Neuroprotective agent

Abstract

Provided are: a novel compound that is useful for the treatment of diseases to be prevented, ameliorated, and / or treated by suppressing axon degeneration; and a pharmaceutical composition containing the same.　The present invention relates to: a compound represented by general formula (I) [in the formula, Ra, Rb, X1, R1, L1, L2, and R2 are as disclosed in the specification and as set forth in the claims] or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition containing the same.

Description

Neuroprotective agents

[0001] The present invention relates to nicotinamide derivatives and pharmaceutical compositions containing same, in particular to nicotinamide derivatives and pharmaceutical compositions containing same for the treatment of diseases that can be prevented, alleviated and / or cured by inhibiting axonal degeneration.

[0002] Axon degeneration is known to occur in many neurodegenerative diseases. Reports have shown that deficiency of Sterile Alpha and TIR Motif-containing 1 (SARM1) significantly attenuates axon degeneration in several models, suggesting that SARM1 regulates axon degeneration through its enzymatic activity. Therefore, compounds that can inhibit SARM1 have attracted attention (see, for example, Patent Document 1).

[0003] Recent studies have suggested that the activity of SARM1 is controlled by the abundance ratio of nicotinamide adenine dinucleotide (NAD) and the substrates and intermediates in the NAD biosynthetic pathway (see, for example, Non-Patent Document 1). Furthermore, since nicotinamide phosphoribosyl transferase (NAMPT) is considered to be the rate-limiting enzyme in the NAD biosynthetic pathway, compounds that do not inhibit NAMPT and can inhibit SARM1, which is involved in NAD decomposition, are expected.

[0004] Special Publication No. 2023-501969

[0005] Li et al., eLife 2021;10:e67381

[0006] The present invention provides novel compounds and pharmaceutical compositions containing same that are useful in the treatment of diseases that are prevented, alleviated and / or cured by the inhibition of axonal degeneration.

[0007] As a result of extensive research into compounds having SARM1 inhibitory activity, the present inventors have found that a series of derivatives having a nicotinamide structure or salts thereof have SARM1 inhibitory activity and / or weak NAMPT inhibitory activity, and are useful for treating diseases that are prevented, alleviated, and / or cured by suppressing axonal degeneration via these, particularly neurodegenerative diseases, and have completed the present invention.

[0008] The present invention is as follows: [1] A compound represented by the following general formula (I): [In the formula, R ａ and R ｂ are independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxy group, a C １～６ Alkyl, haloC １～６ Alkyl, Amino C １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl or C ２～６ alkynyloxy or R on the adjacent carbon atom ａ and R ｂ may be taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted carbocyclic or heterocyclic ring fused to the pyridine ring; １ is a direct bond, -CR １１ =CR １１ -or- (CONR １１ ) ｍ CH ２ - and R １ is a hydrogen atom or C １～６ is alkyl, and L １ is C １～１０ Alkylene, arylene, C １～１０ Alkylene-arylene, arylene-C １～１０ Alkylene, C １～１０ Alkylene-arylene-C １～１０ Alkylene, arylene-C１～１０ Alkylene-arylene, heterocyclylene, C １～１０ Alkylene-heterocyclylene, heterocyclylene-C １～１０ Alkylene or C １～１０ Alkylene-heterocyclylene-C １～１０ alkylene, wherein the alkylene, arylene, or heterocyclylene moiety is selected from the group consisting of halogen, —COOR １２ , -CONHR １２ or oxo, ２ represents a direct bond, —O—, —NR １３ -, -NR １３ SO ２ - or - (OCH ２ CH ２ ) ｎ O- and R ２ represents a hydrogen atom, an azide, a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, —COR １４ , substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, wherein m is 0 or 1, n is 1 to 6, and R １１ are independently a hydrogen atom or C １～６ alkyl, R １２ is a hydrogen atom or C １～６ alkyl, R １３ is a hydrogen atom, C １～６ Alkyl or -COR １４ and R １４ is a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～１０ Cycloalkyl, substituted or unsubstituted C ３～１０ or a pharmaceutically acceptable salt thereof (wherein L is a cycloalkenyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclyl). １ But arylene, C １～３Alkylene-arylene, arylene-C １～３ Alkylene, or C １～３ Alkylene-arylene-C １～３ alkylene, and L ２ is a direct bond, １ But C １～３ alkylene-arylene, and L ２ is —O—, and １ But C １～３ alkylene, and L ２ is —NH—, and R ２ is —CO-5-membered heterocyclyl).

[0009] [2] The compound is represented by the following general formula (Ia): [In the formula, X １ is a direct bond, -CR １１ =CR １１ -or-CONR １１ CH ２ - and R １ is a hydrogen atom or C １～６ is alkyl, and L １ is C １～１０ Alkylene, arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, C １～３ Alkylene-arylene-C １～３ Alkylene, heterocyclylene, C １～３ Alkylene-heterocyclylene, heterocyclylene-C １～３ Alkylene or C １～３ Alkylene-heterocyclylene-C １～３ alkylene, wherein the alkylene moiety is —COOR １２ or -CONHR １２ and L ２ represents a direct bond, —O—, —NR １３ -, -NR １３ SO ２ - or - (OCH ２ CH ２ ) ｎ O- and R ２ represents a hydrogen atom, an azide, a substituted or unsubstituted C １～６Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, —COR １４ , substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, where n is 1 to 6; １１ are independently a hydrogen atom or C １～６ alkyl, R １２ is a hydrogen atom or C １～６ alkyl, R １３ is a hydrogen atom, C １～６ Alkyl or -COR １４ and R １４ is a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl; １ But arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, or C １～３ Alkylene-arylene-C １～３ alkylene, and L ２ is a direct bond, １ But C １～３ alkylene-arylene, and L ２ is —O—, and １ But C １～３ alkylene, and L ２ is —NH—, and R ２ or a pharmaceutically acceptable salt thereof according to [1], wherein R is —CO-5-membered heterocyclyl.

[0010] [3] L ２

[0023]

[0024] The compound according to [1] or [2], wherein is —O— or —NH—, or a pharmaceutically acceptable salt thereof.

[0011] [4] The compound is represented by the following general formula (II): [In the formula, X １１ is a direct bond, -CR １１ =CR １１ -or-CONR１１ CH ２ - and X １２ is a direct bond, C １～３ Alkylene, -CR １１ =CR １１ - or -CH ２ NR １１ CO-, and L １１ is C １～１０ Alkylene, arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, C １～３ Alkylene-arylene-C １～３ Alkylene, heterocyclylene, C １～３ Alkylene-heterocyclylene, heterocyclylene-C １～３ Alkylene or C １～３ Alkylene-heterocyclylene-C １～３ alkylene, and L ２１ is —O— or —NH—, and Y １ is N or CH, R １１ are independently a hydrogen atom or C １～６ alkyl, R １２ is a hydrogen atom or C １～６ alkyl, R ２１ are independently halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl and C ２～６ The compound according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkynyloxy.

[0012] [5] L ２ is a direct bond or -(OCH ２ CH ２ )ｎ The compound according to [1] or [2], wherein R is O—, or a pharmaceutically acceptable salt thereof.

[0013] [6] R ２ is a hydrogen atom, a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ The compound according to [1], [2] or [5], which is alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, or a pharmaceutically acceptable salt thereof.

[0014] [7] The following compound: The compound according to [1], or a pharmaceutically acceptable salt thereof, wherein

[0015] [8] A pharmaceutical composition comprising the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable additive.

[0016] [9] The pharmaceutical composition according to [8], for treating a disease that can be prevented, alleviated, and / or cured by inhibiting axonal degeneration.

[0017]

[10] The pharmaceutical composition according to [9], wherein the disease is a neurodegenerative disease.

[0018]

[11] Use of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease that is prevented, alleviated, and / or treated by inhibiting axonal degeneration.

[0019]

[12] A method for treating a disease that is prevented, alleviated, and / or cured by suppressing axon degeneration, comprising administering a therapeutically effective amount of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0020]

[13] The pharmaceutical composition according to [8], for treating a disease that can be prevented, alleviated, and / or treated by inhibiting SARM1.

[14] The pharmaceutical composition according to

[13] , wherein the disease is a neurodegenerative disease.

[0021]

[15] Use of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease which is prevented, alleviated, and / or treated by SARM1 inhibition.

[16] A method for treating a disease which is prevented, alleviated, and / or treated by SARM1 inhibition, comprising administering a therapeutically effective amount of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0022] The compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof has SARM1 inhibitory activity and / or weak NAMPT inhibitory activity, and has excellent pharmacokinetic properties, and is therefore useful for treating diseases that are prevented, alleviated, and / or cured by suppressing axonal degeneration via these, typically neurodegenerative diseases.

[0023] The meanings of terms used in this specification and claims are explained below. Unless otherwise specified, terms used in this specification and claims have the following meanings.

[0024] In this specification, a numerical range indicated using "to" indicates a range that includes the numerical values ​​before and after "to" as the minimum and maximum values, respectively.

[0025] In the present invention, the compound of general formula (I) encompasses its isotopic isomers. That is, in the compound of general formula (I), all or part of each atom may be replaced with the corresponding isotope atom. An isotopic atom refers to an atom having a mass number different from that found in nature. Examples of such isotopic atoms include hydrogen atoms (H, H), carbon atoms (C, C), nitrogen atoms (N), and oxygen atoms (O, O). In particular, a deuterium atom (H) may be represented as "D." In such cases, in the compound of general formula (I), all of the hydrogen atoms at the specific positions represented by D are replaced with deuterium atoms, resulting in a molecular weight different from that calculated from the mass number found in nature.

[0026] The terms "halogen" or "halo", alone or in combination with other groups, mean a fluorine, chlorine, bromine, or iodine atom.

[0027] "C １～６ "Alkyl," alone or in combination with other groups, means a straight- or branched-chain saturated aliphatic hydrocarbon monovalent radical, having one to six carbon atoms. １～６ Examples of alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl (including various isomers), etc. １～６ A preferred embodiment of alkyl is C １～４ Alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and more preferred embodiments are １～３ It is alkyl.

[0028] "C ３～１０ The term "cycloalkyl," alone or in combination with other groups, means a monovalent monocyclic or polycyclic saturated alicyclic hydrocarbon radical, having 3 to 10 carbon atoms. ３～１０ Examples of cycloalkyl include monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like, or polycyclic groups such as bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl, adamantyl, and the like. ３～１０ A preferred embodiment of cycloalkyl is C ３～６ Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclohexyl, and more preferred embodiments are C ４～６ It is cycloalkyl.

[0029] "C ２～６ The term "alkenyl," alone or in combination with other groups, means a straight- or branched-chain unsaturated aliphatic hydrocarbon monovalent radical containing at least one double bond, having two to six carbon atoms. ２～６ Examples of alkenyl include vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, and 2-pentenyl (including various isomers). ２～６ A preferred embodiment of alkenyl is C ２～４Alkenyl, for example, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, and more preferred embodiments are C ２～３ It is alkenyl.

[0030] "C ３～１０ The term "cycloalkenyl," alone or in combination with other groups, means a monovalent monocyclic or polycyclic unsaturated alicyclic hydrocarbon radical, having 3 to 10 carbon atoms. ３～１０ Examples of cycloalkenyl include monocyclic groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, or polycyclic groups such as bicyclo[2.2.2]octenyl. ３～１０ A preferred embodiment of cycloalkenyl is C ３～６ Cycloalkenyl, for example, cyclopropenyl, cyclobutenyl, cyclohexenyl, and more preferred embodiments are C ４～６ It is a cycloalkenyl.

[0031] "C ２～６ The term "alkynyl," alone or in combination with other groups, means a straight- or branched-chain unsaturated aliphatic hydrocarbon monovalent radical containing at least one triple bond, having two to six carbon atoms. ２～６ Examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 5-hexynyl (including various isomers), and the like. ２～６ A preferred embodiment of alkynyl is C ２～４ Alkynyl, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and more preferred embodiments are C ２～３ It is alkynyl.

[0032] "Mono or di C １～６ "Alkylamino", alone or in combination with other groups, refers to the group -NR'R" (where R' is as defined above). １～６ alkyl, and R" is a hydrogen atom or the above C １～６ Mono- or di-C １～６Examples of alkylamino include mono C alkylamino such as methylamino, ethylamino, and propylamino. １～６ alkylamino, or di-C such as dimethylamino, diethylamino, dipropylamino １～６ Examples thereof include alkylamino.

[0033] "C １～６ "Alkoxy", alone or in combination with other groups, refers to the group -O-R', where R' is as defined above. １～６ C means alkyl. １～６ Examples of alkoxy include methoxy, ethoxy, propoxy, butyloxy, pentyloxy, hexyloxy (including various isomers), and the like. １～６ A preferred embodiment of the alkoxy is C １～４ Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and a more preferred embodiment is C １～３ It is an alkoxy.

[0034] "C ２～６ "Alkenyloxy", alone or in combination with other groups, refers to the group -O-R', where R' is as defined above. ２～６ alkenyl). ２～６ Examples of alkenyloxy include vinyloxy, allyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 1,3-butadienyloxy, and 2-pentenyloxy (including various isomers). ２～６ A preferred embodiment of alkenyloxy is C ２～４ Alkenyloxy, for example, vinyloxy, allyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 1,3-butadienyloxy, and more preferred embodiments are ２～３ It is alkenyloxy.

[0035] "C ２～６ "Alkynyloxy", alone or in combination with other groups, refers to the group -O-R', where R' is as defined above. ２～６ alkynyl). ２～６Examples of alkynyloxy include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 1-butynyloxy, 2-butynyloxy, 3-butynyloxy, 4-pentynyloxy, and 5-hexynyloxy (including various isomers). ２～６ A preferred embodiment of alkynyloxy is C ２～４ Alkynyloxy, for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 1-butynyloxy, 2-butynyloxy, and 3-butynyloxy, and a more preferred embodiment is C ２～３ It is alkynyloxy.

[0036] "Haro C １～６ The term "alkyl" refers to the above-mentioned "C １～６ At least one hydrogen atom at any position of the "alkyl" is substituted with the "halogen atom". １～６ Examples of alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, dichloromethyl, trichloromethyl, and the like.

[0037] "Amino C １～６ The term "alkyl" refers to the above-mentioned "C １～６ At least one hydrogen atom at any position of the alkyl group is selected from the group consisting of amino (NH ２ ) substituted group. １～６ Examples of alkyl include aminomethyl, 2-aminoethyl, 3-aminopropyl, 2,3-diaminopropyl, 4-aminobutyl, and the like.

[0038] "Hydroxy C １～６ The term "alkyl" refers to the above-mentioned "C １～６ It means a group in which at least one hydrogen atom at any position of "alkyl" is replaced with hydroxy (OH). １～６ Examples of alkyl include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, and the like.

[0039] "Haro C １～６ The term "alkoxy" refers to the same as the above "C １～６"Alkoxy" means a group in which at least one hydrogen atom at any position is substituted with the above-mentioned "halogen atom". １～６ Examples of alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, dichloromethoxy, trichloromethoxy, and the like.

[0040] "C １～６ Alkoxy C １～６ The term "alkoxy" refers to the same as the above "C １～６ One of the hydrogen atoms at any position of "alkoxy" is further "C １～６ "C" means a group substituted with "alkoxy". １～６ Alkoxy C １～６ Examples of alkoxy include methoxymethoxy, ethoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, and the like.

[0041] "C １～６ The term "alkoxycarbonyl" refers to the same as the above "C １～６ "Alkoxy" means a group bonded to a carbonyl (-C(=O)-). １～６ Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), and the like.

[0042] The term "aryl," alone or in combination with other groups, means an aromatic hydrocarbon monovalent radical, preferably having 6 to 10 carbon atoms. Examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, and the like.

[0043] "Heterocyclyl", alone or in combination with other groups, means a monovalent saturated or unsaturated, monocyclic, bicyclic, or tricyclic heterocyclic radical containing 1 to 5 heteroatoms selected from the group consisting of O, N, and S, preferably a monovalent saturated or unsaturated, monocyclic, or bicyclic heterocyclic radical containing 2 to 9 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. Examples of heterocyclyl include 3- to 10-membered saturated heterocyclic radicals such as oxetanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholino, thiomorpholino, homomorpholino, homopiperazinyl, and the like; 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 1-pyrrolyl, 2-pyro ... lyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazolyl 1,3,4-oxadiazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl and 1,2,Monocyclic 5- to 10-membered unsaturated heterocyclic groups such as 5-thiadiazol-3-yl; 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, 4-benzoxadiazolyl, 5-benzoxadiazolyl, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-isobenzothienyl, 4-isobenzothienyl, 5-isobenzothienyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, 2-chromenyl, 3-chromenyl, 4-chromenyl, 5-chromenyl, 6-chromenyl, 7-chromenyl, 8-chromenyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl , 1-isoindolyl, 2-isoindolyl, 4-isoindolyl, 5-isoindolyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-indazolyl, 2-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl, 2-purinyl, 6-purinyl, 7-purinyl, 8-purinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4- Isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 2,7-naphthyridin-1-yl, 2,7-naphthyridin-3-yl, 2,7-naphthyridin-4-yl, 2,6-naphthyridin-1-yl, 2,6-naphthyridin-3-yl, 2,6-naphthyridin-4-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 1,7-naphthyridin-2-yl, 1,7-naphthyridin-3-yl, 1,7-naphthyridin-4-yl, 1,7-naphthyridin-5-yl, 1,7-naphthyridin-6-yl, 1,7-naphthyridin-8-yl, 1,6-naphthyridin-2-yl, 1,6-naphthyridin-3-yl, 1,6-naphthyridin-4-yl, 1,6-naphthyridin-5-yl, 1,6-naphthyridin-7-ynyl, 1,6-naphthyridin-8-yl, 1,5-naphthyridin-2-yl, 1,5-naphthyridin-3-yl, 1,5-naphthyridin-4-yl Examples of fused polycyclic 5- to 10-membered unsaturated heterocyclic groups include quinoxalinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, and 7-pteridinyl.

[0044] "Aryloxy", alone or in combination with other groups, means the group -O-R', where R' is aryl as defined above. Examples of aryloxy include phenoxy, naphthoxy, and the like.

[0045] "Aryl-C １～６ The term "alkyl" refers to the above-mentioned "C １～６ At least one hydrogen atom at any position of the "alkyl" is substituted with the above-mentioned "aryl". １～６ Examples of alkyl include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, etc. １～６ "Alkyl" can be used interchangeably with "aralkyl."

[0046] "Aryl-C １～６ The term "alkoxy" refers to the same as the above "C １～６ At least one hydrogen atom at any position of the "alkoxy" is substituted with the above-mentioned "aryl". １～６ Examples of alkoxy include benzyloxy and phenethyloxy. １～６"Alkoxy" can be used interchangeably with "aralkyloxy".

[0047] "Aryl-C ２～６ The term "alkenyl" refers to any of the groups defined above as "C ２～６ At least one hydrogen atom at any position of the "alkenyl" is substituted with the "aryl". ２～６ Examples of alkenyl include 2-phenylvinyl, 3-phenylallyl, and the like.

[0048] "Heterocyclyl-C １～６ The term "alkyl" refers to the above-mentioned "C １～６ At least one hydrogen atom at any position of the "alkyl" is substituted with the "heterocyclyl". １～６ Examples of alkyl include 3-pyridylmethyl, 2-(3-pyridyl)ethyl, 3-(3-pyridyl)propyl, and the like.

[0049] "Heterocyclyl-C ２～６ The term "alkenyl" refers to any of the groups defined above as "C ２～６ At least one hydrogen atom at any position of the "alkenyl" is substituted with the "heterocyclyl". ２～６ Examples of alkenyl include 2-(3-pyridyl)vinyl, 2-(3-pyridyl)-1-propen-1-yl, and the like.

[0050] "Substituted or unsubstituted" means that the group is unsubstituted or substituted with a given group of substituents, for example, halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, Amino C １～６ Alkyl, hydroxy C １～６ Alkyl, mono or di C １～６ Alkylamino, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ Alkynyloxy, —NHCOR１５ , -COR １５ , -C １～６ Alkyl NHCOR １５ , aryl, heterocyclyl, aryloxy, aryl-C １～６ Alkyl, aryl-C １～６ It means that the group is substituted with at least one substituent selected from the group consisting of alkoxy, aralkyloxy-aryl, aralkyloxy-aryloxy, oxo, etc., where R １５ is C １～６ Alkyl, C １～６ Alkoxy, aryl, heterocyclyl, aryl-C １～６ Alkyl, aryl-C ２～６ Alkenyl, heterocyclyl-C １～６ Alkyl or heterocyclyl-C ２～６ alkenyl, and R １５ The aryl or heterocyclyl moiety in １～６ Alkyl, haloC １～６ Alkyl, Amino C １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ It may be substituted with at least one substituent selected from the group consisting of alkynyloxy and oxo. Preferably, R １５ is C １～６ Alkyl, C １～６ Alkoxy, aryl, heterocyclyl, aryl-C ２～６ Alkenyl, or heterocyclyl-C ２～６ alkenyl, wherein the aryl or heterocyclyl moiety is selected from halogen, amino, C １～６ Alkyl, haloC １～６ Alkyl and amino C １～６It may be substituted with at least one substituent selected from the group consisting of alkyl.

[0051] "Substituted or unsubstituted C １～６ A preferred embodiment of "alkyl" is (unsubstituted) C １～６ alkyl, or amino, -NHCOR １５ (R １５ is C １～６ Alkoxy, heterocyclyl, heterocyclyl-C ２～６ alkenyl), aryl, heterocyclyl, and aryloxy; １～６ The aryl or heterocyclyl moiety contained in the substituent is selected from the group consisting of halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, mono or di C １～６ Alkylamino, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ Alkynyloxy, aryl, heterocyclyl, aryloxy, aryl-C １～６ Alkyl and aryl-C １～６ and optionally substituted with at least one substituent selected from the group consisting of alkoxy, preferably halogen, cyano, C １～６ Alkyl, haloC １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, aryl-C １～６ Alkyl and aryl-C １～６ It may be substituted with at least one substituent selected from the group consisting of alkoxy.

[0052] "Substituted or unsubstituted C ２～６A preferred embodiment of "alkenyl" is (unsubstituted) C ２～６ alkenyl, or amino, —NHCOR １５ (R １５ is C １～６ Alkoxy, heterocyclyl, heterocyclyl-C ２～６ alkenyl), aryl, heterocyclyl, and aryloxy; ２～６ alkenyl, and a more preferred embodiment is (unsubstituted) C ２～６ C which is alkenyl or substituted with at least one substituent selected from the group consisting of aryl and heterocyclyl ２～６ The aryl or heterocyclyl moiety contained in the substituent is selected from the group consisting of halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, mono or di C １～６ Alkylamino, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ Alkynyloxy, aryl, heterocyclyl, aryloxy, aryl-C １～６ Alkyl and aryl-C １～６ and optionally substituted with at least one substituent selected from the group consisting of alkoxy, preferably halogen, cyano, C １～６ Alkyl, haloC １～６ Alkyl, mono or di C １～６ Alkylamino, C １～６ Alkoxy and haloC １～６ It may be substituted with at least one substituent selected from the group consisting of alkoxy.

[0053] "Substituted or unsubstituted C ２～６A preferred embodiment of "alkynyl" is (unsubstituted) C ２～６ alkynyl, or amino, —NHCOR １５ (R １５ is C １～６ Alkoxy, heterocyclyl, heterocyclyl-C ２～６ alkenyl), aryl, heterocyclyl, and aryloxy; ２～６ Alkynyl, and more preferred embodiments are (unsubstituted) C ２～６ The aryl or heterocyclyl moiety contained in the substituent is alkynyl. １～６ Alkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, mono or di C １～６ Alkylamino, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ Alkynyloxy, aryl, heterocyclyl, aryloxy, aryl-C １～６ Alkyl and aryl-C １～６ It may be substituted with at least one substituent selected from the group consisting of alkoxy.

[0054] A preferred embodiment of the "substituted or unsubstituted aryl" is (unsubstituted) aryl, or halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, Amino C １～６ Alkyl, hydroxy C １～６ Alkyl, mono or di C １～６ Alkylamino, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ Alkynyloxy, —COR １５ , -C １～６ Alkyl NHCOR １５ , aryl, heterocyclyl, aryloxy, aryl-C １～６ Alkyl and aryl-C １～６ aryl substituted with at least one substituent selected from the group consisting of alkoxy, where R １５ is C １～６ Alkyl, C １～６ It is alkoxy, aryl, or heterocyclyl.

[0055] A preferred embodiment of the "substituted or unsubstituted heterocyclyl" is (unsubstituted) heterocyclyl, or a group selected from the group consisting of halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, Amino C １～６ Alkyl, hydroxy C １～６ Alkyl, mono or di C １～６ Alkylamino, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ Alkynyloxy, —COR １５ , -C １～６ Alkyl NHCOR １５ , aryl, heterocyclyl, aryloxy, aryl-C １～６ Alkyl, aryl-C １～６ A heterocyclyl substituted with at least one substituent selected from the group consisting of alkoxy and oxo, and a more preferred embodiment is (unsubstituted) heterocyclyl, or a heterocyclyl selected from halogen, nitro, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, C２～６ Alkenyl, C ２～６ Alkynyl, —COR １５ , -C １～６ Alkyl NHCOR １５ , aryl, heterocyclyl, aryloxy, aryl-C １～６ Alkyl, aryl-C １～６ and heterocyclyl substituted with at least one substituent selected from the group consisting of alkoxy, and oxo. １５ is C １～６ alkyl, aryl or heterocyclyl, wherein the aryl or heterocyclyl is selected from halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ It may be substituted with at least one substituent selected from the group consisting of alkynyloxy and oxo.

[0056] "C １～１０ The term "alkylene," alone or in combination with other groups, means a straight-chain or branched-chain alkylene having one to ten carbon atoms. １～１０ Examples of alkylene include methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methylpropylene, 2-methylpropylene, dimethylethylene, ethylethylene, pentamethylene, 1-methyl-tetramethylene, 2-methyl-tetramethylene, 1,1-dimethyl-trimethylene, 1,2-dimethyl-trimethylene, 2,2-dimethyl-trimethylene, 1-ethyl-trimethylene, hexamethylene, octamethylene, and decamethylene. １～１０ A preferred embodiment of alkylene is C ２～８Alkylene, for example, ethylene, propylene, trimethylene, tetramethylene, hexamethylene, octamethylene. １～３ "Alkylene," alone or in combination with other groups, means straight-chain or branched alkylene having one to three carbon atoms, examples of which include methylene, ethylene, propylene or trimethylene. The alkylene may be substituted with halogen, -COOR. １２ , -CONHR １２ or oxo (where R １２ is a hydrogen atom or C １～６ alkyl), preferably -COOR １２ or -CONHR １２ (where R １２ is a hydrogen atom or methyl).

[0057] The term "arylene", alone or in combination with other groups, refers to a divalent group obtained by removing one hydrogen atom from any position of the "aryl". Examples of arylene include 1,4-phenylene, 1,3-phenylene, and 1,2-phenylene. The arylene is not particularly limited to halogen, -COOR １２ , -CONHR １２ or oxo (where R １２ is a hydrogen atom or C １～６ It may be substituted with an alkyl group, preferably with a halogen atom.

[0058] "C １～１０ alkylene-arylene," "arylene-C １～１０ alkylene," "C １～１０ Alkylene-arylene-C １～１０ alkylene" or "arylene-C １～１０ The term "alkylene-arylene" refers to the same as defined above. １～１０ "C" means a divalent group formed by bonding "alkylene" and the "arylene". １～３ alkylene-arylene," "arylene-C １～３ alkylene" or "C １～３ Alkylene-arylene-C １～３The term "alkylene" refers to the above-mentioned "C １～３ "Arylene" refers to a divalent group formed by bonding an "alkylene" and the "arylene" described above.

[0059] The term "heterocyclylene", alone or in combination with other groups, refers to a divalent substituent obtained by removing one hydrogen atom from any position of the "heterocyclyl". Examples of heterocyclylene include 1,4-piperazinediyl, 2,5-piperazinediyl, 2,5-pyridinediyl, and 2,6-pyridinediyl. The heterocyclylene is not limited to halogen, -COOR １２ , -CONHR １２ or oxo (where R １２ is a hydrogen atom or C １～６ It may be substituted with an alkyl group, preferably an oxo group.

[0060] "C １～１０ alkylene-heterocyclylene," "heterocyclylene-C １～１０ alkylene" or "C １～１０ Alkylene-heterocyclylene-C １～１０ The term "alkylene" refers to the above-mentioned "C １～１０ It means a divalent group formed by bonding "alkylene" and the "heterocyclylene". １～３ alkylene-heterocyclylene," "heterocyclylene-C １～３ alkylene" or "C １～３ Alkylene-heterocyclylene-C １～３ The term "alkylene" refers to the above-mentioned "C １～３ "Heterocyclylene" refers to a divalent group formed by bonding an "alkylene" and the "heterocyclylene".

[0061] The compound represented by general formula (I) of the present invention includes its stereoisomers (if they exist). Stereoisomers refer to isomers that differ in the arrangement of atoms in space, and include optical isomers such as diastereomers and enantiomers, and geometric isomers. For example, when the compound represented by general formula (I) of the present invention has one or more chiral centers, the compound represented by general formula (I) of the present invention can exist in the form of an optically pure enantiomer, a mixture of enantiomers such as a racemate, an optically pure diastereomer, a mixture of diastereomers, a racemic mixture of diastereomers, a mixture of racemic mixtures of diastereomers, etc.

[0062] Pharmaceutically acceptable salts of the compound of the present invention represented by general formula (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, and phosphate; or organic acid salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, and aspartate. Preferred embodiments of the organic acid salts are salts of dicarboxylic acids such as oxalate, malonate, succinate, maleate, fumarate, and tartrate.

[0063] Other pharmaceutically acceptable salts of the compound represented by general formula (I) of the present invention include metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt; inorganic salts such as ammonium salt; and organic amine salts such as triethylamine salt and guanidine salt.

[0064] The compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof includes a pharmaceutically acceptable solvate. A preferred embodiment of the solvate is a hydrate. The hydrate may be formed as a result of moisture absorption of the compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0065] When the compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof is crystalline, it may exhibit crystalline polymorphism. Crystalline polymorphism means that the same substance has different crystalline structures. Each crystal or a mixture thereof in any ratio is encompassed by the present invention.

[0066] The present invention relates to a compound of general formula (I): [In the formula, R ａ and R ｂ are independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxy group, a C １～６ Alkyl, haloC １～６ Alkyl, Amino C １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl or C ２～６ alkynyloxy or R on the adjacent carbon atom ａ and R ｂ may be taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted carbocyclic or heterocyclic ring fused to the pyridine ring; １ is a direct bond, -CR １１ =CR １１ -or- (CONR １１ ) ｍ CH ２ - and R １ is a hydrogen atom or C １～６ is alkyl, and L １ is C １～１０ Alkylene, arylene, C １～１０ Alkylene-arylene, arylene-C １～１０ Alkylene, C １～１０ Alkylene-arylene-C １～１０ Alkylene, arylene-C １～１０ Alkylene-arylene, heterocyclylene, C１～１０ Alkylene-heterocyclylene, heterocyclylene-C １～１０ Alkylene or C １～１０ Alkylene-heterocyclylene-C １～１０ alkylene, wherein the alkylene, arylene, or heterocyclylene moiety is selected from the group consisting of halogen, —COOR １２ Or, -CONHR １２ or oxo, ２ represents a direct bond, —O—, —NR １３ -, -NR １３ SO ２ - or - (OCH ２ CH ２ ) ｎ O- and R ２ represents a hydrogen atom, an azide, a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, —COR １４ , substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, wherein m is 0 or 1, n is 1 to 6, and R １１ are independently a hydrogen atom or C １～６ alkyl, R １２ is a hydrogen atom or C １～６ alkyl, R １３ is a hydrogen atom, C １～６ Alkyl or -COR １４ and R １４ is a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～１０ Cycloalkyl, substituted or unsubstituted C ３～１０ or a pharmaceutically acceptable salt thereof.

[0067] However, L １ But arylene, C １～３Alkylene-arylene, arylene-C １～３ Alkylene, or C １～３ Alkylene-arylene-C １～３ alkylene, and L ２ is a direct bond, １ But C １～３ alkylene-arylene, and L ２ is —O—, and １ But C １～３ alkylene, and L ２ is —NH—, and R ２ Excluding compounds where is --CO-5-membered heterocyclyl.

[0068] The present invention also relates to compounds of the general formula (Ia): [In the formula, X １ is a direct bond, -CR １１ =CR １１ -or-CONR １１ CH ２ - and R １ is a hydrogen atom or C １～６ is alkyl, and L １ is C １～１０ Alkylene, arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, C １～３ Alkylene-arylene-C １～３ Alkylene, heterocyclylene, C １～３ Alkylene-heterocyclylene, heterocyclylene-C １～３ Alkylene or C １～３ Alkylene-heterocyclylene-C １～３ alkylene, wherein the alkylene moiety is —COOR １２ or -CONHR １２ and L ２ represents a direct bond, —O—, —NR １３ -, -NR １３ SO ２ - or - (OCH ２ CH ２ ) ｎ O- and R ２ represents a hydrogen atom, an azide, a substituted or unsubstituted C １～６Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, —COR １４ , substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, where n is 1 to 6; １１ are independently a hydrogen atom or C １～６ alkyl, R １２ is a hydrogen atom or C １～６ alkyl, R １３ is a hydrogen atom, C １～６ Alkyl or -COR １４ and R １４ is a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ or a pharmaceutically acceptable salt thereof.

[0069] However, L １ But arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, or C １～３ Alkylene-arylene-C １～３ alkylene, and L ２ is a direct bond, １ But C １～３ alkylene-arylene, and L ２ is —O—, and １ But C １～３ alkylene, and L ２ is —NH—, and R ２ Excluding compounds where is --CO-5-membered heterocyclyl.

[0070] The substitutions may be, for example, the following substituent groups: halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, Amino C １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C１～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ Alkynyloxy, —NHCOR １５ , -COR １５ , -C １～６ Alkyl NHCOR １５ , aryl, heterocyclyl, and oxo (where R １５ is C １～６ Alkyl, C １～６ Alkoxy, aryl, heterocyclyl, aryl-C １～６ Alkyl, aryl-C ２～６ Alkenyl, heterocyclyl-C １～６ Alkyl or heterocyclyl-C ２～６ alkenyl, and R １５ The aryl or heterocyclyl moiety in １～６ Alkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl, C ２～６ and oxo).

[0071] In certain embodiments, the present invention provides L ２ is —O— or —NH—, or a pharmaceutically acceptable salt thereof.

[0072] For example, the present invention relates to a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof. General formula (II):

[0073] In the formula, １１ is a direct bond, -CR １１ =CR １１ -or-CONR １１ CH ２ - and X １２ is a direct bond, C １～３ Alkylene, -CR １１ =CR １１ - or -CH ２ NR １１ CO-, and L １１ is C １～１０ Alkylene, arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, C １～３ Alkylene-arylene-C １～３ Alkylene, heterocyclylene, C １～３ Alkylene-heterocyclylene, heterocyclylene-C １～３ Alkylene or C １～３ Alkylene-heterocyclylene-C １～３ alkylene, and L ２１ is —O— or —NH—, and Y １ is N or CH, R １１ are independently a hydrogen atom or C １～６ alkyl, R １２ is a hydrogen atom or C １～６ alkyl, R ２１ are independently halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl and C２～６ alkynyloxy.

[0074] In another particular embodiment, the present invention also provides L ２ is a direct bond or -(OCH ２ CH ２ ) ｎ Further, the present invention relates to a compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R ２ is a hydrogen atom, a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ The present invention relates to a compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl.

[0075] In another particular embodiment, the present invention provides a compound comprising R ａ and R ｂ is a hydrogen atom or an R ａ and R ｂ and (b) may, together with the carbon atom to which they are attached, form a benzene ring fused to a pyridine ring, in accordance with the present invention, and relate to a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0076] In another particular embodiment, the present invention provides a method for the preparation of a compound comprising: １ is a direct bond, -CH ２ -, -CH=CH-, -C(CH ３ )=CH-, -CH=C(CH ３ ) - or -CONHCH ２ The present invention relates to a compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0077] In another particular embodiment, the present invention provides a compound comprising R １ is a hydrogen atom or methyl, or a pharmaceutically acceptable salt thereof.

[0078] In another particular embodiment, the present invention provides a method for producing a compound comprising: １ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, octamethylene, 1,4-phenylene (p-phenylene), 1,3-phenylene (m-phenylene), 1,2-phenylene (o-phenylene), methylene-p-phenylene, methylene-o-phenylene, methylene-m-phenylene, o-phenylene-ethylene-o-phenylene, p-phenylene-ethylene-p-phenylene, p-phenylene-methylene, methylene-p-phenylene-methylene, 2,5-pyridinediyl , 2,6-pyridinediyl, methylene-2,5-pyridinediyl, methylene-2,6-pyridinediyl, methylene-2,5-pyridinediyl-methylene, methylene-2,6-pyridinediyl-methylene, hexamethylene-piperazine-1,4-diyl-ethylene, trimethylene-3,6-dioxopiperazine-2,5-diyl-trimethylene, or tetramethylene-3,6-dioxopiperazine-2,5-diyl-tetramethylene.

[0079] In another particular embodiment, the present invention provides a method for producing a compound comprising: ２ is a direct bond, —O—, —NH—, —NCH ３ -, -OCH ２ CH ２ O-, -(OCH ２ CH ２ ) ２ O- or -(OCH ２ CH ２ ) ３ The present invention relates to a compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R is O—.

[0080] In another particular embodiment, the present invention provides a compound comprising R ２is a hydrogen atom, azide, 2-aminoethyl, 2-[[(3-pyridyl)carbonyl]amino]ethyl, 3-aminopropyl, 3-benzoylaminopropyl, 3-(2-naphthoylamino)propyl, 3-[[(3-pyridyl)carbonyl]amino]propyl, 2-[[3-(3-pyridyl)-2-propenoyl]amino]ethyl, 2-[[3-(3-pyridyl)-2-butenoyl]amino]ethyl, 3-[[3-(3-pyridyl)-2-propenoyl]amino]propyl, 3-[(te rt-butoxycarbonyl)amino]propyl, 2-[(tert-butoxycarbonyl)amino]ethyl, 3-[(3-quinolylcarbonyl)amino]propyl, 3-[(6-quinolylcarbonyl)amino]propyl, 2-propynyl, propanoyl, butyryl, isobutyryl, pivaloyl, pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl, 2-ethylbutanoyl, 3-methylpentanoyl, 4-methylpentanoyl, hexanoyl, 2,2-dimethylbutanoyl, 3,3-dimethylbutanoyl, 4-fluorophenylacetyl, 4-chlorophenylacetyl, 4-methylphenylacetyl, 2-trifluoromethylphenylacetyl, 3-trifluoromethylphenylacetyl, 4-trifluoromethylphenylacetyl, 4-cyanophenylacetyl, 4-benzyloxyphenylacetyl, phenoxyacetyl, 3-trifluoromethylphenoxyacetyl, 4-trifluoromethylphenoxyacetyl, 4-cyanophenoxyacetyl, 4-benzyloxyphenoxyacetyl, 2-naphthylacetyl, 3-(4-methylphenyl)-2-propenoyl, 3-(4-methoxyphenyl)-2-propenoyl, 3-(4-dimethylaminophenyl)-2-propenoyl, 3-(4-cyanophenyl)-2-propenoyl, 3-(4-trifluoromethylphenyl)-2-propenoyl, 3-(4-trifluoromethoxyphenyl)-2-propenoyl 3-phenyl-2-propenoyl, 3-(3-pyridyl)-2-propenoyl, 2-[[(3-pyridyl)carbonyl]amino]ethanoyl, 3-(3-pyridyl)-2-butenoyl, 3-phenylpropanoyl, 3-(4-trifluoromethylphenyl)propanoyl, 3-(4-trifluoromethoxyphenyl)propanoyl, 3-(4-cyanophenyl)propanoyl, 2-butynoyl, 3-phenylpropynoyl, cyclobutanecarbonyl carbonyl, cyclohexanecarbonyl, adamantane-1-carbonyl, benzoyl, 4-cyanobenzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 3,4-difluorobenzoyl, 3,5-difluorobenzoyl, 2,4-difluorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2-toluoyl, 4-toluoyl, 2,4-dimethylbenzoyl, 3,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 4-ethylbenzoyl, 4-methoxybenzoyl, 4-vinylbenzoyl, 2-(trifluoromethyl)benzoyl, 3-(trifluoromethyl)benzoyl, 4-(trifluoromethyl)benzoyl, 3-fluoro-5-(trifluoromethyl)benzoyl, 2-(trifluoromethoxy)benzoyl, 3-(trifluoromethoxy)benzoyl, 4-(trifluoromethoxy)benzoyl, 4-(2-propynyloxy)benzoyl, 4-(3-butynyloxy)benzoyl, biphenyl-4-carbonyl, 1-naphthoyl, 2-naphthoyl, pyridine-2-carbonyl, pyridine-3-carbonyl, pyridine-4-carbonyl, (5-hydroxy-3-pyridyl)carbonyl, [5-(2-propynyloxy)-3-pyridyl]carbonyl, quinoline-3-carbonyl, quinoline-6-carbonyl, oxetane-3 -carbonyl, tetrahydropyran-4-carbonyl, N-tert-butoxycarbonyl-azetidine-3-carbonyl, phenyl, 2-nitrophenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 3-methoxymethoxyphenyl, 4-methoxycarbonylphenyl, 4-(N-acetylaminomethyl)phenyl, 4-[[(3-pyridyl)carbonyl]aminomethyl]phenyl, 4-[N-(benzoyl)aminomethyl]phenyl, N-(4-aminomethylbenzoyl)piperidin-4-yl, N-(2-hydroxyethyl)piperidin-4-yl, N-benzoylpiperidin-4-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-nitro-2,1,3-benzoxazol-7-yl, 1-oxoisoindolin-1-yl, or a pharmaceutically acceptable salt thereof.

[0081] Examples of the compounds represented by general formula (I) of the present invention include the compounds shown in Table 1.

[0082] In a more specific embodiment, the present invention provides the above-mentioned compound Nos. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39, 40, 41, 42, 43, 48, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 11 3, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151 , 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187 and 188.

[0083] In a more specific embodiment, the present invention provides the above-mentioned compound Nos. 2, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 105, 106, 107, 108, 109, 110, 1 11, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 142, 143, 144, 145, 146, 147, 153 , 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 186 and 188.

[0084] In a more particular embodiment, the present invention provides the above-mentioned compound Nos. 1, 2, 3, 4, 5, 6, 7, 8, 9, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 28, 29, 31, 32, 34, 35, 38, 39, 41, 42, 43, 52, 53, 54, 55, 56, 58, 59, 61, 62, 64, 65, 66, 67, 68, 69, 70, 71, 73, 75, 76, 77, 78, 80, 82, 83, 87, 89, 91, 94, 95, 96, 97, 101, 102, 105, 106, 107, 108, 109, 110, 111, 113, 114, 115, 116, 117, 118, 119, 120, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 143, 144, 145, 147, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 179, 180, 181, 182 and 188.

[0085] In a more specific embodiment, the present invention provides the above-mentioned compound Nos. 1, 3, 4, 6, 9, 14, 15, 16, 17, 18, 19, 22, 23, 24, 26, 28, 29, 31, 34, 35, 38, 39, 41, 42, 43, 53, 54, 55, 58, 61, 62, 64, 65, 66, 67, 68, 69, 75, 77, 78, 80, 82, 89, 94, 96, 97, 101, 108, 109, 113, 114, 115, 116, 117, 118, 119, 220, 221, 222, 223, 224, 226, 228, 229, 31, 34, 35, 38, 39, 41, 42, 43, 53, 54, 55, 58, 61, 62, 64, 65, 66, 67, 68, 69, 75, 77, 78, 80, 82, 89, 94, 96, 97, 101, 108, 109, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 13 6, 117, 118, 119, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 143, 144, 145, 147, 154, 155, 156, 160, 164, 165, 166, 167, 169, 170, 179, 180 and 182.

[0086] The compound represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be produced by known methods. Typical production methods for the compound of the present invention or a pharmaceutically acceptable salt thereof are shown below, but the present invention is not limited thereto. Furthermore, the compound represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is not limited to the compound or pharmaceutically acceptable salt thereof produced by the production method below.

[0087] In the production methods described below, if the compound contains a partial structure (e.g., hydroxy, amino, etc.) that inhibits the desired reaction or undergoes a side reaction, the target product can be obtained by introducing a protecting group into the partial structure, carrying out the desired reaction, and then removing the protecting group. The introduction and removal of these protecting groups can be carried out in accordance with methods commonly used in organic synthetic chemistry (e.g., methods described in Protective Groups in Organic Synthesis, 4th Edition, T.W. Greene, P.G.M. Wuts, John Wiley & Sons Inc. (2006)). Specific production methods for each of the compounds of the present invention will be described in detail in the Examples below.

[0088] (Production Method 1)

[0089] In the formula, R ａ , R ｂ , X １ , R １ , L １ , L ２ and R ２ is as defined above, and Hal is a halogen atom.

[0090] Production Method 1 is a method for obtaining a compound represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof by reacting compound (1) with compound (2) in a solvent in the presence of a base. Compound (1) is known and can be obtained from a reagent supplier. Examples include nicotinic acid chloride hydrochloride, trans-3-(3-pyridyl)acrylic acid chloride hydrochloride, and the like. Alternatively, compound (1) can be produced in accordance with known methods using compounds available from reagent suppliers. Compound (2) is known and can be obtained from a reagent supplier. Alternatively, compound (2) can be produced in accordance with known methods using compounds available from reagent suppliers, for example, the method described below in the Examples under "Production of Intermediates." The amount of compound (2) used is usually 0.9 to 5 times, and preferably 1.1 to 3 times, the molar amount per mole of compound (1).

[0091] Examples of the base to be used include alkali metal acetates such as sodium acetate or potassium acetate; alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate; or organic bases such as triethylamine or diisopropylethylamine, and preferably potassium carbonate, cesium carbonate, triethylamine or diisopropylethylamine. The amount of the base to be used is usually 0.9 to 10 times, and preferably 1 to 5 times, the molar amount of compound (1) relative to 1 mole.

[0092] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to some extent. Examples include aromatic hydrocarbons such as benzene, toluene, or xylene; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, or 1,2-dichloroethane; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane; nitriles such as acetonitrile or propionitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; or any mixtures thereof. Preferably, halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, or 1,2-dichloroethane, or ethers such as tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane are used. The amount of the solvent used is not particularly limited, but is usually 1 to 50 times, and preferably 5 to 20 times, the mass of compound (1).

[0093] The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 150°C, preferably 20°C to 120°C. The reaction time varies depending on the reaction temperature, but is usually 1 minute to 48 hours, preferably 0.5 hours to 24 hours. The reaction pressure is appropriately set as needed and may be elevated, reduced, or atmospheric pressure, but is preferably atmospheric pressure. The reaction atmosphere can be appropriately selected as needed, but is preferably air or an inert gas atmosphere such as nitrogen or argon. Furthermore, when the obtained compound represented by general formula (I) contains functional groups (e.g., halogen atoms, hydroxy groups, carbonyl groups, etc.), further desired compounds can be produced by reacting these functional groups with appropriate reaction reagents in accordance with known methods.

[0094] (Production Method 2)

[0095] In the formula, R ａ , R ｂ , X １ , R １ , L １ , L ２and R ２ is as described above.

[0096] Production Method 2 is a method in which compound (3) and compound (2) are reacted in a solvent in the presence of a condensing agent to obtain a compound represented by general formula (I). Compound (3) is known and can be obtained from a reagent supplier. Examples of such compounds include nicotinic acid, trans-3-(3-pyridyl)acrylic acid, 3-(3-pyridyl)-2-butenoic acid, and N-nicotinoylglycine. Alternatively, compound (3) can be produced in accordance with known methods using compounds available from a reagent supplier. Compound (2) is known and can be obtained from a reagent supplier. Alternatively, compound (2) can be produced in accordance with known methods using compounds available from a reagent supplier, for example, the method described below in the Examples under "Production of Intermediates." The amount of compound (2) used is typically 0.9 to 5 times, and preferably 1.1 to 3 times, the molar amount per mole of compound (3).

[0097] The condensing agent used is not particularly limited, and examples thereof include carbodiimide-based condensing agents (e.g., N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDCI)), chloroformate-based condensing agents (e.g., ethyl chloroformate, isobutyl chloroformate), imidazole-based condensing agents (e.g., 1,1'-carbonyldiimidazole (CDI)), phosphonium-based condensing agents (e.g., (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP (registered trademark)), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop (registered trademark))), uronium-based condensing agents (e.g., O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Examples of suitable condensing agents include 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluoroborate (HBTU), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU). The amount of the condensing agent used is typically 0.1 to 20 times, preferably 1 to 10 times, and more preferably 1 to 5 times, the molar amount of the condensing agent relative to 1 mole of compound (3).

[0098] Additives and bases can be used appropriately as long as they do not interfere with the reaction. The additives used are not particularly limited, and examples include N,N-dimethyl-4-aminopyridine (DMAP), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (HOCt), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl (hydroxyimino)cyanoacetate (OxymaPure), and the like. The amount of the additive used is typically 0.1 to 20 times, preferably 0.2 to 10 times, and more preferably 1 to 5 times, molar amount relative to 1 mole of compound (3).

[0099] The base to be used is not particularly limited, and examples thereof include aliphatic amines (e.g., triethylamine, N,N-diisopropylethylamine, N-methylmorpholine), aromatic amines (e.g., dimethylaminopyridine), etc. The amount of the base to be used is usually 1 to 50 times, preferably 1 to 10 times, more preferably 1 to 5 times, molar amount relative to 1 mole of compound (3).

[0100] The solvent used is not particularly limited as long as it does not interfere with the reaction, and examples thereof include halogen-containing hydrocarbon solvents (e.g., dichloromethane, chloroform), aromatic hydrocarbon solvents (e.g., toluene, xylene), ether solvents (e.g., tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyl-t-butyl ether), amide solvents (e.g., N,N-dimethylformamide), nitrile solvents (e.g., acetonitrile), etc. Preferred are halogen-containing hydrocarbon solvents or ether solvents, and more preferred are dichloromethane, tetrahydrofuran, or cyclopentyl methyl ether.

[0101] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to some extent, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; or any mixtures thereof. Preferably, halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane, or ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane are used. The amount of the solvent used is not particularly limited, but is usually 1 to 50 times, and preferably 5 to 20 times, the mass of compound (3).

[0102] The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 150°C, preferably 20°C to 120°C. The reaction time varies depending on the reaction temperature, but is usually 1 minute to 48 hours, preferably 0.5 hours to 24 hours. The reaction pressure is appropriately set as needed and may be elevated, reduced, or atmospheric pressure, but is preferably atmospheric pressure. The reaction atmosphere can be appropriately selected as needed, but is preferably air or an inert gas atmosphere such as nitrogen or argon. Furthermore, when the obtained compound represented by general formula (I) contains functional groups (e.g., halogen atoms, hydroxy, carbonyl, etc.), further desired compounds can be produced by reacting these functional groups with appropriate reaction reagents in accordance with known methods.

[0103] The above-mentioned Production Methods 1 and 2 may be carried out by replacing the compound of formula (2) with an intermediate capable of deriving a precursor of the compound of general formula (I), such as a compound of formula (4) or (5) below.

[0104] In the formula, X １ , R １ , L １ , L ２ and R ２ is as defined above, and X' is a suitable reactive group such as a halogen atom, hydroxy, carbonyl, or the like.

[0105] When such a compound is used, the reactive group of the obtained precursor of the compound represented by general formula (I) (for example, a compound of the following formula (I') or (I")) can be further reacted with an appropriate reaction reagent in accordance with a known method to produce the compound represented by general formula (I).

[0106] In the formula, R ａ , R ｂ , X １ , R １ , L １ , L ２ and X' are as defined above.

[0107] If the resulting compound represented by general formula (I) contains a protecting group, it can be subjected to a deprotection step as necessary. If the compound represented by general formula (I) has at least two different protecting groups, it is possible to selectively remove only one type of protecting group by selecting deprotection conditions. Deprotection can be carried out appropriately under the conditions of a method commonly used in organic synthetic chemistry (e.g., a method described in Protective Groups in Organic Synthesis, 4th Edition, by T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc. (2006)) or in accordance with the examples of this specification.

[0108] In each production method, the compound obtained may be isolated and purified by known means, or may be directly subjected to the next step. Isolation and purification can be carried out using conventional procedures such as filtration, extraction, crystallization, various column chromatography methods, etc.

[0109] In a specific embodiment, the present invention relates to a pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as shown in each of the specific embodiments above, and preferably to a pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as shown in each of the specific embodiments above, and at least one pharmaceutically acceptable excipient.

[0110] In a specific embodiment, the present invention relates to a pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as set forth in each of the specific embodiments above, for the treatment of a disease that is prevented, alleviated, and / or cured by inhibiting axonal degeneration, and preferably relates to a pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as set forth in each of the specific embodiments above, and at least one pharmaceutically acceptable excipient.

[0111] In a specific embodiment, the present invention relates to a pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as set forth in each of the above specific embodiments, for the treatment of a disease that is prevented, alleviated, and / or treated by SARM1 inhibition, and preferably relates to a pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as set forth in each of the above specific embodiments, and at least one pharmaceutically acceptable excipient.

[0112] In a specific embodiment, the present invention relates to a pharmaceutical composition for the treatment of a neurodegenerative disease, particularly for the treatment of a neurodegenerative disease whose pathology involves axonal degeneration, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as set forth in each of the specific embodiments above, and preferably to a pharmaceutical composition comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as set forth in each of the specific embodiments above, and at least one pharmaceutically acceptable excipient.

[0113] In the present invention, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as shown in each of the above specific embodiments may have axonal degeneration suppression or SARM1 inhibitory activity in vivo directly or indirectly via its metabolites. Therefore, the pharmaceutical composition of the present invention may be not only a pharmaceutical composition containing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, but also a pharmaceutical composition containing its metabolite. Typical examples of metabolites of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to, riboside adducts (hereinafter also referred to as "ribosides") in which a sugar (ribose) is introduced into the pyridine skeleton of the compound of the present invention, nicotinamide mononucleotide (NMN)-like metabolites (hereinafter also referred to as "NMN-like metabolites"), which are mononucleotide adducts in which a phosphate moiety is introduced into a riboside, and nicotinamide adenine dinucleotide (NAD)-like metabolites (hereinafter also referred to as "NAD-like metabolites"), which are adenine dinucleotide adducts in which adenosine is further introduced into an NMN-like metabolite via phosphate, as described in the Examples below.

[0114] The disease of the present invention may be a disease that can be prevented, alleviated, and / or treated by suppressing axonal degeneration, a disease that can be prevented, alleviated, and / or treated by inhibiting SARM1, a neurodegenerative disease, or a disease in which axonal degeneration occurs as a result of axonal degeneration, such as an axonopathy, a demyelinating disease, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, and / or metabolic axonal degeneration. Examples of such diseases include central nervous system neurodegenerative diseases, peripheral nervous system neurodegenerative diseases, trauma-related neuropathies (including trauma to the head, spine, and / or PNS), genetic neuropathies, metabolic and / or endocrine-related neuropathies (including diabetic peripheral neuropathy), toxin-related neuropathies (including peripheral neuropathies induced by toxins (including chemotherapeutic agents)), inflammatory neuropathies, and cardiovascular-related disorders (including stroke).

[0115] Specific examples of such diseases include glaucoma, multiple sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Tay-Sachs disease, Gaucher's disease, Hurler syndrome, traumatic brain injury, traumatic spinal cord injury, stroke, post-irradiation injury, neurological complications of chemotherapy (chemotherapy-induced neuropathy: CIPN), neuropathy, acute ischemic optic neuropathy, age-related neurodegeneration (including dementia), chronic traumatic encephalopathy (so-called "punch-drunk syndrome"), shaken baby syndrome, spinal cord injury (compression, amputation, laceration, Neuropathy includes injuries due to stretching or contusion, higher-order neuropathies, peripheral neuropathy or trauma, axonal abnormalities (e.g., Wallerian degeneration), Friedreich's ataxia, Charcot-Marie-Tooth syndrome, diabetic neuropathy, diabetes, chronic renal failure, porphyria, amyloidosis, liver damage, hypothyroidism, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, systemic lupus erythematosus, leprosy, Sjögren's syndrome, Lyme disease, sarcoidosis, polyglutamine diseases (also known as "polyQ diseases"), non-polyglutamine diseases, Kennedy's disease, Leibovitz disease, spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, herpes zoster (postherpetic neuralgia), Leber's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraplegia, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyaviral encephalitis, childhood viral encephalitis, essential tremor, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory Hypertensive autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), hereditary ataxia, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal lobar degeneration, amyloidosis, enteric neuropathy, axonopathy, severe acute motor axonal neuropathy (AMAN), mitochondrial diseases (e.g., chronic progressive external ophthalmoplegia syndrome, mitochondrial encephalomyopathy-lactic acidosis-strokelike episode syndrome, ragged-red fiber myoclonic epilepsy syndrome, Leigh syndrome, etc.), age-related macular degeneration, retinitis pigmentosa, sickle cell disease, fibromyalgia,These include neurological disorders resulting from myalgic encephalomyelitis / chronic fatigue syndrome (ME / CSF), HIV, exposure to certain drugs / toxins (e.g., vincristine, phenytoin, nitrofurantoin, isoniazid, ethyl alcohol, chemotherapy drugs, organometallics, heavy metals, fluoroquinolones, etc.), vitamin B6 overdose, vitamin (e.g., vitamin B12, vitamin A, vitamin E, vitamin B1) deficiency, physical trauma, and radiation exposure.

[0116] Pharmaceutical compositions containing the compound of formula (I) or a pharmaceutically acceptable salt thereof may be in the form of the compound itself (bulk powder) or in the form of preparations such as tablets, capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions, transdermal absorbents, suppositories, ointments, lotions, inhalants, eye drops, or injections prepared by mixing with appropriate pharmaceutically acceptable additives, and may be administered orally or parenterally (intravenously, intramuscularly, intraperitoneally, transdermally, nasally, via the respiratory tract, via the pulmonary route, ophthalmic, intradermally, or subcutaneously, etc.). These preparations are prepared by well-known methods using additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, isotonicity agents, buffers, pH adjusters, solubilizers, thickeners, dispersants, and preservatives (antiseptics).

[0117] Examples of the excipient include organic excipients and inorganic excipients. Examples of the organic excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; and pullulan. Examples of the inorganic excipients include light anhydrous silicic acid and sulfates such as calcium sulfate.

[0118] Examples of lubricants include stearic acid; metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or lime; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; D,L-leucine; sodium lauryl sulfate; silicic acids such as silicic anhydride or silicic acid hydrate; or starch derivatives of the above-mentioned excipients.

[0119] Examples of binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol, and the compounds listed above as excipients.

[0120] Examples of disintegrants include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and internally cross-linked carboxymethyl cellulose calcium; cross-linked polyvinylpyrrolidone; or chemically modified starches or cellulose derivatives such as carboxymethyl starch and carboxymethyl starch sodium.

[0121] Examples of emulsifiers include colloidal clays such as bentonite or veegum; anionic surfactants such as sodium lauryl sulfate; cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, and sucrose fatty acid esters.

[0122] Examples of stabilizers include parahydroxybenzoic acid esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; acetic anhydride; or sorbic acid.

[0123] Examples of flavoring agents include sweeteners such as saccharin sodium or aspartame; acidulants such as citric acid, malic acid or tartaric acid; and flavorings such as menthol, lemon extract or orange extract.

[0124] The diluent is a compound commonly used as a diluent, and examples thereof include water, lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, and mixtures thereof.

[0125] Examples of the isotonic agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, and mannitol.

[0126] Examples of buffering agents include phosphoric acid, phosphate salts, citric acid, acetic acid, and ε-aminocaproic acid.

[0127] Examples of pH adjusters include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, and sodium hydrogen carbonate.

[0128] Examples of the solubilizer include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and macrogol 4000.

[0129] Examples of thickeners and dispersants include cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone, and examples of stabilizers include edetic acid and sodium edetate.

[0130] Examples of preservatives (antiseptics) include commonly used sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, etc., and these preservatives can also be used in combination.

[0131] Other suitable additives can be used depending on the administration form. For example, when the compound represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is made into an aerosol for nasal or respiratory administration, for example, chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide can be used as a propellant.

[0132] In certain embodiments, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, as set forth in each particular embodiment above, for use in the treatment of a disease which is prevented, alleviated and / or cured by the inhibition of axonal degeneration.

[0133] In certain embodiments, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, as set forth in each particular embodiment above, for use in the treatment of a disease which is prevented, alleviated and / or cured by the inhibition of axonal degeneration.

[0134] In certain embodiments, the present invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof as set forth in each of the above specific embodiments for the manufacture of a medicament for the treatment of a disease which is prevented, alleviated and / or cured by the inhibition of axonal degeneration.

[0135] In certain embodiments, the present invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, as set forth in each specific embodiment above, for the manufacture of a medicament for the treatment of a disease which is prevented, alleviated and / or treated by SARM1 inhibition.

[0136] In certain embodiments, the present invention relates to a method for treating diseases that are prevented, alleviated and / or cured by inhibiting axonal degeneration, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I) as set forth in each of the above specific embodiments or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the present invention relates to a method for treating diseases that are prevented, alleviated, and / or cured by SARM1 inhibition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I) as set forth in each of the above specific embodiments, or a pharmaceutically acceptable salt thereof.

[0138] In the present invention, "treating" a disease or "treatment" of a disease includes (1) preventing the disease, i.e., preventing the development of clinical symptoms of the disease in a subject who may be exposed to or susceptible to the disease but who has not yet experienced or displayed symptoms of the disease; (2) inhibiting the disease, i.e., preventing the development of the disease or its clinical symptoms; or (3) ameliorating the disease, i.e., causing a temporary or permanent regression of the disease or its clinical symptoms.

[0139] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of formula (I) of the present invention that, when administered to a subject, will (i) treat or prevent a disease, (ii) reduce, ameliorate, or eliminate one or more symptoms of a disease, or (iii) prevent or delay the onset of one or more symptoms of a disease. The therapeutically effective amount will vary depending on the compound of formula (I) of the present invention used, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0140] Example 1: Production of compound 1 (1) Production of intermediate 1 A known compound (intermediate 1) represented by the following structural formula was synthesized according to the method described in WO2012 / 154194.

[0141] (2) Preparation of Intermediate 2: To a dichloromethane solution (25 ml) of Intermediate 1 (1.38 g, 5.38 mmol), trans-3-(3-pyridyl)acrylic acid chloride hydrochloride (1.21 g, 5.92 mmol) and triethylamine (3.00 ml, 21.5 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Intermediate 2, represented by the following structural formula, was obtained as a yellow solid (1.62 g, 4.18 mmol, 78%).

[0142] (3) Preparation of Intermediate 3: To a dichloromethane solution (6 ml) of Intermediate 2 (219 mg, 0.565 mmol), trifluoroacetic acid (3 ml) was added in an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 1:1) to obtain Intermediate 3, which has the following structural formula, as a yellow solid.

[0143] (4) Preparation of Intermediate 4 A known compound (intermediate 4) represented by the following structural formula was synthesized according to the method described in European Journal of Medicinal Chemistry, 2020, 201, 112411.

[0144] (5) Preparation of Intermediate 5: To a solution of Intermediate 3 in acetonitrile (10 ml), Intermediate 4 (486 mg, 1.94 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Pybop) (1.34 g, 2.58 mmol), and diisopropylethylamine (0.787 ml, 4.52 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 25:1) to obtain Intermediate 5 (292 mg, 0.565 mmol, 99%), which has the following structural formula, as a yellow solid.

[0145] (6) Preparation of Compound 1: Trifluoroacetic acid (2 ml) was added to a dichloromethane solution (4 ml) of intermediate 5 (292 mg, 0.565 mmol) in an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 10:1) to obtain Compound 1 as a yellow solid (239 mg, 0.565 mmol, 99%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ0.97-1.53 ​​(11H, m), 3.13-3.47 (6H, m), 3.73 (2H, s), 6.71 (1H, d, J = 16.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.37 (2H, d, J = 8.0 Hz), 7.40-7.48 (2H, m), 7.97 (1H, d, J = 8.4 Hz), 8.16 (1H, br), 8.54 (1H, d, J = 4.8 Hz), 8.75 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 25 H 32 N4O2Na 421.2604; Found 421.2601. The confirmed structure is:

[0146] Example 2: Preparation of Compound 2 (1) Preparation of Intermediate 6. Nicotinoyl chloride hydrochloride (1.15 g, 6.43 mmol) and triethylamine (2.99 ml, 21.4 mmol) were added to a dichloromethane solution (20 ml) of t-butyl 4-(5-aminopentyl)piperidine-1-carboxylate (1.16 g, 4.29 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 25:1) to obtain Intermediate 6, represented by the following structural formula, as a yellow solid (1.61 g, 4.29 mmol, 69%).

[0147] (2) Preparation of Intermediate 7: To a dichloromethane solution (14 ml) of Intermediate 6 (516 mg, 1.37 mmol), trifluoroacetic acid (5 ml) was added in an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 4:1) to obtain Intermediate 7 (266 mg, 0.966 mmol, 71%), which has the following structural formula, as a yellow solid.

[0148] (3) Preparation of Compound 2. To a dichloromethane solution (14 ml) of intermediate 7 (266 mg, 0.966 mmol), triethylamine (0.404 ml, 2.90 mmol) and bromoethanol (145 mg, 1.16 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 8:1) to obtain compound 2 as a yellow solid (284 mg, 0.889 mmol, 92%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 1.04-1.63 (12H, m), 1.89-2.00 (1H, m), 2.35-3.52 (10H, m), 7.50 (1H, t, J = 6.0 Hz), 8.16 (1H, d, J = 8.4 Hz), 8.63 (1H, br), 8.69 (1H, d, J = 4.4 Hz), 8.98 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 29 N3O2Na 342.2157; Found 342.2153. The confirmed structures are:

[0149] [Example 3: Preparation of compound 3] (1) Preparation of intermediate 8 A known compound (intermediate 8) represented by the following structural formula was synthesized according to the method described in Journal of Materials Chemistry B: Materials for Biology and Medicine, 2016, 4(16), 2819-2827.

[0150] (2) Preparation of Intermediate 9. To a solution of Intermediate 8 (3.82 g, 12.4 mmol) in dimethylformamide (15 ml) was added piperidine ethanol (1.26 ml, 10.3 mmol) and potassium carbonate (14.2 g, 103 mmol) at room temperature, followed by stirring at 100°C for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 25:1) to obtain Intermediate 9, represented by the following structural formula, as a yellow solid (911 mg, 2.53 mmol, 25%).

[0151] (3) Preparation of Intermediate 10: Hydrazine monohydrate (0.246 ml, 5.07 mmol) was added to a solution of Intermediate 9 (911 mg, 2.53 mmol) in ethanol (50 ml) at room temperature, and the mixture was stirred under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 4:1) to obtain Intermediate 10 (245 mg, 1.07 mmol, 42%), which has the following structural formula, as a yellow oil.

[0152] (4) Preparation of Compound 3. To a dichloromethane solution (10 ml) of intermediate 10 (245 mg, 1.07 mmol), trans-3-(3-pyridyl)acrylic acid chloride hydrochloride (262 mg, 1.28 mmol) and triethylamine (0.596 ml, 4.27 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 3 as a yellow solid (291 mg, 0.807 mmol, 75%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 1.22-1.50 (8H, m), 2.18-2.54 (12H, m), 3.16 (2H, q, J = 6.4 Hz), 3.46 (2H, q, J = 5.6 Hz), 4.35 (1H, t, J = 5.6 Hz), 6.72 (1H, d, J = 8.4 Hz), 7.40-7.47 (2H, m), 7.97 (1H, d, J = 8.0 Hz), 8.15 (1H, t, J = 5.2 Hz), 8.54 (1H, d, J = 5.2 Hz), 8.75 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 32 N4O2Na 383.2423; Found 383.2418. The confirmed structure is:

[0153] [Example 4: Production of compound 4] (1) Production of intermediate 11 A known compound (intermediate 11) represented by the following structural formula was synthesized according to the method described in WO2020 / 148153.

[0154] (2) Preparation of Intermediate 12: To a solution of Intermediate 11 (5.81 g, 17.2 mmol) in dimethylformamide (50 ml) was added ethylene glycol (2.87 ml, 51.5 mmol) and sodium hydride (1.50 g, 34.4 mmol) at room temperature, followed by stirring at the same temperature for 14 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain Intermediate 12, represented by the following structural formula, as a yellow oil (2.83 g, 8.86 mmol, 52%).

[0155] (3) Preparation of Intermediate 13: Hydrazine monohydrate (1.29 ml, 26.6 mmol) was added to an ethanol solution (177 ml) of Intermediate 12 (2.83 g, 8.86 mmol) at room temperature, and the mixture was stirred under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 3:1) to obtain Intermediate 13 (1.43 g, 7.55 mmol, 85%), which has the following structural formula, as a yellow oil.

[0156] (4) Preparation of Compound 4. Nicotinoyl chloride hydrochloride (1.61 g, 9.06 mmol) and triethylamine (4.21 ml, 30.2 mmol) were added to a dichloromethane solution (80 ml) of intermediate 13 (1.43 g, 7.55 mmol) at room temperature, followed by stirring at the same temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 20:1) to obtain compound 4 as a yellow oil (2.02 g, 6.86 mmol, 92%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 1.23-1.56 (12H, m), 3.22-3.50 (8H, m), 4.56 (1H, br), 7.49 (1H, t, J = 6.4 Hz), 8.16 (1H, d, J = 7.6 Hz), 8.63 (1H, br), 8.69 (1H, d, J = 4.4 Hz), 8.98 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 16 H 26 N2O3Na 317.1841; Found 317.1840. The confirmed structures are:

[0157] [Example 5: Production of compound 5] (1) Production of intermediate 14 A known compound (intermediate 14) represented by the following structural formula was synthesized according to the method described in Tetrahedron Letters, 2011, 52(20), 2533-2535.

[0158] (2) Preparation of Compound 5. To a solution of compound 4 (161 mg, 0.546 mmol) in dichloromethane (5 mL), intermediate 14 (200 mg, 1.09 mmol) and diisopropylethylamine (0.381 mL, 2.18 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 10:1) to obtain compound 5 as a yellow solid (179 mg, 0.391 mmol, 72%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 1.22-1.55 (12H, m), 3.21-3.27 (2H, m), 3.48 (2H, t, J = 6.0 Hz), 3.82-3.86 (2H, m), 4.50-4.59 (2H, m), 7.09 (1H, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 27 N5O6Na 480.1859; Found 480.1855. The confirmed structure is:

[0159] Example 6: Preparation of Compound 6 (1) Preparation of Intermediate 15: Diethylene glycol (2.42 ml, 25.5 mmol) and sodium hydride (740 mg, 17.0 mmol) were added to a dimethylformamide (25 ml) solution of Intermediate 11 (2.87 g, 8.48 mmol) in an ice bath, and the mixture was stirred at the same temperature for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:9) to obtain Intermediate 15, represented by the following structural formula, as a yellow oil (1.34 g, 3.69 mmol, 43%).

[0160] (2) Preparation of Intermediate 16: Hydrazine monohydrate (0.520 ml, 10.7 mmol) was added to a solution of Intermediate 15 (1.30 g, 3.58 mmol) in ethanol (75 ml) at room temperature, and the mixture was stirred under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 3:1) to obtain Intermediate 16 (738 mg, 3.16 mmol, 88%), which has the following structural formula, as a yellow oil.

[0161] (3) Preparation of Compound 6. Nicotinoyl chloride hydrochloride (660 mg, 3.71 mmol) and triethylamine (1.72 ml, 12.4 mmol) were added to a dichloromethane solution (40 ml) of intermediate 16 (721 mg, 3.09 mmol) at room temperature, followed by stirring at the same temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 15:1) to obtain compound 6 as a yellow oil (2.02 g, 6.86 mmol, 92%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 1.24-1.57 (12H, m), 3.23-3.52 (12H, m), 4.58 (1H, t, J = 5.2 Hz), 7.50 (1H, t, J = 6.4 Hz), 8.16 (1H, d, J = 7.6 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 30 N2O4Na 361.2103; Found 361.2098. The confirmed structure is:

[0162] Example 7: Preparation of Compound 7. To a dichloromethane solution (5 ml) of compound 6 (185 mg, 0.546 mmol), intermediate 14 (200 mg, 1.09 mmol) and diisopropylethylamine (0.381 ml, 2.18 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 10:1) to obtain compound 7 as a yellow solid (202 mg, 0.403 mmol, 74%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 1.18-1.33 (12H, m), 3.20-3.52 (6H, m), 3.60-3.65 (2H, m), 3.87-3.93 (2H, m), 4.55-4.59 (2H, m), 7.09 (1H, d, J = HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 24 H 31N5O7Na 524.2121; Found 524.2120. The confirmed structure is:

[0163] Example 8: Preparation of Compound 8 (1) Preparation of Intermediate 17. Triethylene glycol (6.65 ml, 49.8 mmol) and sodium hydride (1.45 g, 33.2 mmol) were added to a dimethylformamide (60 ml) solution of Intermediate 11 (5.61 g, 16.6 mmol) in an ice bath, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 4:1) to obtain Intermediate 17, represented by the following structural formula, as a yellow oil (2.83 g, 6.94 mmol, 42%).

[0164] (2) Preparation of Intermediate 18: Hydrazine monohydrate (0.379 ml, 7.80 mmol) was added to a solution of Intermediate 17 (1.06 g, 2.60 mmol) in ethanol (50 ml) at room temperature, and the mixture was stirred under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 3:1) to obtain Intermediate 18 (670 mg, 2.42 mmol, 93%), which has the following structural formula, as a yellow oil.

[0165] (3) Preparation of Compound 8. Nicotinoyl chloride hydrochloride (516 mg, 2.90 mmol) and triethylamine (1.35 mL, 9.66 mmol) were added to a dichloromethane solution (25 mL) of intermediate 18 (670 mg, 2.42 mmol) at room temperature, followed by stirring at the same temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 20:1) to obtain compound 8 as a yellow oil (771 mg, 2.02 mmol, 83%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 1.23-1.57 (12H, m), 3.23-3.51 (16H, m), 4.58 (1H, t, J = 5.2 Hz), 7.49 (1H, dd, J = 8.0, 4.4 Hz), 8.16 (1H, d, J = HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 34 N2O5Na 405.2365; Found 405.2361. The confirmed structure is:

[0166] Example 9: Preparation of Compound 9 (1) Preparation of Intermediate 19. To a dichloromethane solution (5 ml) of compound 8 (560 mg, 1.46 mmol), triethylamine (0.612 ml, 4.39 mmol) and mesyl chloride (0.134 ml, 1.76 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 20:1) to obtain intermediate 19, represented by the following structural formula, as a yellow oil (643 mg, 1.39 mmol, 95%).

[0167] (2) Preparation of Intermediate 20 Sodium azide (109 mg, 1.67 mmol) was added to a dimethylformamide solution (5 ml) of Intermediate 19 (643 mg, 1.39 mmol) at room temperature, and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=25:1) to obtain Intermediate 20 (566 mg, 1.39 mmol, 99%), which is represented by the following structural formula, as a yellow oil.

[0168] (3) Preparation of Compound 9. Triphenylphosphine (421 mg, 1.61 mmol) was added to a tetrahydrofuran solution (7.3 mL) of intermediate 20 (595 mg, 1.46 mmol) at room temperature, and the mixture was stirred at room temperature for 24 hours. Water (0.0788 mL, 4.38 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 7:1) to obtain compound 9 as a yellow oil (474 ​​mg, 1.24 mmol, 85%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 1.22-1.56 (12H, m), 3.21-3.60 (16H, m), 7.47-7.52 (1H, m), 8.16 (1H, d, J = 7.6 Hz), 8.60-8.73 (2H, m), 8.98 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 35 N3O4Na 404.2525; Found 404.2520. The confirmed structure is:

[0169] Example 10: Preparation of Compound 10. To a dichloromethane solution (5 ml) of compound 8 (209 mg, 0.546 mmol), intermediate 14 (200 mg, 1.09 mmol) and diisopropylethylamine (0.381 ml, 2.18 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 20:1) to obtain compound 10 as a yellow solid (166 mg, 0.297 mmol, 54%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 1.20-1.56 (12H, m), 3.20-3.63 (12H, m), 3.88-3.93 (2H, m), 4.56-4.60 (2H, m), 7.09 (1H, d, J = 8.8 Hz), 7.48-7.53 (1H, m), 8.14-8.20 (1H, m), 8.60-8.76 (3H, m), 8.98 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 26 H 35 N5O8Na 568.2383; Found 568.2386. The confirmed structure is:

[0170] Example 11: Preparation of Compound 11. Nicotinoyl chloride hydrochloride (74.7 mg, 0.420 mmol) and triethylamine (0.120 mL, 0.861 mmol) were added to a dichloromethane solution (3 mL) of 2-[2-(2-propyn-1-yloxy)ethoxy]ethanamine (50.0 mg, 0.349 mmol) at room temperature, followed by stirring at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 10:1) to obtain SYK-79 as a yellow oil (81.4 mg, 0.328 mmol, 94%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CDCl3, 400 MHz): δ 2.44 (1H, t, J = 2.4 Hz), 3.68-3.73 (8H, m), 4.20 (2H, d, J = 2.4 Hz), 6.86 (1H, br), 7.39 (1H, dd, J = 7.6, 4.0 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 13 H 16 N2O3Na 271.1059; Found 271.1060. The confirmed structure is:

[0171] Example 12: Preparation of Compound 12 (1) Preparation of Intermediate 21. To a dichloromethane solution (6 ml) of trans-3-(3-pyridyl)acrylic acid (100 mg, 0.670 mmol), t-butyl (3-aminopropyl)carbamate (140 mg, 0.803 mmol), N,N-diisopropylethylamine (0.240 ml, 1.38 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (510 mg, 1.34 mmol), and dimethylaminopyridine (16.0 mg, 0.132 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 5:1) to obtain Intermediate 21 (187 mg, 0.612 mmol, 91%), which has the following structural formula, as a yellow oil. HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 16 H 23N3O3Na 328.1637; Found 328.1637.

[0172] (2) Preparation of Intermediate 22: To a dichloromethane solution (5 ml) of Intermediate 21 (230 mg, 0.753 mmol), hydrochloric acid (4 M dioxane solution, 3.8 ml) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain Intermediate 22 (148 mg, 0.721 mmol, 96%), which has the following structural formula, as a pale yellow solid. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 11 H 16 N3O 206.1293; Found 206.1289.

[0173] (3) Preparation of Compound 12. 1-Benzoyl-4-piperidone (445 mg, 2.19 mmol), sodium triacetoxyborohydride (93.0 mg, 0.439 mmol), and acetic acid (1 ml) were added to a methanol solution (1.5 ml) of intermediate 22 (45.0 mg, 0.219 mmol) at 60°C, followed by stirring at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 5:1) to obtain compound 12 as a yellow oil (5.00 mg, 0.0127 mmol, 5.8%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CD3OD, 400 MHz): δ 1.35-2.20 (6H, m), 2.85-3.46 (5H, m), 3.73-3.86 (2H, m), 4.62-4.74 (2H, m), 6.75 (1H, d, J = 16.4 Hz), 7.38-7.52 (6H, m), 7.59 (1H, d, J = 16.4 Hz), 8.06 (1H, d, J = 7.6 Hz), 8.53 (1H, s), 8.72 (1H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 23 H 29 N4O2393.2291; Found 393.2283. The confirmed structure is:

[0174] [Example 13: Production of compound 13] (1) Production of intermediate 23 A known compound (intermediate 23) represented by the following structural formula was synthesized according to the method described in European Journal of Organic Chemistry, 2020, 32, 5153-5160.

[0175] (2) Preparation of Intermediate 24 A known compound (intermediate 24) represented by the following structural formula was synthesized according to the method described in Dalton Transactions, 2017, 46(47), 16387-16389.

[0176] (3) Preparation of Intermediate 25: Intermediate 24 (1.50 g, 5.03 mmol) and potassium carbonate (690 mg, 4.99 mmol) were added to a dimethylformamide solution (20 ml) of Intermediate 23 (830 mg, 3.65 mmol) at room temperature, and the mixture was stirred at 80°C for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate 100%) to obtain Intermediate 25 (1.20 g, 2.70 mmol, 74%), which has the following structural formula, as a yellow solid. 1H NMR (DMSO, 400 MHz): δ 3.65-3.78 (6H, m), 3.96-3.99 (2H, m), 4.38 (2H, d, J = 6.0 Hz), 6.78 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.43-7.55 (3H, m), 7.79-7.90 (6H, m), 8.97 (1H, t, J = 6.0 Hz).

[0177] (4) Preparation of Intermediate 26 Hydrazine monohydrate (0.650 ml, 13.5 mmol) was added to an ethanol solution (5.4 ml) of Intermediate 25 (1.20 g, 2.70 mmol) at room temperature, and the mixture was stirred at 80° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 1:1, ammonia water:methanol = 5:95) to obtain Intermediate 26 (400 mg, 1.27 mmol, 47%), which is represented by the following structural formula, as a yellow oil. 1 H NMR (DMSO, 400 MHz): δ 2.63-2.68 (2H, m), 3.48 (2H, q, J = 5.2 Hz), 3.68-3.72 (2H, m), 4.04-4.08 (2H, m), 4.40 (2H, d, J = 6.0 Hz), 6.89 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8 Hz), 7.43-7.55 (3H, m), 7.87 (2H, d, J = 6.8 Hz).

[0178] (5) Preparation of Compound 13. Nicotinic acid (102 mg, 0.829 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (158 mg, 0.824 mmol), and dimethylaminopyridine (10.1 mg, 0.0827 mmol) were added to a dichloromethane solution (15 ml) of intermediate 26 (130 mg, 0.413 mmol) at room temperature, followed by stirring at the same temperature for 24 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain compound 13 as a yellow solid (167 mg, 0.398 mmol, 96%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 3.46 (2H, q, J = 6.0 Hz), 3.61 (2H, t, J = 6.0 Hz), 3.75 (2H, t, J = 4.8 Hz), 4.06 (2H, t, J = 4.8 Hz), 4.40 (2H, d, J = 6.0 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.44-7.55 (4H, m), 7.86-7.89 (2H, m), 8.16 (1H, dt, J = 8.0, 2.0 Hz), 8.68 (1H, dd, J = 4.8, 2.4 Hz), 8.77 (1H, t, J = 5.6 Hz), 8.96-9.01 (2H, m); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 24 H 25 N3O4Na 442.1743; Found 442.1735. The confirmed structure is:

[0179] Example 14: Preparation of Compound 14. To a dichloromethane solution (15 ml) of Intermediate 26 (130 mg, 0.413 mmol), trans-3-(3-pyridyl)acrylic acid (123 mg, 0.825 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (158 mg, 0.824 mmol), and dimethylaminopyridine (10.1 mg, 0.0827 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 24 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to obtain Compound 14 as a yellow solid (180 mg, 0.404 mmol, 98%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 3.37 (2H, q, J = 5.6 Hz), 3.54 (2H, t, J = 5.6 Hz), 3.74 (2H, t, J = 4.8 Hz), 4.07 (2H, t, J = 4.8 Hz), 4.39 (2H, d, J = 6.0 Hz), 6.77 (1H, d, J = 16.0 Hz), 6.90 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.41-7.55 (5H, m), 7.87 (2H, d, J = 7.2 Hz), 7.96 (1H, dt, J = 7.6, 2.0 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 26 H 27 N3O4Na 468.1899; Found 468.1896. The confirmed structure is:

[0180] Example 15: Preparation of compound 15 (1) Preparation of intermediate 27 A known compound (intermediate 27) represented by the following structural formula was synthesized according to the method described in European Journal of Medicinal Chemistry, 2018, 158, 51-67.

[0181] (2) Preparation of Intermediate 28: Intermediate 27 (1.00 g, 3.73 mmol), potassium carbonate (773 mg, 5.59 mmol), and sodium iodide (112 mg, 0.747 mmol) were added to a dimethylformamide solution (10 ml) of Intermediate 23 (932 mg, 4.10 mmol) at room temperature, and the mixture was stirred at 60°C for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Intermediate 28, represented by the following structural formula, was obtained as a yellow solid (1.54 g, 3.72 mmol, 99%). 1 H NMR (DMSO, 400 MHz): δ 1.98-2.09 (2H, m), 3.71-3.78 (2H, m), 3.94-4.01 (2H, m), 4.36 (2H, d, J = 6.0 Hz), 6.74 (2H, d, J = 6.4 Hz), 7.18 (2H, d, J = 6.4 Hz), 7.43-7.55 (3H, m), 7.80-7.89 (6H, m), 8.97 (1H, br).

[0182] (3) Preparation of Intermediate 29 Hydrazine monohydrate (1.17 ml, 24.1 mmol) was added to a solution of Intermediate 28 (2.00 g, 4.82 mmol) in ethanol (60 ml) at room temperature, and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 9:1, ammonia water:methanol = 10:90) to obtain Intermediate 29 (600 mg, 2.11 mmol, 44%), which is represented by the following structural formula, as a yellow oil. 1H NMR (DMSO, 400 MHz): δ1.73-1.80 (2H, m), 2.68 (2H, t, J = 6.4 Hz), 3.99 (2H, t, J = 6.4 Hz), 4.40 (2H, d, J = 6.0 Hz), 6.87 (2H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.44-7.55 (3H, m), 7.87 (2H, d, J = 6.8 Hz).

[0183] (4) Preparation of Compound 15. Nicotinic acid (102 mg, 0.829 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (158 mg, 0.824 mmol), and dimethylaminopyridine (10.1 mg, 0.0827 mmol) were added to a dichloromethane solution (15 ml) of intermediate 29 (200 mg, 0.704 mmol) at room temperature, followed by stirring at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 98:2) to obtain compound 15 as a yellow solid (210 mg, 0.540 mmol, 73%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 1.97 (2H, q, J = 6.4 Hz), 3.43 (2H, q, J = 6.0 Hz), 4.02 (2H, t, J = 6.0 Hz), 4.40 (2H, d, J = 6.0 Hz), 6.89 (2H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.43-7.55 (4H, m), 7.87 (2H, d, J = 7.2 Hz), 8.17 (1H, dt, J =8.0, 2.0 Hz), 8.69 (1H, dd, J = 4.8, 1.6 Hz), 8.74 (1H, t, J = 5.6 Hz), 8.96-9.01 (2H, m); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 23 N3O3Na 412.1637; Found 412.1631. The confirmed structure is:

[0184] Example 16: Preparation of Compound 16. To a dichloromethane solution (15 ml) of Intermediate 29 (200 mg, 0.704 mmol), trans-3-(3-pyridyl)acrylic acid (209 mg, 1.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (268 mg, 1.40 mmol), and dimethylaminopyridine (17.1 mg, 0.140 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 96:4) to obtain Compound 16 as a yellow solid (50.0 mg, 0.120 mmol, 17%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CDCl3, 400 MHz): δ 1.90 (2H, q, J = 6.4 Hz), 3.34 (2H, q, J = 6.0 Hz), 3.99 (2H, t, J = 6.0 Hz), 4.40 (2H, d, J = 6.4 Hz), 6.72 (1H, d, J = 8.4 Hz), 6.89 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.8 Hz), 7.41-7.55 (5H, m), 7.87 (2H, d, J = 8.0 Hz), 7.97 (1H, dt, J = 7.6, 2.0 Hz), 8.28 (1H, t, J = 5.6 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 25 H 25 N3O3Na 438.1794; Found 438.1790. The confirmed structure is:

[0185] Example 17: Preparation of compound 17 (1) Preparation of intermediate 30 A known compound (intermediate 30) represented by the following structural formula was synthesized according to the method described in WO97 / 02242.

[0186] (2) Preparation of Compound 17. To a dichloromethane solution (4 mL) of Intermediate 30 (75.0 mg, 0.414 mmol), trans-3-(3-pyridyl)acrylic acid (123 mg, 0.825 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (159 mg, 0.829 mmol), and dimethylaminopyridine (10.1 mg, 0.0827 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 9 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to obtain Compound 17 as a yellow solid (86.5 mg, 0.277 mmol, 67%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 3.37 (2H, q, J = 6.0 Hz), 3.55 (2H, t, J = 5.6 Hz), 3.76 (2H, t, J = 4.4 Hz), 4.09 (2H, t, J = 4.4 Hz), 6.77 (1H, d, 8.55 (1H, dd, J = 4.8, 1.6 Hz), 8.74 (1H, d, J = 2.0 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 20 N2O3Na 335.1372; Found 335.1370. The confirmed structure is:

[0187] Example 18: Preparation of compound 18 (1) Preparation of intermediate 31 A known compound (intermediate 31) represented by the following structural formula was synthesized according to the method described in WO2015 / 071657.

[0188] (2) Preparation of Compound 18. To a dichloromethane solution (5 mL) of Intermediate 31 (100 mg, 0.552 mmol), trans-3-(3-pyridyl)acrylic acid (164 mg, 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (211 mg, 1.10 mmol), and dimethylaminopyridine (13.4 mg, 0.110 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 20 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to obtain Compound 18 as a yellow solid (72.0 mg, 0.230 mmol, 41%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ1.90 (2H, q, J = 6.4 Hz), 3.33 (2H, t, J = 6.8 Hz), 3.72 (3H, s), 4.00 (2H, t, J = 6.4 Hz), 6.47-6.54 (3H, m), 6.72 (1H, d, J = 16.0 Hz), 7.17 (1H, t, J = 8.0 Hz), 7.42-7.48 (2H, m), 7.98 (1H, dt, J = 8.0, 2.0 Hz), 8.29 (1H, t, J = 5.6 Hz), 8.55 (1H, dd, J = 4.8, 1.6 Hz), 8.75 (1H, d, J = 2.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 20 N2O3Na 335.1372; Found 335.1368. The confirmed structure is:

[0189] [Example 19: Preparation of Compound 19] (1) Preparation of Intermediate 32 A known compound (intermediate 32) represented by the following structural formula was synthesized according to the method described in New Journal of Chemistry, 2021, 45(12), 5621-5630.

[0190] (2) Preparation of Compound 19. To a dichloromethane solution (3 mL) of Intermediate 32 (55.0 mg, 0.329 mmol), trans-3-(3-pyridyl)acrylic acid (98 mg, 0.657 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126 mg, 0.657 mmol), and dimethylaminopyridine (8.00 mg, 0.0655 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 20 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to obtain Compound 19 as a yellow solid (63.6 mg, 0.213 mmol, 65%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 3.56 (2H, q, J = 5.6 Hz), 3.73 (3H, s), 4.04 (2H, t, J = 5.6 Hz), 6.50-6.56 (3H, m), 6.79 (1H, d, J = 16.0 Hz), 7.18 (1H, t, J = 8.4 Hz), 7.42-7.51 (2H, m), 7.98 (1H, d, J = 8.4 Hz), 8.45 (1H, t, J = 5.2 Hz), 8.55 (1H, d, J = 5.2 Hz), 8.76 (1H, d, J = 1.6 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 17 H 18 N2O3Na 321.1215; Found 321.1209. The confirmed structure is:

[0191] Example 20: Preparation of compound 20 (1) Preparation of intermediate 33 A known compound (intermediate 33) represented by the following structural formula was synthesized according to the method described in Journal of Medicinal Chemistry, 2008, 51(24), 7800-7805.

[0192] (2) Preparation of Intermediate 34: Intermediate 27 (1.00 g, 3.73 mmol), potassium carbonate (773 mg, 5.59 mmol), and sodium iodide (112 mg, 0.747 mmol) were added to a dimethylformamide solution (10 ml) of Intermediate 33 (677 mg, 4.10 mmol) at room temperature, and the mixture was stirred at 60°C for 9 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Intermediate 34, represented by the following structural formula, was obtained as a yellow solid (1.30 g, 3.69 mmol, 99%). 1 H NMR (DMSO, 400 MHz): δ 1.84 (3H, s), 2.01-2.07 (2H, m), 3.75 (2H, t, J = 6.8 Hz), 3.98 (2H, t, J = 6.8 Hz), 4.14 (2H, d, J = 6.0 Hz), 6.73 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.80-7.89 (4H, m).

[0193] (3) Preparation of Intermediate 35 Hydrazine monohydrate (0.900 ml, 18.5 mmol) was added to an ethanol solution (7.4 ml) of Intermediate 34 (1.30 g, 3.69 mmol) at room temperature, and the mixture was stirred at 80° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=9:1, ammonia water:methanol=10:90) to obtain Intermediate 35 (600 mg, 2.70 mmol, 73%), which is represented by the following structural formula, as a yellow oil. 1H NMR (DMSO, 400 MHz): δ 1.80-1.88 (2H, m), 1.84 (3H, s), 2.78 (2H, t, J = 7.2 Hz), 4.00 (2H, t, J = 7.2 Hz), 4.15 (2H, d, J = 6.0 Hz), 6.86 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J = 8.8 Hz).

[0194] (4) Preparation of Compound 20. Nicotinic acid (299 mg, 2.43 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (464 mg, 2.42 mmol), and dimethylaminopyridine (29.6 mg, 0.242 mmol) were added to a dichloromethane solution (12 mL) of intermediate 35 (270 mg, 1.21 mmol) at room temperature, followed by stirring at the same temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain compound 20 as a yellow solid (5.00 mg, 0.0153 mmol, 1.3%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 1.84 (3H, s), 1.97 (2H, q, J = 6.4 Hz), 3.43 (2H, q, J =6.0 Hz), 4.02 (2H, t, J = 6.0 Hz), 4.16 (2H, d, J = 5.6 Hz), 6.87 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 8.0, 5.2 Hz), 8.17 (1H, dt, J = 8.4, 2.0 Hz), 8.25 (1H, t, J = 5.2 Hz), 8.69 (1H, dd, J = 4.8, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 21 N3O3Na 350.1481; Found 350.1474. The confirmed structure is:

[0195] Example 21: Preparation of Compound 21 (1) Preparation of Intermediate 36 Intermediate 24 (1.00 g, 3.35 mmol), potassium carbonate (694 mg, 5.02 mmol), and sodium iodide (100 mg, 0.667 mmol) were added to a dimethylformamide solution (10 ml) of Intermediate 33 (609 mg, 3.69 mmol) at room temperature, followed by stirring at 60°C for 4 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Intermediate 36, represented by the following structural formula, was obtained as a yellow solid (1.28 g, 3.35 mmol, 99%). 1H NMR (CDCl3, 400 MHz): δ 2.00 (3H, s), 3.72-3.85 (6H, m), 3.89-3.04 (2H, m), 4.33 (2H, d, J = 5.6 Hz), 6.81 (2H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.69-7.73 (2H, m), 7.80-7.87 (2H, m).

[0196] (2) Preparation of Intermediate 37 Hydrazine monohydrate (0.830 ml, 17.0 mmol) was added to an ethanol solution (34 ml) of Intermediate 36 (1.30 g, 3.40 mmol) at room temperature, and the mixture was stirred at 80° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 9:1, methanol 100%) to obtain Intermediate 37 (510 mg, 2.02 mmol, 59%), which is represented by the following structural formula, as a yellow oil. 1 H NMR (DMSO, 400 MHz): δ 1.94 (3H, s), 2.78-2.84 (2H, m), 3.50-3.55 (2H, m), 3.73-3.80 (2H, m), 4.04-4.09 (2H, m), 4.27 (2H, d, J = 5.6 Hz), 6.83 (2H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz).

[0197] (3) Preparation of Compound 21. To a solution of intermediate 37 (200 mg, 0.793 mmol) in dichloromethane (15 ml) was added nicotinic acid (195 mg, 1.58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (303 mg, 1.58 mmol), and dimethylaminopyridine (19.3 mg, 0.158 mmol) at room temperature, followed by stirring at the same temperature for 22 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 21 as a yellow solid (18.0 mg, 0.0504 mmol, 6.4%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 2.03 (3H, s), 3.67-3.76 (4H, m), 3.86 (2H, t, J = 3.2 Hz), 4.17 (2H, t, J =2.4 Hz), 4.36 (2H, d, J = 5.6 Hz), 6.52 (1H, br), 6.58 (1H, br), 6.88 (2H, d, J = 7.2 Hz), 7.19 (2H, d, J = 7.2 Hz), 7.37 (1H, dd, J = 7.2, 5.6 Hz), 8.13 (1H, d, J = 8.0 Hz), 8.59 (1H, s), 8.68 (1H, d, J = 4.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 23 N3O4Na 380.1586; Found 380.1580. The confirmed structure is:

[0198] Example 22: Preparation of Compound 22. To a dichloromethane solution (3 ml) of Intermediate 37 (200 mg, 0.793 mmol), trans-3-(3-pyridyl)acrylic acid (236 mg, 1.58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (303 mg, 1.58 mmol), and dimethylaminopyridine (19.3 mg, 0.158 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 22 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 22 as a yellow solid (20.0 mg, 0.0522 mmol, 6.6%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 2.06 (3H, s), 3.62 (2H, q, J = 4.8 Hz), 3.76 (2H, t, J = 4.8 Hz), 3.90 (2H, t, J = 4.4 Hz), 4.15 (2H, t, J = 4.4 Hz), 4.40 (2H, d, J = 4.8 Hz), 6.26 (1H, d, J = 15.6 Hz), 6.54 (1H, br), 6.94 (2H, d, J = 8.0 Hz), 7.22-7.57 (5H, m), 7.93 (1H, br), 8.24 (1H, s), 8.56 (1H, d, J = 4.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 21 H 25 N3O4Na 406.1743; Found 406.1739. The confirmed structure is:

[0199] Example 23: Preparation of compound 25 (1) Preparation of intermediate 38 A known compound (intermediate 38) represented by the following structural formula was synthesized according to the method described in WO2011 / 146845.

[0200] (2) Preparation of Intermediate 39: Intermediate 27 (1.50 g, 5.59 mmol) and potassium carbonate (1.16 g, 8.39 mmol) were added to a dimethylformamide solution (15 ml) of Intermediate 38 (948 mg, 6.15 mmol) at room temperature, and the mixture was stirred at 80°C for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to obtain Intermediate 39 (1.31 g, 3.83 mmol, 69%), which has the following structural formula, as a yellow solid. 1 H NMR (CDCl3, 400 MHz): δ 2.17 (2H, q, J = 6.8 Hz), 3.46 (3H, s), 3.90 (2H, t, J = 6.8 Hz), 4.01 (2H, t, J = 6.8 Hz), 5.13 (2H, s), 6.46 (1H, d, J = 8.4 Hz), 6.51 (1H, s), 6.61 (1H, d, J = 8.4 Hz), 7.13 (1H, t, J = 8.4 Hz), 7.70-7.74 (2H, m), 7.83-7.86 (2H, m).

[0201] (3) Preparation of Intermediate 40: Hydrazine monohydrate (0.372 ml, 7.66 mmol) was added to a solution of Intermediate 39 (1.31 g, 3.83 mmol) in ethanol (10 ml) at room temperature, and the mixture was stirred at 80°C for 14 hours. After filtration through Celite, the reaction mixture was concentrated under reduced pressure. Intermediate 40, represented by the following structural formula, was obtained as a yellow oil (809 mg, 3.83 mmol, 99%). 1H NMR (DMSO, 400 MHz): δ 1.80 (2H, q, J = 6.4 Hz), 2.72 (2H, t, J = 6.4 Hz), 3.36 (3H, s), 3.99 (2H, t, J = 6.4 Hz), 5.16 (2H, s), 7.16 (2H, t, J = 8.0 Hz), 7.78-7.82 (1H, m), 8.04-8.07 (1H, m).

[0202] (4) Preparation of Compound 25. Nicotinic acid (175 mg, 1.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (272 mg, 1.42 mmol), and dimethylaminopyridine (17.3 mg, 0.142 mmol) were added to a dichloromethane solution (5 mL) of intermediate 40 (150 mg, 0.710 mmol) at room temperature, followed by stirring at the same temperature for 19 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to obtain compound 25 as a yellow solid (143 mg, 0.452 mmol, 64%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 1.97 (2H, q, J = 6.4 Hz), 3.36 (3H, s), 3.44 (2H, q, J = 6.4 Hz), 4.02 (2H, t, J = 6.4 Hz), 5.16 (2H, s), 6.55-6.61 (3H, m), 7.18 (1H, t, J = 8.0 Hz), 7.50 (1H, dd, J = 8.0, 4.8 Hz), 8.18 (1H, dt, J = 6.4, 2.0 Hz), 8.69 (1H, dd, J = 4.8, 1.6 Hz), 8.76 (1H, t, J = 5.6 Hz), 8.99 (1H, d, J = 2.0 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C17 H 20 N2O4Na 339.1321; Found 339.1314. The confirmed structure is:

[0203] Example 24: Preparation of Compound 24. To a dichloromethane solution (5 mL) of Intermediate 40 (150 mg, 1.41 mmol), trans-3-(3-pyridyl)acrylic acid (212 mg, 1.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (272 mg, 1.42 mmol), and dimethylaminopyridine (17.3 mg, 0.142 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain Compound 24 as a yellow solid (152 mg, 0.444 mmol, 63%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 1.90 (2H, q, J = 2.4 Hz), 3.34 (2H, q, J = 6.4 Hz), 3.36 (3H, s), 3.99 (2H, t, J = 6.4 Hz), 5.16 (2H, s), 6.56-6.61 (3H, m), 6.72 (1H, d, J = 16.0 Hz), 7.18 (1H, t, J = 8.0 Hz), 7.42-7.48 (2H, m), 7.98 (1H, dt, J = 8.0, 2.0 Hz), 8.29 (1H, t, J = 5.6 Hz), 8.55 (1H, dd, J = 4.8, 1.6 Hz), 8.75 (1H, d, J = 2.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 22 N2O4Na 365.1477; Found 365.1473. The confirmed structure is:

[0204] Example 25: Preparation of Compound 23. To a solution of compound 24 (50.0 mg, 0.146 mmol) in acetonitrile (0.7 ml), trimethylsilyl iodide (0.0400 ml, 0.292 mmol) was added at room temperature, followed by stirring at the same temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Compound 23 was obtained as a yellow solid (16.2 mg, 0.0543 mmol, 37%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 1.89 (2H, q, J = 6.4 Hz), 3.34 (2H, q, J = 6.4 Hz), 3.94 (2H, t, J = 6.4 Hz), 6.30-6.38 (2H, m), 6.72 (1H, d, J = 16.0 Hz), 7.04 (1H, t, J = 8.0 Hz), 7.41-7.49 (2H, m), 7.98 (1H, d, J = 7.6 Hz), 8.29 (1H, t, J = 5.6 Hz), 8.54 (1H, d, J = 4.4 Hz), 8.75 (1H, s), 9.38 (1H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 17 H 19 N2O3299.1396; Found 299.1394. The confirmed structure is:

[0205] Example 26: Preparation of Compound 30 (1) Preparation of Intermediate 41 Intermediate 24 (1.50 g, 5.03 mmol), potassium carbonate (1.04 g, 7.55 mmol), and sodium iodide (150 mg, 1.00 mmol) were added to a dimethylformamide solution (20 ml) of Intermediate 38 (853 mg, 5.53 mmol) at room temperature, followed by stirring at 80°C for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to obtain Intermediate 41, represented by the following structural formula, as a yellow solid (402 mg, 1.08 mmol, 22%). 1 H NMR (CDCl3, 400 MHz): δ 3.46 (3H, s), 3.80-3.86 (4H, m), 3.91-3.96 (2H, m), 4.02-4.06 (2H, m), 5.14 (2H, s), 6.49 (1H, d, J = 8.4 Hz), 6.55 (1H, s), 6.60 (1H, d, J = 8.4 Hz), 7.12 (1H, t, J = 8.4 Hz), 7.68-7.72 (2H, m), 7.81-7.85 (2H, m).

[0206] (2) Preparation of Intermediate 42: Hydrazine monohydrate (0.100 ml, 2.15 mmol) was added to an ethanol solution (10 ml) of Intermediate 41 (400 mg, 1.08 mmol) at room temperature, and the mixture was stirred at 80°C for 14 hours. After filtration through Celite, the reaction mixture was concentrated under reduced pressure. Intermediate 42, represented by the following structural formula, was obtained as a yellow oil (260 mg, 1.08 mmol, 99%). 1H NMR (DMSO, 400 MHz): δ 2.68 (2H, t, J = 6.0 Hz), 3.36 (3H, s), 3.43 (2H, t, J = 6.0 Hz), 3.70 (2H, t, J = 4.4 Hz), 4.06 (2H, t, J = 4.4 Hz), 5.16 (2H, s), 6.55-6.62 (1H, m), 7.15-7.20 (1H, m), 7.83-7.88 (1H, m), 8.04-8.08 (1H, m).

[0207] (3) Preparation of Compound 30. Nicotinic acid (153 mg, 1.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (238 mg, 1.24 mmol), and dimethylaminopyridine (15.1 mg, 0.124 mmol) were added to a dichloromethane solution (6 mL) of intermediate 42 (150 mg, 0.622 mmol) at room temperature, followed by stirring at the same temperature for 7 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain compound 30 as a yellow solid (90.0 mg, 0.260 mmol, 42%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 3.35 (3H, s), 3.46 (2H, q, J = 6.0 Hz), 3.61 (2H, t, J = 6.0 Hz), 3.75 (2H, t, J = 4.4 Hz), 4.06 (2H, t, J = 4.4 Hz), 5.15 (2H, s), 6.54-6.61 (3H, m), 7.16 (1H, t, J = 8.8 Hz), 7.49 (1H, dd, J = 8.0, 4.8 Hz), 8.17 (1H, dt, J = 7.6, 2.0 Hz), 8.69 (1H, d, J = 5.2 Hz), 8.77 (1H, t, J = 5.2 Hz), 8.99 (1H, d, J = 2.0 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 22 N2O5Na 369.1426; Found 369.1424. The confirmed structure is:

[0208] Example 27: Preparation of Compound 29. To a dichloromethane solution (6 mL) of Intermediate 42 (150 mg, 0.622 mmol), trans-3-(3-pyridyl)acrylic acid (185 mg, 1.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (238 mg, 1.24 mmol), and dimethylaminopyridine (15.1 mg, 0.124 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 15 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to obtain Compound 29 as a yellow solid (118 mg, 0.318 mmol, 51%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 3.46 (3H, s), 3.48 (2H, q, J = 6.0 Hz), 3.66 (2H, t, J = 5.6 Hz), 3.85 (2H, t, J = 4.4 Hz), 4.18 (2H, t, J = 4.4 Hz), 5.26 (2H, s), 6.66-6.71 (3H, m), 6.88 (1H, d, J = 7.6 Hz), 7.28 (1H, t, J = 8.8 Hz), 7.52-7.59 (2H, m), 8.07 (1H, d, J = 8.0 Hz), 8.38 (1H, t, J = 5.6 Hz), 8.65 (1H, d, J = 4.8 Hz), 8.85 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 24 N2O5Na 395.1583; Found 395.1580. The confirmed structure is:

[0209] Example 28: Preparation of Compound 27. Trimethylsilyl iodide (0.0210 ml, 0.156 mmol) was added to a solution of compound 30 (27 mg, 0.146 mmol) in acetonitrile (0.5 ml) at room temperature, followed by stirring at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Compound 27 was obtained as a yellow solid (20.0 mg, 0.662 mmol, 85%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 3.46 (2H, q, J = 6.0 Hz), 3.60 (2H, t, J = 6.0 Hz), 3.73 (2H, t, J = 4.4 Hz), 4.01 (2H, t, J = 4.4 Hz), 6.28-6.36 (3H, m), 7.02 (1H, t, J = 8.0 Hz), 7.49 (1H, dd, J = 8.0, 4.8 Hz), 8.17 (1H, d, J = 7.6 Hz), 8.69 (1H, d, J = 4.8 Hz), 8.77 (1H, t, J = 5.6 Hz), 8.99 (1H, s), 9.39 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 16 H 18 N2O4Na 325.1164; Found 325.1162. The confirmed structure is:

[0210] Example 29: Preparation of Compound 26. Trimethylsilyl iodide (0.0340 ml, 0.248 mmol) was added to a solution of compound 29 (46 mg, 0.124 mmol) in acetonitrile (0.7 ml) at room temperature, followed by stirring at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Compound 26 was obtained as a yellow solid (27.2 mg, 0.0828 mmol, 67%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 3.37 (2H, q, J = 5.6 Hz), 3.54 (2H, t, J = 5.6 Hz), 3.73 (2H, t, J = 4.8 Hz), 4.02 (2H, t, J = 4.8 Hz), 6.30-6.37 (3H, m), 6.77 (1H, d, J = 16.0 Hz), 7.03 (1H, t, J = 8.0 Hz), 7.42-7.48 (2H, m), 7.97 (1H, dt, J = 6.0, 2.0 Hz), 8.27 (1H, t, J = 6.0 Hz), 8.55 (1H, dd, J = 4.8, 1.6 Hz), 8.75 (1H, d, J = 2.0 Hz), 9.38 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 20 N2O4Na 351.1321; Found 351.1317. The confirmed structure is:

[0211] Example 30: Preparation of Compound 28 (1) Preparation of Intermediate 43 Intermediate 24 (1.00 g, 3.35 mmol), potassium carbonate (695 mg, 5.03 mmol), and sodium iodide (100 mg, 0.667 mmol) were added to a solution of 3-methoxyphenol (0.400 ml, 3.69 mmol) in dimethylformamide (11 ml) at room temperature, and the mixture was stirred at 80°C 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, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Intermediate 43, represented by the following structural formula, was obtained as a yellow solid (569 mg, 1.67 mmol, 50%). 1H NMR (CDCl3, 400 MHz): δ3.76 (3H, s), 3.80-3.86 (4H, m), 3.93 (2H, t, J = 5.2 Hz), 4.05 (2H, t, J = 4.8 Hz), 6.40-6.49 (3H, m), 7.12 (1H, t, J = 8.0 Hz), 7.67-7.72 (2H, m), 7.80-7.85 (2H, m).

[0212] (2) Preparation of Intermediate 44: Hydrazine monohydrate (0.240 ml, 4.94 mmol) was added to an ethanol solution (17 ml) of Intermediate 43 (569 mg, 1.67 mmol) at room temperature, and the mixture was stirred at 80°C for 4 hours. After filtration through Celite, the reaction mixture was concentrated under reduced pressure. Intermediate 44, represented by the following structural formula, was obtained as a yellow oil (352 mg, 1.67 mmol, 99%). 1 H NMR (DMSO, 400 MHz): δ2.66 (2H, t, J = 5.6 Hz), 3.41 (2H, t, J = 6.0 Hz), 3.70 (2H, t, J = 4.4 Hz), 4.06 (2H, t, J = 4.4 Hz), 6.47-6.54 (2H, m), 7.12-7.28 (2H, m).

[0213] (3) Preparation of Compound 28. To a dichloromethane solution (5 mL) of intermediate 44 (181 mg, 0.857 mmol), trans-3-(3-pyridyl)acrylic acid (255 mg, 1.71 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (328 mg, 1.71 mmol), and dimethylaminopyridine (20.9 mg, 0.171 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain compound 28 as a yellow solid (182 mg, 0.532 mmol, 62%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 3.37 (2H, q, J = 6.0 Hz), 3.55 (2H, t, J = 6.0 Hz), 3.71 (3H, s), 3.74 (2H, t, J = 4.8 Hz), 4.08 (2H, t, J = 4.8 Hz), 6.48-6.54 (3H, m), 6.77 (1H, d, J = 16.0 Hz), 7.16 (1H, t, J = 8.4 Hz), 7.42-7.48 (2H, m), 7.96 (1H, dt, J = 7.6, 2.0 Hz), 8.27 (1H, t, J = 5.6 Hz), 8.55 (1H, dd, J = 4.8, 1.6 Hz), 8.74 (1H, d, J = 2.0 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 22 N2O4Na 365.1477; Found 365.1475. The confirmed structure is:

[0214] Example 31: Preparation of Compound 32 (1) Preparation of Intermediate 45 Intermediate 24 (2.00 g, 6.71 mmol), potassium carbonate (1.39 g, 10.1 mmol), and sodium iodide (201 mg, 1.34 mmol) were added to a dimethylformamide solution (25 ml) of methyl 4-hydroxybenzoate (1.64 g, 10.8 mmol) at room temperature, followed by stirring at 60°C for 24 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain Intermediate 45, represented by the following structural formula, as a yellow solid (3.50 g, 9.48 mmol, 88%). 1 H NMR (CDCl3, 400 MHz): δ 3.80-3.89 (4H, m), 3.88 (3H, s), 3.93 (2H, t, J = 6.0 Hz), 4.09-4.15 (2H, m), 6.83 (2H, d, J = 8.8 Hz), 7.67-7.71 (2H, m), 7.80-7.83 (2H, m), 7.91 (2H, d, J = 8.8 Hz).

[0215] (2) Preparation of Intermediate 46: Hydrazine monohydrate (1.65 ml, 33.9 mmol) was added to a solution of Intermediate 45 (2.50 g, 6.77 mmol) in ethanol (68 ml) at room temperature, and the mixture was stirred at 80 °C for 1 hour. After filtration through Celite, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 1:1, ammonia water:methanol = 10:90) to obtain Intermediate 46 (1.60 g, 6.60 mmol, 99%), which has the following structural formula, as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 2.88 (2H, t, J = 5.2 Hz), 3.57 (2H, t, J = 5.2 Hz), 3.83 (2H, t, J = 4.8 Hz), 3.87 (3H, s), 4.17 (2H, t, J = 4.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.97 (2H, d, J = 8.8 Hz).

[0216] (3) Preparation of Compound 32. Nicotinic acid (823 mg, 6.69 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.28 g, 6.68 mmol), and dimethylaminopyridine (81.6 mg, 0.668 mmol) were added to a solution of intermediate 46 (800 mg, 3.34 mmol) in dimethylformamide (10 mL) at room temperature, followed by stirring at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 32 as a yellow solid (40.0 mg, 0.116 mmol, 3.5%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 3.56 (2H, q, J = 6.0 Hz), 3.72 (2H, t, J = 6.0 Hz), 3.89 (2H, t, J = 4.4 Hz), 3.91 (3H, s), 4.29 (2H, t, J = 4.4 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.59 (1H, dd, J = 8.0, 4.8 Hz), 7.98 (2H, d, J = 8.8 Hz), 8.26 (1H, dt, J = 8.0, 2.0 Hz), 8.79 (1H, dd, J = 4.8, 2.0 Hz), 8.87 (1H, t, J = 4.8 Hz), 9.09 (1H, dd, J = 2.4, 0.8 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 20 N2O5Na 367.1270; Found 367.1263. The confirmed structure is:

[0217] Example 32: Preparation of Compound 31. To a solution of Intermediate 46 (800 mg, 3.34 mmol) in dimethylformamide (10 mL) was added trans-3-(3-pyridyl)acrylic acid (996 mg, 6.68 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.28 g, 6.68 mmol), and dimethylaminopyridine (81.6 mg, 0.668 mmol) at room temperature, followed by stirring at the same temperature for 19 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 93:7) to obtain Compound 31 as a yellow solid (400 mg, 1.08 mmol, 32%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ 3.37 (2H, q, J = 6.0 Hz), 3.56 (2H, t, J = 6.0 Hz), 3.78 (2H, t, J = 4.4 Hz), 3.79 (3H, s), 4.19 (2H, t, J = 4.4 Hz), 6.75 (1H, d, J = 16.0 Hz), 7.05 (2H, d, J = 8.8 Hz), 7.41-7.47 (2H, m), 7.88 (2H, d, J = 8.8 Hz), 7.95 (1H, dt, J = 8.0, 2.0 Hz), 8.27 (1H, t, J = 5.6 Hz), 8.54 (1H, dd, J = 4.8, 1.6 Hz), 8.74 (1H, d, J = 2.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 22 N2O5Na 393.1426; Found 393.1419. The confirmed structure is:

[0218] Example 33: Preparation of Compound 33. To a solution of 3-aminophenol (500 mg, 4.58 mmol) in dichloromethane (10 ml) was added trans-3-(3-pyridyl)acrylic acid (683 mg, 4.58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.63 g, 13.7 mmol), and dimethylaminopyridine (112 mg, 0.916 mmol) at room temperature, followed by stirring at the same temperature for 25 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 92:8) to obtain Compound 33 as a yellow solid (23.1 mg, 0.0961 mmol, 2.1%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CDCl3, 400 MHz): δ 6.64 (1H, d, J = 16.0 Hz), 6.71 (1H, d, J =16.8 Hz), 6.96 (1H, d, J = 6.8 Hz), 7.32-7.43 (4H, m), 7.64-7.95 (6H, m), 8.63 (2H, dd, J = 24.0, 4.0 Hz), 8.81 (2H, d, J = 8.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 17 N3O3Na 394.1168; Found 394.1166. The confirmed structure is:

[0219] Example 34: Preparation of Compound 34. Nicotinoyl chloride hydrochloride (300 mg, 1.69 mmol) and triethylamine (0.376 ml, 2.70 mmol) were added to a dichloromethane solution (3 ml) of 2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-amine) (100 mg, 0.675 mmol) in an ice bath, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Compound 34 was obtained as a yellow solid (129 mg, 0.360 mmol, 53%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ3.64-3.76 (12H, m), 7.46 (2H, dd, J =7.6, 4.8 Hz), 7.71 (2H, br), 8.30 (2H, d, J = 7.6 Hz), 8.71 (2H, d, J = 5.2 Hz), 9.22 (2H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 22 N4O4Na 381.1539; Found 381.1531. The confirmed structure is:

[0220] Example 35: Preparation of Compound 35. Triethylamine (0.32 ml, 2.27 mmol) and nicotinoyl chloride hydrochloride (252 mg, 1.42 mmol) were added to a dichloromethane solution (2 ml) of 3,3'-(ethane-1,2-diylbis(oxy))bis(propan-1-amine) (100 mg, 0.567 mmol) in an ice bath, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Compound 35 was obtained as a yellow solid (18.2 mg, 0.0471 mmol, 8.3%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 1.91 (4H, q, J = 6.0 Hz), 3.61 (4H, q, J = 5.2 Hz), 3.66 (4H, s), 3.70 (4H, t, J = 5.6 Hz), 7.41 (2H, dd, J = 8.0, HRMS (ESI-TOF) m / z: [M + H] + calcd for C 20 H 27 N4O4 387.2032; Found 387.2026. The confirmed structure is:

[0221] Example 36: Preparation of Compound 36. Triethylamine (5.40 ml, 38.8 mmol) and nicotinoyl chloride hydrochloride (3.62 g, 20.4 mmol) were added to a dichloromethane solution (20 ml) of N-(2-aminoethyl)ethane-1,2-diamine (1.00 g, 9.69 mmol) in an ice bath, and the mixture was stirred at the same temperature for 6 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 36 as a yellow solid (74.8 mg, 0.179 mmol, 1.8%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 3.59-3.95 (8H, m), 7.17 (1H, t, J = 6.0 Hz), 7.37-7.48 (3H, m), 7.69 (1H, br), 8.10-8.26 (3H, m), 8.44 (1H, s), 8.57 (1H, d, J = 4.8 Hz), 8.72 (2H, s), 9.15 (2H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 22 N6O3Na 441.1651; Found 441.1645. The confirmed structure is:

[0222] Example 37: Preparation of Compound 37. To a dichloroethane solution (19 ml) of 2,2'-oxybis(ethan-1-amine) (200 mg, 1.92 mmol), trans-3-(3-pyridyl)acrylic acid (604 mg, 4.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.10 g, 5.74 mmol), and dimethylaminopyridine (47.0 mg, 0.385 mmol) were added at room temperature, and the mixture was stirred at 60°C for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 37 as a yellow solid (16.0 mg, 0.0437 mmol, 2.3%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 3.56-3.64 (8H, m), 6.61 (2H, d, J = 16.0 Hz), 7.01 (2H, t, J = 4.8 Hz), 7.23 (2H, dd, J = 8.0, 4.8 Hz), 7.59 (2H, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 22 N4O3Na 389.1590; Found 389.1587. The confirmed structure is:

[0223] Example 38: Preparation of Compound 38. To a solution of hexane-1,6-diamine (100 mg, 0.960 mmol) in dichloroethane (10 ml), trans-3-(3-pyridyl)acrylic acid (286 mg, 1.92 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (552 mg, 2.88 mmol), and dimethylaminopyridine (23.0 mg, 0.188 mmol) were added at room temperature, and the mixture was stirred at 60°C for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 38 as a yellow solid (8.50 mg, 0.0225 mmol, 2.3%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 1.29-1.35 (4H, m), 1.42-1.51 (4H, m), 3.18 (4H, q, J = 6.4 Hz), 6.72 (2H, d, J = 16.4 Hz), 7.41-7.47 (4H, m), 7.97 (2H, dt, J = 8.4, 2.0 Hz), 8.18 (2H, t, J = 5.2 Hz), 8.54 (2H, dd, J = 4.8, 1.6 Hz), 8.74 (2H, d, J = 2.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 26 N4O2Na 401.1953; Found 401.1950. The confirmed structure is:

[0224] Example 39: Preparation of Compound 39. To a solution of propane-1,3-diamine (50.0 mg, 0.674 mmol) in dichloromethane (3 mL), trans-3-(3-pyridyl)acrylic acid (251 mg, 1.69 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (388 mg, 2.02 mmol), and dimethylaminopyridine (16.5 mg, 0.135 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH2-silica gel, chloroform:methanol = 19:1) to obtain Compound 39 as a yellow solid (43.5 mg, 0.129 mmol, 19%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 1.78 (2H, q, J = 6.0 Hz), 3.49 (4H, q, J = 6.0 Hz), 6.54 (2H, d, J = 16.0 Hz), 6.59 (2H, t, J = 6.0 Hz), 7.32 (2H, dd, J = 7.6, 5.2 Hz), 7.65 (2H, d, J = 16.0 Hz), 7.82 (2H, dt, J = 7.6, 2.0 Hz), 8.58 (2H, dd, J = 4.8, 1.6 Hz), 8.76 (2H, d, J = 2.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 20 N4O2Na 359.1484; Found 359.1482. The confirmed structures are:

[0225] Example 40: Preparation of Compound 40. N-nicotinoylglycine (658 mg, 3.65 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (636 mg, 3.32 mmol), and dimethylaminopyridine (40.6 mg, 0.332 mmol) were added to a dichloromethane solution (5 ml) of ethane-1,2-diamine (100 mg, 1.66 mmol) at room temperature, followed by stirring at the same temperature for 1 hour. Water was added to the reaction mixture, which was then concentrated under reduced pressure. The crystals were collected by filtration using a separatory funnel and washed with methanol to give Compound 40 as a yellow solid (257 mg, 0.669 mmol, 40%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 3.15 (4H, t, J = 2.4 Hz), 3.86 (4H, d, J = 6.0 Hz), 7.51 (2H, dd, J = 7.6, 4.4 Hz), 8.05 (2H, br), 8.21 (2H, dt, J = HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 20 N6O4Na 407.1444; Found 407.1444. The confirmed structure is:

[0226] Example 41: Preparation of Compound 41. N-nicotinoylglycine (341 mg, 1.89 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (330 mg, 1.72 mmol), and dimethylaminopyridine (21.0 mg, 0.172 mmol) were added to a dichloromethane solution (4 ml) of hexane-1,6-diamine (100 mg, 0.861 mmol) at room temperature, followed by stirring at the same temperature for 15 hours. Water was added to the reaction mixture, which was then concentrated under reduced pressure. The crystals were collected by filtration using a separatory funnel and washed with methanol to give Compound 41 as a yellow solid (267 mg, 0.607 mmol, 71%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 1.22-1.29 (4H, m), 1.35-1.43 (4H, m), 3.06 (4H, q, J = 6.4 Hz), 3.85 (4H, d, J = 5.6 Hz), 7.52 (2H, dd, J = 8.4, 4.8 Hz), 7.94 (2H, t, J = 5.6 Hz), 8.21 (2H, dt, J = 8.4, 2.0 Hz), 8.71 (2H, dd, J = 4.8, 1.6 Hz), 8.95 (2H, t, J = 6.0 Hz), 9.03 (2H, d, J = 1.2 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 28 N6O4Na 463.2070; Found 463.2067. The confirmed structure is:

[0227] Example 42: Preparation of Compound 42. To a solution of hexane-1,6-diamine (20 mg, 0.172 mmol) in dichloromethane (2 ml), trans-3-pyridyl-2-butenoic acid (70.0 mg, 0.429 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.860 mmol), and dimethylaminopyridine (8.40 mg, 0.0688 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the solid was filtered using a separatory funnel and washed with ethyl acetate to give Compound 42 as a yellow solid (30.5 mg, 0.0750 mmol, 43%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ 1.40-1.46 (4H, m), 1.55-1.63 (4H, m), 2.51 (6H, d, J = 1.6 Hz), 3.29 (4H, q, J = 6.8 Hz), 6.25 (2H, d, J = 1.6 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 24 H 30 N4O2Na 429.2266; Found 429.2262. The confirmed structure is:

[0228] Example 43: Preparation of Compound 43 To a dichloromethane solution (3 ml) of 2,2'-oxybis(ethan-1-amine) (30 mg, 0.288 mmol), trans-3-pyridyl-2-butenoic acid (103 mg, 0.634 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (221 mg, 1.15 mmol), and dimethylaminopyridine (14.1 mg, 0.115 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1). 1,4-Dioxane (1.5 ml) and hydrochloric acid (4 M dioxane solution) were added to the residue, and the crystals were collected by filtration using a separatory funnel and washed with chloroform to give compound 43 as a yellow solid (31.5 mg, 0.0719 mmol, 28%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ 2.57 (6H, s), 3.50 (4H, t, J = 5.6 Hz), 3.63 (4H, t, J = 5.6 Hz), 6.56 (2H, s), 8.12 (2H, dd, J = 8.0, 5.6 Hz), 8.78 (2H, dd, J = 4.4, 0.8 Hz), 8.84 (2H, d, J = 5.6 Hz), 9.03 (2H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 22 H 27 N4O3395.2083; Found 395.2082. The confirmed structures are as follows:

[0229] Example 44: Preparation of Compound 44. Nicotinoyl chloride hydrochloride (1.91 g, 10.7 mmol) and triethylamine (3.59 ml, 25.8 mmol) were added to a dichloromethane solution (30 ml) of lysine methyl ester (1.00 g, 4.29 mmol) in an ice bath, and the mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to obtain Compound 44 as a yellow solid (1.10 g, 2.96 mmol, 69%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ1.43-2.08 (6H, m), 3.46-3.58 (2H, m), 3.80 (3H, s), 4.76-4.84 (1H, m), 6.76 (1H, br), 7.23 (1H, br), 7.36-7.45 (2H, m), 8.16 (2H, t, J = 8.0 Hz), 8.67-8.78 (2H, m), 9.06-9.18 (2H, m); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 22 N4O4Na 393.1539; Found 393.1536. The confirmed structure is:

[0230] Example 45: Preparation of Compound 45. To a methanol solution (1 ml) of compound 44 (152 mg, 0.410 mmol), potassium carbonate (142 mg, 1.03 mmol) was added at room temperature, followed by stirring at 50°C for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Methanol was added to the residue, and the insoluble matter was removed by filtration. The filtrate was concentrated. Compound 45 was obtained as a yellow solid (144 mg, 0.405 mmol, 99%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ 1.50-2.09 (6H, m), 3.42 (2H, t, J = 3.2 Hz), 4.54 (1H, dd, J = 8.8, 4.8 Hz), 7.50-7.56 (2H, m), 8.21 (1H, dt, J = HRMS (ESI-TOF) m / z: [M + H] + calcd for C 18 H 21 N4O4357.1563; Found 357.1559. The confirmed structure is:

[0231] Example 46: Preparation of Compound 46. Aqueous ammonia (1 M, 0.424 ml, 0.424 mmol) was added to a methanol solution (0.8 ml) of compound 44 (157 mg, 0.424 mmol) at room temperature, and the mixture was stirred at the same temperature for 13 hours and then concentrated under reduced pressure. Ethyl acetate was added to the residue, and the crystals were collected by filtration using a separatory funnel to give compound 46 as a yellow solid (43.1 mg, 0.121 mmol, 29%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CD3OD, 400 MHz): δ 1.50-2.03 (6H, m), 3.43 (2H, t, J = 6.4 Hz), 4.57 (1H, dd, J = 8.8, 4.8 Hz), 7.48-7.57 (2H, m), 8.20 (1H, d, J = HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 21 N5O3Na 378.1542; Found 378.1540. The confirmed structure is:

[0232] Example 47: Preparation of Compound 47. Aqueous ethylamine solution (70%, 0.0210 ml, 0.372 mmol) was added to a methanol solution (0.5 ml) of compound 44 (91.9 mg, 0.248 mmol) at room temperature, followed by stirring at 50°C for 3 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the crystals were collected by filtration using a separatory funnel to give compound 47 as a yellow solid (2.20 mg, 0.00597 mmol, 2.4%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ 1.13 (3H, t, J = 7.2 Hz), 1.46-1.98 (6H, m), 3.24 (2H, q, J = 7.2 Hz), 3.43 (2H, t, J = 6.8 Hz), 4.51 (1H, dd, J = 8.8, 5.2 Hz), 7.50-7.55 (2H, m), 8.20 (1H, d, J = 7.6 Hz), 8.27 (1H, d, J = 7.6 Hz), 8.67 (2H, t, J = 5.6 Hz), 8.94 (1H, s), 9.01 (1H, s); HRMS (ESI-TOF) m / z: [M + Na]+ calcd for C 20 H 25 N5O3Na 406.1855; Found 406.1851. The confirmed structure is:

[0233] Example 48: Preparation of Compound 48. Nicotinoyl chloride hydrochloride (2.03 g, 11.4 mmol) and triethylamine (3.81 ml, 27.4 mmol) were added to a dichloromethane solution (25 ml) of methyl 2,5-diaminopentanoate (1.00 g, 4.56 mmol) in an ice bath, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 85:15) to obtain Compound 48 as a yellow solid (1.22 g, 3.43 mmol, 75%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ1.72-2.12 (4H, m), 3.47 (2H, t, J = 6.8 Hz), 3.76 (3H, s), 4.68 (1H, dd, J =9.2, 5.2 Hz), 7.52-7.58 (2H, m), 8.24 (1H, dt, J = 8.4, 2.0 Hz), 8.28 (1H, dt, J = 8.0, 2.0 Hz), 8.66-8.72 (2H, m), 8.97 (1H, s), 9.01 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 20 N4O4Na 379.1382; Found 379.1377. The confirmed structure is:

[0234] Example 49: Preparation of Compound 49. Potassium carbonate (113 mg, 0.817 mmol) was added to a methanol solution (1 ml) of compound 48 (146 mg, 0.409 mmol) at room temperature, followed by stirring at 50°C for 19 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then concentrated under reduced pressure. Methanol was added to the residue, and the insoluble matter was removed by filtration. The filtrate was then concentrated. Compound 49 was obtained as a yellow solid (105 mg, 0.305 mmol, 75%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ 1.73-2.12 (4H, m), 3.44-3.49 (2H, m), 4.56 (1H, dd, J = 8.4, 4.8 Hz), 7.51-7.57 (2H, m), 8.25 (1H, dt, J = 7.6, HRMS (ESI-TOF) m / z: [M + H] + calcd for C 17 H 19 N4O4343.1406; Found 343.1406. The confirmed structure is:

[0235] Example 50: Preparation of Compound 50. Aqueous ammonia (1 M, 0.408 ml, 0.408 mmol) was added to a methanol solution (1 ml) of compound 48 (145 mg, 0.408 mmol) at room temperature, followed by stirring at 50°C for 6 hours and concentration under reduced pressure. Diisopropyl ether and methanol were added to the residue, and the crystals were collected by filtration using a separatory funnel to give compound 50 as a yellow solid (41.1 mg, 0.120 mmol, 30%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CD3OD, 400 MHz): δ 1.71-2.08 (4H, m), 3.42-3.55 (2H, m), 4.60-4.66 (1H, m), 7.52-7.58 (2H, m), 8.24 (1H, dt, J = 8.0, 1.6 Hz), 8.30 (1H, dt, J = 7.6, 2.0 Hz), 8.69 (2H, t, J = 4.8 Hz), 8.97 (1H, s), 9.04 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 17 H 19 N5O3Na 364.1386; Found 364.1386. The confirmed structure is:

[0236] Example 51: Preparation of Compound 51. A solution of compound 48 (188 mg, 0.528 mmol) in tetrahydrofuran and methanol (2 ml / 1 ml) was added to an aqueous solution of ethylamine (70%, 0.170 ml, 2.12 mmol) at room temperature and stirred at the same temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain compound 51 as a yellow solid (45.9 mg, 0.124 mmol, 23%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ1.14 (3H, t, J = 7.2 Hz), 1.68-2.03 (4H, m), 3.25 (2H, q, J = 7.2 Hz), 3.43-3.52 (2H, m), 4.53-4.60 (1H, m), 7.52-7.58 (2H, m), 8.24 (1H, d, J = 6.4 Hz), 8.30 (1H, d, J = 8.0 Hz), 8.65-8.71 (2H, m), 8.97 (1H, s), 9.03 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H23 N5O3Na 392.1699; Found 392.1694. The confirmed structure is:

[0237] [Example 52: Production of compound 52] (1) Production of intermediate 47 A known compound (intermediate 47) represented by the following structural formula was synthesized according to the method described in European Journal of Medicinal Chemistry, 2019, 182, 111588.

[0238] (2) Preparation of Intermediate 48: To a solution of Intermediate 47 (2.50 g, 11.2 mmol) in dimethylformamide (20 ml) was added Intermediate 27 (3.70 g, 12.4 mmol), potassium carbonate (2.30 g, 16.6 mmol), and sodium iodide (336 mg, 62.3 mmol) at room temperature, followed by stirring at 60°C for 18 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 2:1) to obtain Intermediate 48, represented by the following structural formula, as a yellow solid (3.60 g, 8.17 mmol, 73%). 1 H NMR (DMSO, 400 MHz): δ1.38 (9H, s), 3.64-3.80 (6H, m), 3.95-3.99 (2H, m), 6.75 (2H, d, J = 8.4 Hz), 7.07 (2H, d, J = 8.4 Hz), 7.79-7.88 (4H, m).

[0239] (3) Preparation of Intermediate 49: Trifluoroacetic acid (10 ml) was added to a dichloromethane solution (20 ml) of Intermediate 48 (3.60 g, 8.77 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then chloroform and saturated aqueous sodium bicarbonate solution were added, followed by stirring at room temperature for 1 hour. After separation, the separated organic layer was concentrated under reduced pressure to obtain Intermediate 49 (2.72 g, 8.77 mmol, 99%), which has the following structural formula, as a yellow oil.1 H NMR (DMSO, 400 MHz): δ2.05 (2H, q, J = 6.0 Hz), 3.76 (2H, t, J = 6.8 Hz), 3.90-4.04 (4H, m), 6.82 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.82-7.87 (4H, m).

[0240] (4) Preparation of Intermediate 50: To a dichloromethane solution (10 ml) of Intermediate 49 (300 mg, 0.967 mmol), triethylamine (0.297 ml, 2.13 mmol) and nicotinoyl chloride hydrochloride (206 mg, 1.16 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 8:2) to obtain Intermediate 50, represented by the following structural formula, as a yellow solid (401 mg, 0.965 mmol, 99%). 1 H NMR (DMSO, 400 MHz): δ 2.04 (2H, q, J = 6.4 Hz), 3.75 (2H, t, J = 6.4 Hz), 3.98 (2H, t, J = 6.4 Hz), 4.40 (2H, d, J = 6.0 Hz), 6.75 (2H, d, J = 8.8 Hz), 7.20 (2H, d, J = 8.8 Hz), 7.48-7.52 (1H, m), 7.81-7.87 (4H, m), 8.21 (1H, dt, J = 7.6, 2.0 Hz), 8.70 (1H, dd, J = 5.2, 1.6 Hz), 9.03 (1H, d, J = 2.0 Hz), 9.16 (1H, t, J = 5.6 Hz).

[0241] (5) Preparation of Intermediate 51 Hydrazine monohydrate (0.235 ml, 4.83 mmol) was added to an ethanol solution (10 ml) of Intermediate 50 (401 mg, 0.965 mmol) at room temperature, and the mixture was stirred at 80° C. for 22 hours. The reaction mixture was concentrated under reduced pressure to obtain Intermediate 51 (275 mg, 0.964 mmol, 99%), which is represented by the following structural formula, as a yellow oil. 1 H NMR (DMSO, 400 MHz): δ 1.93-2.02 (2H, m), 3.40-3.44 (2H, m), 4,00-4.40 (2H, m), 4.42 (2H, d, J = 6.0 Hz), 6.90 (2H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.48-7.52 (1H, m), 8.19-8.23 (1H, m), 8.68-8.71 (1H, m), 9.03 (1H, d, J = 2.0 Hz), 9.20 (1H, t, J = 6.0 Hz).

[0242] (6) Preparation of Compound 52. Nicotinoyl chloride hydrochloride (68.6 mg, 0.385 mmol) and triethylamine (0.970 mL, 6.96 mmol) were added to a dichloromethane solution (3 mL) of intermediate 51 (100 mg, 0.350 mmol) in an ice bath, and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain compound 52 as a yellow solid (13.9 mg, 0.0356 mmol, 10%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CDCl3, 400 MHz): δ 2.13-2.18 (2H, m), 3.69-3.76 (2H, m), 4.12-4.16 (2H, m), 4.80 (2H, s), 6.87 (2H, d, J = 8.8 Hz), 7.31 (2H, d, J = 8.8 Hz), 7.40-7.48 (2H, m), 7.91 (1H, d, J = 7.6 Hz), 8.15-8.23 (1H, m), 8.39 (1H, d, J = 8.0 Hz), 8.64 (1H, d, J = 3.2 Hz), 8.72-8.84 (3H, m), 9.30 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 22 N4O3Na 413.1590; Found 413.1584. The confirmed structure is:

[0243] Example 53: Preparation of Compound 53. To a dichloromethane solution (3 mL) of Intermediate 51 (100 mg, 0.350 mmol), trans-3-(3-pyridyl)acrylic acid (104 mg, 0.697 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (134 mg, 0.699 mmol), and dimethylaminopyridine (8.60 mg, 0.0704 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 13 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 53 as a yellow solid (7.80 mg, 0.0187 mmol, 5.3%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CDCl3, 400 MHz): δ 2.02 (2H, q, J = 6.0 Hz), 3.54 (2H, q, J = 6.0 Hz), 3.98 (2H, t, J = 6.0 Hz), 4.52 (2H, d, J = 5.6 Hz), 6.47 (1H, d, J = 15.2 Hz), 6.78 (2H, d, J = 8.0 Hz), 6.89 (1H, t, J = 7.2 Hz), 7.17-7.36 (4H, m), 7.48 (1H, d, J = 15.2 Hz), 7.48-7.53 (1H, m), 7.70 (1H, d, J = 8.4 Hz), 8.16 (1H, d, J = 8.0 Hz), 8.48 (1H, s), 8.54 (1H, s), 8.65 (1H, s), 9.00 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 24 H 24 N4O3Na 439.1746; Found 439.1744. The confirmed structure is:

[0244] Example 54: Preparation of compound 54 (1) Preparation of intermediate 52 A known compound (intermediate 52) represented by the following structural formula was synthesized according to the method described in DE2320387 A1.

[0245] (2) Preparation of Intermediate 53: Intermediate 24 (718 mg, 2.41 mmol), potassium carbonate (454 mg, 3.29 mmol), and sodium iodide (65.7 mg, 0.438 mmol) were added to a dimethylformamide solution (20 ml) of intermediate 52 (500 mg, 2.19 mmol) at room temperature, followed by stirring at the same temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 95:5) to obtain intermediate 53, represented by the following structural formula, as a yellow solid (200 mg, 0.449 mmol, 21%).1 H NMR (CDCl3, 400 MHz): δ 3.78-3.86 (4H, m), 3.91 (2H, t, J = 5.6 Hz), 4.05 (2H, t, J = 4.8 Hz), 4.57 (2H, d, J = 5.6 Hz), 6.81 (2H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 7.6, 4.8 Hz), 7.68-7.71 (2H, m), 7.80-7.83 (2H, m), 8.32 (1H, d, J = 8.0 Hz), 8.70 (1H, d, J = 3.6 Hz), 9.19 (1H, s).

[0246] (3) Preparation of Intermediate 54 Hydrazine monohydrate (0.110 ml, 2.26 mmol) was added to an ethanol solution (4 ml) of Intermediate 53 (200 mg, 0.449 mmol) at room temperature, and the mixture was stirred at 80° C. for 5 hours. After filtration through Celite, the reaction mixture was concentrated under reduced pressure to obtain Intermediate 54 (141 mg, 0.447 mmol, 99%), which is represented by the following structural formula, as a yellow oil. 1 H NMR (CDCl3, 400 MHz): δ 2.87-2.91 (2H, m), 3.57 (2H, t, J = 4.8 Hz), 3.81 (2H, t, J = 4.8 Hz), 4.12 (2H, t, J = 4.8 Hz), 4.57 (2H, d, J = 5.2 Hz), 6.76 (1H, br), 6.89 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.37 (1H, dd, J = 8.0, 4.8 Hz), 8.14 (1H, dt, J = 7.6, 2.0 Hz), 8.69 (1H, dd, J = 4.8, 2.4 Hz), 8.98 (1H, d, J = 1.6 Hz).

[0247] (4) Preparation of Compound 54. Nicotinic acid (117 mg, 0.950 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (242 mg, 1.26 mmol), and dimethylaminopyridine (15.4 mg, 0.126 mmol) were added to a dichloromethane solution (6 mL) of intermediate 54 (200 mg, 0.634 mmol) at room temperature, followed by stirring at the same temperature for 21 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 85:15) to obtain compound 54 as a yellow solid (10.3 mg, 0.0245 mmol, 3.9%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 3.65-3.75 (4H, m), 3.83-3.87 (2H, m), 4.17-4.20 (2H, m), 4.59 (2H, d, J = 5.6 Hz), 6.65 (1H, br), 6.89 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.33-7.41 (2H, m), 7.79 (1H, br), 8.15 (1H, d, J = 6.4 Hz), 8.22 (1H, d, J = 6.0 Hz), 8.46 (1H, s), 8.54 (1H, d, J = 3.6 Hz), 8.70 (1H, d, J = 3.6 Hz), 9.10 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 24 N4O4Na 443.1695; Found 443.1692. The confirmed structure is:

[0248] Example 55: Preparation of Compound 55. To a dichloromethane solution (2 mL) of Intermediate 54 (50 mg, 0.159 mmol), trans-3-(3-pyridyl)acrylic acid (28.0 mg, 0.188 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.9 mg, 0.318 mmol), and dimethylaminopyridine (3.90 mg, 0.0319 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 89:11) to obtain Compound 55 as a yellow solid (9.40 mg, 0.0187 mmol, 2.1%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 3.58 (2H, q, J = 5.2 Hz), 3.76 (2H, t, J = 4.8 Hz), 3.91 (2H, t, J = 4.0 Hz), 4.13 (2H, t, J = 4.4 Hz), 4.64 (2H, d, J = 6.0 Hz), 6.06 (1H, d, J = 16.0 Hz), 6.55 (1H, br), 6.97 (2H, d, J = 8.4 Hz), 7.28-7.43 (5H, m), 7.67 (1H, d, J = 8.0 Hz), 7.97 (1H, s), 8.25 (1H, dt, J = 7.6, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 25 H 26 N4O4Na 469.1852; Found 469.1847. The confirmed structure is:

[0249] Example 56: Preparation of Compound 56. To a dichloromethane solution (2 mL) of Intermediate 54 (50 mg, 0.159 mmol), trans-3-pyridyl-2-butenoic acid (31.1 mg, 0.191 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.9 mg, 0.318 mmol), and dimethylaminopyridine (3.90 mg, 0.0319 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 23 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 88:12) to obtain Compound 56 as a yellow solid (24.5 mg, 0.0532 mmol, 33%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 2.48 (3H, s), 3.55 (2H, q, J = 5.2 Hz), 3.75 (2H, t, J = 5.2 Hz), 3.88 (2H, t, J = 4.0 Hz), 4.13 (2H, t, J = 4.0 Hz), 4.60 (2H, d, J = 6.0 Hz), 5.75 (1H, s), 6.35 (1H, br), 6.92 (2H, d, J = 8.8 Hz), 7.26-7.39 (5H, m), 7.72 (1H, dt, J = 8.0, 2.0 Hz), 8.03 (1H, d, J = 1.6 Hz), 8.24 (1H, dt, J = 8.4, 2.0 Hz), 8.49 (1H, br), 8.69 (1H, dd, J = 4.4, 1.6 Hz), 9.10 (1H, d, J = 1.6 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 26 H 28 N4O4Na 483.2008; Found 483.2003. The confirmed structure is:

[0250] Example 57: Preparation of compound 57 (1) Preparation of intermediate 55 A known compound (intermediate 55) represented by the following structural formula was synthesized according to the method described in Journal of Inorganic Biochemistry, 2015, 148, 2-10.

[0251] (2) Preparation of Compound 57: To a solution of intermediate 55 (120 mg, 0.542 mmol) in dimethylformamide (5 mL) was added 5-hydroxynicotinic acid (90.5 mg, 0.651 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (208 mg, 1.08 mmol), and dimethylaminopyridine (13.2 mg, 0.108 mmol) at room temperature, followed by stirring at the same temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain compound 57 as a yellow solid (5.6 mg, 0.0164 mmol, 1.6%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 1.43-1.49 (4H, m), 1.61-1.71 (4H, m), 3.34-3.43 (4H, m), 7.42 (1H, t, J = 2.0 Hz), 7.54 (1H, dd, J = 8.0, 4.8 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 22 N4O3Na 365.1590; Found 365.1584. The confirmed structure is:

[0252] Example 58: Preparation of Compound 58. To a solution of benzene-1,4-diamine (100 mg, 0.925 mmol) in dichloromethane (3 mL), trans-3-(3-pyridyl)acrylic acid (290 mg, 1.94 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (709 mg, 3.70 mmol), and dimethylaminopyridine (45.2 mg, 0.370 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then methanol was added to the residue. The crystals were collected by filtration using a separatory funnel to give Compound 58 as a yellow solid (155 mg, 0.418 mmol, 45%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 6.93 (2H, d, J = 16.0 Hz), 7.45-7.52 (2H, m), 7.62 (2H, d, J = 16.0 Hz), 7.69 (4H, s), 8.04 (2H, d, J = 6.8 Hz), 8.57-8.60 (2H, m), 8.82 (2H, s); HRMS (ESI-TOF) m / z: [M - H] - calcd for C 22 H 17 N4O2369.1352; Found 369.1364. The confirmed structures are:

[0253] Example 59: Preparation of Compound 59. To a chloroform solution (3 mL) of pyridine-2,6-diamine (80.0 mg, 0.733 mmol), trans-3-(3-pyridyl)acrylic acid (219 mg, 1.47 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (422 mg, 2.20 mmol), and dimethylaminopyridine (18.0 mg, 0.147 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 59 as a yellow solid (8.10 mg, 0.0218 mmol, 2.9%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 5.51 (2H, d, J = 8.0 Hz), 6.16 (2H, d, J = 14.8 Hz), 6.57-6.72 (5H, m), 6.88 (2H, d, J = 16.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.73 (2H, s), 7.96 (2H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 21 H 17 N5O2Na 394.1280; Found 394.1279. The confirmed structure is:

[0254] Example 60: Preparation of Compound 60. To a dichloromethane solution (10 ml) of 2-(aminomethyl)aniline (120 mg, 0.982 mmol), trans-3-(3-pyridyl)acrylic acid (310 mg, 2.08 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (565 mg, 2.95 mmol), and dimethylaminopyridine (23.9 mg, 0.196 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 15 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 89:11) to obtain Compound 60 as a yellow solid (29.6 mg, 0.0770 mmol, 7.8%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 4.46 (2H, d, J = 6.0 Hz), 6.81 (1H, d, J = 16.0 Hz), 7.04 (1H, d, J = 16.0 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.28-7.35 (2H, m), 7.44 (1H, dd, J = 8.0, 4.8 Hz), 7.50 (1H, dd, J = 8.0, 4.8 Hz), 7.56 (1H, d, J = 16.0 Hz), 7.66 (1H, d, J = 16.0 Hz), 7.79 (1H, d, J = 3.6 Hz), 7.99 (1H, d, J = 7.6 Hz), 8.09 (1H, d, J = 7.6 Hz), 8.55 (1H, dd, J = 4.8, 1.6 Hz), 8.60 (1H, dd, J = 4.8, 1.6 Hz), 8.75 (1H, d, J = 2.4 Hz), 8.83-8.90 (2H, m); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 20N4O2Na 407.1484; Found 407.1480. The confirmed structure is:

[0255] Example 61: Preparation of Compound 61. To a solution of 3-(aminomethyl)aniline (150 mg, 1.23 mmol) in dichloromethane (12 ml), trans-3-(3-pyridyl)acrylic acid (385 mg, 2.58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (495 mg, 2.58 mmol), and dimethylaminopyridine (30.1 mg, 0.246 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 23 hours. The reaction mixture was concentrated under reduced pressure. Chloroform was added to the residue, and the crystals were collected by filtration using a separatory funnel to give Compound 61 as a yellow solid (24.3 mg, 0.0632 mmol, 5.1%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 4.41 (2H, d, J = 5.6 Hz), 6.82 (1H, d, J = 16.0 Hz), 6.93 (1H, d, J = 16.0 Hz), 7.02 (1H, d, J = 8.0 Hz), 7.31 (1H, t, J = 8.0 Hz), 7.43-7.69 (7H, m), 7.98-8.04 (2H, m), 8.55-8.59 (2H, m), 8.74 (1H, t, J = 6.0 Hz), 8.78 (1H, d, J = 2.4 Hz), 8.81 (1H, d, J = 2.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 20 N4O2Na 407.1484; Found 407.1482. The confirmed structures are:

[0256] Example 62: Preparation of compound 63 (1) Preparation of intermediate 56 A known compound (intermediate 56) represented by the following structural formula was synthesized according to the method described in EP556738A1.

[0257] (2) Preparation of Compound 63. To a solution of intermediate 56 (202 mg, 1.13 mmol) in dichloromethane (3 mL) was added nosyl chloride (250 mg, 1.13 mmol) and triethylamine (0.189 mL, 1.36 mmol) at room temperature, followed by stirring at the same temperature for 17 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 92:8) to obtain Compound 63 as a yellow solid (390 mg, 1.07 mmol, 94%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ1.83-1.95 (2H, m), 3.22-3.29 (2H, m), 3.61-3.70 (2H, m), 6.31 (1H, br), 7.60-7.76 (4H, m), 7.84 (1H, d, J = 9.2 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 15 H 16 N4O5Na 387.0739; Found 387.0736. The confirmed structure is:

[0258] Example 63: Preparation of Compound 68. To a solution of Intermediate 55 (35 mg, 0.158 mmol) in dichloromethane (2 ml), 4-(3-butyn-1-yloxy)benzoic acid (30.0 mg, 0.158 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61.3 mg, 0.320 mmol), and dimethylaminopyridine (19.5 mg, 0.160 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 6 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Compound 68 was obtained as a yellow solid (11.0 mg, 0.0280 mmol, 18%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 1.40-1.54 (4H, m), 1.59-1.72 (4H, m), 2.05 (1H, t, J = 2.8 Hz), 2.70 (2H, dt, J =6.8, 2.8 Hz), 3.44-3.53 (4H, m), 4.12 (2H, t, J = 7.2 Hz), 6.35 (1H, br), 6.91 (2H, d, J = 8.4 Hz), 7.64 (1H, dd, J = 8.0, 4.8 Hz), 7.72-7.76 (3H, m), 8.58 (1H, d, J = 7.6 Hz), 8.72 (1H, d, J = 4.0 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 27 N3O3Na 416.1950; Found 416.1945. The confirmed structure is:

[0259] Example 64: Preparation of Compound 69. To a dichloroethane solution (5 mL) of 3,3'-(ethane-1,2-diylbis(oxy))bis(propan-1-amine) (118 mg, 0.669 mmol), trans-3-(3-pyridyl)acrylic acid (200 mg, 1.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (255 mg, 1.33 mmol), and dimethylaminopyridine (163 mg, 1.33 mmol) were added at 60°C, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 7:3) to give Compound 69 as a yellow oil (100 mg, 0.228 mmol, 34%). The results of the NMR measurement spectrum and mass analysis by HR-ESI-MS are as follows. 1 H NMR (DMSO, 400 MHz): δ 3.20-3.26 (4H, m), 3.42-3.47 (10H, m), 6.71 (2H, d, J = 16.0 Hz), 7.40-7.46 (4H, m), 7.97 (2H, d, J = 6.4 Hz), 8.21 (2H, t, J = 5.6 Hz), 8.53 (2H, d, J = 8.8 Hz), 8.74 (2H, d, J = 2.0 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 24 H 30 N4O4Na 461.2165; Found 461.2164. The confirmed structure is:

[0260] Example 65: Preparation of Compound 70. Di-t-butyl dicarbonate (1.00 g, 4.58 mmol) was added to a chloroform solution (40 ml) of 3,3'-(ethane-1,2-diylbis(oxy))bis(propan-1-amine) (2.47 ml, 13.7 mmol), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure (quantitative). Nicotinic acid (100 mg, 0.814 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (312 mg, 1.63 mmol), and dimethylaminopyridine (13.0 mg, 0.109 mmol) were added to a dichloromethane solution (4 ml) of the crude (150 mg, 0.543 mmol) at room temperature, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain compound 70 as a yellow oil (207 mg, 0.543 mmol, 99%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ1.43 (9H, s), 1.68-1.77 (2H, m), 1.89-1.98 (2H, m), 3.15-3.21 (2H, m), 3.52-3.73 (10H, m), 5.69 (1H, s), 7.40 (1H, s), 7.55 (1H, s), 8.23 ​​(1H, d, J = 7.6 Hz), 8.75 (1H, br), 8.99 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 31 N3O5Na 404.2161; Found 404.2156. The confirmed structure is:

[0261] Example 66: Preparation of Compound 71. Di-t-butyl dicarbonate (1.00 g, 4.58 mmol) was added to a chloroform solution (40 ml) of 2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-amine) (3.36 ml, 22.9 mmol), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure (quantitative). Nicotinic acid (316 mg, 2.57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (985 mg, 5.14 mmol), and dimethylaminopyridine (62.8 mg, 0.514 mmol) were added to a dichloromethane solution (5 ml) of the crude product (637 mg, 2.57 mmol) at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain compound 71 as a yellow oil (908 mg, 2.57 mmol, 99%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 1.62 (9H, s), 3.25-3.35 (2H, m), 3.54-3.71 (10H, m), 6.95 (1H, s), 7.37-7.43 (1H, m), 8.15 (1H, d, J = 8.4 Hz), 8.73 (1H, br), 9.04 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 17 H 27 N3O5Na 376.1848; Found 376.1842. The confirmed structure is:

[0262] Example 67: Preparation of Compound 62. To a solution of 4-(aminomethyl)aniline (300 mg, 2.46 mmol) in dichloromethane (3 mL), trans-3-(3-pyridyl)-acrylic acid (771 mg, 5.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.18 g, 6.16 mmol), and dimethylaminopyridine (60.1 mg, 0.492 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 15 hours. Water was added to the reaction mixture, and the resulting solid was filtered using a separatory funnel. After washing with water and methanol, Compound 62 was obtained as a yellow solid (19.5 mg, 0.0507 mmol, 2.1%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 4.37 (2H, d, J = 6.0 Hz), 6.80 (1H, d, J = 16.0 Hz), 6.92 (1H, d, J = 15.6 Hz), 7.28 (2H, d, J = 8.8 Hz), 7.42-7.50 (2H, m), 7.51 (1H, d, J = 16.0 Hz), 7.52 (1H, d, J = 15.6 Hz), 7.67 (2H, d, J = 8.8 Hz), 8.01 (2H, ddt, J = 16.8, 8.0, 2.0 Hz), 8.57 (1H, ddd, J = 11.6, 4.8, 1.6 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 20 N4O2Na 407.1484; Found 407.1480. The confirmed structure is:

[0263] Example 68: Preparation of compound 64 (1) Preparation of intermediate 63 A known compound (intermediate 63) represented by the following structural formula was synthesized according to the method described in Molecules, 2023, 28(1), 5.

[0264] (2) Preparation of Compound 64. To a dichloromethane solution (5 mL) of Intermediate 63 (180 mg, 0.533 mmol), trans-3-(3-pyridyl)-acrylic acid (131 mg, 0.878 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (305 mg, 1.59 mmol), and dimethylaminopyridine (19.4 mg, 0.159 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then chloroform was added. The resulting solid was filtered using a separatory funnel to give Compound 64 as a yellow solid (22.8 mg, 0.0638 mmol, 12%). The NMR spectrum and HR-ESI-MS mass analysis results are as follows: 1 H NMR (DMSO, 400 MHz): δ 4.45 (2H, d, J = 6.0 Hz), 6.92 (1H, d, J = 16.0 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.42-7.56 (4H, m), 7.61 (1H, d, J = 16.0 Hz), 7.66 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 7.2 Hz), 8.03 (1H, dt, J = 8.4, 2.0 Hz), 8.58 (1H, dd, J = 4.8, 1.6 Hz), 8.81 (1H, d, J = 1.6 Hz), 9.03 (1H, t-like, J = 2.0 Hz), 10.28 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 19 N3O2Na 380.1375; Found 380.1371. The confirmed structures are:

[0265] [Example 69: Preparation of compound 65] (1) Preparation of intermediate 64 A known compound (intermediate 64) represented by the following structural formula was synthesized according to the method described in European Journal of Medicinal Chemistry, 2020, 185, 111823.

[0266] (2) Preparation of Compound 65. Phenylpropionic acid (312 mg, 2.08 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (598 mg, 3.12 mmol), and dimethylaminopyridine (25.0 mg, 0.205 mmol) were added to a dichloromethane solution (5 mL) of intermediate 64 (250 mg, 1.04 mmol) at room temperature, followed by stirring at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to obtain compound 65 as a yellow solid (30.5 mg, 0.0817 mmol, 7.9%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ 2.53 (2H, t, J = 7.6 Hz), 2.92 (2H, t, J = 7.6 Hz), 4.30 (2H, s), 4.56 (2H, s), 7.07-7.30 (9H, m), 7.55 (1H, dd, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 23 N3O2Na 396.1688; Found 396.1682. The confirmed structure is:

[0267] Example 70: Preparation of Compound 66. To a dichloromethane solution (5 ml) of intermediate 64 (270 mg, 1.12 mmol), cinnamic acid (332 mg, 2.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (644 mg, 3.36 mmol), and dimethylaminopyridine (27.4 mg, 0.224 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain compound 66 as a yellow solid (9.00 mg, 0.0242 mmol, 2.2%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ4.49 (2H, s), 4.58 (2H, s), 6.65 (1H, d, J = 16.0 Hz), 7.30-7.42 (7H, m), 7.50-7.59 (4H, m), 8.26 (1H, dt, J = HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 21 N3O2Na 394.1531; Found 394.1527. The confirmed structure is:

[0268] Example 71: Preparation of Compound 67 (1) Preparation of Intermediate 62. Triethylamine (0.76 ml, 5.41 mmol) and nicotinoyl chloride hydrochloride (394 mg, 2.21 mmol) were added to a dichloromethane solution (25 ml) of 4-(aminomethyl)aniline (300 mg, 2.46 mmol) in an ice bath, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the insoluble matter was removed by filtration. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 94:6) to obtain Intermediate 62 (300 mg, 1.32 mmol, 54%), which has the following structural formula, as a yellow oil. HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 13 H 13 N3ONa 250.0951; Found 250.0956.

[0269] (2) Preparation of Intermediate 65. 5-Hydroxynicotinic acid (67.3 mg, 0.484 mmol) and N,N'-dicyclohexylcarbodiimide (182 mg, 0.882 mmol) were added to a dichloromethane solution (3 ml) of Intermediate 62 (100 mg, 0.440 mmol) at room temperature, and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 90:10) to obtain Intermediate 65 as a yellow solid (153 mg, 0.439 mmol, 99%). HRMS (ESI-TOF) m / z: [M - H] - calcd for C 19 H 15 N4O3347.1144; Found 347.1138.

[0270] (3) Preparation of Compound 67. To a solution of intermediate 65 (10.0 mg, 0.0287 mmol) in acetone (2 ml), propargyl bromide (4.10 mg, 0.0345 mmol) and potassium carbonate (4.80 mg, 0.0347 mmol) were added at room temperature, and the mixture was stirred at 50°C 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, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Chloroform was added, and the resulting solid was filtered using a separatory funnel to obtain compound 67 as a yellow solid (9.00 mg, 0.0233 mmol, 81%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ3.69 (1H, t, J = 2.4 Hz), 4.49 (2H, d, J = 6.0 Hz), 5.00 (2H, d, J = 2.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.53 (1H, dd, J = 8.0, 4.8 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.90 (1H, t, J = 2.4 Hz), 8.24 (1H, dt, J = 8.4, 2.0 Hz), 8.52 (1H, d, J = 2.8 Hz), 8.72 (1H, dd, J = 4.8, 1.2 Hz), 8.76 (1H, d, J = 1.6 Hz), 9.06 (1H, d, J = 2.0 Hz), 9.25 (1H, t-like, J = 5.6 Hz), 10.42 (1H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 22 H 19 N4O3387.1457; Found 387.1452. The confirmed structures are:

[0271] Example 72: Preparation of Compound 72 (1) Preparation of Intermediate 57. Triethylamine (0.710 ml, 5.04 mmol), dimethylaminopyridine (61.5 mg, 0.505 mmol), and di-t-butyl dicarbonate (1.38 g, 6.30 mmol) were added to a dichloromethane solution (3 ml) of 6-aminonicotinonitrile (300 mg, 2.52 mmol) at room temperature, and the mixture was stirred at the same temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to obtain Intermediate 57 (747 mg, 2.34 mmol, 93%), which has the following structural formula, as white crystals. HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 16 H 21 N3O4Na 342.1424; Found 342.1426.

[0272] (2) Preparation of Intermediate 58. Nickel chloride hexahydrate (7.02 g, 29.5 mmol) and sodium borohydride (3.35 g, 88.6 mmol) were added to a methanol solution (100 ml) of intermediate 57 (9.43 g, 29.5 mmol) in an ice bath and stirred at the same temperature for 1 hour. Triethylamine (8.30 ml, 59.1 mmol), nicotinoyl chloride hydrochloride (10.5 g, 59.1 mmol), and dichloromethane (100 ml) were added and stirred at the same temperature for an additional 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to obtain intermediate 58, represented by the following structural formula, as a yellow oil (4.37 g, 10.2 mmol, 34%). HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 28 N4O5Na 451.1952; Found 451.1957.

[0273] (3) Preparation of Intermediate 59: To a solution of Intermediate 58 (150 mg, 0.340 mmol) in dichloromethane (3 ml), hydrochloric acid (4 M dioxane solution, 1.70 ml, 6.80 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give Intermediate 59 (114 mg, 0.340 mmol, 99%), which has the following structural formula, as a yellow solid. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 12 H 13 N4O 229.1084; Found 229.1089.

[0274] (4) Preparation of Compound 72. To a dichloromethane solution (2 ml) of intermediate 59 (50.0 mg, 0.148 mmol), isobutyryl chloride (0.0180 ml, 0.172 mmol) and triethylamine (0.310 ml, 2.22 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain Compound 72 as a yellow solid (18.4 mg, 0.0617 mmol, 42%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ1.23 (6H, d, J = 6.4 Hz), 2.55 (1H, q, J = 6.4 Hz), 4.59 (2H, d, J = 5.2 Hz), 7.14 (1H, s), 7.37 (1H, s), 7.67 (1H, d, J = 8.0 Hz), 8.04-8.24 (4H, m), 8.69 (1H, br), 9.00 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 16 H 18N4O2Na 321.1322; Found 321.1327. The confirmed structures are:

[0275] Example 73: Preparation of Compound 73. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 4-cyanobenzoic acid (26.2 mg, 0.178 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.379 mmol), and dimethylaminopyridine (3.60 mg, 0.0296 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 73 as a yellow solid (16.0 mg, 0.0448 mmol, 30%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 4.51 (2H, d, J = 6.0 Hz), 7.52 (1H, dd, J = 7.6, 5.2 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.99 (2H, d, J = 8.0 Hz), 8.12-8.17 (3H, m), 8.22 (1H, d, J = 8.0 Hz), 8.39 (1H, s), 8.72 (1H, J = 4.8 Hz), 9.04 (1H, s), 9.28 (1H, t-like, J = 5.2 Hz), 11.13 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 15 N5O2Na 380.1123; Found 380.1115. The confirmed structure is:

[0276] Example 74: Preparation of Compound 74. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), cinnamic acid (33.8 mg, 0.228 mmol), N,N-diisopropylethylamine (0.330 ml, 1.92 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0377 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to give compound 74 as a yellow solid (25.1 mg, 0.0700 mmol, 37%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ4.48 (2H, d, J = 5.6 Hz), 7.04 (1H, d, J = 16.0 Hz), 7.39-7.71 (7H, m), 7.79 (1H, d, J = 8.4 Hz), 8.19-8.24 (2H, m), 8.33 (1H, d, J = 8.0 Hz), 8.72 (1H, d, J = 4.8 Hz), 9.04 (1H, s), 9.24 (1H, t-like, J = 6.0 Hz), 10.72 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 21 H 18 N4O2Na 381.1327; Found 381.1321. The confirmed structure is:

[0277] Example 75: Preparation of Compound 75 To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), trans-3-(3-pyridyl)acrylic acid (34.3 mg, 0.230 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.379 mmol), and dimethylaminopyridine (3.60 mg, 0.0296 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 4:1) to give compound 75 as a yellow solid (12.0 mg, 0.0334 mmol, 23%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ4.48 (2H, d, J = 6.0 Hz), 7.14 (1H, d, J = 15.6 Hz), 7.46-7.54 (2H, m), 7.67 (1H, d, J = 15.6 Hz), 7.80 (1H, dd, J = 8.4, 2.0 Hz), 8.00 (1H, d, J = 7.6 Hz), 8.18-8.25 (2H, m), 8.34 (1H, d, J = 1.6 Hz), 8.59 (1H, d, J = 4.0 Hz), 8.72 (1H, d, J = 4.0 Hz), 8.81 (1H, s), 9.05 (1H, s), 9.29 (1H, t-like, J = 5.6 Hz), 10.79 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 17 N5O2Na 382.1280; Found 382.1274. The confirmed structure is:

[0278] Example 76: Preparation of Compound 76. Pivaloyl chloride (0.0300 ml, 0.246 mmol) and triethylamine (0.260 ml, 1.88 mmol) were added to a dichloromethane solution (2 ml) of intermediate 59 (50.0 mg, 0.148 mmol) at room temperature, followed by stirring at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 76 as a yellow solid (40.9 mg, 0.131 mmol, 89%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ1.22 (9H, s), 4.46 (2H, d, J = 5.2 Hz), 7.52 (1H, dd, J = 8.0, 5.2 Hz), 7.74 (1H, d, J = 8.8 Hz), 8.00 (1H, d, J = HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 17 H 20 N4O2Na 335.1484; Found 335.1479. The confirmed structure is:

[0279] Example 77: Preparation of Compound 77 (1) Preparation of Intermediate 60 To a methanol solution (2 ml) of Intermediate 57 (200 mg, 0.626 mmol), nickel chloride hexahydrate (149 mg, 0.626 mmol) and sodium borohydride (71.1 mg, 1.88 mmol) were added in an ice bath, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. To a dichloromethane solution (2 ml) of the residue, triethylamine (0.260 ml, 1.87 mmol) and nicotinoyl chloride hydrochloride (270 mg, 1.52 mmol) were added at room temperature, and the mixture was further stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain Intermediate 60 represented by the following structural formula as a yellow oil (160 mg, 0.352 mmol, 56%). 1 H NMR (DMSO, 400 MHz): δ1.46 (18H, s), 4.35 (2H, d, J = 5.6 Hz), 6.76 (1H, d, J = 16.0 Hz), 7.42-7.53 (2H, m), 7.65 (1H, d, J = 8.4 Hz), 7.75 (1H, d, J = 8.8 Hz), 7.99 (1H, d, J = 6.0 Hz), 8.18 (1H, s), 8.55 (1H, s), 8.67 (1H, s), 8.76 (1H, br).

[0280] (2) Preparation of Intermediate 61: To a dichloromethane solution (3 ml) of Intermediate 60 (160 mg, 0.352 mmol), hydrochloric acid (4 M dioxane solution, 1.80 ml, 7.20 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain Intermediate 61 (128 mg, 0.352 mmol, 99%), which has the following structural formula, as a yellow solid. 1H NMR (DMSO, 400 MHz): δ4.29 (2H, d, J = 5.2 Hz), 6.85 (1H, d, J = 16.0 Hz), 7.00 (1H, d, J = 9.2 Hz), 7.55 (1H, d, J = 16.0 Hz), 7.69 (1H, br), 7.85-7.91 (2H, m), 8.05 (2H, br), 8.26 (1H, br), 8.68 (1H, br), 8.80-8.93 (2H, m).

[0281] (3) Preparation of Compound 77. To a dichloromethane solution (2 ml) of intermediate 61 (50.0 mg, 0.148 mmol), benzoyl chloride (0.0300 ml, 0.258 mmol) and triethylamine (0.120 ml, 0.861 mmol) were added at room temperature, and the mixture was stirred at the same 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, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain compound 77 as a yellow solid (34.0 mg, 0.0949 mmol, 64%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ4.40 (2H, d, J = 5.2 Hz), 6.76 (1H, d, J = 16.0 Hz), 7.41-7.61 (6H, m), 7.74-7.83 (4H, m), 7.99 (1H, d, J = 7.6 Hz), 8.24 (1H, s), 8.55 (1H, d, J = 4.4 Hz), 8.72-8.79 (2H, m); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 21 H 18 N4O2Na 381.1327; Found 381.1319. The confirmed structure is:

[0282] Example 78: Preparation of Compound 78. To a solution of Intermediate 61 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), p-toluic acid (27.8 mg, 0.204 mmol), N,N-diisopropylethylamine (0.150 ml, 0.861 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (129 mg, 0.339 mmol), and dimethylaminopyridine (3.60 mg, 0.0296 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 78 as a yellow solid (14.3 mg, 0.0384 mmol, 26%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ2.43 (3H, s), 4.59 (2H, d, J = 6.0 Hz), 6.01 (1H, br), 6.49 (1H, d, J = 15.6 Hz), 7.29-7.34 (3H, m), 7.69 (1H, d, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 20 N4O2Na 395.1484; Found 395.1477. The confirmed structure is:

[0283] Example 79: Preparation of Compound 79. To a dichloromethane solution (2 ml) of Intermediate 59 (50.0 mg, 0.148 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol) and benzenesulfonyl chloride (40.6 mg, 0.230 mmol) were added at room temperature, followed by stirring at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 4:1) to obtain Compound 79 as a yellow solid (50.0 mg, 0.136 mmol, 92%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ 4.41 (2H, d, J = 5.6 Hz), 7.40 (1H, d, J = 9.6 Hz), 7.51-7.62 (3H, m), 7.80-7.91 (4H, m), 8.20 (1H, dt, J = 8.0, HRMS (ESI-TOF) m / z: [M + H] + calcd for C 18 H 17 N4SO3369.1021; Found 369.1014. The confirmed structure is:

[0284] Example 80: Preparation of Compound 80. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), p-vinylbenzoic acid (32.0 mg, 0.242 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.379 mmol), and dimethylaminopyridine (3.60 mg, 0.0296 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain compound 80 as a yellow solid (4.50 mg, 0.0126 mmol, 8.5%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 4.79 (2H, d, J = 4.0 Hz), 5.42 (1H, d, J = 10.4 Hz), 5.89 (1H, d, J = 17.2 Hz), 6.71-6.88 (1H, m), 7.52-7.62 (2H, m), 8.11 (1H, t-like, J = 6.4 Hz), 8.25 (1H, d, J = 8.4 Hz), 8.33 (1H, d, J = 8.0 Hz), 8.45 (1H, t-like, J = 6.8 Hz), 8.82 (1H, d-like, J = 6.0 Hz), 8.93 (1H, d, J = 9.2 Hz), 9.03-9.13 (2H, m), 10.22 (2H, br); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 21 H 19 N4O2359.1508; Found 359.1501. The confirmed structures are as follows:

[0285] Example 81: Preparation of Compound 81. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), o-trifluoromethylbenzoic acid (44.0 mg, 0.231 mmol), N,N-diisopropylethylamine (0.160 ml, 0.918 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.378 mmol), and dimethylaminopyridine (5.00 mg, 0.0411 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 81 as a yellow solid (5.00 mg, 0.0125 mmol, 8.4%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.66 (2H, d, J = 5.6 Hz), 6.78 (1H, br), 7.44 (1H, dd, J = 7.6, 3.2 Hz), 7.57-7.88 (6H, m), 8.19 (1H, d, J = 7.6 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 15 F3N4O2Na 423.1045; Found 423.1040. The confirmed structure is:

[0286] Example 82: Preparation of Compound 82. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), m-trifluoromethylbenzoic acid (44.0 mg, 0.231 mmol), N,N-diisopropylethylamine (0.160 ml, 0.918 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.378 mmol), and dimethylaminopyridine (5.00 mg, 0.0411 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 82 as a yellow solid (11.5 mg, 0.0287 mmol, 19%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.69 (2H, d, J = 5.6 Hz), 6.50 (1H, br), 7.42 (1H, dd, J = 8.0, 4.8 Hz), 7.67 (1H, t, J = 8.4 Hz), 7.82-7.87 (2H, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 15 F3N4O2Na 423.1045; Found 423.1039. The confirmed structure is:

[0287] Example 83: Preparation of Compound 83. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), p-trifluoromethylbenzoic acid (44.0 mg, 0.231 mmol), N,N-diisopropylethylamine (0.160 ml, 0.918 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.378 mmol), and dimethylaminopyridine (5.00 mg, 0.0411 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 83 as a yellow solid (17.1 mg, 0.0427 mmol, 29%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.69 (2H, d, J = 6.0 Hz), 6.57 (1H, br), 7.43 (1H, dd, J = 8.4, 4.8 Hz), 7.74 (1H, d, J = 8.0 Hz), 7.79 (2H, d, J = 8.8 Hz), 8.09 (2H, d, J = 8.8 Hz), 8.17 (1H, d, J = 8.4 Hz), 8.20 (1H, d, J = 8.0 Hz), 8.36 (1H, s), 8.43 (1H, d, J = 8.8 Hz), 8.76 (1H, d, J = 5.6 Hz), 9.01 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 15 F3N4O2Na 423.1045; Found 423.1039. The confirmed structure is:

[0288] Example 84: Preparation of Compound 84. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 3-fluoro-5-trifluoromethylbenzoic acid (47.0 mg, 0.226 mmol), N,N-diisopropylethylamine (0.160 ml, 0.918 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.378 mmol), and dimethylaminopyridine (4.60 mg, 0.0378 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to give compound 84 as a yellow solid (24.4 mg, 0.0583 mmol, 39%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.70 (2H, d, J = 6.0 Hz), 6.55 (1H, br), 7.43 (1H, dd, J = 8.0, 3.2 Hz), 7.56 (1H, d, J = 7.2 Hz), 7.85-7.91 (2H, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 14 F4N4O2Na 441.0951; Found 441.0947. The confirmed structure is:

[0289] Example 85: Preparation of Compound 85. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), o-trifluoromethoxybenzoic acid (47.0 mg, 0.228 mmol), N,N-diisopropylethylamine (0.160 ml, 0.918 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.378 mmol), and dimethylaminopyridine (5.00 mg, 0.0411 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 85 as a yellow solid (16.2 mg, 0.0389 mmol, 26%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.69 (2H, d, J = 6.0 Hz), 7.33-7.71 (4H, m), 7.92-7.99 (2H, m), 8.17 (1H, s), 8.42 (1H, d, J = 8.8 Hz), 8.44 (1H, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 15 F3N4O3Na 439.0994; Found 439.0989. The confirmed structure is:

[0290] Example 86: Preparation of Compound 86 To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), m-trifluoromethoxybenzoic acid (47.0 mg, 0.228 mmol), N,N-diisopropylethylamine (0.160 ml, 0.918 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.378 mmol), and dimethylaminopyridine (5.00 mg, 0.0411 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 86 as a yellow solid (15.4 mg, 0.0370 mmol, 25%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.78 (2H, d, J = 3.6 Hz), 7.46 (2H, d, J = 8.4 Hz), 7.59 (1H, t, J = 8.0 Hz), 7.95-8.03 (2H, m), 8.24 -8.41 (2H, m), 8.72-8.86 (2H, m), 8.94-9.02 (2H, m), 9.80 (1H, br), 10.07 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 15 F3N4O3Na 439.0994; Found 439.0990. The confirmed structure is:

[0291] Example 87: Preparation of Compound 87. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), p-trifluoromethoxybenzoic acid (47.0 mg, 0.228 mmol), N,N-diisopropylethylamine (0.160 ml, 0.918 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.378 mmol), and dimethylaminopyridine (5.00 mg, 0.0411 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 87 as a yellow solid (13.4 mg, 0.0322 mmol, 22%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.80 (2H, d, J = 4.4 Hz), 7.36 (2H, d, J = 8.4 Hz), 8.11-8.16 (1H, m), 8.39 (2H, d, J = 8.4 Hz), 8.47 (1H, d, J = HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 15 F3N4O3Na 439.0994; Found 439.0992. The confirmed structure is:

[0292] Example 88: Preparation of Compound 88. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 2,2-dimethylbutanoic acid (27.9 mg, 0.240 mmol), N,N-diisopropylethylamine (0.170 ml, 0.975 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.378 mmol), and dimethylaminopyridine (3.60 mg, 0.0296 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 88 as a yellow solid (6.00 mg, 0.0184 mmol, 12%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ0.89 (3H, t, J = 7.2 Hz), 1.65 (2H, q, J = 7.2 Hz), 4.62 (2H, d, J = 6.0 Hz), 6.65 (1H, br), 7.39 (1H, dd, J = 8.0, 4.8 Hz), 7.72 (1H, d, J = 8.8 Hz), 8.05 (1H, s), 8.13 (1H, d, J = 7.6 Hz), 8.24 (1H, d, J = 8.0 Hz), 8.27 (1H, s), 8.72 (1H, d, J = 4.8 Hz), 8.98 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 22 N4O2Na 349.1640; Found 349.1635. The confirmed structure is:

[0293] Example 89: Preparation of Compound 89. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), p-trifluoromethylphenylacetic acid (78.0 mg, 0.382 mmol), N,N-diisopropylethylamine (0.160 ml, 0.918 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.378 mmol), and dimethylaminopyridine (5.00 mg, 0.0411 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to give compound 89 as a yellow solid (44.0 mg, 0.106 mmol, 72%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.01 (2H, s), 4.74 (2H, s), 6.73 (1H, d, J = 6.4 Hz), 7.55 (2H, d, J = 8.0 Hz), 7.59 (2H, d, J = 8.0 Hz), 8.08 (1H, t, J = 6.4 Hz), 8.20 (1H, t, J = 6.4 Hz), 8.43 (1H, d, J = 8.0 Hz), 8.53 (1H, d, J = 8.0 Hz), 8.73 (1H, s), 8.94 (1H, d, J = 5.2 Hz), 9.11 (1H, d, J = 8.8 Hz), 10.18 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 21 H 17 F3N4O2Na 437.1201; Found 437.1195. The confirmed structure is:

[0294] Example 90: Preparation of compound 91 (1) Preparation of intermediate 66 A known compound (intermediate 66) represented by the following structural formula was synthesized according to the method described in Bioorganic & Medicinal Chemistry Letters, 2009, 19(14), 3716-3720.

[0295] (2) Preparation of Compound 91: To a dichloromethane solution (2 ml) of Intermediate 59 (50.0 mg, 0.148 mmol), Intermediate 66 (27.9 mg, 0.240 mmol), N,N-diisopropylethylamine (0.190 ml, 1.09 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (167 mg, 0.438 mmol), and dimethylaminopyridine (5.30 mg, 0.0436 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 38 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain Compound 91 as a yellow solid (2.40 mg, 0.00621 mmol, 4.2%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CDCl3, 400 MHz): δ2.56 (1H, t, J = 2.0 Hz), 4.66 (2H, d, J = 5.6 Hz), 4.77 (2H, d, J = 2.0 Hz), 6.51 (1H, br), 7.07 (2H, d, J = 8.8 Hz), 7.41 (1H, dd, J = 8.0, 4.8 Hz), 7.78 (1H, dd, J = 8.4, 2.4 Hz), 7.90 (2H, d, J = 8.8 Hz), 8.14 (1H, dt, J = 8.4, 2.0 Hz), 8.32 (1H, d, J = 2.0 Hz), 8.37 (1H, d, J = 8.8 Hz), 8.52 (1H, s), 8.75 (1H, d, J = 5.2 Hz), 9.00 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 18 N4O3Na 409.1277; Found 409.1273. The confirmed structure is:

[0296] Example 91: Preparation of Compound 90 (1) Preparation of Intermediate 67 A known compound (intermediate 67) represented by the following structural formula was synthesized according to the method described in Journal of the American Chemical Society, 2008, 130(38), 12564-12565.

[0297] (2) Preparation of Compound 90. Triethylamine (1.44 ml, 10.3 mmol) and nicotinyl chloride hydrochloride (690 mg, 3.86 mmol) were added to a dichloromethane solution (3 ml) of intermediate 67 (420 mg, 2.58 mmol) at room temperature, followed by stirring at the same temperature for 2.5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 1:1) to obtain Compound 90 as a yellow solid (545 mg, 2.03 mmol, 79%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.45 (2H, s), 4.80 (2H, d, J = 4.4 Hz), 7.23-7.31 (2H, m), 7.41 (1H, dd, J = 8.0, 4.8 Hz), 7.69 (1H, br), 7.74 (1H, t, J = 7.6 Hz), 8.20 (1H, dt, J = 8.0, 2.0 Hz), 8.75 (1H, d, J = 3.6 Hz), 9.11 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 13 H 12 N6ONa 291.0970; Found 291.0964. The confirmed structures are as follows:

[0298] Example 92: Preparation of Compound 92 (1) Preparation of Intermediate 68 A known compound (intermediate 68) represented by the following structural formula was synthesized according to the method described in Journal of the American Chemical Society, 2008, 130(38), 12564-12565.

[0299] (2) Preparation of Intermediate 69. Sodium hydride (160 mg, 6.62 mmol) was added to a dimethylformamide solution (15 ml) of isoindolinone (440 mg, 3.31 mmol) in an ice bath, and the mixture was stirred at the same temperature for 20 minutes. A dimethylformamide solution (5 ml) of intermediate 68 (950 mg, 3.31 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 4:1) to obtain intermediate 69, represented by the following structural formula, as a yellow solid (1.01 g, 2.64 mmol, 80%). HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 17 N3O3Na 406.1162; Found 406.1165.

[0300] (3) Preparation of Intermediate 70: Hydrazine monohydrate (160 mg, 6.62 mmol) was added to a methanol solution (2 ml) of Intermediate 69 (100 mg, 0.261 mmol) at room temperature, and the mixture was stirred at the same temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Intermediate 70, represented by the following structural formula, was obtained as a yellow solid (60.5 mg, 0.0239 mmol, 92%).

[0301] (4) Preparation of Compound 92. Triethylamine (0.100 ml, 0.720 mmol) and nicotinyl chloride hydrochloride (52 mg, 0.290 mmol) were added to a dichloromethane solution (2 ml) of intermediate 70 (60.5 mg, 0.239 mmol) at room temperature, followed by stirring at the same temperature for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain Compound 92 as a yellow solid (19.5 mg, 0.0544 mmol, 23%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.63 (2H, s), 4.99 (2H, s), 5.30 (2H, s), 7.42-7.61 (5H, m), 7.79-7.87 (3H, m), 8.21 (1H, br), 8.56 (1H, br), 8.78 (1H, d, J = 4.0 Hz), 9.28 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 21 H 18 N4O2Na 381.1327; Found 381.1322. The confirmed structures are:

[0302] Example 93: Preparation of Compound 93. Oxetane-3-carboxylic acid (49.4 mg, 0.48 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (93.0 mg, 0.48 mmol), and 1-hydroxybenzotriazole (65 mg, 0.48 mmol) were added to a solution of Intermediate 62 (100 mg, 0.44 mmol) in dimethylformamide (1.5 ml) at room temperature, and the mixture was stirred at the same temperature for 3 days. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 → 93:7) to give Compound 93 as a white solid (24 mg, 0.077 mmol, 18%). 1 H NMR (DMSO, 400 MHz): δ3.89-3.99 (1H, m), 4.43 (2H, d, J = 6.0 Hz), 4.64-4.73 (4H, m), 7.27 (2H, d, J = 7.2 Hz), 7.50-7.58 (3H, m), 8.20-8.24 (1H, m), 8.70-8.72 (1H, m), 9.03-9.05 (1H, m), 9.18-9.24 (1H, m), 9.93 (1H, s); ESI-MS m / z: 312 [M+H] + The confirmed structure is as follows:

[0303] Example 94: Preparation of Compound 94 (1) Preparation of Intermediate 71 Diisopropylethylamine (1.92 mL, 11.0 mmol) and nicotinoyl chloride hydrochloride (979 mg, 5.50 mmol) were added to a chloroform solution (20 mL) of t-butyl (5-(aminomethyl)pyridin-2-yl)carbamate (1.12 g, 5.00 mmol) at room temperature, followed by stirring at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 100:0 → 92:8) to obtain Intermediate 71 (1.54 g, 4.67 mmol, 93%), which has the following structural formula, as a white solid.

[0304] (2) Preparation of Intermediate 72: To a solution of Intermediate 71 (1.54 g, 4.67 mmol) in 1,4-dioxane (23 ml), hydrochloric acid (4 M dioxane solution, 23 ml) and methanol (5 ml) were added at room temperature, and the mixture was stirred at the same temperature for 18 hours. The precipitate was filtered, washed with ethyl acetate, and then dried in vacuo to obtain Intermediate 72 (1.25 g, 4.13 mmol, 88%), which has the following structural formula, as a white solid.

[0305] (3) Preparation of Compound 94. Oxalyl chloride (66 μL, 0.75 mmol) was added to a tetrahydrofuran solution (10 mL) of 1-(t-butyloxycarbonyl)azetidine-3-carboxylic acid (151 mg, 0.75 mmol) at room temperature, followed by stirring at the same temperature for 1 hour. Subsequently, intermediate 72 (151 mg, 0.50 mmol) and diisopropylethylamine (437 μL, 2.50 mmol) were added at room temperature, followed by stirring at the same temperature for 2 hours. Saturated aqueous ammonium chloride was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 100:0 → 92:8) to give compound 94 as a white solid (116 mg, 0.282 mmol, 56%). 1H NMR (DMSO, 400 MHz): δ1.45 (9H, s), 3.34-3.41 (1H, br), 4.12-4.23 (4H, m), 4.65 (2H, d, J = 6.0 Hz), 6.47 (1H, t, J = 6.0 Hz), 7.40-7.44 (1H, m), 7.77 (1H, dd, J = 8.4, 2.4 Hz), 8.05 (1H, m), 8.13-8.15 (1H, m), 8.23-8.26 (1H, m), 8.29 (1H d, J = 2.0 Hz), 8.76 (1H, dd, 4.8, 1.6 Hz), 8.98 (1H, d, 2.0 Hz); ESI-MS m / z: 412 [M+H] + The confirmed structure is as follows:

[0306] Example 95: Preparation of Compound 95. To a solution of Intermediate 10 (441 mg, 1.92 mmol) in dichloromethane (10 ml), nicotinoyl chloride hydrochloride (411 mg, 2.31 mmol) and triethylamine (1.07 ml, 7.69 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 10:1) to obtain Compound 95 as a yellow solid (266 mg, 0.605 mmol, 32%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ1.22-1.56 (8H, m), 2.20-2.52 (10H, m), 2.68 (2H, t, J = 5.6 Hz), 3.25 (2H, q, J = 6.4 Hz), 4.40 (2H, t, J = 5.6 Hz), 7.49 (1H, dd, J = 7.2, 5.2 Hz), 7.58 (1H, dd, J = 7.2, 5.2 Hz), 8.16 (1H, d, J = 8.0 Hz), 8.28 (1H, d, J = 8.0 Hz), 8.61 (1H, br), 8.68 (1H, d, J = 3.6 Hz), 8.82 (1H, d, J = 3.6 Hz), 8.98 (1H, s), 9.08 (1H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 24 H 34 N5O3 440.2656; Found 440.2654. The confirmed structures are:

[0307] Example 96: Preparation of Compound 96 (1) Preparation of Intermediate 71. To a dichloromethane solution (7 ml) of compound 4 (677 mg, 2.30 mmol), mesyl chloride (0.214 ml, 2.76 mmol) and triethylamine (0.962 ml, 6.90 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 20:1) to obtain intermediate 71 as a yellow oil (856 mg, 2.30 mmol, 99%).

[0308] (2) Preparation of Intermediate 72: Sodium azide (189 mg, 2.91 mmol) was added to a solution of Intermediate 71 (904 mg, 2.43 mmol) in dimethylformamide (8 ml) at room temperature, and the mixture was stirred at 80°C for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 30:1) to give Intermediate 72 as a yellow oil (683 mg, 2.14 mmol, 88%).

[0309] (3) Preparation of Compound 96. Triphenylphosphine (617 mg, 2.35 mmol) was added to a solution of intermediate 72 (683 mg, 2.14 mmol) in tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred at room temperature for 24 hours. Water (0.115 ml, 6.41 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 7:1) to obtain compound 96 as yellow crystals (573 mg, 1.95 mmol, 91%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ1.24-1.34 (8H, m), 1.43-1.58 (4H, m), 2.50 (2H, br), 2.62 (2H, t, J = 5.6 Hz), 3.23-3.37 (6H, m), 7.49 (1H, dd, J = HRMS (ESI-TOF) m / z: [M + H] + calcd for C 16 H 28 N3O2294.2176; Found 294.2174. The confirmed structure is:

[0310] Example 97: Preparation of Compound 97 (1) Preparation of Intermediate 73. To a dichloromethane solution (7 ml) of compound 6 (580 mg, 1.71 mmol), mesyl chloride (0.159 ml, 2.06 mmol) and triethylamine (0.717 ml, 5.14 mmol) were added under ice cooling conditions, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 20:1) to give intermediate 73 as a yellow oil (651 mg, 1.56 mmol, 91%).

[0311] (2) Preparation of Intermediate 74. Sodium azide (122 mg, 1.88 mmol) was added to a dimethylformamide solution (5 ml) of Intermediate 73 (651 mg, 1.56 mmol) at room temperature, and the mixture was stirred at 80°C for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 30:1) to give Intermediate 74 as a yellow oil (439 mg, 1.21 mmol, 78%).

[0312] (3) Preparation of Compound 97. Triphenylphosphine (348 mg, 1.33 mmol) was added to a solution of intermediate 74 (438 mg, 1.21 mmol) in tetrahydrofuran (6 mL) at room temperature, and the mixture was stirred at room temperature for 24 hours. Water (0.0651 mL, 3.62 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 7:1) to obtain Compound 97 as a yellow oil (408 mg, 1.21 mmol, 99%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CDCl3, 400 MHz): δ1.31-1.67 (12H, m), 2.85 (2H, t, J = 5.6 Hz), 3.43-3.53 (6H, m), 3.55-3.64 (4H, m), 6.36 (1H, br), 7.39 (1H, dd, J HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 31 N3O3Na 360.2263; Found 360.2254. The confirmed structure is:

[0313] Example 98: Preparation of compound 98 (1) Preparation of intermediate 79 A known compound (intermediate 79) represented by the following structural formula was synthesized according to the method described in WO97 / 02242.

[0314] (2) Preparation of Compound 98. Nicotinic acid (121 mg, 0.983 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 0.991 mmol), and dimethylaminopyridine (12.6 mg, 0.103 mmol) were added to a dichloromethane solution (3 mL) of intermediate 79 (75 mg, 0.415 mmol) at room temperature, followed by stirring at the same temperature for 13 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain Compound 98 as a yellow oil (30.8 mg, 0.108 mmol, 22%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (DMSO, 400 MHz): δ3.47 (2H, t, J = 6.0 Hz), 3.62 (2H, t, J = 6.0 Hz), 3.76 (2H, t, J = 4.8 Hz), 4.08 (2H, t, J = 4.8 Hz), 6.89-6.94 (3H, m), 7.23-7.29 (2H, m), 7.49 (1H, dd, J = 8.0, 4.8 Hz), 8.17 (1H, dt, J = 8.8, 2.0 Hz), 8.32 (1H, s), 8.70 (1H, dd, J = 4.8, 1.6 Hz), 8.77 (1H, t, J = 4.8 Hz); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 16 H 19 N2O3287.1390; Found 287.1388. The confirmed structure is:

[0315] Example 99: Preparation of Compound 99. To a dichloromethane solution (8 ml) of 2-(2-(3-methoxyphenoxy)ethoxy)ethan-1-amine (175 mg, 0.828 mmol), nicotinic acid (204 mg, 1.66 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (318 mg, 1.66 mmol), and dimethylaminopyridine (20.0 mg, 0.166 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 99 as a yellow oil (174 mg, 0.550 mmol, 66%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CDCl3, 400 MHz): δ3.64-3.77 (4H, m), 3.76 (3H, s), 3.85 (2H, t, J = 4.0 Hz), 4.13 (2H, t, J = 4.0 Hz), 6.44-6.53 (3H, m), 6.75 (1H, HRMS (ESI-TOF) m / z: [M + H] + calcd for C 17 H 21 N2O4317.1496; Found 317.1493. The confirmed structure is:

[0316] Example 100: Preparation of Compound 100. Nicotinic acid (145 mg, 1.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (271 mg, 1.41 mmol), and dimethylaminopyridine (11.5 mg, 0.0942 mmol) were added to a dichloromethane solution (2 mL) of 2,2'-ethylenedianiline (100 mg, 0.471 mmol) at room temperature, followed by stirring at the same temperature for 5 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give Compound 100 as a yellow solid (34.8 mg, 0.0824 mmol, 17%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ3.00 (4H, s), 7.15-7.29 (6H, m), 7.37 (2H, dd, J = 8.0, 4.8 Hz), 7.57-7.62 (4H, m), 7.95 (2H, d, J = 8.0 Hz), 8.74 (2H, d, J = 4.8 Hz), 8.80 (2H, s); HRMS (ESI-TOF) m / z: [M + H]+ calcd for C 26 H 23 N4O2 423.1816; Found 423.1812. The confirmed structures are:

[0317] Example 101: Preparation of Compound 101. Nicotinic acid (145 mg, 1.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (271 mg, 1.41 mmol), and dimethylaminopyridine (11.5 mg, 0.0942 mmol) were added to a dichloromethane solution (2 mL) of 4,4'-ethylenedianiline (100 mg, 0.471 mmol) at room temperature, followed by stirring at the same temperature for 8 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give Compound 101 as a yellow solid (16.5 mg, 0.0391 mmol, 8.3%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ2.87 (4H, s), 7.21 (4H, d, J = 3.6 Hz), 7.57 (2H, dd, J = 8.0, 4.8 Hz), 7.66 (4H, d, J = 3.6 Hz), 8.28 (2H, d, J = 8.0 Hz), 8.75 (2H, br), 9.10 (2H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 26 H 23 N4O2 423.1816; Found 423.1815. The confirmed structures are:

[0318] Example 102: Preparation of Compound 102. Nicotinoyl chloride hydrochloride (308 mg, 1.73 mmol) and triethylamine (0.280 ml, 2.77 mmol) were added to a dichloromethane solution (3 ml) of N,N'-dimethyl-1,6-hexanediamine (100 mg, 0.693 mmol) in an ice bath, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Compound 102 was obtained as a yellow solid (70.9 mg, 0.200 mmol, 29%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ1.16-2.36 (8H, m), 2.92-3.62 (10H, m), 7.39 (2H, s), 7.78 (2H, d, J = 6.4 Hz), 8.60-8.70 (4H, m); HRMS (ESI-TOF) m / z: [M+H] + calcd for C 20 H 27 N4O2355.2129; Found 355.2128. The confirmed structures are as follows:

[0319] Example 103: Preparation of compound 103 (1) Preparation of intermediate 80 A known compound (intermediate 80) represented by the following structural formula was synthesized according to the method described in CN107459524.

[0320] (2) Preparation of Compound 103. To a solution of Intermediate 80 (124 mg, 0.271 mmol) in dimethylformamide (0.9 mL) was added nicotinic acid (100 mg, 0.813 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (208 mg, 1.08 mmol), N,N-diisopropylethylamine (0.142 mL, 0.813 mmol), and dimethylaminopyridine (13.2 mg, 0.108 mmol) at room temperature, followed by stirring at the same temperature for 3 hours. Methanol was added to the reaction mixture, and the resulting crystals were filtered using a separatory funnel to obtain Compound 103 as a yellow solid (33.8 mg, 0.0771 mmol, 44%). The NMR spectrum and HR-ESI-MS mass analysis results are as follows: 1 H NMR (DMSO, 400 MHz): δ1.46-1.80 (8H, m), 3.26 (4H, q, J = 6.4 Hz), 3.84-3.91 (2H, m), 7.46-7.52 (2H, m), 8.13-8.21 (4H, m), 8.64-8.70 (4H, m), 8.98 (2H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 22 H 27 N6O4439.2088; Found 439.2089. The confirmed structure is:

[0321] Example 104: Preparation of compound 104 (1) Preparation of intermediate 81 A known compound (intermediate 81) represented by the following structural formula was synthesized according to the method described in WO2017 / 173202.

[0322] (2) Preparation of Compound 104. Nicotinic acid (103 mg, 0.837 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (214 mg, 1.12 mmol), N,N-diisopropylethylamine (0.146 mL, 0.837 mmol), and dimethylaminopyridine (13.6 mg, 0.112 mmol) were added to a solution of Intermediate 81 (135 mg, 0.279 mmol) in dimethylformamide (0.9 mL) at room temperature, followed by stirring at the same temperature for 4 hours. Methanol was added to the reaction mixture, and the resulting crystals were filtered using a separatory funnel to obtain Compound 104 as a yellow solid (8.90 mg, 0.0191 mmol, 6.8%). The NMR spectrum and HR-ESI-MS mass analysis results are as follows: 1 H NMR (DMSO, 400 MHz): δ1.24-1.76 (12H, m), 3.25 (4H, q, J = 6.4 Hz), 3.78-3.85 (2H, m), 7.46-7.52 (2H, m), 8.12-8.18 (4H, m), 8.61-8.70 (4H, m), 8.98 (2H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 24 H 31 N6O4467.2401; Found 467.2403. The confirmed structures are as follows:

[0323] Example 105: Preparation of Compound 105. To a dichloromethane solution (3 ml) of intermediate 59 (100 mg, 0.296 mmol), benzoyl chloride (0.0500 ml, 0.434 mmol) and triethylamine (0.410 ml, 4.06 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic, 100% ethyl acetate) to obtain compound 105 as a pale yellow solid (76.5 mg, 0.230 mmol, 78%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.67 (2H, d, J = 6.0 Hz), 6.57 (1H, br), 7.42 (1H, dd, J = 8.0, 4.8 Hz), 7.49-7.61 (3H, m), 7.82 (1H, dd, J = 8.4, 2.0 Hz), 7.94 (2H, d, J = 7.6 Hz), 8.16 (1H, dt, J = 8.0, 2.0 Hz), 8.34 (1H, d, J = 2.4 Hz), 8.42 (1H, d, J = 8.8 Hz), 8.72-8.78 (2H, m), 9.01 (1H, d, J = 2.0 Hz); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 19 H 17 N4O2333.1352; Found 333.1349. The confirmed structure is:

[0324] Example 106: Preparation of Compound 106. Nicotinoyl chloride hydrochloride (100 mg, 0.562 mmol) and triethylamine (0.156 ml, 1.12 mmol) were added to a dichloromethane solution (5 ml) of 3-[2-(3-aminopropoxy)ethoxy]propan-1-amine (0.100 ml, 0.560 mmol) at room temperature, followed by stirring at the same temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1), solidified with 4 M HCl / dioxane (5 ml), and collected by filtration to give Compound 106 as a yellow solid (18.3 mg, 0.0517 mmol, 9.2%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ1.76 (2H, q, J = 6.4 Hz), 3.29-3.52 (14H, m), 7.49 (1H, dd, J = 8.0, 4.8 Hz), 8.16 (1H, d, J = 7.6 Hz), 8.63-8.70 (2H, m), 8.98 (1H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 14 H 24 N3O3282.1812; Found 282.1812. The confirmed structure is:

[0325] Example 107: Preparation of Compound 107. Nicotinoyl chloride hydrochloride (100 mg, 0.562 mmol) and triethylamine (0.156 ml, 1.12 mmol) were added to a dichloromethane solution (5 ml) of 2-[2-(2-aminoethoxy)ethoxy]ethan-1-amine (83.0 mg, 0.560 mmol) at room temperature, followed by stirring at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1), solidified with 4 M HCl / dioxane (5 ml), and collected by filtration to give Compound 107 as a yellow solid (23.8 mg, 0.0730 mmol, 13%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 12 H 19 N3O3Na 276.1324; Found 276.1317. The confirmed structure is:

[0326] Example 108: Preparation of Compound 108. To a solution of Intermediate 62 (100 mg, 0.440 mmol) in dichloroethane (5 mL), oxane-4-carboxylic acid (114 mg, 0.876 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 0.876 mmol), and triethylamine (0.120 mL, 0.861 mmol) were added at 60°C, and the mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 85:15) to obtain Compound 108 as a yellow solid (110 mg, 0.324 mmol, 74%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ1.62-1.89 (4H, m), 2.49-2.57 (1H, m), 3.38-3.76 (4H, m), 4.55 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 16.0 Hz), 7.50-7.57 (3H, m), 8.26 (1H, t, J = 8.0 Hz), 8.68 (1H, s), 8.99 (1H, d, J = 6.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 21 N3O3Na 362.1481; Found 362.1478. The confirmed structure is:

[0327] Example 109: Preparation of Compound 109. To a solution of Intermediate 62 (100 mg, 0.440 mmol) in dichloroethane (5 mL), cyclobutanecarboxylic acid (88.1 mg, 0.880 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 0.876 mmol), and triethylamine (0.120 mL, 0.861 mmol) were added at 60°C, and the mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 85:15) to obtain Compound 109 as a yellow solid (136 mg, 0.440 mmol, 99%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ1.14-1.20 (2H, m), 1.82-2.08 (4H, m), 2.28-2.39 (1H, m), 4.55 (2H, s), 7.32 (2H, d, J = 8.4 Hz), 7.51-7.58 (3H, m), 8.26 (1H, d, J = 7.6 Hz), 8.68 (1H, s), 9.00 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 19 N3O2Na 332.1375; Found 332.1373. The confirmed structures are:

[0328] Example 110: Preparation of Compound 110. Nicotinoyl chloride hydrochloride (87.6 mg, 0.492 mmol) and triethylamine (0.110 ml, 0.789 mmol) were added to a dichloromethane solution (5 ml) of N-[4-(2-aminomethyl)-2-fluorophenyl]benzamide (100 mg, 0.409 mmol) at room temperature, followed by stirring at the same temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 110 as a yellow solid (50.0 mg, 0.143 mmol, 35%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ4.61 (2H, s), 7.21-7.27 (2H, m), 7.50-7.77 (6H, m), 7.93-7.98 (2H, m), 8.29 (1H, d, J = 8.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 16 N4O2Na 372.1124; Found 372.1121. The confirmed structures are:

[0329] Example 111: Preparation of compound 111 (1) Preparation of intermediate 82 A known compound (intermediate 82) represented by the following structural formula was synthesized according to the method described in WO2008 / 126731.

[0330] (2) Preparation of Intermediate 75. To a methanol solution (1.4 ml) of Intermediate 82 (247 mg, 0.700 mmol), nickel chloride hexahydrate (166 mg, 0.698 mmol) and sodium borohydride (79.4 mg, 2.10 mmol) were added in an ice bath, and the mixture was stirred at the same temperature for 15 minutes. The insoluble matter was filtered through Celite and concentrated under reduced pressure. To a dichloromethane solution (2.3 ml) of the residue, nicotinoyl chloride hydrochloride (250 mg, 1.40 mmol) and triethylamine (0.210 ml, 1.51 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. After filtration through Celite, the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=97:3) to give Intermediate 75 as a yellow solid (226 mg, 0.489 mmol, 70%).

[0331] (3) Preparation of Intermediate 76. To a dichloromethane solution (10 ml) of Intermediate 75 (226 mg, 0.489 mmol), trifluoroacetic acid (0.19 ml) was added in an ice bath, and the mixture was stirred at room temperature for 16 hours. Insoluble matter was filtered through Celite, and the mixture was concentrated under reduced pressure. To a dichloromethane solution (2.3 ml) of the residue, nicotinoyl chloride hydrochloride (250 mg, 1.40 mmol) and triethylamine (0.210 ml, 1.51 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Intermediate 76 was obtained as a yellow solid (127 mg, 0.485 mmol, 99%).

[0332] (4) Preparation of Compound 111. Benzoyl chloride (0.0200 ml, 0.172 mmol) and triethylamine (0.0300 ml, 0.215 mmol) were added to a dichloromethane solution (0.2 ml) of intermediate 76 (28.1 mg, 0.107 mmol) in an ice bath, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 10:1) to obtain Compound 111 as a yellow solid (32.0 mg, 0.0875 mmol, 82%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ4.50 (2H, d, J = 6.0 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.40-7.75 (8H, m), 7.96 (1H, dd, J = 6.8, 6.8 Hz), 8.22 (1H, dt, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 16 ClN3O2Na 388.0829; Found 388.0824. The confirmed structure is:

[0333] Example 112: Preparation of Compound 112. To a dichloromethane solution (0.2 ml) of Intermediate 76 (27.5 mg, 0.105 mmol), nicotinoyl chloride (29.4 mg, 0.165 mmol) and triethylamine (0.0300 ml, 0.215 mmol) were added under ice cooling conditions, and the mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 10:1) to obtain Compound 112 as a yellow solid (22.0 mg, 0.0600 mmol, 57%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ4.52 (2H, d, J = 6.0 Hz), 7.36 (1H, d, J = 6.0 Hz), 7.51-7.60 (4H, m), 8.22-8.33 (3H, m), 8.73 (1H, d, J = 3.2 Hz), 8.78 (1H, d, J = 3.2 Hz), 9.06 (1H, s), 9.13 (1H, s), 9.33 (1H, t, J = 5.6 Hz); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 19 H 16 ClN4O2367.0962; Found 367.0958. The confirmed structure is:

[0334] Example 113: Preparation of Compound 113. To a solution of Intermediate 59 (150 mg, 0.444 mmol) in dichloromethane (5 mL) was added cyclohexanecarboxylic acid (0.083 mL, 0.666 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.888 mmol), diisopropylethylamine (0.390 mL, 2.24 mmol), and dimethylaminopyridine (5.40 mg, 0.0442 mmol) at room temperature, followed by stirring at the same temperature for 15 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain SYK-221 as a yellow solid (23.5 mg, 0.0694 mmol, 16%). The results of the NMR measurement spectrum and mass analysis by HR-ESI-MS are as follows. 1 H NMR (CDCl3, 400 MHz): δ1.18-2.31 (11H, m), 4.63 (2H, d, J = 5.6 Hz), 6.50 (1H, br), 7.41 (1H, dd, J = 7.2, 4.4 Hz), 7.72 (1H, dd, J = 8.4, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 22 N4O2Na 361.1640; Found 361.1637. The confirmed structure is:

[0335] Example 114: Preparation of Compound 114. To a solution of Intermediate 59 (100 mg, 0.296 mmol) in dichloromethane (5 mL) was added oxane-4-carboxylic acid (54.6 mg, 0.420 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72.8 mg, 0.380 mmol), triethylamine (0.520 mL, 3.73 mmol), and dimethylaminopyridine (9.30 mg, 0.0761 mmol) at room temperature, followed by stirring at the same temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 94:6) to give Compound 114 as a yellow solid (15.0 mg, 0.0441 mmol, 15%). The results of the NMR measurement spectrum and mass analysis by HR-ESI-MS are as follows. 1 H NMR (CDCl3, 400 MHz): δ1.85-1.91 (4H, m), 2.50-2.59 (1H, m), 3.46 (2H, dt, J = 12.0, 3.2 Hz), 4.06 (2H, dt, J = 10.8, 3.2 Hz), 4.65 (2H, d, J = 6.0 Hz), 6.52 (1H, br), 7.42 (1H, dd, J = 8.0, 4.8 Hz), 7.77 (1H, dd, J = 8.8, 2.4 Hz), 8.09 (1H, br), 8.14 (1H, dt, J = 8.0, 2.0 Hz), 8.24 (1H, d, J = 8.4 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 20 N4O3Na 363.1433; Found 363.1429. The confirmed structure is:

[0336] Example 115: Preparation of Compound 115. To a solution of Intermediate 59 (51.7 mg, 0.196 mmol) in dichloroethane (5 mL) was added 3-phenylpropionic acid (32.3 mg, 0.215 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (37.5 mg, 0.196 mmol), triethylamine (0.270 mL, 1.94 mmol), and dimethylaminopyridine (4.80 mg, 0.0393 mmol) at room temperature, followed by stirring at 60°C for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 94:6) to give Compound 115 as a yellow solid (7.20 mg, 0.0200 mmol, 10.2%). The results of the NMR measurement spectrum and mass analysis by HR-ESI-MS are as follows. 1 H NMR (CDCl3, 400 MHz): δ2.70 (2H, t, J = 7.6 Hz), 3.05 (2H, t, J = 7.6 Hz), 4.62 (2H, d, J = 5.6 Hz), 6.67 (1H, br), 7.18-7.32 (5H, m), 7.39 (1H, dd, J = 8.0, 4.8 Hz), 7.72 (1H, dd, J = 8.8, 2.0 Hz), 7.97 (1H, br), 8.13 (1H, dt, J = 8.0, 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.25 (1H, J = 2.0 Hz), 8.73 (1H, dd, J = 4.8, 1.6 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 21 H 20 N4O2Na 383.1484; Found 383.1477. The confirmed structure is:

[0337] Example 116: Preparation of Compound 116. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 3-fluorobenzoic acid (31.8 mg, 0.227 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72.6 mg, 0.379 mmol), triethylamine (0.260 ml, 1.87 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at 60°C for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 94:6) to give Compound 116 as a yellow solid (10.8 mg, 0.0308 mmol, 21%). The results of the NMR measurement spectrum and mass analysis by HR-ESI-MS are as follows. 1 H NMR (CDCl3, 400 MHz): δ4.62 (2H, d, J = 6.0 Hz), 7.08 (1H, br), 7.22-7.77 (6H, m), 8.14 (1H, d, J = 7.6 Hz), 8.24-8.31 (2H, m), 8.70 (1H, br), 8.86 (1H, s), 9.01 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 15 FN4O2Na 373.1077; Found 373.1072. The confirmed structures are:

[0338] Example 117: Preparation of Compound 117. Oxalyl chloride (0.0210 ml, 0.245 mmol) and dimethylformamide (1 drop) were added to a dichloroethane solution (5 ml) of 4-fluorobenzoic acid (32.0 mg, 0.228 mmol), and the mixture was stirred at 60°C for 1 hour. After concentration under reduced pressure, a dichloroethane solution of the residue (2 ml) was added to Intermediate 59 (50.0 mg, 0.148 mmol) and triethylamine (0.320 ml, 2.28 mmol), and the mixture was stirred at 60°C for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain Compound 117 as a white solid (7.10 mg, 0.0203 mmol, 8.9%). The results of the NMR measurement spectrum and mass analysis by HR-ESI-MS are as follows. 1 H NMR (CDCl3, 400 MHz): δ4.64 (2H, d, J = 5.6 Hz), 6.86 (1H, br), 7.03 (2H, d, J = 8.8 Hz), 7.23 (1H, d, J = 8.0 Hz), 7.40 (1H, dd, J = 8.0, HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 15 FN4O2Na 373.1077; Found 373.1068. The confirmed structure is:

[0339] Example 118: Preparation of Compound 118. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 mL), 4-chlorobenzoic acid (36.0 mg, 0.230 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73.0 mg, 0.381 mmol), and triethylamine (0.260 mL, 1.87 mmol) were added at room temperature, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 95:5) to obtain Compound 118 as a yellow solid (6.20 mg, 0.0169 mmol, 11%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ4.74 (2H, s), 7.63 (2H, d, J = 8.4 Hz), 7.87 (1H, s), 8.05-8.11 (3H, m), 8.47-8.51 (2H, m), 8.90 (1H, d, J = 8.0 Hz), 8.97 (1H, s), 9.29 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 15 ClN4O2Na 389.0781; Found 389.0777. The confirmed structure is:

[0340] Example 119: Preparation of Compound 119. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 mL), 4-methylbenzoic acid (31.0 mg, 0.228 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73.0 mg, 0.381 mmol), and triethylamine (0.260 mL, 1.87 mmol) were added at room temperature, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 95:5) to obtain Compound 119 as a yellow solid (13.6 mg, 0.0393 mmol, 27%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CD3OD, 400 MHz): δ2.41 (3H, s), 4.59 (2H, s), 7.26 (1H, d, J = 7.6 Hz), 7.33 (2H, d, J =7.6 Hz), 7.54 (1H, dd, J = 8.0, 4.8 Hz), 7.83-7.91 (3H, m), 8.20 (1H, d, J = 8.4 Hz), 8.26 (1H, d, J = 7,6 Hz), 8.68 (1H, s), 9.00 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 18 N4O2Na 369.1327; Found 369.1321. The confirmed structures are:

[0341] Example 120: Preparation of Compound 120. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloroethane (2 mL), nicotinoyl chloride hydrochloride (37.0 mg, 0.208 mmol) and triethylamine (0.184 mL, 1.32 mmol) were added under ice cooling conditions, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain Compound 120 as a yellow solid (14.3 mg, 0.0429 mmol, 29%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.64 (2H, d, J = 6.0 Hz), 7.06 (1H, br), 7.29-7.46 (3H, m), 7.75-7.82 (1H, m), 8.05 (1H, dt, J = 8.0, 2.0 Hz), 8.11-8.18 (1H, m), 8.28-8.34 (2H, m), 8.67-8.73 (2H, m), 8.90 (1H, d, J = 1.6 Hz), 9.00 (1H, t, J = 2.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 15 N5O2Na 356.1123; Found 356.1118. The confirmed structure is:

[0342] Example 121: Preparation of Compound 121. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 mL) was added 1-naphthalenecarboxylic acid (39.3 mg, 0.228 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72.8 mg, 0.380 mmol), triethylamine (0.260 mL, 1.87 mmol), and dimethylaminopyridine (7.30 mg, 0.0598 mmol) at room temperature, followed by stirring at the same temperature for 72 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give Compound 121 as a yellow solid (46.9 mg, 0.123 mmol, 83%). The results of the NMR measurement spectrum and mass analysis by HR-ESI-MS are as follows. 1 H NMR (CDCl3, 400 MHz): δ4.47 (2H, d, J = 5.6 Hz), 6.97 (1H, br), 7.31 (1H, dd, J = 8.0, 5.6 Hz), 7.44-7.97 (8H, m), 8.07 (1H, d, J = 8.0 HRMS (ESI-TOF) m / z: [M + H] + calcd for C 23 H 19 N4O2 383.1508; Found 383.1501. The confirmed structures are:

[0343] Example 122: Preparation of Compound 122. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 mL) was added 6-quinolinecarboxylic acid (39.5 mg, 0.228 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72.8 mg, 0.380 mmol), triethylamine (0.260 mL, 1.87 mmol), and dimethylaminopyridine (7.30 mg, 0.0598 mmol) at room temperature, followed by stirring at the same temperature for 96 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 5:1) to give Compound 122 as a yellow solid (36.9 mg, 0.0962 mmol, 65%). The results of the NMR measurement spectrum and mass analysis by HR-ESI-MS are as follows. 1 H NMR (CDCl3, 400 MHz): δ4.67 (2H, d, J = 5.6 Hz), 6.86 (1H, br), 7.39-8.50 (11H, m), 8,74 (1H, dd, J = 4.8, 2.0 Hz), 9.02 (1H, dd, J = 4.8, 2.0 Hz), 9.04 (1H, d, J = 2.0 Hz); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 22 H 18 N5O2 384.1460; Found 384.1458. The confirmed structures are:

[0344] Example 123: Preparation of Compound 123. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 2-naphthaleneacetic acid (42.8 mg, 0.230 mmol), N,N-diisopropylethylamine (0.330 ml, 1.89 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 123 as a yellow solid (54.9 mg, 0.138 mmol, 93%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ3.89 (2H, s), 4.45 (2H, d, J = 6.4 Hz), 7.45-7.53 (3H, m), 7.73 (1H, d, J = 8.0 Hz), 7.82-7.90 (4H, m), 8.02 (1H, d, J = 8.0 Hz), 8.20 (1H, d, J = 8.0 Hz), 8.30-8.32 (2H, m), 8.70 (1H, d, J = 5.6 Hz), 9.02 (1H, s), 9.22 (1H, t, J = 5.6 Hz), 10.80 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 24 H 20 N4O2Na 419.1484; Found 419.1478. The confirmed structure is:

[0345] Example 124: Preparation of Compound 124. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 4-pyridinecarboxylic acid (28.3 mg, 0.230 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.379 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to give compound 124 as a yellow solid (25.0 mg, 0.0750 mmol, 51%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ4.52 (2H, d, J = 6.0 Hz), 7.52 (1H, dd, J = 8.0, 4.8 Hz), 7.85 (1H, d, J = 8.8 Hz), 7.91 (2H, d, J = 6.0 Hz), 8.16 (1H, d, J = 8.8 Hz), 8.22 (1H, d, J = 7.6 Hz), 8.40 (1H, s), 8.72 (1H, d, J = 4.8 Hz), 8.76 (2H, d, J = 6.0 Hz), 9.05 (1H, s), 9.27 (1H, t, J = 5.6 Hz), 11.14 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 15 N5O2Na 356.1123; Found 356.1118. The confirmed structure is:

[0346] Example 125: Preparation of Compound 125. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 2-pyridinecarboxylic acid (36.7 mg, 0.298 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.379 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 125 as a yellow solid (48.3 mg, 0.145 mmol, 98%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ4.52 (2H, d, J = 5.6 Hz), 7.52 (1H, t, J = 6.0 Hz), 7.73 (1H, d, J = 5.2 Hz), 7.88 (1H, d, J = 8.4 Hz), 8.12 (1H, t, J = 8.0 Hz), 8.19-8.27 (3H, m), 8.39 (1H, s), 8.72 (1H, d, J = 4.4 Hz), 8.76 (1H, d, J = 4.4 Hz), 9.05 (1H, s), 9.28 (1H, t, J = 4.8 Hz), 10.44 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 18 H 15 N5O2Na 356.1123; Found 356.1116. The confirmed structure is:

[0347] Example 126: Preparation of Compound 126 To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 3-quinolinecarboxylic acid (39.8 mg, 0.230 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.379 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic, chloroform:methanol = 19:1) to give compound 126 as a yellow solid (20.0 mg, 0.0522 mmol, 35%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ4.52 (2H, s), 7.53 (1H, br), 7.72 (1H, t, J = 6.8 Hz), 7.83-7.94 (2H, m), 8.08-8.27 (4H, m), 8.42 (1H, s), 8.72 (1H, s), 9.06 (2H, s), 9.30 (1H, br), 9.37 (1H, s), 11.24 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 22 H 17 N5O2Na 406.1280; Found 406.1270. The confirmed structures are:

[0348] Example 127: Preparation of Compound 127. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 2-naphthalenecarboxylic acid (39.6 mg, 0.230 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.379 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 127 as a yellow solid (5.00 mg, 0.0131 mmol, 8.9%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.71 (2H, d, J = 5.6 Hz), 7.51-7.63 (3H, m), 7.85-8.14 (6H, m), 8.44 (1H, d, J = 7.6 Hz), 8.50 (1H, s), 8.61-8.69 (3H, m), 8.77 (1H, d, J = 4.4 Hz), 9.39 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 18 N4O2Na 405.1327; Found 405.1320. The confirmed structure is:

[0349] Example 128: Preparation of Compound 128. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 mL) was added [1,1'-biphenyl]-4-carboxylic acid (45.6 mg, 0.230 mmol), triethylamine (0.260 mL, 1.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72.6 mg, 0.379 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) at room temperature, followed by stirring at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to give Compound 128 as a yellow solid (52.2 mg, 0.128 mmol, 86%). The results of the NMR measurement spectrum and mass analysis by HR-ESI-MS are as follows. 1 H NMR (DMSO, 400 MHz): δ4.52 (2H, d, J = 5.6 Hz), 7.40-7.55 (4H, m), 7.74-7.85 (5H, m), 8.11-8.25 (4H, m), 8.39 (1H, s), 8.72 (1H, d, J = HRMS (ESI-TOF) m / z: [M + H] + calcd for C 25 H 21 N4O2409.1665; Found 409.1658. The confirmed structure is:

[0350] Example 129: Preparation of Compound 129. 4-Methoxybenzoyl chloride (39.2 mg, 0.230 mmol) and triethylamine (0.130 mL, 0.953 mmol) were added to a dichloroethane solution (2 mL) of Intermediate 59 (50.0 mg, 0.148 mmol) at room temperature, followed by stirring at room temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain Compound 129 as a yellow solid (8.70 mg, 0.0240 mmol, 16%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ3.87 (3H, s), 4.67 (2H, d, J = 5.2 Hz), 6.98 (2H, d, J = 8.4 Hz), 7.40-7.47 (2H, m), 7.96 (1H, d, J = 8.8 Hz), 8.00 (2H, d, J = 8.8 Hz), 8.25 (1H, d, J = 8.0 Hz), 8.36 (1H, s), 8.49 (1H, d, J = 8.4 Hz), 8.74 (1H, br), 9.14 (1H, br), 9.60 (1H, br); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 18 N4O3Na 385.1277; Found 385.1270. The confirmed structure is:

[0351] Example 130: Preparation of Compound 130. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 2-methylbenzoic acid (31.3 mg, 0.230 mmol), N,N-diisopropylethylamine (0.330 ml, 1.89 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain compound 130 as a yellow solid (12.9 mg, 0.0372 mmol, 25%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ2.09 (3H, s), 4.49 (2H, d, J = 6.4 Hz), 7.24-7.55 (5H, m), 7.81 (1H, d, J = 8.0 Hz), 8.15 (1H, d, J = 8.8 Hz), 8.22 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 20 H 18 N4O3Na 369.1327; Found 369.1320. The confirmed structure is:

[0352] Example 131: Preparation of compound 131 (1) Preparation of intermediate 83 A known compound (intermediate 83) represented by the following structural formula was synthesized according to the method described in Catalysis Science Technology (2023), 13(8), 2508-2516.

[0353] (2) Preparation of Compound 131: To a dichloromethane solution (2 ml) of Intermediate 59 (50.0 mg, 0.148 mmol), 4-ethylbenzoic acid (Intermediate 83) (28.1 mg, 0.187 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.379 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain Compound 131 as a yellow solid (2.00 mg, 0.00555 mmol, 3.8%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ1.35 (3H, t, J = 7.6 Hz), 2.71 (2H, q, J = 7.6 Hz), 4.78 (2H, s), 7.36 (2H, d, J = 7.6 Hz), 8.12 (1H, s), 8.20 (2H, d, J = 7.6 Hz), 8.43 (1H, d, J = 8.0 Hz), 8.80 (1H, s), 8.93 (1H, d, J = 8.4 Hz), 9.05-9.14 (2H, m), 10.20-10.27 (2H, m), 12.13 (1H, s); HRMS (ESI-TOF) m / z: [M + H] + calcd for C21 H 21 N4O2361.1665; Found 361.1656. The confirmed structure is:

[0354] Example 132: Preparation of Compound 132 To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 3-chlorobenzoic acid (36.0 mg, 0.230 mmol), N,N-diisopropylethylamine (0.170 ml, 0.976 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (144 mg, 0.379 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to give compound 132 as a yellow solid (16.9 mg, 0.0461 mmol, 31%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ4.46 (2H, d, J = 5.6 Hz), 7.45-7.52 (2H, m), 7.61 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 8.8 Hz), 7.92 (1H, d, J = 7.6 Hz), 8.02 (1H, s), 8.09 (1H, d, J = 8.8 Hz), 8.17 (1H, d, J = 8.0 Hz), 8.34 (1H, s), 8.67 (1H, d, J = 3.6 Hz), 9.00 (1H, s), 9.22 (1H, t, J = 6.0 Hz), 10.91 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 15ClN4O2Na 389.0781; Found 389.0774. The confirmed structure is:

[0355] Example 133: Preparation of Compound 133. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 2-fluorobenzoic acid (32.2 mg, 0.230 mmol), N,N-diisopropylethylamine (0.330 ml, 1.89 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to give compound 133 as a yellow solid (18.8 mg, 0.0537 mmol, 36%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.70 (2H, d, J = 6.0 Hz), 7.20 (1H, dd, J = 8.0, 4.8 Hz), 7.31 (1H, t, J = 7.6 Hz), 7.51-7.58 (1H, m), 7.71 (1H, t, J = 6.4 Hz), 7.95 (1H, d, J = 8.8 Hz), 8.12 (1H, t, J = 8.0 Hz), 8.25 (1H, br), 8.42-8.50 (2H, m), 8.60 (1H, d, J = 7.6 Hz), 8.79 (1H, d, J = 4.4 Hz), 9.46 (1H, d, J = 12.0 Hz), 9.60 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 15FN4O2Na 373.1077; Found 373.1069. The confirmed structure is:

[0356] Example 134: Preparation of Compound 134. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 3,4-dimethylbenzoic acid (34.5 mg, 0.230 mmol), N,N-diisopropylethylamine (0.330 ml, 1.89 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 134 as a yellow solid (15.0 mg, 0.0416 mmol, 28%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (DMSO, 400 MHz): δ2.29 (6H, s), 4.50 (2H, d, J = 5.6 Hz), 7.26 (1H, d, J = 8.0 Hz), 7.52 (1H, dd, J = 8.0, 4.8 Hz), 7.74-7.86 (3H, m), 8.15 (1H, d, J = 8.4 Hz), 8.22 (1H, d, J = 8.4 Hz), 8.37 (1H, s), 8.72 (1H, d, J = 4.4 Hz), 9.05 (1H, s), 9.26 (1H, t, J = 5.6 Hz), 10.62 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 21 H 20N4O2Na 383.1484; Found 383.1478. The confirmed structure is:

[0357] Example 135: Preparation of Compound 135. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 2,4-dimethylbenzoic acid (34.5 mg, 0.230 mmol), N,N-diisopropylethylamine (0.330 ml, 1.89 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to give compound 135 as a yellow solid (6.80 mg, 0.0189 mmol, 13%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ2.35 (3H, s), 2.48 (3H, s), 4.63 (2H, d, J = 6.0 Hz), 7.04-7.15 (3H, m), 7.41-7.49 (2H, m), 7.84 (1H, d, J = 8.8 HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 21 H 20 N4O2Na 383.1484; Found 383.1475. The confirmed structure is:

[0358] Example 136: Preparation of Compound 136 To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 3,5-dimethylbenzoic acid (34.5 mg, 0.230 mmol), N,N-diisopropylethylamine (0.330 ml, 1.89 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to give compound 136 as a yellow solid (11.8 mg, 0.0327 mmol, 22%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ2.38 (6H, s), 4.65 (2H, d, J = 6.0 Hz), 7.14 (1H, br), 7.20 (1H, s), 7.42 (1H, dd, J = 8.0, 4.8 Hz), 7.57 (1H, s), 7.71 (1H, s), 7.83 (1H, d, J = 8.8 Hz), 8.21 (1H, d, J = 8.0 Hz), 8.32 (1H, s), 8.41 (1H, d, J = 8.8 Hz), 8.73 (1H, d, J = 4.8 Hz), 9.09 (1H, s), 9.25 (1H, br); HRMS (ESI-TOF) m / z: [M + H] + calcd for C 21 H 21 N4O2361.1665; Found 361.1658. The confirmed structure is:

[0359] Example 137: Preparation of Compound 137. To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 3,4-difluorobenzoic acid (36.4 mg, 0.230 mmol), N,N-diisopropylethylamine (0.330 ml, 1.89 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give compound 137 as a yellow solid (16.8 mg, 0.0456 mmol, 31%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.74 (2H, d, J = 5.6 Hz), 7.28-7.36 (1H, m), 7.78 (1H, t, J = 8.0 Hz), 7.85-8.05 (4H, m), 8.19 (1H, d, J = 8.8 Hz), 8.54 (1H, s), 8.64-8.71 (2H, m), 8.85 (1H, d, J = 5.2 Hz), 9.69 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 14 F2N4O2Na 391.0983; Found 391.0976. The confirmed structure is:

[0360] Example 138: Preparation of Compound 138 To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 3,5-difluorobenzoic acid (36.4 mg, 0.230 mmol), N,N-diisopropylethylamine (0.330 ml, 1.89 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to give compound 138 as a yellow solid (25.5 mg, 0.0692 mmol, 47%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.83 (2H, d, J = 6.0 Hz), 6.97-7.05 (2H, m), 7.41-7.61 (4H, m), 7.85 (1H, dd, J = 8.8, 1.6 Hz), 8.24-8.30 (2H, m), 8.39 (1H, d, J = 8.8 Hz), 8.73 (1H, d, J = 3.6 Hz), 9.14 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 14 F2N4O2Na 391.0983; Found 391.0975. The confirmed structure is:

[0361] Example 139: Preparation of Compound 139 To a solution of Intermediate 59 (50.0 mg, 0.148 mmol) in dichloromethane (2 ml), 2,4-difluorobenzoic acid (36.4 mg, 0.230 mmol), N,N-diisopropylethylamine (0.330 ml, 1.89 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145 mg, 0.381 mmol), and dimethylaminopyridine (4.60 mg, 0.0376 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to give compound 139 as a yellow solid (22.2 mg, 0.0603 mmol, 41%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1 H NMR (CDCl3, 400 MHz): δ4.67 (2H, d, J = 6.0 Hz), 6.91-6.98 (1H, m), 7.02-7.09 (1H, m), 7.20 (1H, br), 7.49 (1H, dd, J = 8.0, 4.8 Hz), 7.82 (1H, d, J = 8.4 Hz), 8.12-8.20 (1H, m), 8.26-8.38 (3H, m), 8.74 (1H, s), 9.09 (1H, d, J = 12.4 Hz), 9.18 (1H, s); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 14 F2N4O2Na 391.0983; Found 391.0975. The confirmed structure is:

[0362] Example 140: Preparation of Compound 140 (1) Preparation of Intermediate 95 To a methanol solution (2 ml) of Intermediate 57 (100 mg, 0.313 mmol), nickel chloride hexahydrate (73.7 mg, 0.310 mmol) and sodium borohydride (35.2 mg, 0.930 mmol) were added in an ice bath, and the mixture was stirred at the same temperature for 0.5 hours. Triethylamine (0.0900 ml, 0.646 mmol) and 3-quinolinecarbonyl chloride (119 mg, 0.621 mmol) were added at the same temperature, and the mixture was further stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to give Intermediate 95 as a yellow oil (100 mg, 0.352 mmol, 21%).

[0363] (2) Preparation of Intermediate 96: To a solution of Intermediate 95 (100 mg, 0.352 mmol) in dichloromethane (1.5 ml) was added 4 M HCl / dioxane (1 ml), and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to give Intermediate 96 (64.8 mg, 0.167 mmol, 47%).

[0364] (3) Preparation of Compound 140. To a dichloromethane solution (2 ml) of Intermediate 96 (64.8 mg, 0.167 mmol), benzoyl chloride (0.0300 ml, 0.280 mmol) and N,N-diisopropylethylamine (0.200 ml, 1.15 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 97:3) to obtain Compound 140 as a yellow solid (40.6 mg, 0.106 mmol, 63%). The NMR spectrum and HR-ESI-MS mass spectrometry results are as follows: 1H NMR (CDCl3, 400 MHz): δ4.65 (2H, d, J = 6.0 Hz), 7.20-7.93 (12H, m), 8.13 (1H, d, J = 8.4 Hz), 8.33 (1H, s), 8.62 (1H, s), 9.30 (1H, d, J = 2.4 Hz); HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 23 H 18 N4O2Na 405.1327; Found 405.1320. The confirmed structure is:

[0365] Example 141: Preparation of Compound 141 (1) Preparation of Intermediate 97 Nickel chloride hexahydrate (73.7 mg, 0.310 mmol) and sodium borohydride (35.2 mg, 0.930 mmol) were added to a methanol solution (2 ml) of Intermediate 57 (100 mg, 0.313 mmol) in an ice bath, and the mixture was stirred at the same temperature for 0.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. To a solution of the residue in dichloromethane (2 ml), 3-pyridineacetic acid (51.0 mg, 0.372 mmol), N,N-diisopropylethylamine (0.270 ml, 1.55 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (236 mg, 0.621 mmol), and dimethylaminopyridine (7.60 mg, 0.0622 mmol) were added at room temperature, and the mixture was stirred at the ...

Claims

1. A compound represented by the following general formula (I): [In the formula, R ａ and R ｂ are independently a hydrogen atom, a halogen atom, a nitro, a cyano, an amino, a hydroxyl, １～６ Alkyl, haloC １～６ Alkyl, Amino C １～６ Alkyl, Hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl or C ２～６ alkynyloxy or R on the adjacent carbon atom ａ and R ｂ may together with the carbon atom to which they are attached form a substituted or unsubstituted carbocyclic or heterocyclic ring fused to the pyridine ring; １ is a direct bond, -CR １１ =CR １１ -or- (CONR １１ ) ｍ CH ２ - and R １ is a hydrogen atom or C １～６ is alkyl; L １ is C １～１０ Alkylene, arylene, C １～１０ Alkylene-arylene, arylene-C １～１０ Alkylene, C １～１０ Alkylene-arylene-C １～１０ Alkylene, arylene-C １～１０ Alkylene-arylene, heterocyclylene, C １～１０ Alkylene-heterocyclylene, heterocyclylene-C １～１０ Alkylene or C １～１０ Alkylene-heterocyclylene-C １～１０ alkylene, where the alkylene, arylene or heterocyclylene moiety is selected from halogen, —COOR １２ , -CONHR １２ or oxo, ２ is a direct bond, —O—, —NR １３ --, --NR １３ SO ２ - or - (OCH ２ CH ２ ) ｎ O-, R ２ is a hydrogen atom, azide, a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, -COR １４ , substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, where m is 0 or 1, n is 1 to 6, R １１ are independently a hydrogen atom or C １～６ is alkyl, R １２ is a hydrogen atom or C １～６ is alkyl, R １３ is a hydrogen atom, C １～６ Alkyl or -COR １４ And R １４ is a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～１０ Cycloalkyl, substituted or unsubstituted C ３～１０ or a pharma- ceutically acceptable salt thereof (wherein L is a cycloalkenyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclyl). １ But, arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, or C １～３ Alkylene-arylene-C １～３ alkylene, and L ２ is a direct bond, １ But, C １～３ alkylene-arylene, L ２ is —O—, and １ But, C １～３ alkylene, and L ２ is -NH-, and R ２ is -CO-5-membered heterocyclyl).

2. The compound has the following general formula (Ia): [In the formula, X １ is a direct bond, -CR １１ =CR １１ -or- CONR １１ CH ２ - and R １ is a hydrogen atom or C １～６ is alkyl; L １ is C １～１０ Alkylene, arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, C １～３ Alkylene-arylene-C １～３ Alkylene, Heterocyclylene, C １～３ Alkylene-heterocyclylene, heterocyclylene-C １～３ Alkylene or C １～３ Alkylene-heterocyclylene-C １～３ alkylene, wherein the alkylene moiety is -COOR. １２ Or -CONHR １２ and L ２ is a direct bond, —O—, —NR １３ --, --NR １３ SO ２ - or - (OCH ２ CH ２ ) ｎ O-, R ２ is a hydrogen atom, azide, a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, -COR １４ , substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, where n is 1 to 6; R １１ are independently a hydrogen atom or C １～６ is alkyl, R １２ is a hydrogen atom or C １～６ is alkyl, R １３ is a hydrogen atom, C １～６ Alkyl or -COR １４ And R １４ is a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl; １ But, arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, or C １～３ Alkylene-arylene-C １～３ alkylene, and L ２ is a direct bond, １ But, C １～３ alkylene-arylene, L ２ is —O—, and １ But, C １～３ alkylene, and L ２ is -NH-, and R ２ or a pharma- ceutically acceptable salt thereof according to claim 1, wherein R is --CO-5-membered heterocyclyl.

3. L ２ The compound according to claim 1 or 2, wherein is -O- or -NH-, or a pharma- ceutically acceptable salt thereof.

4. The compound has the following general formula (II): [In the formula, X １１ is a direct bond, -CR １１ =CR １１ -or- CONR １１ CH ２ - and X １２ is a direct bond, C １～３ Alkylene, -CR １１ =CR １１ -or-CH ２ N.R. １１ CO-, L １１ is C １～１０ Alkylene, arylene, C １～３ Alkylene-arylene, arylene-C １～３ Alkylene, C １～３ Alkylene-arylene-C １～３ Alkylene, Heterocyclylene, C １～３ Alkylene-heterocyclylene, heterocyclylene-C １～３ Alkylene or C １～３ Alkylene-heterocyclylene-C １～３ alkylene; L ２１ is —O— or —NH—; Y １ is N or CH; R １１ are independently a hydrogen atom or C １～６ is alkyl, R １２ is a hydrogen atom or C １～６ is alkyl, R ２１ are independently halogen, nitro, cyano, amino, hydroxy, C １～６ Alkyl, haloC １～６ Alkyl, Hydroxy C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C １～６ Alkoxycarbonyl, C ２～６ Alkenyl, C ２～６ Alkenyloxy, C ２～６ Alkynyl and C ２～６ 4. The compound according to claim 3, wherein the compound is selected from the group consisting of:

5. L ２ is a direct bond or -(OCH ２ CH ２ ) ｎ The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein R is O-.

6. R ２ is a hydrogen atom, a substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ 6. The compound of claim 5, which is alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, or a pharma- ceutically acceptable salt thereof.

7. The following compound:

2. The compound of claim 1, wherein:

8. A pharmaceutical composition comprising the compound according to claim 1 or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient.

9. A pharmaceutical composition according to claim 8 for the treatment of diseases which are prevented, alleviated and / or cured by the inhibition of axonal degeneration.

10. The pharmaceutical composition according to claim 9, wherein the disease is a neurodegenerative disease.

11. Use of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease which is prevented, alleviated and / or cured by the inhibition of axonal degeneration.

12. A method for treating a disease prevented, alleviated and / or cured by inhibition of axonal degeneration, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 8 for the treatment of a disease which is prevented, alleviated and / or cured by SARM1 inhibition.

14. The pharmaceutical composition according to claim 13, wherein the disease is a neurodegenerative disease.

15. Use of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease which is prevented, alleviated and / or cured by SARM1 inhibition.

16. A method for treating a disease prevented, alleviated and / or cured by SARM1 inhibition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof.

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