1H),1.93-1.82(m,4H),1.78-1.70(m,1H),1 .67(d,J=12.6Hz,1H),1.62-1.34(m,13H),1.31-1.21(m,7H),1.17-1.11(m,6H),0.9 3(t,J=7.2Hz,3H),0.84(d,J=6.3Hz,3H),0.82-0.74(m,4H); MSm / z978.5912[M+NH4] + .

[0845] Preparation of Compound I-132

[0846] After dissolving the compound I-48 (25 mg, 0.026 mmol) obtained in [Manufacturing of Compound I-48] in DMF (0.53 mL), DIPEA (0.037 mL, 0.211 mmol), 5-aminopyrimidine (10 mg, 0.105 mmol) and 50% propylphosphonic anhydride ethyl acetate solution (0.062 mL, 0.105 mmol) were added and stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with a mixed solution of ethyl acetate / hexane, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin layer silica gel column chromatography (n-hexane: ethyl acetate = 1: 2) to obtain compound I-132 (yield 19.5 mg, yield 72%).

[0847] 1H-NMR(500MHz,CD3OD,δ):9.07(s,2H),8.88(s,1H),5.93-5.86(m,2H),5.79-5.67(m,1H),5.34 -5.31(m,1H),5.19-5.10(m,2H),4.96(s,1H),4.80-4.77(m,1H),4.71(d,J=5.2Hz,4H),3.98(br s,1H),3.91-3.83(m,1H),3.74-3.61(m,3H),3.40(s,3H),3.39(s,3H),3.44-3.37(m,1H),3.25(br d,J=8.6Hz,1H),3.17(t,J=8.9Hz,1H),3.01(t,J=9.2Hz,1H),2.85-2.80(m,1H),2 .69-2.59(m,2H),2.32-2.25(m,4H),2.04-2.00(m,1H),1.94-1.79(m,3H),1.63-1 .44(m,12H),1.28-1.19(m,8H),1.15(d,J=6.9Hz,3H),1.12(d,J=6.3Hz,3H),0.95 (t,J=7.5Hz,3H),0.86(d,J=6.9Hz,3H),0.83-0.77(m,4H); MSm / z1025.5698[M+H] + .

[0848] Preparation of Compound I-133

[0849] After dissolving the compound I-23 (20 mg, 0.021 mmol) obtained in [Manufacturing of Compound I-23] in dichloromethane (0.45 mL), DIPEA (0.011 mL, 0.064 mmol) and 2,5-dioxopyrrolidine-1-yl methylcarbamate (4.4 mg, 0.026 mmol) were added and stirred at room temperature for 4 hours. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with chloroform, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol system) to obtain compound I-133 (yield 16.1 mg, yield 76%).

[0850] 1H-NMR (500MHz, CDCl3, δ): 5.83 (dt, J = 10.3, 2.3Hz, 1H), 5.77-5.65 (m, 2H), 5.44-5.33 (m, 2H), 4.98-4.91 (m, 2H), 4.76 (br d,J=3.4Hz,1H),4.72-4.57(m,2H),4.23-4.09(m,2H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.72(m,1H),3.71-3.57(m,2H),3.43(s,3H),3.41(s,3H),3.52-3.43(m,2H),3.29-3. 18(m,2H),3.16(t,J=9.2Hz,1H),2.85-2.77(m,1H),2.73(s,3H),2.68-2.56(m,1H),2.56-2.42(m,1H),2.37-2.30(m,2 H),2.30-2.16(m,2H),1.96-1.76(m,3H),1.78-1.69(m,1H),1.66(d,J=12.60Hz,1H),1.59-1.35(m,13H),1.31-1.23( m,8H),1.16(d,J=6.87Hz,5H),0.91(t,J=7.45Hz,3H),0.83(d,J=6.87Hz,3H),0.81-0.74(m,4H); MSm / z990.5902[M+H] + .

[0851] Preparation of Compound I-134

[0852] Compound I-134 (yield 4.6 mg, 17%) was obtained by the same method as in [Production of Compound I-133] using Compound I-11 obtained in [Production of Compound I-11] instead of Compound I-23 in [Production of Compound I-133].

[0853] 1H-NMR (500MHz, CDCl3, δ): 5.88-5.80 (m, 1H), 5.76-5.63 (m, 2H), 5.43-5.3 3(m,2H),4.98-4.89(m,2H),4.78-4.60(m,4H),4.34-4.20(m,4H),3.93(br s,1H),3.86-3.79(m,1H),3.79-3.72(m,1H),3.71-3.58(m,2H),3.52-3.38(m,8H),3.27 -3.13(m,3H),2.81-2.73(m,4H),2.64-2.54(m,1H),2.53-2.46(m,1H) ,2.36-2.30(m,2H),2.28-2.19(m,2H),1.95-1.78(m,4H),1.78-1.71(m ,1H),1.69-1.63(m,1H),1.59-1.34(m,7H),1.31-1.23(m,8H),1.19-1 .10(m,7H),0.96-0.88(m,3H),0.87-0.72(m,8H); MSm / z991.5743[M+H] + .

[0854] Preparation of Compound I-135

[0855] Compound I-135 (yield 19.7 mg, 90%) was obtained by the same method as in [Production of Compound I-133] using 2-isocyanate propane instead of 2,5-dioxopyrrolidin-1-ylmethylcarbamate.

[0856] 1H-NMR (500MHz, CDCl3, δ): 5.84 (dd, J=10.31, 2.29Hz, 1H), 5.76-5.64 (m, 2H), 5.41-5.35 (m, 2H), 4.98-4.90 (m, 2H), 4.76 (br s,1H),4.69-4.60(m,2H),4.18-4.09(m,2H),3.93(br s,1H),3.84-3.72(m,3H),3.69-3.59(m,2H),3.49-3.38(m,8H),3.38-3.32(m,1H),3.26-3. 12(m,3H),2.84-2.77(m,1H),2.66-2.57(m,1H),2.53-2.46(m,1H),2.35-2.18(m,4H),1.94 -1.81(m,3H),1.73(d,J=10.31Hz,1H),1.65(d,J=10.31Hz,1H),1.58-1.35(m,11H),1.28-1.22(m,7H),1.18-1. 12(m,6H),1.12-1.07(m,6H),0.96-0.89(m,3H),0.89-0.80(m,4H),0.80-0.72(m,4H); MSm / z1018.6223[M+NH4] + .

[0857] Reference Example 18

[0858] (1) Production of (S)-2-((5-oxopyrrolidin-3-yl)oxy)isoindoline-1,3-dione

[0859] 2-Hydroxyisoindoline-1,3-dione (1.63 g, 10.0 mmol), (R)-4-hydroxypyrrolidin-2-one (1.01 g, 10.0 mmol), and triphenylphosphine (3.66 g, 21.0 mmol) were dissolved in THF (100 mL) and cooled to 0°C. A 2.2 M solution of diethyl (E)-diazene-1,2-dicarboxylate in toluene (9.55 mL, 21.0 mmol) was then added dropwise, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain (S)-2-((5-oxopyrrolidin-3-yl)oxy)isoindoline-1,3-dione (yield 0.300 g, 12%).

[0860] 1H-NMR (500MHz, CDCl3, δ): 7.88-7.85 (m, 2H), 7.80-7.78 (m, 2H), 5.12-5.08 (m, 1H), 3.83-3.81 (m, 1H), 3.74-3.70 (m, 1H), 2.80-2.69 (m, 2H).

[0861] (2) Production of (S)-4-(aminooxy)pyrrolidin-2-one

[0862] (S)-2-((5-oxopyrrolidin-3-yl)oxy)isoindoline-1,3-dione (yield 0.300 g, 1.22 mmol) obtained in Reference Example 18-(1) was dissolved in dichloromethane (12.2 mL), and methylhydrazine (0.0710 mL, 1.46 mmol) was added, followed by stirring at room temperature for 2 hours. The suspension was filtered, and the solvent was distilled off under reduced pressure to obtain (S)-4-(aminooxy)pyrrolidin-2-one (yield 0.120 g, yield 85%).

[0863] 1 H-NMR (500MHz, CDCl3, δ): 4.43-4.41(m,1H), 3.56-3.49(m,2H), 2.55-2.50(m,1H), 2.41-2.37(m,1H).

[0864] Preparation of Compound I-136

[0865] Compound I-136 (yield 12.8 mg, 38%) was obtained by the same method using (S)-4-(aminooxy)pyrrolidin-2-one obtained in Reference Example 18-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0866] 1H-NMR (500MHz, CDCl3, δ): 5.90-5.80 (m, 1H), 5.79-5.65 (m, 3H), 5.45-5.3 7(m,2H),4.99-4.93(m,2H),4.90-4.86(m,1H),4.80-4.75(m,1H),4.70-4. 58(m,2H),3.94(brs,1H),3.87-3.81(m,1H),3.81-3.73(m,1H),3.71-3.6 0(m,3H),3.58-3.46(m,2H),3.45(s,3H),3.43(s,3H),3.28-3.20(m,2H),3 .17(t,J=9.2Hz,1H),2.93-2.76(m,1H),2.69-2.59(m,2H),2.57-2.46(m, 2H),2.38-2.19(m,5H),1.95-1.82(m,4H),1.79-1.72(m,1H),1.69-1.65(m ,1H),1.60-1.37(m,12H),1.31-1.24(m,8H),1.21-1.14(m,5H),0.93(t,J= 7.4Hz, 3H), 0.85 (d, J=6.9Hz, 3H), 0.81-0.75 (m, 4H); MSm / z973.5626[M+H] + .

[0867] Reference Example 19

[0868] Preparation of O-amino-D-serine dihydrochloride

[0869] (R)-4-aminoisothiazolinone Oxazolidin-3-one ((R)-4-aminoisoxazolidine-3-one) (0.102 g, 1.00 mmol), 4N hydrogen chloride in 1,4-diol The oxane solution (2.50 mL, 10.0 mmol) was dissolved in water (1 mL) and stirred at 60° C. for 19 hours. The solvent was distilled off under reduced pressure to obtain O-amino-D-serine dihydrochloride (yield 0.222 g, quantitative).

[0870] 1 H-NMR (500MHz, CDCl3, δ): 4.60-4.51 (m, 2H), 4.49-4.47 (m, 1H).

[0871] Preparation of Compound I-137

[0872] Compound I-137 (yield 48.2 mg, 86%) was obtained by the same method using O-amino-D-serine dihydrochloride obtained in Reference Example 19 instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0873] 1 H-NMR (500MHz, CD3OD, δ): 5.94-5.82 (m, 2H), 5.78-5.69 (m, 1H), 5.34 (d, J = 2.9Hz, 1H), 5.20-5.10 (m, 2H), 4.85 (s,1H),4.80(d,J=2.9Hz,1H),4.67(s,2H),4.51(dd,J=12.0,3.4Hz,1H),4.34(dd,J=12.0,7.5Hz,1H),3.99(br s,1H),3.93-3.83(m,2H),3.79-3.62(m,3H),3.45-3.42(m,4H),3.46 -3.41(m,1H),3.42(m,3H),3.40(s,3H),3.32-3.25(m,3H),3.19(t,J=8.9Hz,1H),3.03(t,J=9 .2Hz,1H),2.81(dd,J=12.9,3.2Hz,1H),2.70-2.56(m,2H),2.34-2.25(m,4H),2.06-2.01(m,1 H),1.95-1.79(m,3H),1.43-1.40(m,1H),1.71-1.37(m,13H),1.33-1.20(m,9H),1.20-1.13(m ,6H),0.96(t,J=7.5Hz,3H),0.88(d,J=6.9Hz,3H),0.81(d,J=5.7Hz,4H); MSm / z977.5604[M+H] + .

[0874] Preparation of Compound I-138

[0875] Compound I-138 (yield 2.46 mg, 13%) was obtained by using compound I-137 obtained in [Production of Compound I-137] instead of compound I-48 in [Production of Compound I-132] and methylamine hydrochloride instead of 5-aminopyrimidine in the same manner as [Production of Compound I-132].

[0876] 1H-NMR(500MHz,CD3OD,δ):5.92-5.82(m,2H),5.76-5.69(m,1H),5.35(d,J=3.4Hz,1H) ,5.20-5.11(m,2H),4.81-4.79(m,1H),4.67-4.63(m,1H),4.34-4.17(m,2H),3.99(br s,1H),3.93-3.84(m,1H),3.75-3.61(m,4H),3.46-3.43(m,1H),3.42(s,3H),3.40(s,3H),3.28-3.24(m,1H),3.19( t,J=8.9Hz,1H),3.03(t,J=9.2Hz,1H),2.83-2.78(m,1H),2.77-2.72(m,3H),2.69-2.52(m,2H),2.34-2.26(m,4H), 2.07-2.01(m,1H),1.92-1.75(m,3H),1.67-1.38(m,12H),1.31-1.24(m,7H),1.22(d,J=6.3Hz,3H),1.17(d,J=6.9H z,3H),1.14(d,J=6.3Hz,3H),0.96(t,J=7.4Hz,3H),0.88(d,J=6.9Hz,3H),0.83-0.69(m,4H); MSm / z990.5907[M+H] + .

[0877] Reference Example 20

[0878] (1) Production of methyl (R)-2-((1,3-dioxoisoindolin-2-yl)oxy)propionate

[0879] By using methyl (S)-2-hydroxypropanoate instead of (R)-4-hydroxypyrrolidin-2-one in Reference Example 18-(1), methyl (R)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (yield 1.91 g, yield 77%) was obtained by the same method as Reference Example 18-(1).

[0880] 1 H-NMR (500MHz, CDCl3, δ): 7.86-7.83 (m, 2H), 7.77-7.74 (m, 2H), 4.87 (q, J = 6.9Hz, 1H), 3.79 (s, 3H), 1.65 (d, J = 6.9Hz, 3H).

[0881] (2) Production of methyl (R)-2-(aminooxy)propionate

[0882] By using (R)-2-((1,3-dioxoisoindolin-2-yl)oxy)propionic acid methyl ester obtained in Reference Example 20-(2) instead of (S)-2-((5-oxopyrrolidin-3-yl)oxy)isoindolin-1,3-dione in Reference Example 18-(2), (R)-2-(aminooxy)propionic acid methyl ester was obtained by the same method as in Reference Example 18-(2) (yield 0.892 g, yield 98%).

[0883] 1 H-NMR (500MHz, CDCl3, δ): 4.45 (q, J=6.9Hz, 1H), 3.80 (s, 3H), 1.47 (d, J=7.4Hz, 3H).

[0884] Preparation of Compound I-139

[0885] Compound I-139 (yield 25.8 mg, 46%) was obtained by the same method using (R)-2-(aminooxy)propionic acid methyl ester obtained in Reference Example 20-(2) instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0886] 1 H-NMR (500MHz, CDCl3, δ): 5.91-5.80(m,1H),5.77-5.66(m,2H),5.46-5.36(m,2H),5.01(s,1H),4.98-4.93(m,1H),4.80-4.53(m,5H),3.94(br s,1H),3.88-3.75(m,2H),3.73(s,3H),3.71-3.61(m,2H),3.53-3.46(m,2H),3.45(s,3H),3.43 (s,3H),3.27-3.20(m,2H),3.17(t,J=9.2Hz,1H),2.84-2.78(m,1H),2.68-2.57(m,1H),2.50(br s,1H),2.39-2.20(m,5H),1.98-1.81(m,3H)1.76(br s,1H),1.71-1.62(m,1H)1.59-1.39(m,16H),1.32-1.22(m,12H),1.19-1.14(m,3H), 1.13-1.10(m,2H),0.93(t,J=7.2Hz,3H),0.90-0.75(m,9H); MSm / z993.5910[M+NH4] + .

[0887] Preparation of Compound I-140

[0888] After dissolving the compound I-139 (13.8 mg, 0.0141 mmol) and methylamine hydrochloride (5.73 mg, 0.0849 mmol) obtained in [Manufacturing of Compound I-139] in dichloromethane (0.47 mL), DIPEA (0.030 mL, 0.170 mmol) and 1.4 M trimethylaluminum hexane solution (0.061 mL, 0.0849 mmol) were added sequentially and stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate = 1: 2) to obtain compound I-140 (yield 7.35 mg, yield 53%).

[0889] 1 H-NMR (500MHz, CDCl3, δ): 6.52-6.37 (m, 1H), 5.71 (s, 2H), 5.40 (d, J = 3.4Hz, 2H), 4.94 (s, 2H), 4.73-4.60 (m, 4H), 3.93 (br s,1H),3.86-3.73(m,2H),3.71-3.60(m,2H),3.51-3.45(m,1H),3.44(s,3H),3.42(s,3H),3.28-3.19(m,2H ),3.17(t,J=9.2Hz,1H),2.79(d,J=5.2Hz,2H),2.85-2.78(m,3H),2.77-2.72(m,1H),2.65-2.56(m,1H),2. 52-2.46(m,1H),2.36-2.19(m,4H),1.91(s,4H),1.81-1.36(m,15H),1.26(dd,J=10.9,6.3Hz,7H),1.16(dd ,J=6.9,4.6Hz,6H),0.92(t,J=7.4Hz,3H),0.84(d,J=6.9Hz,3H),0.81-0.73(m,4H); MSm / z992.6062[M+NH4] + .

[0890] Preparation of Compound I-141

[0891] After dissolving the compound I-48 (25 mg, 0.026 mmol) obtained in [Manufacturing of Compound I-48] in THF (0.53 mL), DIPEA (0.033 mL, 0.190 mmol), 2-aminopyrazine (12 mg, 0.127 mmol), DMAP (11.6 mg, 0.095 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (18.20 mg, 0.095 mmol) were added and stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with a mixed solution of ethyl acetate / hexane, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-141 (yield 6.1 mg, yield 19%).

[0892] 1 H-NMR (500MHz, CDCl3, δ): 9.55 (d, J = 2.86Hz, 1H), 9.04-8.99 (m, 1H), 8.38-8.33 (m, 1H), 8.32-8.26 (m, 1H), 5.93-5 .85(m,1H),5.80-5.68(m,2H),5.43-5.35(m,2H),5.10-5.02(m,2H),4.98-4.92(m,1H),4.80-4.73(m,4H),3.95(br s,1H),3.85-3.71(m,2H),3.69-3.60(m,2H),3.56-3.55(m,1H),3.49-3.38(m,7H), 3.27-3.19(m,2H),3.18-3.12(m,1H),2.85-2.79(m,1H),2.78-2.67(m,1H),2.54-2. 46(m,2H),2.38-2.17(m,5H),1.94-1.82(m,3H),1.79-1.71(m,1H),1.69-1.37(m,6 H),1.30-1.21(m,9H),1.20-1.09(m,7H),0.98-0.73(m,12H); MSm / z1025.5698[M+H] + .

[0893] Preparation of Compound I-142

[0894] Compound I-142 was obtained as a mixture of isomers that were difficult to separate (yield 4.0 mg, 6%) using 3-amino-1,2,4-triazole instead of 5-aminopyrimidine in the same manner as in the production of compound I-132.

[0895] 1 H-NMR (500MHz, CDCl3, δ):7.73-7.80(m,0.5H),7.43-7.49(m,0.5H),6.37-6.55(m,1H),5 .81-5.93(m,1H),5.66-5.79(m,2H),5.34-5.46(m,2H),5.27-5.34(m,1H),5.08(d,J=5.7 Hz,1H),4.89-5.02(m,1H),4.81-4.85(m,1H),4.74-4.81(m,2H),4.59-4.74(m,2H),3.89 -3.98(m,1H),3.74-3.85(m,2H),3.60-3.71(m,2H),3.47-3.52(m,1H),3.43-3.47(m,3H) ,3.40-3.42(m,3H),3.19-3.28(m,2H),3.12-3.19(m,1H),2.69-2.84(m,2H),2.59-2.68( m,1H),2.46-2.53(m,1H),2.19-2.36(m,4H),2.03-2.08(m,1H),1.80-1.96(m,2H),1.71- 1.79(m,1H),1.61-1.68(m,1H),1.36-1.59(m,10H),1.23-1.29(m9,H),1.11-1.18(m,6H) ,0.89-0.95(m,3H),0.84(dd,J=6.9,1.7Hz,3H),0.76-0.80(m,4H);MSm / z1014.5651[M+H] + .

[0896] Preparation of Compound I-143

[0897] Compound I-143 (yield 31.0 mg, 94%) was obtained by the same method as in [Production of Compound I-132] using pyridin-3-ylmethylamine instead of 5-aminopyrimidine.

[0898] 1H-NMR (500MHz, CDCl3, δ): 8.72 (br s, 1H), 8.64 (d, J = 4.6Hz, 1H), 7.95 (d, J = 7.4Hz, 1H), 7.48 (dd, J = 6.6Hz, 1H), 7.30 (br s,1H),5.85-5.80(m,1H),5.77-5.63(m,2H),5.38(d,J=3.4Hz,1H),5.35-5.29(m,1H),5.00(s,1H) ,4.98-4.86(m,2H),4.76(d,J=2.9Hz,1H),4.67-4.59(m,5H),4.46(dd,J=15.2,5.4Hz,1H),3.93(br s,1H),3.84-3.74(m,2H),3.68-3.59(m,2H),3.50-3.44(m,1H),3.42(s,3H),3.41(s,3H),3.26-3.19(m,2H),3. 16(t,J=9.2Hz,1H),2.73(dd,J=12.9,3.2Hz,1H),2.66-2.55(m,2H),2.55-2.42(m,2H),2.35-2.18(m,4H),1.94 -1.85(m,1H),1.88-1.70(m,2H),1.66(d,J=12.6Hz,1H),1.57-1.35(m,9H),1.29-1.21(m,10H),1.14(d,J=6.9H z,3H),1.12-1.09(m,3H),0.91(t,J=7.2Hz,3H),0.84(d,J=6.9Hz,3H),0.79-0.76(m,4H); MSm / z1038.589[M+H] + .

[0899] Preparation of Compound I-144

[0900] Compound I-144 (yield 303 mg, 92%) was obtained by the same method as in [Production of Compound I-132] using pyridin-2-ylmethylamine (0.558 mL, 0.949 mmol) instead of 5-aminopyrimidine.

[0901] 1H-NMR (500MHz, CDCl3, δ):8.69-8.65(m,1H),7.98-7.86(m,1H),7.76-7.64 (m,1H),7.63-7.53(m,1H),7.49-7.36(m,1H),5.97-5.91(m,1H),5.81-5.68 (m,2H),5.43-5.39(m,1H),5.36-5.27(m,1H),5.10(s,1H),4.97(d,J=10.6H z,1H),4.87-4.80(m,1H),4.78(d,J=3.5Hz,1H),4.76-4.58(m,4H),3.94(br s,1H),3.88-3.81(m,1H),3.80-3.74(m,1H),3.72-3.60(m,2H),3.54-3.47(m,1H),3.46-3.44(m,3H),3.43(s,3H),3.30 -3.21(m,2H),3.18(t,J=9.2Hz,1H),2.81(dd,J=12.6,3.4Hz,1H),2.70-2.61(m,1H),2.56-2.48(m,2H),2.38-2.17(m,5H ),2.06-2.04(m,1H),2.02-1.95(m,1H),1.94-1.71(m,2H),1.68-1.65(m,1H),1.59-1.31(m,11H),1.31-1.24(m,9H),1.1 7(d,J=6.9Hz,3H),1.07(d,J=6.9Hz,3H),0.95-0.91(m,3H),0.87-0.84(m,3H),0.82-0.77(m,4H); MSm / z1038.5884[M+H] + .

[0902] Preparation of Compound I-145

[0903] Compound I-145 (yield 294 mg, 91%) was obtained by the same method as in [Production of Compound I-132] using 1-methyl-1H-pyrazol-3-amine (0.929 mL, 1.58 mmol) instead of 5-aminopyrimidine.

[0904] 1H-NMR(500MHz,CDCl3,δ):8.95(br s,1H),7.28-7.27(m,1H),6.72(d,J=1.7Hz,1H),5.91(dt,J=10.3,2.3Hz,1H),5.81-5.68(m,2H),5.43-5.34(m,2H),5.08(s,1H),4.99(br d,J=11.0Hz,1H),4.80-4.67(m,5H),3.95(br s,1H),3.88-3.85(m,3H),3.85-3.76(m,2H),3.73-3.60(m,2H),3.53-3.46(m,1H),3.45(s,3H),3.43(s,3H),3.28-3 .20(m,2H),3.18(t,J=8.9Hz,1H),2.85-2.80(m,1H),2.75-2.67(m,1H),2.57-2.48(m,2H),2.38-2.20(m,5H),2.05(s ,1H),1.97-1.86(m,3H),1.81-1.74(m,1H),1.70-1.65(m,1H),1.61-1.36(m,10H),1.31-1.24(m,8H),1.17(d,J=6.9 Hz,3H),1.15(d,J=6.9Hz,3H),0.94(t,J=7.2Hz,3H),0.85(d,J=6.9Hz,3H),0.83-0.77(m,4H); MSm / z1027.5848[M+H] + .

[0905] Reference Example 21

[0906] Production of 5-(chloromethyl)pyrimidine

[0907] Thionyl chloride (0.011 mL, 0.152 mmol) was added to a solution of pyrimidin-5-yl-methanol (11 mg, 0.101 mmol) in dichloromethane (0.10 mL), and the mixture was stirred at 0° C. for 30 minutes. The solvent of the reaction solution was distilled off under reduced pressure to obtain 5-(chloromethyl)pyrimidine as a crude product.

[0908] Preparation of Compound I-146

[0909] After dissolving the compound I-2 (30 mg, 0.034 mmol) obtained in [Manufacture of compound I-2] in DMF (0.67 mL), 5-(chloromethyl)pyrimidine and potassium carbonate (56 mg, 0.034 mmol) and sodium iodide (0.50 mg, 0.003 mmol) obtained in Reference Example 21 were added, and the mixture was stirred at 50°C for 2 hours. The mixture was then heated to 70°C and stirred for 1 hour. Saturated sodium bicarbonate water was added to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / methanol system) to obtain compound I-146 (yield 15.0 mg, yield 45%).

[0910] 1 H-NMR (500MHz, CDCl3, δ): 9.17 (s, 1H), 8.77 (s, 2H), 5.83 (dt, J = 10.5, 2.5Hz, 1H), 5.76-5.61 (m, 2H), 5. 42-5.36(m,2H),5.16-5.11(m,2H),4.95-4.90(m,2H),4.76(d,J=2.9Hz,1H),4.71-4.59(m,3H),3.92(br s,1H),3.82(dd,J=9.7,6.3Hz,1H),3.80-3.73(m,1H),3.69-3.58(m,2H),3.51-3.45(m,1H),3.43(s,3H),3.42(s,3H ),3.28-3.18(m,2H),3.16(t,J=9.2Hz,1H),2.77(dd,J=11.7,3.7Hz,1H),2.64-2.56(m,1H),2.48(ddd,J=9.6,7.0,2 .3Hz,1H),2.36-2.18(m,6H),1.92-1.82(m,3H),1.77-1.69(m,1H),1.68-1.61(m,1H),1.58-1.35(m,9H),1.29-1.23 (m,8H),1.14(t,J=6.9Hz,7H),0.92(t,J=7.4Hz,3H),0.83(d,J=6.9Hz,3H),0.79-0.73(m,4H); MSm / z982.5637[M+H] + .

[0911] Preparation of Compound I-147

[0912] Compound I-147 (yield 27.7 mg, 88%) was obtained by the same method as in [Production of Compound I-132] using (1-methyl-1H-pyrazol-4-yl)methanamine (0.015 mL, 0.158 mmol) instead of 5-aminopyrimidine.

[0913] 1 H-NMR (500MHz, CDCl3, δ): 7.44 (s, 1H), 7.37 (s, 1H), 6.74 (t, J = 5.7Hz, 1H), 5.81 (dt, J = 11.0, 2.5Hz, 1H), 5.79-5.72 (m, 1H), 5.69-5.62 (m, 1H), 5. 43-5.36(m,2H),4.97-4.93(m,2H),4.77(d,J=3.4Hz,1H),4.71-4.55(m, 5H),4.40(dd,J=14.9,6.3Hz,1H),4.21(dd,J=14.9,5.2Hz,1H),3.93(br s,1H),3.90-3.88(m,3H),3.84-3.75(m,2H),3.70-3.60(m,2H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.26-3. 19(m,2H),3.16(t,J=9.2Hz,1H),2.74(dd,J=13.2,2.9Hz,1H),2.65-2.58(m,1H),2.53-2.46(m,1H),2.36-2.31(m,2H) ,2.28-2.19(m,2H),1.90-1.82(m,3H),1.79-1.67(m,3H),1.59-1.36(m,12H),1.26(dd,J=10.9,6.3Hz,7H),1.17-1.1 4(m,3H),1.10(d,J=6.9Hz,3H),0.93(t,J=7.4Hz,3H),0.84(d,J=6.9Hz,3H),0.79-0.75(m,4H); MSm / z1041.5997[M+H] + .

[0914] Preparation of Compound I-148

[0915] use Compound I-148 (yield 5.5 mg, 17%) was obtained by the same method as in [Production of Compound I-132] using oxazol-2-amine (13 mg, 0.158 mmol) instead of 5-aminopyrimidine.

[0916] 1 H-NMR(500MHz,CDCl3,δ):9.61(br s,1H),7.45(d,J=1.0Hz,1H),7.03(d,J=1.1Hz,1H),5.90(dt,J=10.9,2.4 Hz,1H),5.82-5.68(m,2H),5.47-5.38(m,2H),5.11-5.03(m,2H),4.96(br d,J=10.3Hz,1H),4.81-4.72(m,4H),3.95(br s,1H),3.87-3.80(m,1H),3.80-3.74(m,1H),3.73-3.60(m,2H),3.52 -3.47(m,1H),3.46(s,3H),3.43(s,3H),3.29-3.20(m,2H),3.18(t,J=9.2Hz,1H),2.83-2. 78(m,1H),2.77-2.69(m,1H),2.55-2.47(m,2H),2.38-2.20(m,4H),1.97-1.84(m,3H),1.79 -1.73(m,1H),1.70-1.38(m,11H),1.32-1.28(m,4H),1.28-1.23(m,5H),1.17(t ,J=6.9Hz,6H),0.94(t,J=7.4Hz,3H),0.90-0.75(m,8H);MSm / z1014.5522[M+H] + .

[0917] Preparation of Compound I-149

[0918] After dissolving compound I-139 (0.728 g, 0.746 mmol) obtained in [Manufacture of compound I-139] in THF (7.5 mL), 1 M potassium hydroxide aqueous solution (2.24 mL, 2.24 mmol) was added and stirred at 0°C for 15 minutes. Then, the temperature was raised to room temperature and stirred for 2 hours and 45 minutes. An aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-149 (yield 0.495 g, yield 69%).

[0919] 1H-NMR (500MHz, CDCl3, δ): 5.94-5.80 (m, 1H), 5.78-5.62 (m, 2H), 5.47-5.33 (m, 2H), 4.94 (s, 1H), 4.94 (d, J = 9.0Hz, 1H), 4.85-4.50 (m, 5H), 3.93 (br s,1H),3.86-3.72(m,2H),3.71-3.56(m,2H),3.53-3.45(m,1H),3.45(s,3H),3.42(s,3H),3.32-3.19 (m,2H),3.17(t,J=9.5Hz,1H)2.96-2.85(m,1H),2.81-2.69(m,1H),2.68-2.57(m,1H),2.55-2.42(m,1 H),2.39-2.17(m,4H),1.97-1.81(m,2H),1.78-1.70(m,1H),1.70-1.61(m,1H),1.59-1.34(m,12H),1 .30-1.20(m,10H),1.18-1.10(m,5H),0.92(t,J=7.5Hz,3H),0.83(d,J=7.0Hz,3H),0.80-0.72(m,4H).

[0920] Preparation of Compound I-150

[0921] Compound I-150 (yield 0.230 g, 58%) was obtained by the same method as in [Production of Compound I-132] using Compound I-149 instead of Compound I-48 and ammonium chloride instead of 5-aminopyrimidine.

[0922] 1H-NMR (500MHz, CDCl3, δ): 6.40 (d, J = 2.9 Hz, 1H), 5.93-5.79 (m, 1H), 5.78-5.64 (m, 2H), 5.48-5.37 (m, 3H), 4.94 (s, 1H), 4.97-4.92 (m, 2H), 4.76 (1br d,J=3.4Hz,1H),4.71-4.63(m,4H),3.93(br s,1H),3.85-3.70(m,2H),3.70-3.58(m,2H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H),3.16(t ,J=9.2Hz,1H),2.73(dd,J=12.6,2.9Hz,1H),2.64-2.53(m,2H),2.53-2.46(m,1H),2.36-2.29(m,2H),2.29-2.19(m, 2H),1.97-1.81(m,3H),1.77-1.71(m,1H),1.69-1.63(m,2H),1.58-1.37(1m,6H),1.28-1.23(m,7H),1.17(d,J=6.9H z,3H),1.15(d,J=6.9Hz,3H),0.92(t,J=7.2Hz,3H),0.83(d,J=6.9Hz,3H),0.81-0.74(m,4H); MSm / z978.592[M+NH4] + .

[0923] Preparation of Compound I-151

[0924] Compound I-151 (yield 38.2 mg, 65%) was obtained by the same method as in [Production of Compound I-132] using 2-(aminomethyl)aniline instead of 5-aminopyrimidine.

[0925] 1H-NMR (500MHz, CDCl3, δ): 8.09 (d, J = 6.2 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 6.96 (t, J=6.7Hz,1H),6.53(t,J=6.8Hz,1H),5.83-5.73(m,2H),5.68-5.62(m,1H),5.42- 5.35(m,2H),4.97-4.93(m,2H),4.88-4.83(m,1H),4.76(d,J=4.0Hz,1H),4.69- 4.58(m,4H),4.47(dd,J=14.9,7.4Hz,1H),4.25(dd,J=14.9,5.7Hz,1H),3.93(br s,1H),3.85-3.73(m,2H),3.70-3.59(m,2H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.27-3.19(m,2H ),3.16(t,J=9.2Hz,1H),2.75-2.70(m,1H),2.63-2.46(m,3H),2.36-2.14(m,4H),1.92-1.86(m,1H),1.84- 1.79(m,1H),1.74-1.64(m,2H),1.60-1.38(1m,2H),1.26(dd,J=10.3,6.3Hz,7H),1.15(d,J=6.9Hz,3H),1. 07(d,J=6.3Hz,3H),0.93(t,J=7.4Hz,3H),0.85(d,J=6.9Hz,3H),0.80-0.74(m,4H); MSm / z1053.6022[M+H] + .

[0926] Preparation of Compound I-152

[0927] Compound I-152 (yield 29.8 mg, 56%) was obtained by the same method as in [Production of Compound I-132] using pyrazin-2-yl-methanamine instead of 5-aminopyrimidine.

[0928] 1H-NMR (500MHz, CDCl3, δ): 8.61 (s, 1H), 8.56 (s, 1H), 8.50 (d, J = 2.9Hz, 1H), 7.31 (t, J = 6.0Hz, 1H), 5.84 (dt, J = 10.9, 2.3Hz, 1H), 5.76-5.6 7(m,2H),5.41-5.34(m,2H),5.03(s,1H),4.96-4.92(m,2H),4.81-4.75(m,2H),4.71-4.61(m,4H),4.47(dd,J=15.8,5.4Hz,1H),3.93(br s,1H),3.85-3.73(m,2H),3.69-3.59(m,2H),3.51-3.44(m,1H),3.43(s,3H),3.41(s,3H),3.26-3.19(m,2H),3.16( t,J=9.2Hz,1H),2.80(dd,J=13.2,2.9Hz,1H),2.69-2.62(m,1H),2.56-2.46(m,2H),2.35-2.30(m,2H),2.30-2.18(m ,2H),1.93-1.85(m,2H),1.79-1.69(m,2H),1.69-1.61(m,1H),1.58-1.34(m,1H),1.28-1.23(m,7H),1.15(d,J=6.9H z,3H),1.11(d,J=6.9Hz,3H),0.91(t,J=7.4Hz,3H),0.84(d,J=6.9Hz,3H),0.80-0.74(m,4H); MSm / z1039.5867[M+H] + .

[0929] Preparation of Compound I-153

[0930] After dissolving the compound I-2 (200 mg, 0.224 mmol) obtained in [Manufacturing of Compound I-2] in DMF (2.2 mL), cesium carbonate (370 mg, 1.12 mmol) and ethyl 2-bromo-2-fluoroacetate (0.13 mL, 1.12 mmol) were added and stirred at room temperature for 1 hour. Water was added to the reaction solution to stop the reaction. After extraction with a mixed solvent of ethyl acetate and hexane, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-153 (yield 81.1 mg, yield 36%) as a mixture of isomers that are difficult to separate.

[0931] 1H-NMR(500MHz,CDCl3,δ):6.13-6.08(m,0.5H),6.03-5.94(m,0.5H),5.88-5.82(m, 1H),5.78-5.66(m,2H),5.44-5.37(m,2H),4.96(d,J=12.0Hz,1H),4.92(s,1H),4.7 8(d,J=3.4Hz,1H),4.68(s,2H),4.66(s,0.5H),4.56(s,0.5H),4.38-4.24(m,2H),3 .94(brs,1H),3.89-3.74(m,2H),3.72-3.61(m,2H),3.53-3.47(m,1H),3.45(s,3H), 3.44(s,3H),3.28-3.21(m,2H),3.18(t,J=9.2Hz,1H),2.84-2.77(m,1H),2.73-2.6 2(m,1H),2.53-2.49(m,2H),2.40-2.20(m,4H),1.99-1.82(m,3H),1.79-1.50(m,10H ),1.47-1.38(m,3H),1.38-1.32(m,3H),1.31-1.25(m,8H),1.22-1.13(m,6H),0.93 (t,J=7.4Hz,3H),0.85(d,J=6.3Hz,3H),0.81-0.76(m,4H); MSm / z1011.5790[M+NH4] + .

[0932] Preparation of Compound I-154

[0933] After dissolving the compound I-153 (77 mg, 0.078 mmol) obtained in [Manufacture of compound I-153] in THF (3.4 mL), add 1M potassium hydroxide aqueous solution (0.78 mL, 0.78 mmol) and stir at room temperature for 30 minutes. Add saturated ammonium chloride aqueous solution to the reaction solution to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / methanol system) to obtain compound I-154 (yield 66.6 mg, yield 89%) as a mixture of isomers that are difficult to separate. The following 1 The H-NMR spectrum is the analytical data of the main isomer.

[0934] 1H-NMR (500MHz, CDCl3, δ): 5.98-5.90 (m, 1H), 5.89-5.79 (m, 2H), 5.76-5.6 4(m,2H),5.41-5.22(m,3H),5.01-4.90(m,2H),4.86-4.80(m,1H),4.76(br s,2H),4.74-4.67(m,1H),4.65-4.58(m,3H),3.96-3.90(m,2H),3.89-3.80(m,2H),3.80 -3.73(m,2H),3.71-3.62(m,4H),3.54-3.46(m,4H),3.46-3.36(m,3H),3.26-3.09(m,3H),2.80-2.56(m,3H),2.55-2.45(m,2H),2. 38-2.18(m,3H),2.12-1.60(m,4H),1.58-1.34(m,6H),1.33-1.21(m,3H),1.21-1.08(m,4H),0.97-0.88(m,6H),0.85-0.70(m,9H).

[0935] Preparation of Compound I-155

[0936] Compound I-155 (yield 7.1 mg, yield 21%) was obtained by using compound I-154 obtained in [Manufacture of compound I-154] instead of compound I-48 in [Manufacture of compound I-132] and using methylamine hydrochloride instead of 5-aminopyrimidine in the same manner as [Manufacture of compound I-132].

[0937] 1H-NMR (500MHz, CDCl3, δ): 6.48-6.43 (m, 1H), 6.12-6.00 (m, 1H), 5.85 (dt, J = 10.7, 2.4Hz, 1H), 5.78-5.65 (m, 2 H),5.43-5.36(m,2H),4.96(d,J=10.9Hz,1H),4.91(s,1H),4.78(d,J=3.4Hz,1H),4.71-4.63(m,2H),3.94(br s,1H),3.87-3.75(m,2H),3.72-3.62(m,2H),3.53-3.47(m,1H),3.45(s,3H),3.43(s,3H),3.29-3.20(m,2H),3.18(t,J= 9.2Hz,1H),2.89(d,J=5.2Hz,3H),2.81(dd,J=12.6,3.4Hz,1H),2.75-2.62(m,1H),2.55-2.47(m,1H),2.38-2.32(m,2H), 2.31-2.20(m,2H),2.16-1.98(m,2H),1.96-1.87(m,4H),1.78-1.71(m,1H),1.67(d,J=12.6Hz,1H),1.60-1.38(m,11H),1 .32-1.23(m,7H),1.21-1.14(m,6H),0.93(t,J=7.2Hz,3H),0.88-0.82(m,3H),0.82-0.75(m,4H); MSm / z996.5801[M+NH4] + .

[0938] Preparation of Compound I-156

[0939] Compound I-154 obtained in [Production of Compound I-154] was used instead of Compound I-48 in [Production of Compound I-132], and ammonium chloride was used instead of 5-aminopyrimidine to obtain Compound I-156 (yield 7.0 mg, yield 20%) in the same manner as [Production of Compound I-132].

[0940] 1H-NMR(500MHz,CDCl3,δ):6.40(br S,1H),6.11-5.99(m,1H),5.88-5.82(m,1H),5.82-5.66(m,3H),5.45-5.36(m,2H),4 .96(d,J=10.9Hz,1H),4.91(s,1H),4.78(d,J=3.4Hz,1H),4.73-4.63(m,2H),3.94(br s,1H),3.87-3.74(m,2H),3.71-3.57(m,2H),3.53-3.46(m,1H),3.45(s,3H),3.43(s,3H),3.31-3.20(m,2 H),3.18(t,J=9.2Hz,1H),2.81(dd,J=12.6,3.4Hz,1H),2.75-2.61(m,1H),2.59-2.43(m,1H),2.37-2.18( m,4H),2.07-1.78(m,6H),1.77-1.70(m,2H),1.67(d,J=12.6Hz,2H),1.60-1.38(m,10H),1.31-1.24(m,6H ),1.23-1.12(m,6H),0.93(t,J=7.4Hz,3H),0.89-0.82(m,3H),0.82-0.74(m,4H); MSm / z982.5658[M+NH4] + .

[0941] Reference Example 22

[0942] Production of methyl (S)-2-(p-tolylsulfoxyl)butyrate

[0943] (S)-2-hydroxybutyric acid methyl ester (300 μL, 2.67 mmol) was dissolved in acetonitrile (5.3 mL). Triethylamine (0.74 mL, 5.33 mmol), methylamine hydrochloride (25.5 mg, 0.267 mmol), and p-toluenesulfonyl chloride (760 mg, 4.00 mmol) were added sequentially, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Water was added to the reaction mixture to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate system) to obtain (S)-2-(p-tolylsulfoxylated)butyric acid methyl ester (yield 712 mg, yield 98%).

[0944] 1H-NMR (500MHz, CDCl3, δ): 7.86-7.79 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.80 (dd, J = 7. 4,5.2Hz,1H),3.67(s,3H),2.46(s,3H),1.92-1.79(m,2H),0.91(t,J=7.4Hz,3H).

[0945] Preparation of Compound I-157

[0946] Using (S)-2-(p-tolylsulfoxylated)butanoic acid methyl ester obtained in Reference Example 22, instead of ethyl 2-bromo-2-fluoroacetate in [Production of Compound I-153], the same method as [Production of Compound I-153] was used to obtain Compound I-157 (yield 91.0 mg, yield 82%) as a mixture of isomers that were difficult to separate. 1 The H-NMR spectrum is the analytical data of the main isomer.

[0947] 1 H-NMR (500MHz, CDCl3, δ):5.89-5.79(m,1H),5.79-5.64(m,2H),5.44-5.32(m,2H),5.01(s,1H),4.96( d,J=11.5Hz,1H),4.78(d,J=2.9Hz,1H),4.71-4.65(m,2H),4.64(s,1H),4.57(t,J=6.6Hz,1H),3.95(br s,1H),3.88-3.76(m,2H),3.74(s,3H),3.72-3.61(m,2H),3.53-3.47(m,1H),3.45(s,3H),3. 44(s,3H),3.29-3.14(m,3H),2.85-2.75(m,1H),2.68-2.58(m,2H),2.55-2.47(m,2H),2.39-2 .20(m,5H),1.93-1.81(m,5H),1.77-1.59(m,13H),1.57-1.48(m,6H),1.48-1.40(m,1H),1.31 -1.25(m,6H),1.19-1.09(m,4H),0.98(t,J=7.4Hz,2H),0.96-0.91(m,2H),0.89-0.77(m,4H).

[0948] Preparation of Compound I-158

[0949] Using compound I-157 obtained in [Production of compound I-157] instead of compound I-153 in [Production of compound I-154], compound I-158 (yield 65.6 mg, yield 77%) was obtained as a mixture of isomers that were difficult to separate by the same method as [Production of compound I-154]. 1 The H-NMR spectrum is the analytical data of the main isomer.

[0950] 1 H-NMR (500MHz, CD3OD, δ): 5.93-5.80 (m, 2H), 5.76-5.69 (m, 1H), 5.35 (d, J= 3.4Hz,1H),5.17-5.11(m,2H),4.90(s,1H),4.80(d,J=3.4Hz,1H),4.65(d, J=1.7Hz,2H),4.47(dd,J=6.9,5.7Hz,1H),3.99(s,1H),3.92-3.84(m,1H), 3.75-3.63(m,3H),3.42(s,3H),3.41(s,3H),3.46-3.38(m,7H),3.28-3.24 (m,1H),3.19(t,J=8.9Hz,1H),3.03(t,J=9.2Hz,1H),2.82(dd,J=12.9,3.2 Hz,1H),2.69-2.55(m,2H),2.34-2.26(m,4H),2.06-2.01(m,1H),1.92-1.7 7(m,4H),1.68-1.40(m,10H),1.30-1.20(m,8H),1.19-1.15(m,3H),1.11(d ,J=6.9Hz,3H),1.02-0.93(m,6H),0.88(d,J=6.9Hz,3H),0.85-0.77(m,4H).

[0951] Preparation of Compound I-159

[0952] Compound I-159 (yield 36.8 mg, yield 56%) was obtained by using compound I-158 obtained in [Manufacture of compound I-158] instead of compound I-48 in [Manufacture of compound I-132], and using methylamine hydrochloride instead of 5-aminopyrimidine in the same manner as [Manufacture of compound I-132].

[0953] 1H-NMR (500MHz, CDCl3, δ): 6.52 (q, J = 5.2Hz, 1H), 5.88 (dt, J = 10.7, 2.4Hz, 1H), 5.79-5.67 (m, 2H), 5.45-5.39 (m, 2H) ,4.98-4.93(m,2H),4.77(d,J=3.4Hz,1H),4.71(d,J=2.3Hz,2H),4.69(s,1H),4.56(dd,J=8.0,4.0Hz,1H),3.95(br s,1H),3.86-3.75(m,2H),3.72-3.61(m,2H),3.53-3.46(m,1H),3.46-3.44(m,3H),3.44-3.42(m,3H),3.2 7-3.20(m,2H),3.18(t,J=9.2Hz,1H),2.80(d,J=5.2Hz,3H),2.75(dd,J=12.6,2.9Hz,1H),2.64-2.55(m,2H ),2.54-2.47(m,1H),2.38-2.21(m,4H),1.99-1.83(m,4H),1.81-1.71(m,2H),1.71-1.64(m,4H),1.60-1.3 8(m,7H),1.31-1.23(m,8H),1.20-1.14(m,6H),0.98-0.91(m,6H),0.90-0.77(m,8H); MSm / z989.5950[M+H] + .

[0954] Preparation of Compound I-160

[0955] Compound I-160 (yield 38.8 mg, 53%) was obtained by the same method as in [Manufacture of Compound I-132] using compound I-158 obtained in [Manufacture of Compound I-158] instead of compound I-48 in [Manufacture of Compound I-132] and using ammonium chloride instead of 5-aminopyrimidine.

[0956] 1H-NMR (500MHz, CDCl3, δ): 8.04 (br s,2H),6.80(d,J=2.9Hz,1H),6.72(d,J=2.9Hz,1H),5.88(dt,J=10.7,2.4Hz,1H),5 .80-5.65(m,2H),5.47-5.35(m,2H),4.98-4.91(m,2H),4.78(d,J=3.4Hz,1H),4.71 -4.64(m,2H),4.57(dd,J=7.7,4.3Hz,1H),3.94(brs,1H),3.87-3.74(m,2H),3.72- 3.59(m,2H),3.53-3.47(m,2H),3.45(s,3H),3.43(s,3H),3.28-3.20(m,2H),3.18( t,J=9.2Hz,1H),2.73(dd,J=12.6,2.9Hz,1H),2.64-2.57(m,1H),2.55-2.46(m,1H) ,2.37-2.21(m,4H),1.99-1.79(m,5H),1.78-1.73(m,1H),1.67(d,J=13.2Hz,1H),1 .60-1.38(m,15H),1.30-1.24(m,6H),1.22-1.13(m,3H),1.00(t,J=7.4Hz,3H),0.9 3(t,J=7.2Hz,3H),0.84(d,J=6.3Hz,3H),0.82-0.75(m,4H); MSm / z992.6063[M+NH4] + .

[0957] Preparation of Compound I-161

[0958] Compound I-150 (15.0 mg, 0.016 mmol) obtained in [Production of Compound I-150] was dissolved in dichloromethane (0.32 mL), and sodium bicarbonate (7.87 mg, 0.094 mmol) and Dess-Martin periodinane (19.9 mg, 0.047 mmol) were added sequentially, followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by thin-layer preparative silica gel column chromatography (n-hexane:ethyl acetate = 1:2) to obtain Compound I-161 (yield 9.0 mg, yield 60%).

[0959] 1H-NMR (500MHz, CDCl3, δ): 6.45 (d, J = 2.3Hz, 1H), 5.92-5.82 (m, 1H), 5.80-5.65 (m, 3H), 5.57-5.49 (m, 1H), 5.48-5.36 (m, 1 H),4.99-4.92(m,2H),4.84-4.74(m,1H),4.74-4.60(m,3H),4.41(q,J=6.3Hz,1H),4.20(dd,J=12.0,6.3Hz,1H),3.94(br s,1H),3.89(dq,J=9.8,6.3Hz,1H),3.74-3.63(m,2H),3.50(s,3H),3.46(s,3H),3.39-3.30(m,1H),3.21(d,J=7.4Hz,1H),2.73(dd,J =12.6,2.9Hz,1H),2.67-2.55(m,2H),2.55-2.45(m,1H),2.38-2.31(m,1H),2.31-2.22(m,2H),2.13(td,J=12.3,4.0Hz,1H),2.07(br s,1H),1.98-1.83(m,3H),1.77-1.70(m,1H),1.68-1.63(m,1H),1.58-1.37(m,14H),1.29-1.23(m,7H) ,1.19-1.14(m,5H),0.92(t,J=7.4Hz,3H),0.85-0.82(m,3H),0.81-0.73(m,4H); MSm / z959.5489[M+H] + .

[0960] Preparation of Compound I-162

[0961] Compound I-162 (yield 28.0 mg, 67%) was obtained by the same method as in [Production of Compound I-132] using O-ethylhydroxylamine hydrochloride instead of 5-aminopyrimidine.

[0962] 1H-NMR (500MHz, CDCl3, δ): 9.20 (s, 1H), 5.87-5.81 (m, 1H), 5.79-5.64 (m, 2H), 5.44-5.36 (m, 2H), 4.96-4.90 (m, 2H), 4.88 (s, 1H), 4.76 (br s,1H),4.74-4.61(m,4H),3.99-3.89(m,3H),3.85-3.79(m,1H),3.79-3.72(m,1H),3.70-3.59(m,2H),3.52-3.45(m,1 H),3.43(s,3H),3.41(s,3H),3.26-3.18(m,2H),3.16(t,J=9.2Hz,1H),2.77(d,J=11.5Hz,1H),2.69-2.55(m,2H),2.54 -2.44(m,1H),2.36-2.18(m,4H),1.96-1.78(m,1H),1.78-1.71(m,2H),1.66(d,J=10.9Hz,1H),1.58-1.35(m,12H),1. 30-1.21(m,11H),1.20-1.10(m,6H),0.95-0.89(m,3H),0.85-0.81(m,3H),0.80-0.74(m,4H):MSm / z1008.6008[M+NH4] + .

[0963] Preparation of Compound I-163

[0964] Compound I-163 was obtained as a mixture of isomers that were difficult to separate (yield 167 mg, 74%) using methyl 2-bromo-3-methoxypropionate instead of ethyl 2-bromo-2-fluoroacetate in the same manner as in [Production of Compound I-153].

[0965] 1H-NMR (500MHz, CDCl3, δ): 5.93-5.81 (m, 1H), 5.78-5.66 (m, 2H), 5.47-5.30 (m, 2H), 5.06 (s, 0.5H), 5.02 (s,0.5H),5.00-4.91(m,1H),4.89-4.86(m,0.5H),4.85-4.82(m,0.5H),4.78(d,J=4.0Hz,1H),4.67(br s,2H),4.62(s,0.5H),4.51(s,0.5H),3.94(br s,1H),3.87-3.79(m,3H),3.79-3.74(m,4H),3.73-3.61(m,2H),3.53-3.48(m,1H),3.47-3.42(m,6H),3 .42-3.36(m,3H),3.29-3.14(m,3H),2.85-2.76(m,1H),2.69-2.57(m,1H),2.54-2.44(m,2H),2.37-2.1 9(m,4H),1.96-1.81(m,3H),1.79-1.72(m,1H),1.69-1.59(m,2H),1.57-1.35(m,11H),1.31-1.24(m,8H ),1.19-1.15(m,3H),1.15-1.10(m,3H),0.93(t,J=7.4Hz,3H),0.85(d,J=6.9Hz,3H),0.81-0.75(m,3H).

[0966] Preparation of Compound I-164

[0967] Compound I-163 obtained in [Production of Compound I-163] was used instead of Compound I-153 in [Production of Compound I-154] to obtain Compound I-164 as a mixture of isomers that were difficult to separate (yield 57.9 mg, yield 71%) in the same manner as [Production of Compound I-154].

[0968] 1H-NMR(500MHz,CD3OD,δ):5.91-5.79(m,1H),5.79-5.58(m,2H),5.43-5.26(m,2H),5.03-4.88(m,1H),4.84-4.56(m,4H),3.94(br s,1H),3.87-3.70(m,4H),3.69-3.58(m,2H),3.52-3.32(m,10H),3.27-3.12(m,3H),2.70-2.60(m,1H),2.56-2.45(m,2H ),2.40-2.18(m,3H),1.92-1.34(m,30H),1.30-1.23(m,8H),1.22-1.11(m,7H),0.92(t,J=7.4Hz,3H),0.86-0.73(m,7H).

[0969] Preparation of Compound I-165

[0970] Compound I-164 obtained in [Production of Compound I-164] was used instead of compound I-48 in [Production of Compound I-132], and methylamine hydrochloride was used instead of 5-aminopyrimidine to obtain compound I-165 (yield 7.8 mg, yield 29%) in the same manner as [Production of Compound I-132].

[0971] 1H-NMR (500MHz, CDCl3, δ): 6.64 (q, J=4.6Hz, 1H), 5.88 (dt, J=10.7, 2.4Hz, 1H), 5.79-5.65 (m, 2H), 5.44-5. 38(m,2H),5.00(s,1H),4.96(d,J=10.9Hz,1H),4.79-4.76(m,2H),4.74-4.67(m,2H),4.65(s,1H),3.95(br s,1H),3.87-3.74(m,4H),3.72-3.59(m,2H),3.53-3.46(m,1H),3.45(s,3H),3.43(s,3H),3.36(s,3H), 3.28-3.20(m,2H),3.18(t,J=9.2Hz,1H),2.82(d,J=5.2Hz,3H),2.75(dd,J=12.6,2.9Hz,1H),2.67-2.58 (m,1H),2.58-2.47(m,2H),2.38-2.20(m,4H),2.00-1.81(m,3H),1.78-1.63(m,6H),1.60-1.39(m,8H),1 .32-1.23(m,7H),1.17(t,J=6.6Hz,6H),0.93(t,J=7.2Hz,3H),0.87-0.76(m,7H); MSm / z1005.5908[M+H] + .

[0972] Preparation of Compound I-166

[0973] Using compound I-164 obtained in [Manufacture of compound I-164] instead of compound I-48 in [Manufacture of compound I-132], and using ammonium chloride (8.2 mg, 0.157 mmol) instead of 5-aminopyrimidine, compound I-166 was obtained by the same method as [Manufacture of compound I-132] (yield 7.3 mg, yield 24%).

[0974] 1H-NMR (500MHz, CDCl3, δ): 6.63 (d, J = 2.9Hz, 1H), 5.89-5.85 (m, 1H), 5.79-5.66 (m, 2H), 5.53 (d, J = 2.9Hz, 1 H),5.46-5.36(m,1H),5.00(s,1H),4.96(d,J=11.5Hz,1H),4.81-4.76(m,2H),4.71-4.62(m,3H),3.95(br s,1H),3.87-3.75(m,4H),3.71-3.59(m,2H),3.53-3.46(m,1H),3.45(s,3H),3.43(s,3H),3.38(s,3H),3.2 9-3.20(m,2H),3.18(t,J=9.2Hz,1H),2.74(dd,J=12.6,2.9Hz,1H),2.67-2.58(m,1H),2.55-2.46(m,1H),2 .39-2.31(m,2H),2.31-2.18(m,2H),2.03-1.81(m,4H),1.79-1.63(m,8H),1.60-1.39(m,14H),1.31-1.24( m,3H),1.23-1.12(m,3H),0.93(t,J=7.4Hz,3H),0.89-0.82(m,3H),0.82-0.75(m,4H); MSm / z991.5753[M+H] + .

[0975] Preparation of Compound I-167

[0976] After dissolving compound I-2 (200 mg, 0.225 mmol) obtained in [Production of Compound I-2] in THF (2.30 mL), sodium hydride (9.00 mg, 0.225 mmol) and methyl (E)-2-butenoate (23.7 μL, 0.225 mmol) were added sequentially at 0°C, and the mixture was stirred overnight at 40°C. A saturated aqueous sodium chloride solution was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound I-167 (yield 41.3 mg, yield 19%) as a mixture of isomers that were difficult to separate.

[0977] 1H-NMR (500MHz, CDCl3, δ): 5.87-5.80 (m, 1H), 5.77-5.64 (m, 2H), 5.45-5.35 (m, 2H), 4.96 (d, J = 9.7Hz, 1H), 4.91(dd,J=8.9,2.0Hz,1H),4.77(d,J=3.4Hz,1H),4.68-4.59(m,3.5H),4.54(d,J=6.3Hz,0.5H),3.94(br s,1H),3.87-3.75(m,2H),3.73-3.60(m,4H),3.53-3.46(m,1H),3.45(s,3H),3.44(s,3H),3.27-3.20(m,2H ),3.18(t,J=9.5Hz,1H),2.84-2.75(m,2H),2.64-2.55(m,1H),2.53-2.47(m,2H),2.45-2.40(m,1H),2.38-2 .21(m,4H),1.93-1.81(m,3H),1.78-1.73(m,1H),1.67(d,J=12.0Hz,1H),1.62-1.46(m,12H),1.46-1.36(m ,3H),1.33-1.23(m,8H),1.16(d,J=6.3Hz,6H),0.93(t,J=7.4Hz,3H),0.86-0.82(m,3H),0.82-0.75(m,4H).

[0978] Preparation of Compound I-168

[0979] Using compound I-167 obtained in [Production of compound I-167] instead of compound I-153 in [Production of compound I-154], compound I-168 (yield 25.7 mg, yield 63%) was obtained as a mixture of isomers that were difficult to separate by the same method as [Production of compound I-154]. 1 The H-NMR spectrum is the analytical data of the main isomer.

[0980] 1H-NMR (500MHz, CDCl3, δ): 5.89-5.79 (m, 1H), 5.79-5.65 (m, 2H), 5.46-5.33 (m, 2H), 5.00-4.93 (m, 1H), 4.92 (d, J = 2.3Hz, 1H), 4.78 (d ,J=2.9Hz,1H),4.67(d,J=1.1Hz,3H),3.98-3.92(m,1H),3.88-3.76(m,2H),3.73-3.61(m,2H),3.53-3.47(m,1H),3.45(s,3H),3.44( s,3H),3.28-3.21(m,2H),3.18(t,J=9.2Hz,1H),2.88-2.75(m,2H),2.68-2.47(m,4H),2.37-2.20(m,4H),1.94-1.83(m,3H),1.76-1. 43(m,14H),1.36-1.33(m,3H),1.30-1.25(m,8H),1.21-1.14(m,6H),0.93(t,J=7.4Hz,3H),0.85(d,J=6.3Hz,3H),0.81-0.78(m,4H).

[0981] Preparation of Compound I-169 and Compound I-170

[0982] Using compound I-168 obtained in [Manufacture of compound I-168], instead of compound I-48 in [Manufacture of compound I-132], and using ammonium chloride instead of 5-aminopyrimidine, compound I-169 (yield 7.4 mg, yield 29%) and compound I-170 (yield 7.3 mg, yield 28%) were obtained by the same method as [Manufacture of compound I-132].

[0983] (Compound I-169)

[0984] 1H-NMR (500 MHz, CDCl3, δ): 6.24 (br s, 1H), 5.86 (dt, J = 10.5, 2.5 Hz, 1H), 5.79 - 5.64 (m, 3H), 5.46 - 5.36 (m, 2H), 4.96 (d, J = 10.9 Hz, 1H), 4.90 (s, 1H), 4.78 (d, J = 3.4 Hz, 1H), 4.70 - 4.61 (m, 2H), 4.61 - 4.54 (m, 1H), 3.94 (br s, 1H), 3.86 - 3.75 (m, 2H), 3.71 - 3.61 (m, 2H), 3.52 - 3.46 (m, 1H), 3.45 (s, 3H), 3.43 (s, 3H), 3.27 - 3.20 (m, 2H), 3.18 (t, J = 9.2 Hz, 1H), 2.76 (dd, J = 12.9, 3.2 Hz, 1H), 2.66 - 2.58 (m, 1H), 2.56 - 2.53 (m, 2H), 2.52 - 2.47 (m, 1H), 2.38 - 2.19 (m, 5H), 1.97 - 1.82 (m, 3H), 1.78 - 1.72 (m, 1H), 1.67 (d, J = 12.6 Hz, 1H), 1.60 - 1.38 (m, 13H), 1.33 (d, J = 6.9 Hz, 3H), 1.31 - 1.24 (m, 7H), 1.20 (d, J = 6.9 Hz, 3H), 1.16 (d, J = 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.85 (d, J = 6.3 Hz, 3H), 0.82 - 0.76 (m, 4H); MS m / z 997.5613 [M+Na] + .

[0985] (Compound I-170)

[0986] 1H-NMR (500MHz, CDCl3, δ): 6.03 (br s, 1H), 5.87-5.80 (m, 1H), 5.78-5.65 (m, 2H), 5.47 (br s,1H),5.44-5.37(m,2H),4.98-4.91(m,2H),4.78(d,J=3.4Hz,1H),4.70-4.59(m,3H),3.94(br s,1H),3.87-3.75(m,2H),3.71-3.60(m,2H),3.54-3.47(m,1H),3.45(s,3H),3.44(s,3H),3.27-3.20(m,2H) ,3.18(t,J=9.2Hz,1H),2.86-2.75(m,1H),2.70-2.62(m,1H),2.62-2.45(m,4H),2.38-2.18(m,5H),1.96-1.7 9(m,4H),1.79-1.71(m,2H),1.67(d,J=12.6Hz,2H),1.60-1.38(m,9H),1.35-1.31(m,3H),1.31-1.24(m,7H), 1.17(t,J=6.6Hz,6H),0.93(t,J=7.4Hz,3H),0.85(d,J=6.9Hz,3H),0.82-0.75(m,4H); MSm / z997.5616[M+Na] + .

[0987] Preparation of Compound I-171 and Compound I-172

[0988] Compound I-168 obtained in [Manufacture of Compound I-168] was used instead of Compound I-48 in [Manufacture of Compound I-132], and methylamine hydrochloride was used instead of 5-aminopyrimidine to obtain Compound I-171 (yield 1.7 mg, yield 16%) and Compound I-172 (yield 1.5 mg, yield 14%) by the same method as [Manufacture of Compound I-132].

[0989] (Compound I-171)

[0990] 1H-NMR(500 MHz, CDCl3, δ): 6.28 - 6.18 (m, 1H), 5.88 - 5.82 (m, 1H), 5.76 - 5.65 (m, 2H), 5.44 - 5.37 (m, 2H), 4.95 (br d, J = 11.5 Hz, 1H), 4.89 (s, 1H), 4.76 (d, J = 3.4 Hz, 1H), 4.68 - 4.61 (m, 3H), 4.57 - 4.50 (m, 1H), 3.93 (br s, 1H), 3.86 - 3.73 (m, 2H), 3.69 - 3.60 (m, 2H), 3.51 - 3.45 (m, 1H), 3.44 (s, 3H), 3.42 (s, 3H), 3.26 - 3.19 (m, 2H), 3.16 (t, J = 9.2 Hz, 1H), 2.76 - 2.74 (m, 3H), 2.77 - 2.72 (m, 1H), 2.60 (dd, J = 12.3, 6.6 Hz, 1H), 2.51 - 2.47 (m, 3H), 2.36 - 2.19 (m, 4H), 1.96 - 1.84 (m, 3H), 1.77 - 1.72 (m, 1H), 1.70 - 1.39 (m, 13H), 1.33 - 1.23 (m, 11H), 1.19 (d, J = 6.9 Hz, 3H), 1.15 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 0.81 - 0.75 (m, 4H); MS m / z 989.5947 [M + H] + . <​​​​H-NMR (500MHz, CDCl3, δ): 6.03-5.98 (m, 1H), 5.83 (td, J = 2.3, 10.3Hz, 1H), 5.77-5.65 (m, 2H), 5.45 -5.36(m,2H),4.99-4.92(m,2H),4.80-4.70(m,2H),4.70-4.63(m,2H),4.61-4.54(m,1H),3.93(br s,1H),3.87-3.73(m,2H),3.70-3.61(m,2H),3.52-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.27-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.83 -2.78(m,1H),2.74(d,J=4.6Hz,3H),2.69-2.61(m,1H),2.54-2.41(m,3H),2.36-2.19(m,4H),1.92-1.82(m,3H),1.75-1.71(m,1H),1.68 -1.36(m,13H),1.31-1.23(m,10H),1.16(d,J=6.9Hz,6H),1.17-1.14(m,6H),0.9 2(t,J=7.4Hz,3H),0.84(d,J=6.3Hz,3H),0.82-0.75(m,4H); MSm / z989.5945[M+H] + .

[0993] Reference Example 23

[0994] Production of methyl (S)-3-aminooxy-2-methylpropionate

[0995] With reference to European Journal of Medicinal Chemistry (2001), 36, 799-807, (S)-3-hydroxy-2-methylpropionic acid methyl ester (1.50 g, 12.7 mmol) was used as a starting material to obtain (yield 435 mg, yield 79%) of (S)-3-aminooxy-2-methylpropionic acid methyl ester.

[0996] 1 H-NMR (500MHz, D2O, δ): 3.74-3.68(m,1H), 3.68-3.61(m,1H), 3.61-3.56(m,3H), 2.81-2.73(m,1H), 1.01-0.97(m,3H).

[0997] Preparation of Compound I-173

[0998] Compound I-173 (yield 443 mg, 78%) was obtained by the same method using (S)-3-aminooxy-2-methylpropionic acid methyl ester obtained in Reference Example 23 instead of hydroxylamine hydrochloride in [Production of Compound I-2].

[0999] 1 H-NMR (500MHz, CDCl3, δ): 5.87-5.80 (m, 1H), 5.76-5.64 (m, 2H), 5.43-5.35 (m, 2H), 4.95 (br d, J = 9.2Hz, 1H), 4.88 (s, 1H), 4.76 (br d,J=3.4Hz,1H),4.70-4.60(m,2H),4.60-4.51(m,1H),4.33(dd,J=11.2,6. 6Hz,1H),4.08(dd,J=11.2,6.6Hz,1H),3.93(brs,1H),3.86-3.72(m,2H),3. 67(s,3H),3.71-3.59(m,2H),3.52-3.45(m,1H),3.44(s,3H),3.42(s,3H), 3.26-3.19(m,2H),3.16(t,J=9.2Hz,1H),2.92-2.82(m,1H),2.79-2.75(m,1 H),2.61-2.46(m,2H),2.34(dd,J=4.6,12.6Hz,2H),2.30-2.16(m,2H),1.9 2-1.85(m,2H),1.85-1.79(m,1H),1.76-1.71(m,1H),1.69-1.36(m,12H),1. 29-1.23(m,8H),1.16(t,J=6.6Hz,8H),0.92(t,J=7.4Hz,3H),0.88(t,J=6. 9Hz,1H),0.83(d,J=6.9Hz,3H),0.82-0.74(m,4H); MSm / z1007.5834[M+NH4] + .

[1000] Preparation of Compound I-174

[1001] Compound I-173 obtained in [Production of Compound I-173] was used instead of Compound I-153 in [Production of Compound I-154] to obtain Compound I-174 (yield 195 mg, 90%) in the same manner as [Production of Compound I-154].

[1002] 1H-NMR (500MHz, CDCl3, δ): 5.86-5.80 (m, 1H), 5.76-5.64 (m, 2H), 5.44-5.34 (m, 2H), 4.94 (br d, J = 10.3Hz, 1H), 4.89 (s, 1H), 4.76 (br d,J=2.9Hz,1H),4.65(br s,2H),4.36-4.30(m,1H),4.16-4.11(m,1H),3.93(br s,1H),3.86-3.72(m,2H),3.70-3.56(m,2H),3.48(ddd,J=4.6,9.2,11.5Hz,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H ),3.17(t,J=9.2Hz,1H),2.93-2.87(m,1H),2.77(dd,J=12.3,3.2Hz,1H),2.64-2.56(m,1H),2.52-2.46(m,1H),2.36-2.19(m ,2H),1.96-1.80(m,3H),1.77-1.71(m,1H),1.68-1.63(m,1H),1.59-1.36(m,12H),1.29-1.24(m,9H),1.20(d,J=7.4Hz,3H), 1.15(dd,J=6.6,2.6Hz,6H),0.92(t,J=7.4Hz,3H),0.88(s,1H),0.85-0.82(m,3H),0.80-0.74(m,4H); MSm / z998.5208[M+Na] + .

[1003] Preparation of Compound I-175

[1004] Compound I-174 obtained in [Production of Compound I-174] was used instead of Compound I-48 in [Production of Compound I-132], and ammonium chloride was used instead of 5-aminopyrimidine to obtain Compound I-175 (yield 15.7 mg, yield 39%) in the same manner as [Production of Compound I-132].

[1005] 1H-NMR (500MHz, CDCl3, δ): 7.25(s,1H),5.97(br s,1H),5.86-5.80(m,1H),5.76-5.64(m,2H),5.49(br s,1H),5.45-5.36(m,2H),4.94(br d,J=10.3Hz,1H),4.91-4.88(m,1H),4.76(d,J=3.4Hz,1H),4.70-4.59(m,3H),4.25-4.18(m,1H),4.16-4.09(m,1H),3.92(br s,1H),3.85-3.72(m,2H),3.70-3.57(m,2H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.27-3. 18(m,2H),3.16(t,J=9.2Hz,1H),2.79-2.67(m,2H),2.65-2.46(m,2H),2.36-2.19(m,4H),1.93-1. 80(m,2H),1.75-1.71(m,1H),1.66(d,J=12.6Hz,1H),1.58-1.35(m,12H),1.28-1.23(m,9H),1.19- 1.11(m,8H),0.92(t,J=7.2Hz,3H),0.83(d,J=6.9Hz,3H),0.81-0.74(m,4H); MSm / z997.5370[M+Na] + .

[1006] Preparation of Compound I-176

[1007] Compound I-174 obtained in [Production of Compound I-174] was used instead of Compound I-48 in [Production of Compound I-132], and methylamine hydrochloride was used instead of 5-aminopyrimidine to obtain Compound I-176 (yield 24.0 mg, yield 59%) by the same method as [Production of Compound I-132].

[1008] 1H-NMR(500MHz,CDCl3,δ):5.93(br s,1H),5.83(d,J=10.3Hz,1H),5.77-5.64(m,2H),5.43-5.36(m,2H),4.94(d,J=11.5Hz ,1H),4.89(s,1H),4.76(d,J=4.0Hz,1H),4.73-4.57(m,3H),4.22-4.09(m,2H),3.93(br s,1H),3.85-3.73(m,2H),3.71-3.58(m,2H),3.51-3.46(m,1H),3.44(s,3H),3.42(s,3H),3.26-3.19(m,2H),3.1 6(t,J=8.9Hz,1H),2.78-2.73(m,3H),2.65-2.57(m,2H),2.53-2.45(m,1H),2.33(dd,J=12.6,4.0Hz,2H),2.27-2 .19(m,2H),1.92-1.81(m,2H),1.76-1.69(m,1H),1.69-1.61(m,1H),1.59-1.37(m,13H),1.26(dd,J=10.9,6.3Hz ,8H),1.18-1.11(m,8H),0.92(t,J=7.4Hz,3H),0.83(d,J=6.9Hz,3H),0.80-0.74(m,4H); MSm / z1011.5554[M+Na] + .

[1009] Preparation of Compound II-1 and Compound II-2

[1010] Ethyl 2-(diethoxyphosphoryl)acetate (37.7 μL, 0.189 mmol) was dissolved in THF and cooled to 0°C. A 1M solution of lithium bistrimethylsilylamide in THF (0.189 mL, 0.189 mmol) was then added dropwise, and the mixture was stirred at the same temperature for 30 minutes. 3,4β-dihydro-5-oxo-ivermectin B1a (50.0 mg, 0.0570 mmol) dissolved in THF (0.457 mL) was slowly added dropwise, and the mixture was further stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate = 3:2) to obtain Compound II-1 (yield 5.2 mg, yield 10%) and Compound II-2 (yield 19.4 mg, yield 36%).

[1011] (Compound II-1)

[1012] 1 H-NMR (500 MHz, CDCl3, δ): 5.93 (s, 1H), 5.88 - 5.81 (m, 1H), 5.76 - 5.66 (m, 2H), 5.46 - 5.38 (m, 2H), 4.95 (d, J = 10.88 Hz, 1H), 5.78 - 5.65 (m, 3H), 4.60 - 4.55 (m, 1H), 4.19 - 4.10 (m, 2H), 4.08 - 4.01 (m, 1H), 3.93 (br s, 1H), 3.86 - 3.74 (m, 3H), 3.72 - 3.60 (m, 2H), 3.51 - 3.40 (m, 7H), 3.28 - 3.13 (m, 3H), 2.93 (d, J = 13.75 Hz, 1H), 2.52 - 2.46 (m, 2H), 2.36 - 2.15 (m, 5H), 1.94 - 1.86 (m, 1H), 1.79 - 1.70 (m, 1H), 1.69 - 1.64 (m, 1H), 1.59 - 1.38 (m, 17H), 1.31 - 1.23 (m, 13H), 1.15 (d, J = 6.87 Hz, 3H), 0.94 - 0.74 (m, 10H); MS m / z 962.5745 [M + NH4] + 。

[1013] (Compound II-2)

[1014] 1H-NMR (500MHz, CDCl3, δ): 6.01 (s, 1H), 5.88-5.76 (m, 1H), 5.75-5.66 (m, 2H), 5.45-5.35 (m, 2H), 5.17 (s, 1H) ,4.94(d,J=10.31Hz,1H),4.76(d,J=3.44Hz,1H),4.72-4.62(m,2H),4.52(s,1H),4.17-4.09(m,3H),3.93(br s,1H),3.87-3.71(m,2H),3.70-3.59(m,2H),3.52-3.35(m,7H),3.27-3.11(m,3H),2. 95-2.88(m,1H),2.75-2.67(m,1H),2.55-2.46(m,2H),2.36-2.19(m,5H),1.93-1.84( m,1H),1.83-1.71(m,1H),1.67-1.60(m,3H),1.58-1.37(m,13H),1.30-1.22(m,13H), 1.19-1.11(m,3H),0.91(t,J=7.16Hz,3H),0.86-0.74(m,7H); MSm / z962.5745[M+NH4] + .

[1015] Preparation of Compound II-3

[1016] Compound II-3 (yield 29.6 mg, 55%) was obtained by the same method using 3,4α-dihydro-5-oxo-ivermectin B1a instead of 3,4β-dihydro-5-oxo-ivermectin B1a in [Production of Compound II-1 and Compound II-2].

[1017] 1H-NMR (500MHz, CDCl3, δ): 5.95 (d, J = 1.7Hz, 1H), 5.84-5.77 (m, 1H), 5.74-5.66 (m, 2H), 5.41-5.33 (m, 3H) ,4.96-4.91(m,1H),4.76(d,J=3.4Hz,1H),4.67(d,J=2.3Hz,2H),4.46(s,1H),4.17-4.11(m,2H),3.92(br s,1H),3.85-3.73(m,2H),3.69-3.59(m,2H),3.50-3.46(m,1H),3.46-3.4 0(m,6H),3.25-3.13(m,3H),2.89-2.83(m,1H),2.67-2.60(m,1H),2.56(br s,1H),2.49(t,J=6.6Hz,1H),2.36-2.19(m,4H),1.92-1.85(m,1H),1.82-1.61(m,6H),1.57-1.36(m,14H),1 .29-1.22(m,10H),1.13(d,J=9.16Hz,3H),0.91(t,J=7.5Hz,3H),0.85-0.74(m,7H); MSm / z962.5745[M+NH4] + .

[1018] Preparation of Compound II-4

[1019] The compound II-2 (18.0 mg, 19.0 μmol) obtained by [Manufacturing of compound II-1 and compound II-2] was dissolved in dichloromethane (224 μL) and cooled to -78 ° C. After that, 1M diisobutylaluminum hydride dichloromethane solution (66.7 μL, 66.7 μmol) was added dropwise and stirred at the same temperature for 4 hours. Methanol and a saturated Rochelle salt aqueous solution were added dropwise thereto, and after stirring at room temperature for 30 minutes, the reaction solution was extracted with chloroform. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (n-hexane: ethyl acetate = 1: 3) to obtain compound II-4 (yield 13.2 mg, yield 77%).

[1020] 1H-NMR (500MHz, CDCl3, δ):5.97-5.89(m,1H),5.88-5.81(m,1H),5.77-5.63 (m,3H),5.40(d,J=3.4Hz,2H),4.98-4.90(m,1H),4.78-4.74(m,1H),4.70( s,1H),4.67-4.54(m,2H),4.40-4.36(m,1H),4.32(s,1H),4.25-4.14(m,2H ),3.94-3.89(m,1H),3.86-3.71(m,2H),3.70-3.60(m,2H),3.52-3.38(m,7H ),3.26-3.14(m,3H),2.87-2.76(m,1H),2.72-2.62(m,1H),2.58-2.53(m.1 H),2.49(t,J=6.87Hz,1H),2.38-2.30(m,2H),2.30-2.16(m,3H),1.94-1.85 (m,2H),1.79-1.71(m,2H),1.71-1.62(m,4H),1.58-1.37(m,14H),1.30-1. 19(m,9H),0.92(t,J=7.5Hz,3H),0.86-0.75(m,7H); MSm / z920.5573[M+NH4] + .

[1021] Preparation of Compound II-5

[1022] Compound II-5 was obtained by the same method using Compound II-3 instead of Compound II-2 in [Production of Compound II-4] (yield 20.3 mg, yield 76%).

[1023] 1H-NMR (500MHz, CDCl3, δ): 5.90 (td, J = 7.0, 2.0Hz, 1H), 5.86-5.78 (m, 1H), 5.76-5.63 (m, 2H), 5.41-5.35 (m, 2H), 4.97-4 .91(m,1H),4.79-4.73(m,2H),4.63(dd,J=6.9,2.3Hz,2H),4.38(s,1H),4.31-4.26(m,1H),4.23-4.17(m,1H),3.92(br s,1H),3.86-3.71(m,2H),3.69-3.60(m,2H),3.52-3.38(m,7H),3.25-3.13(m,3H),2.7 8(dd,J=12.9,3.15Hz,1H),2.60(s,1H),2.52-2.45(m,2H),2.35-2.19(m,4H),1.93-1.8 0(m,2H),1.77-1.70(m,4H),1.68-1.60(m,2H),1.58-1.37(m,14H),1.28-1.22(m,6H),1 .13(d,J=12.0Hz,3H),0.91(t,J=7.5Hz,3H),0.84-0.74(m,7H); MSm / z920.5573[M+NH4] + .

[1024] Preparation of Compound II-6

[1025] After dissolving the compound II-5 (98.0 mg, 0.109 mmol) obtained in [Manufacturing of Compound II-5] in dichloromethane (2.17 mL), manganese dioxide (385 mg, 4.34 mmol) was added and stirred at room temperature for 14 hours. After filtering the reaction solution using cerium silicate, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain compound II-6 (yield 67.7 mg, yield 69%).

[1026] 1H-NMR (500MHz, CDCl3, δ): 10.13 (d, J=7.5Hz, 1H), 6.13 (dd, J=8.0, 1.7Hz, 1H), 5.85 (s, 1H), 5.73(dd,J=17.2,9.7Hz,2H),5.40(d,J=4.0Hz,2H),4.98(s,2H),4.79-4.67(m,6H),3.94(br s,1H),3.86-3.73(m,2H),3.71-3.58(m,2H),3.43(d,J=9.7Hz,7H),3.23(d,J=9.2H z,2H),3.17(s,1H),2.85(s,1H),2.76-2.66(m,1H),2.50(d,J=1.2Hz,2H),2.33(br s,4H),1.82(s,4H),1.65(br s,1H),1.59-1.49(m,16H),1.41(t,J=12.0Hz,3H),1.31-1.22(m,7H),1.16(d, J=6.3Hz, 6H), 0.92 (t, J=7.5Hz, 3H), 0.86-0.75 (m, 7H); MSm / z920.5573[M+NH4] + .

[1027] Preparation of Compound II-7

[1028] Compound II-7 (yield 26.8 mg, 71%) was obtained by the same method using compound II-6 instead of 3,4β-dihydro-5-oxo-ivermectin B1a in the production of [Production of Compound II-1 and Compound II-2].

[1029] 1H-NMR (500MHz, CDCl3, δ): 7.67 (dd, J = 15.2, 11.7Hz, 1H), 6.32 (d, J = 11.5Hz, 1H), 5.95 (d, J = 14.9Hz, 1H), 5.88-5.80 (m, 1H), 5.76-5.67 (m, 2 H),5.43-5.35(m,2H),4.94(d,J=10.9Hz,1H),4.76(d,J=3.4Hz,1H),4.70-4.60(m,4H),4.21-4.15(m,2H),3.93(brs,1H),3.86-3.72(m,2H) ,3.72-3.57(m,2H),3.48-3.38(m,7H),3.27-3.13(m,3H),2.83(dd,J=12.6,3.44Hz,1H),2.64-2.54(m,2H),2.54-2.46(m,1H),2.37-2.18( m,4H),1.89(dd,J=11.5,4.6Hz,1H),1.80-1.61(m,6H),1.58-1.36(m,14H),1.31-1.14(m,17H),0.93-0.74(m,11H); MSm / z988.6065[M+NH4] + .

[1030] Preparation of Compound II-8

[1031] After dissolving the compound II-6 (15.0 mg, 17.0 μmol) obtained in [Manufacturing of Compound II-6] in methanol (200 μL), 2-(aminooxy)ethane-1-ol (5.13 mg, 67.0 μmol) and sodium acetate (5.46 mg, 67.0 μmol) were added and stirred at room temperature for 14 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with chloroform. After distilling the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (n-hexane: acetone = 2: 1) to obtain compound II-8 (yield 12.6 mg, yield 79%) as a mixture of isomers that were difficult to separate.

[1032] 1H-NMR (500MHz, CDCl3, δ): 8.20 (d, J = 10.3Hz, 1H), 7.45 (d, J = 9.7Hz, 1H), 6.27 (dd, J = 10.3, 1.7Hz, 1H), 5.87-5.80 (m, 1H), 5.71 (t, J = 9.7Hz, 2H) ,5.45-5.33(m,2H),4.94(d,J=10.9Hz,1H),4.76(d,J=3.4Hz,1H),4.70 -4.60(m,3H),4.51(s,0.3H),4.43(s,0.7H),4.24-4.14(m,2H),3.93(br s,1H),3.89-3.71(m,4H),3.72-3.60(m,2H),3.52-3.38(m,7H),3.26-3.13(m,3H),2. 80(dd,J=12.6,3.4Hz,1H),2.63-2.53(m,2H),2.53-2.43(m,1H),2.36-2.16(m,5H),1 .89(dd,J=12.6,4.6Hz,1H),1.82-1.69(m,3H),1.68-1.62(m,3H),1.58-1.37(m,13H) ,1.29-1.14(m,12H),0.91(t,J=7.5Hz,3H),0.85-0.74(m,7H);MSm / z982.5557[M+Na] + .

[1033] Preparation of Compound II-9

[1034] After dissolving the compound II-6 (15.0 mg, 17.0 μmol) obtained in [Manufacturing of Compound II-6] in THF (333 μL), 2-aminoethane-1-ol (3.02 μL, 50.0 μmol), acetic acid (9.53 μL, 166 μmol), zinc chloride (3.40 mg, 25.0 μmol) and sodium cyanoborohydride (5.23 mg, 83.0 μmol) were added and stirred at room temperature for 14 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with chloroform. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (chloroform: methanol: ammonium aqueous solution = 90: 10: 1) to obtain compound II-9 (yield 8.5 mg, yield 54%).

[1035] 1H-NMR (500MHz, CDCl3, δ):5.87-5.81(m,1H),5.79-5.68(m,3H),5.40-5.31(m,2H),4.9 8-4.91(m,1H),4.76(d,J=3.4Hz,1H),4.63(dd,J=4.6,2.3Hz,2H),4.38(s,1H),3.93(br s,1H),3.85-3.73(m,2H),3.69-3.60(m,4H),3.52-3.41(m,8H),3.38-3.33(m,1H) ,3.26-3.14(m,3H),2.83-2.73(m,3H),2.61-2.38(m,7H),2.38-2.17(m,6H),1.94 -1.88(m,1H),1.77-1.61(m,4H),1.58-1.35(m,14H),1.35-1.21(m,8H),1.13(dd, J=15.2,6.6Hz,7H),0.91(t,J=7.5Hz,3H),0.87-0.73(m,8H); MSm / z946.5779[M+H] + .

[1036] Preparation of Compound II-10

[1037] The compound II-7 (19.3 mg, 20.0 μmol) obtained in [Manufacture of compound II-7] was dissolved in methanol (397 μL) and cooled to 0°C. Thereafter, nickel chloride hexahydrate (0.95 mg, 3.97 μmol) and sodium borohydride (3.76 mg, 99.0 μmol) were added, and the mixture was stirred at the same temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and after warming to room temperature, it was extracted with chloroform. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer chromatography (n-hexane: ethyl acetate = 1:1) to obtain compound II-10 (yield 5.2 mg, yield 10%) as a mixture of isomers that were difficult to separate. The following 1 The H-NMR spectrum is the analytical data of the main isomer.

[1038] 1H-NMR (500MHz, CDCl3, δ): 5.86-5.75 (m, 1H), 5.73-5.50 (m, 3H), 5.41-5.32 (m, 2H), 4.94 (d, J = 11.5Hz ,1H),4.76(d,J=2.3Hz,1H),4.62(t,J=2.7,2.7Hz,1H),4.59-4.46(m,2H),4.14-4.08(m,2H),3.92(br s,1H),3.84-3.60(m,5H),3.50-3.37(m,7H),3.25-3.14(m,3H),3.07-3.06(m ,1H),2.77dd,J=12.9,3.2Hz,1H),2.58-2.40(m,4H),2.382.20(m,5H),1.92-1 .85(m,1H),1.79-1.70(m,2H),1.68-1.36(m,15H),1.27-1.21(m,10H),1.14(d ,J=6.9Hz,3H),1.08-1.03(m,2H),0.94-0.77(m,13H); MSm / z990.6157[M+NH4] + .

[1039] Preparation of Compound II-11

[1040] After dissolving the compound II-7 (7.00 mg, 7.21 μmol) obtained in [Manufacturing of Compound II-7] in dichloromethane (290 μL), the mixture was cooled to -78 ° C. 1M diisobutylaluminum hydride dichloromethane solution (36.0 μL, 36.0 μmol) was then added dropwise and stirred at the same temperature for 4 hours. Methanol and a saturated Rochelle salt solution were added dropwise thereto, and after stirring at room temperature for 30 minutes, the reaction solution was extracted with chloroform / methanol (9: 1). After distilling off the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (chloroform: methanol = 9: 1) to obtain compound II-11 (yield 5.30 mg, yield 79%).

[1041] 1H-NMR (500MHz, CDCl3, δ): 6.66 (dd, J=14.9, 10.9Hz, 1H), 6.25 (dd, J=10.9, 1.7Hz, 1H), 5.94 (d, J=14.9Hz, 1H), 5.87-5.78 (m, 1H), 5.76- 5.66(m,2H),5.41-5.35(m,2H),4.98-4.89(m,1H),4.76(d,J=2.9Hz,1H),4.70-4.59(m,3H),4.57(s,1H),4.18(d,J=5.2Hz,2H),3.93(br s,1H),3.88-3.58(m,5H),3.52-3.41(m,7H),3.28-3.12(m,3H),2.80(s,1H),2.51(br s,3H),2.36-2.30(m,2H),2.27(s,2H),1.93-1.83(m,1H),1.77-1.62(m,5H),1.61-1.40(m,19H),1.38(s,2H ),1.30-1.22(m,8H),1.15(d,J=6.9Hz,6H),0.91(t,J=7.5Hz,3H),0.84-0.75(m,7H); MSm / z946.5919[M+NH4] + .

[1042] Preparation of Compound II-12

[1043] The compound II-5 (30.6 mg, 34.0 μmol) obtained by [Manufacturing of Compound II-5] was dissolved in dichloromethane (339 μL) and ice-cooled to 0 ° C. After that, pyridine (5.48 μL, 68.0 μmol), 4-methylbenzoyl chloride (5.82 μL, 44.0 μmol) and DMAP (0.414 mg, 3.39 μmol) were added, the temperature was raised to room temperature, and the mixture was stirred at the same temperature for 24 hours. After that, the reagent was added again and stirred at room temperature for a further 24 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with chloroform. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer chromatography (n-hexane: ethyl acetate = 1: 1) to obtain compound II-12 (yield 5.00 mg, yield 15%).

[1044] 1H-NMR (500MHz, CDCl3, δ): 7.93 (d, J = 7.6Hz, 2H), 7.21 (d, J = 8.0Hz, 2H), 5.89-5.82 (m, 2H), 5.75-5.68 (m, 2H), 5.42-5 .33(m,2H),5.02-4.92(m,3H),4.77(d,J=3.4Hz,1H),4.65(dd,J=5.2,2.3Hz,2H),4.53(s,1H),4.47(s,1H),3.93(br s,1H),3.87-3.72(m,2H),3.71-3.58(m,2H),3.51-3.36(m,7H),3.27-3.14(m,3H), 2.83-2.78(m,1H),2.50(brs,3H),2.39(s,3H),2.37-2.30(m,2H),2.30-.2.17(m,2H ),1.95-1.83(m,1H),1.79-1.62(m,5H),1.60-1.39(m,21H),1.31-1.21(m,7H),1.14 (d,J=3.4Hz,3H),0.92(t,J=7.2Hz,3H),0.86-0.76(m,7H);MSm / z1038.6484[M+NH4] + .

[1045] Preparation of Compound II-13

[1046] Compound II-13 (yield 91.3 mg, 84%) was obtained by the same method using allyl 2-(diethoxyphosphoryl)acetate instead of ethyl 2-(diethoxyphosphoryl)acetate in [Production of Compound II-3].

[1047] 1H-NMR (500MHz, CDCl3, δ): 5.98 (d, J = 1.7Hz, 1H), 5.95-5.87 (m, 1H), 5.82-5.79 (m, 1H), 5.74-5.63 (m, 2H), 5.40-5.27 (m, 4H), 5 .24-5.18(m,1H),4.93(d,J=10.9Hz,1H),4.75(d,J=3.4Hz,1H),4.67(d,J=2.3Hz,2H),4.63-4.55(m,2H),4.46(s,1H),3.92(br s,1H),3.85-3.73(m,2H),3.69-3.60(m,2H),3.51-3.39(m,7H),3.25-3.13(m,3H),2.88-2.84(m,1H),2.65(dd,J=5.2,2.9Hz,1H),2.60(br s,1H),2.48(br s,1H),2.35-2.19(m,4H),1.92-1.87(m,1H),1.82-1.70(m,4H),1.64(d,J=12.6Hz,1H),1.57-1.35(m,14H),1. 35-1.21(m,8H),1.14(dd,J=8.6,6.9Hz,6H),0.91(t,J=7.5Hz,3H),0.86-0.74(m,7H); MSm / z974.6138[M+NH4] + .

[1048] Preparation of Compound II-14

[1049] The compound II-13 (15.0 mg, 16.0 μL) obtained in [Manufacture of compound II-13] was dissolved in dichloromethane (313 μL) and ice-cooled to 0°C. After that, morpholine (13.7 μL, 157 μmol) and tetrakis(triphenylphosphine)palladium (1.81 mg, 1.57 μmol) were added and stirred at the same temperature for 30 minutes. Then, the mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was diluted with chloroform and washed with 1N hydrochloric acid. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer chromatography (n-hexane: ethyl acetate = 1: 3) to obtain compound II-14 (yield 11.6 mg, yield 81%).

[1050] 1H-NMR (500MHz, CDCl3, δ): 7.69-7.63 (m, 1H), 7.53 (dd, J = 7.2, 1.4Hz, 1H), 7.50-7.41 (m, 1H), 5.98 (s, 1H), 5. 85-5.78(m,1H),5.75-5.66(m,2H),5.42-5.33(m,3H),4.95(d,J=9.74Hz,1H),4.76(d,J=3.4Hz,1H),4.68(br s,2H),3.93(br s,1H),3.86-3.72(m,2H),3.72-3.57(m,2H),3.52-.3.40(m,7H),3.29-3.11(m,3H),2.94-2 .82(m,1H),2.72-2.62(m,1H),2.54-2.43(m,1H),2.38-2.16(m,5H),1.90(dd,J=12.0,4.0H z,1H),1.84-1.71(m,3H),1.65(d,J=12.6Hz,1H),1.58-1.36(m,14H),1.35-1.21(m,7H),1. 14(dd,J=6.3,3.4Hz,6H),0.91(t,J=7.5Hz,3H),0.87-0.73(m,7H); MSm / z934.5815[M+NH4] + .

[1051] Preparation of Compound II-15

[1052] Compound II-10 (13.4 mg, 14.0 μmol) obtained in [Manufacture of Compound II-10] was dissolved in THF (275 μL) and ice-cooled to 0°C. Thereafter, lithium triethylborate (62.0 μL, 62.0 μmol) was added and stirred at the same temperature for 1 hour. Methanol and saturated aqueous sodium bicarbonate solution were added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer chromatography (n-hexane: ethyl acetate = 1:2) to obtain compound II-15 (yield 7.90 mg, yield 62%) as a mixture of isomers that were difficult to separate. The following 1 The H-NMR spectrum is the analytical data of the main isomer.

[1053] 1H-NMR (500MHz, CDCl3, δ):5.83-5.76(m,1H),5.74-5.66(m,2H),5.52-5.49(m,1H),5.40-5.34( m,2H),4.95-4.93(m,1H),4.76(d,J=2.3Hz,1H),4.63-4.61(m,1H),4.58-4.46(m,2H),3.92(br s,1H),3.85-3.74(m,2H),3.69-3.56(m,4H),3.50-3.40(m,7H),3.25-3.14(m, 3H),2.59-2.44(m,3H),2.35-2.20(m,5H),1.89-1.85(m,1H),1.75-1.36(m,25 H),1.26(dd,J=12.3Hz,6.0Hz,7H),1.16-1.10(m,4H),1.07-1.02(m,1H),0.95 -0.88(m,6H),0.83(d,J=6.3Hz,3H),0.79-0.76(m,4H); MSm / z948.5929[M+NH4] + .

[1054] Preparation of Compound II-16

[1055] The compound II-14 (11.6 mg, 13.0 μmol) obtained in [Production of Compound II-14] was dissolved in a dichloromethane solution (506 μL) and ice-cooled to 0°C. Subsequently, aniline (2.31 μL, 25.0 μmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropane-1-amine hydrochloride (4.85 mg, 25.0 μmol) and DMAP (3.09 mg, 25.0 μmol) were added and stirred at room temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with chloroform. After the solvent was distilled off under reduced pressure, the residue was purified by preparative thin layer chromatography (n-hexane: ethyl acetate = 1: 1) to obtain compound II-16 (yield 9.80 mg, yield 78%).

[1056] 1H-NMR (500MHz, CDCl3, δ): 8.10 (s, 1H), 7.55 (d, J = 8.0Hz, 2H), 7.30 (t, J = 7.7Hz, 2H), 7.08 (s, 1H), 6.11 (d, J = 1.7Hz, 1H), 5.82 (d, J = 10.3Hz,1H),5.76-5.61(m,2H),5.39(d,J=3.4Hz,2H),4.95(d,J=9.7Hz,1H),4.80(s,1H),4.74(s,2H),4.71-4.59(m,2H),3.92(br s,1H),3.86-3.72(m,2H),3.71-3.58(m,2H),3.42(d,J=10.3Hz,7H),3.23(s,3H),2.87-2.78 (m,1H),2.69-2.58(m,1H),2.58-2.53(m,1H),2.51-2.43(m,1H),2.37-2.18(m,1H),1.95-1.8 7(m,1H),1.87-1.71(m,3H),1.66(s,7H),1.58-1.37(m,13H),1.25(dd,J=12.6,6.3Hz,7H),1. 15(dd,J=18.9,6.9Hz,6H),0.92(t,J=7.5Hz,3H),0.86-0.76(m,7H); MSm / z1009.6273[M+NH4] + .

[1057] Preparation of Compound II-17

[1058] Compound II-17 was obtained by the same method using ethylamine instead of aniline in [Production of Compound II-16] (yield 10.6 mg, yield 77%).

[1059] 1H-NMR (500MHz, CDCl3, δ): 6.09 (t, J = 5.7Hz, 1H), 5.96 (d, J = 2.3Hz, 1H), 5.87-5.79 (m, 1H), 5.76-5. 62(m,2H),5.39(d,J=4.0Hz,2H),4.98-4.91(m,1H),4.77-4.72(m,2H),4.68-4.57(m,3H),3.93(br s,1H),3.87-3.72(m,2H),3.71-3.58(m,2H),3.51-3.39(m,7H),3.36-3.14(m,5H),2.79 (dd,J=12.3,3.7Hz,1H),2.59-2.52(m,2H),2.51-2.45(m,1H),2.36-2.29(m,2H),2.29-2 .19(m,2H),1.94-1.86(m,1H),1.82-1.62(m,9H),1.58-1.36(m,13H),1.27(d,J=6.3Hz, 7H),1.17-1.10(m,9H),0.91(t,J=7.5Hz,3H),0.85-0.74(m,7H); MSm / z961.6087[M+NH4] + .

[1060] Preparation of Compound II-18

[1061] Compound II-18 (yield 18.9 mg, 57%) was obtained by the same method using thiophen-2-ylmethanamine instead of 2-aminoethane-1-ol in [Production of Compound II-9].

[1062] 1H-NMR (500MHz, CDCl3, δ): 7.19 (dd, J=4.9, 1.4Hz, 1H), 6.95-6.91 (m, 2H), 5.86-5.80 (m, 1H), 5.77 (t, 1H), 5.74-5.66 (m, 2H),5.45-5.29(m,2H),4.95(d,J=10.9Hz,1H),4.78-4.75(m,1H),4.66-4.57(m,2H),4.34(s,1H),3.98(s,2H),3.93(br s,1H),3.86-3.73(m,2H),3.70-3.60(m,2H),3.50-3.35(m,9H),3.27-3.14(m,3 H),2.77(dd,J=12.9,3.2Hz,1H),2.52-2.42(m,3H),2.40-2.17(m,8H),1.91(dd ,J=11.7,4.3Hz,1H),1.77-1.69(m,2H),1.68-1.61(m,2H),1.60-1.35(m,13H), 1.32-1.21(m,7H),1.21-1.05(m,6H),0.94-0.75(m,10H); MSm / z998.6152[M+H] + .

[1063] Preparation of Compound II-19

[1064] Compound II-19 was obtained by the same method using aniline instead of 2-aminoethane-1-ol in [Production of Compound II-9] (yield 23.1 mg, yield 72%).

[1065] 1H-NMR (500MHz, CDCl3, δ): 7.16 (t, J = 6.8 Hz, 2H), 6.70 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.5 Hz, 2H), 5.87-5.79 (m, 2H), 5.74-5.65 (m,2H),5.43-5.36(m,2H),4.94(d,J=10.9Hz,1H),4.79-4.72(m,1H),4.68(s,1H),4.67-4.58(m,2H),4.42(s,1H),3.92(br s,1H),3.87-3.73(m,5H),3.73-3.60(m,2H),3.43(d,J=10.9Hz,7H),3.26-3.14(m,3H),2.81(d d,J=12.9,3.15Hz,1H),2.53(s,1H),2.51-2.44(m,2H),2.36-2.19(m,4H),1.90(dd,J=12.0,3.4 Hz,1H),1.77-1.70(m,2H),1.69-1.60(m,4H),1.59-1.38(m,14H),1.31-1.21(m,7H),1.13(dd, J=10.6,6.6Hz,6H),0....

Claims

1. A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, In the above formula (I), n represents an integer 0, 1 or 2, X represents CH, CF, CCl, N, CHCH=N, CHCH=CH or CHCH=CF, Y represents O, NH or a single bond, Z represents a hydroxyl group or an oxo group, R 1 represents a hydrogen atom; a halogen atom; a C1-C6 alkyl group; a 3-membered to 6-membered cycloalkyl group; a 4-membered to 8-membered heterocycloalkyl group; a 6-membered to 10-membered aryl group; a 5-membered to 10-membered heteroaryl group; a C2-C6 alkenyl group; a C2-C6 alkynyl group; -CO-R 2 The group shown; -COO-R 2 The group shown; -CONH-R 2 The group shown; or -B(OR 4 )OR 5 The basis shown, where R 1 When it is not a hydrogen atom or a C1-C6 alkyl group, the above R 1 It may also be substituted by one or more substituents selected from the following atoms or groups: halogen atoms, hydroxyl groups, amino groups, cyano groups, nitro groups, formyl groups, mercapto groups, oxo groups, C1-C3 alkyl groups, C1-C3 hydroxyalkyl groups, C1-C6 alkoxy groups, C1-C3 aminoalkyl groups, C1-C3 haloalkyl groups, -NR 2 R 3 The group shown, -COO-R 2 The group shown, -CONH-R 2 The group shown, -NHCO-R 2 The group shown, -NHSO2-R 2 The group shown and -NHSO2NH-R 2 The base shown, R 1 In the case of a C1-C6 alkyl group, the C1-C6 alkyl group may be substituted by one or more substituents selected from the following atoms or groups: a halogen atom; a hydroxyl group; an amino group; a nitro group; a cyano group; an oxo group; or a hydroxyl group, an amino group, -CONH-R 2 The group shown, -NHCO-R 2 The group shown or -NHSO2-R 2 3- to 6-membered cycloalkyl substituted by the group shown; 4- to 8-membered heterocycloalkyl which may be substituted by an oxo group; 6- to 10-membered aryl which may be substituted by a halogen atom or a C1-C3 alkyl group; 5- to 10-membered heteroaryl; -OR 2 The group shown; -O-CO-R 2 The group shown; -O-CONH-R 2 The group shown; -NR 2 R 3 The base shown; -SR 2 The group shown; -CONH-R 2 The group shown; -NHCO-R 2 The group shown; -COO-R 2 The group shown; -NHCOO-R 2 The group shown; -NHCONH-R 2 The group shown; -NHSO2-R 2 The group shown; -CO-R 2 The group shown; -SO2-R 2 The group shown; and -NHSO2NH-R 2 The base shown, R 2 represents a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C3 haloalkyl group, a hydroxyl group, a C1-C3 hydroxyalkyl group, a C1-C6 alkoxy group, a C1-C3 haloalkoxy group, a 3-membered to 6-membered cycloalkyl group, a 3-membered to 6-membered cycloalkyl C1-C3 alkyl group, a 4-membered to 8-membered heterocycloalkyl group, a 6-membered to 10-membered aryl group, a 6-membered to 10-membered aryl C1-C3 alkyl group, a 5-membered to 10-membered heteroaryl group, a 5-membered to 10-membered heteroaryl C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkyl group, an amino group, a C1-C6 alkylamino group, a C1-C6 dialkylamino group, a mercapto group or a C1-C6 trialkylsilyl group, wherein R 2 The 5- to 10-membered heteroaryl group shown may be further selected from halogen atoms, hydroxyl groups, amino groups, cyano groups, C1-C3 alkyl groups, C1-C3 hydroxyalkyl groups, C1-C6 alkoxy groups, C1-C3 aminoalkyl groups, C1-C3 haloalkyl groups, -NR 2 R 3 The group shown and -CONH-R 2 The group shown is substituted by one or more substituents, R 2 The heteroaryl group of the 5-membered to 10-membered heteroaryl C1-C3 alkyl group shown may be further substituted by an amino group or a C1-C3 alkyl group. R 3 represents a hydrogen atom or a C1-C6 alkyl group, R 4 and R 5 are all hydrogen atoms, or R 4 and R 5 Each independently represents a C1-C10 alkyl group which may be bonded to each other to form a ring structure, The numbers 3, 4, 22, and 23 represent the position numbers of carbon atoms, respectively. There can be a single bond or a double bond between the 3rd and 4th positions, and between the 22nd and 23rd positions, respectively, independently.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein In the above formula (I), X is N, Y is O, and there is a single bond between the 3-position and the 4-position.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein In the above formula (I), R 1 It is a C1-C6 alkyl group which may be substituted.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein In the above formula (I), R 1 is a 5- to 10-membered heteroaryl group, -CONH-R 2 The group shown or -CO-R 2 C1-C6 alkyl substituted with the group shown.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein In the above formula (I), X is N, Y is O, and there is a double bond between the 3-position and the 4-position.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein In the above formula (I), X is N, Y is O, and R 1 is a hydrogen atom; a C2-C6 alkenyl group; a C2-C6 alkynyl group; a halogen atom; a 3- to 6-membered cycloalkyl group which may be substituted with a hydroxyl group; a 4- to 8-membered heterocycloalkyl group; or a group selected from -OR 2 The group shown, -O-CONH-R 2 The group shown, -COO-R 2 The group shown, -CONH-R 2 The group shown, -NHCONH-R 2 The group shown, -CO-R 2 The group shown and -NHSO2-R 2 The group shown is a C1-C6 alkyl group substituted with one or more substituents.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound represented by the above formula (I) is selected from the compounds represented by the following formulas (1) to (94), 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein In the above formula (I), X is CH, CF or CHCH=CH, and there is a single bond between the 3-position and the 4-position.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein In the above formula (I), X is CH, CF or CHCH=CH, and there is a double bond between the 3-position and the 4-position.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein In the above formula (I), X is CH, CF or CHCH=CH, and Y is a single bond. R 1 -COO-R is a 4- to 8-membered heterocycloalkyl group which may be substituted by an oxo group; 2 can also be selected from halogen atoms, hydroxyl, amino, cyano, formyl, oxo, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C6 alkoxy, C1-C3 haloalkyl, -NR 2 R 3 The group shown, -NHCO-R 2 The group shown and -CONH-R 2 5- to 10-membered heteroaryl groups substituted with one or more substituents in the group shown; or may be selected from hydroxyl, amino, nitro, oxo, -CONH-R 2 The groups shown and -COO-R 2 A C1-C6 alkyl group substituted with one or more substituents in the group shown.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound represented by the above formula (I) is selected from the compounds represented by the following formulas (201) to (271), 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein In the above formula (I), X is N, Y is NH, R 1 -CO-R 2 The base shown.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which has antiviral activity against coronavirus.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein The above coronavirus is classified into the Betacoronavirus genus.

15. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein The above-mentioned coronavirus is at least one selected from human coronavirus (HCoV), severe acute respiratory syndrome coronavirus (SARS-CoV), new coronavirus (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV).

16. A composition for treating or preventing a disease or condition involving coronavirus, comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.

17. The composition of claim 16, wherein The above coronavirus is classified into the Betacoronavirus genus.

18. The composition of claim 16, wherein The above-mentioned coronavirus is at least one selected from human coronavirus (HCoV), severe acute respiratory syndrome coronavirus (SARS-CoV), new coronavirus (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV).

19. A method for treating or preventing a disease or condition involving coronavirus, comprising administering the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof to a subject.

20. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the manufacture of a composition for treating or preventing a disease or condition involving a coronavirus.

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