Novel 3,5-diaminobenzoic acid-based compounds, Pin1 inhibitors using the same, and therapeutic agents for inflammatory diseases

Abstract

[Problem] To develop novel compounds having an activity of inhibiting the function of Pin1 so as to use these compounds as pharmaceutical candidate compounds. [Solution] A compound represented by formula (I) or a salt thereof, and a Pin1 inhibitor, a pharmaceutical composition, a therapeutic or prophylactic agent for inflammatory diseases, a therapeutic or prophylactic agent for fatty liver diseases, a therapeutic or prophylactic agent for obesity, and a therapeutic or prophylactic agent for COVID-19, each using the aforesaid compound or a salt thereof.

Description

Technical Field

[0001] The present invention relates to a novel low-molecular organic compound of the 3,5-diaminobenzoic acid type, and further to a Pin1 inhibitor, a pharmaceutical composition, a therapeutic or prophylactic agent for inflammatory diseases including non-alcoholic steatohepatitis (NASH), inflammatory bowel disease, and pulmonary fibrosis, a therapeutic or prophylactic agent for fatty liver disease, and a therapeutic or prophylactic agent for obesity using the compound. Furthermore, the present invention relates to a therapeutic or prophylactic agent for viral diseases that infect humans using the compound, for example, coronavirus infection, particularly coronavirus infection caused by beta coronavirus, especially coronavirus infection (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Background Art

[0002] Pin1 is a kind of peptidyl-prolyl cis-trans isomerase (PPIase) that catalyzes the cis / trans conformational change of proline in proteins, and has the characteristic of specifically acting on proline located next to phosphorylated serine or threonine to change the conformational structure. Therefore, Pin1 is a molecule that links protein phosphorylation to protein structural changes and is considered to play an important role in intracellular signal transduction. Regarding Pin1, it has been reported that Pin1 inhibitors suppress the growth of cancer cells (Non-Patent Documents 1 and 2). In addition, the present inventors have previously reported that Pin1, a kind of cis-trans isomerase, binds to IRS-1, which plays a central role in insulin signaling, and enhances its signal transduction (Non-Patent Document 3).

[0003] As compounds that inhibit Pin1, phenylalaninol phosphate derivatives, indole or benzimidazole alanine derivatives, fredericamycin A compounds, phenylimidazole derivatives, naphthyl-substituted amino acid derivatives, glutamic acid or aspartic acid derivatives, etc. have been reported (Patent Documents 1 to 4 and Non-Patent Documents 1, 2, and 4).

[0004] The present inventors previously found that Pin1 knockout mice are resistant to the development of NASH and obesity caused by a high-fat diet (Non-Patent Document 5). And when the present inventors administered the compound Juglone having Pin1 inhibitory activity with the following structure to mice induced with NASH, they found that the development of NASH was improved (Non-Patent Documents 6 and 7).

[0005]

Chemical formula

[0006] In addition, when the present inventors orally administered a known Pin1 inhibitor to mice induced with colonic inflammation, they found that the development of colonic inflammation was suppressed (Non-Patent Document 8).

[0007] Furthermore, the present inventors developed novel ester compounds, amide compounds, and anthranilic acid compounds that can be Pin1 inhibitors, and found that these compounds can be used as therapeutic or prophylactic agents for inflammatory diseases including non-alcoholic steatohepatitis (NASH) and inflammatory bowel disease, therapeutic or prophylactic agents for fatty liver diseases, therapeutic or prophylactic agents for obesity, and therapeutic or prophylactic agents for cancer (Patent Documents 5 to 8).

[0008] By the way, the coronavirus is a virus that infects not only humans but also animals and causes various diseases. In addition to domestic animals such as dogs, cats, cows, pigs, chickens, horses, alpacas, and camels, coronaviruses (animal coronaviruses) specific to each animal have been detected from dolphins, giraffes, ferrets, skunks, bats, and sparrows. The species specificity of coronaviruses is high, and it rarely infects other animals across species barriers. Coronaviruses that infect humans are known as four types of coronaviruses that infect humans daily (Human Coronavirus: HCoV), namely HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, and two types of severe pneumonia viruses that infect from animals, namely Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV).

[0009] Around December 2019, the infection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was confirmed as a novel coronavirus, and it spread around the world in an instant, becoming a global pandemic, and there is still no sign of its end. The infectious disease (COVID-19) caused by SARS-CoV-2 mainly spreads through human-to-human infection via droplets in the air scattered by the coughs and sneezes of infected individuals. COVID-19 shows symptoms such as fever, respiratory symptoms, headache, and fatigue, and may also cause olfactory and gustatory disorders. In particular, the fatality rate of COVID-19 is high among the elderly and patients with underlying diseases (cardiovascular diseases, diabetes, chronic respiratory diseases, chronic kidney diseases, hypertension, obesity). Under such circumstances, effective therapeutic and preventive drugs for COVID-19 are strongly desired. The novel coronavirus is a type of RNA virus (single-stranded RNA virus) that has RNA as its genetic information and has a double membrane made of lipids called an "envelope" on the outermost layer of the particle. It is spherical with a diameter of about 100 nm, has protrusions on its surface, and its morphology resembles a crown. The novel coronavirus cannot multiply on its own but attaches to and enters cells such as human mucous membranes to proliferate. Virologically, it is classified into the order Nidovirales, subfamily Coronavirinae, and family Coronaviridae, and is classified into four groups, α, β, γ, and δ, based on genetic characteristics. HCoV-229E and HCoV-NL63 are classified as α-coronaviruses, and MERS-CoV, SARS-CoV, SARS-CoV-2, HCoV-OC43, and HCoV-HKU1 are classified as β-coronaviruses.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Non-Patent Documents

[0011]

Non-Patent Document 1

Non - Patent Document 2

Non - Patent Document 3

Non - Patent Document 4

Non - Patent Document 5

Non - Patent Document 6

Non - Patent Document 7

Non-Patent Document 8

Summary of the Invention

Problems to be Solved by the Invention

[0012] In view of the above conventional situation, the object of the present invention is to develop a novel group of compounds having an activity of inhibiting the function of Pin1 and use them as candidate compounds for pharmaceuticals.

Means for Solving the Problems

[0013] As a result of intensive research to solve the above problems, the inventors of the present invention developed a novel group of compounds by synthesizing a large number of derivatives of 3,5-diaminobenzoic acid. These novel compounds have an activity of inhibiting the function of Pin1 and have been found to be therapeutic agents for inflammatory diseases such as non-alcoholic steatohepatitis, fatty liver diseases, and obesity, thus completing the present invention. Furthermore, as a result of intensive research, the inventors of the present invention found that in COVID-19, the fatality rate of obese patients is high, and the Pin1 expression level is significantly increased in the livers of human subjects with fatty liver. Therefore, they investigated the effect of Pin1 on SARS-CoV-2 proliferation and found that the proliferation of SARS-CoV-2 can be suppressed by using a Pin1 inhibitor, thus completing the present invention.

[0014] That is, the present invention provides the following first invention related to a novel compound or a salt thereof, the following second invention related to a Pin1 inhibitor, the following third invention related to a pharmaceutical composition, the following fourth invention related to a therapeutic or prophylactic agent for inflammatory diseases, the following fifth invention related to a therapeutic or prophylactic agent for fatty liver diseases, the following sixth invention related to a therapeutic or prophylactic agent for obesity, and the following seventh invention related to a therapeutic or prophylactic agent for COVID-19.

[0015] The first invention provides a compound represented by the following formula (I) or a salt thereof.

[0016] [Chemical formula] (In the formula, ring A represents a monocyclic or polycyclic aromatic ring or heterocyclic ring which may have a substituent. R1 represents a group represented by any one of the following formulas (II) to (V).

[0017] [Chemical formula] (In the formula, ring B represents a monocyclic heterocyclic ring which may have a substituent, ring C and ring D each independently represent a monocyclic or polycyclic aromatic ring, heterocyclic ring or cycloalkane which may have a substituent, and ring B, ring C and ring D form a fused ring.)

[0018] [Chemical formula] (In the formula, ring E represents a monocyclic heterocyclic ring which may have a substituent, ring F represents a monocyclic or polycyclic aromatic ring, heterocyclic ring or cycloalkane which may have a substituent, and ring E and ring F form a fused ring.)

[0019] [Chemical formula] (In the formula, ring G and ring H each represent a monocyclic or polycyclic aromatic ring or heterocyclic ring which may have a substituent.)

[0020]

Chemical formula

[0021] In the compound of the first invention or a salt thereof, it is preferable that the ring A is a polycyclic aromatic ring or heterocyclic ring which may have a substituent. In this case, it is preferable that the ring A is a ring represented by the following formula (VI).

[0022]

Chemical formula

[0023]

Chemical formula

Advantages of the Invention

[0024] The compound or its salt of the first invention can be a compound or its precursor having the activity of inhibiting the function of Pin1, or can be a therapeutic agent, prophylactic agent or its prodrug for inflammatory diseases, fatty liver diseases or obesity, so it can be used for the development of Pin1 inhibitors or the development of pharmaceuticals, etc. The Pin1 inhibitor of the second invention exhibits the activity of inhibiting the function of Pin1. The pharmaceutical composition of the third invention has the effect of treating or preventing diseases with the inhibition of the function of Pin1 as one mechanism of action. The therapeutic or prophylactic agent for inflammatory diseases of the fourth invention can reduce the symptoms of inflammatory diseases such as non-alcoholic steatohepatitis, inflammatory bowel disease, pulmonary fibrosis, etc. or prevent the onset of inflammatory diseases by suppressing inflammation. The therapeutic or prophylactic agent for fatty liver diseases of the fifth invention can reduce the symptoms of fatty liver diseases or prevent the onset of fatty liver diseases by suppressing the accumulation of fat. The therapeutic or prophylactic agent for obesity of the sixth invention can treat obesity or prevent becoming obese by suppressing the accumulation of fat. The therapeutic or prophylactic agent for COVID-19 of the seventh invention can treat or prevent coronavirus infections caused by SARS-CoV2.

Brief Description of the Drawings

[0025]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Mode for Carrying Out the Invention

[0026] 1. Compound or a salt thereof 1-1. Structure of the compound 1-1-1. General formula of the compound The compound of the present invention has a chemical structure represented by the following formula (I).

[0027]

Chemical formula

[0028] 1-1-2. Regarding ring A In formula (I), ring A represents a monocyclic or polycyclic aromatic ring or heterocyclic ring which may have a substituent. C in ring A represents a carbon atom, and ring A is linked to X via a carbon atom. When X is a single bond, ring A will be linked to a carbonyl group (-CO-) via a carbon atom.

[0029] In the present invention, the "aromatic ring" is an unsaturated carbon organic compound composed of carbon and hydrogen that forms a ring. Examples of the monocyclic aromatic ring include, but are not limited to, benzene ring, cyclopentadiene ring, etc. Examples of the polycyclic aromatic ring include, but are not limited to, naphthalene ring, indene ring, azulene ring, fluorene ring, phenanthrene ring, anthracene ring, tetracene ring, pentacene ring, benzopyrene ring, chrysene ring, pyrene ring, triphenylene ring, etc.

[0030] In the present invention, the "heterocyclic ring" refers to an organic compound composed of carbon, hydrogen, and other atoms that forms a single ring. Examples of monocyclic heterocyclic rings include, but are not limited to, pyrrole ring, imidazole ring, pyrrolidine ring, furan ring, tetrahydrofuran ring, 1,3-dioxolane ring, thiophene ring, pyridine ring, pyrazine ring, pyrimidine ring, piperazine ring, pyran ring, 1,4-dioxane ring, and the like. Examples of polycyclic aromatic rings include, but are not limited to, indole ring, quinoline ring, quinoxaline ring, quinazoline ring, purine ring, isobenzofuran ring, chroman ring, benzodioxane ring, benzodioxole ring, carbazole ring, acridine ring, phenoxazine ring, 4H-pyrido[2,3-c]carbazole ring, and the like.

[0031] In the present invention, the "cyclic hydrocarbon" refers to a saturated carbon organic compound composed of carbon and hydrogen that forms a ring. Examples of monocyclic cyclic hydrocarbons include, but are not limited to, cyclopentane, cyclohexane, cycloheptane, and the like. Examples of polycyclic cyclic hydrocarbons include, but are not limited to, tricycloheptane, tricyclododecane, perhydro-1,4-ethanoanthracene, and the like.

[0032] In the present invention, the "substituent" refers to a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), an alkyl group (e.g., a C 1-6 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, etc.), a cycloalkyl group (e.g., a C 3-6 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.), an alkynyl group (e.g., a C 2-6 alkynyl group such as ethynyl group, 1-propynyl group, propargyl group, etc.), an alkenyl group (e.g., a C 2-6(alkenyl group), aralkyl group (e.g., C of benzyl group, α-methylbenzyl group, phenethyl group, etc.) 7-11 (aralkyl group), aryl group (e.g., C of phenyl group, naphthyl group, etc.) 6-10 (aryl group, etc., preferably phenyl group), alkoxy group (e.g., C of methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy, etc.) 1-6 (alkoxy group), aryloxy group (e.g., C of phenoxy, etc.) 6-10 (aryloxy group), alkanoyl group (e.g., formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, etc., C of alkyl-carbonyl group) 1-6 (arylcarbonyl group, e.g., C of benzoyl group, naphthoyl group, etc.) 6-10 (aryl-carbonyl group), alkanoyloxy group (e.g., formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, etc., C of alkyl-carbonyl-oxy group) 1-6 (arylcarbonyl-oxy group, e.g., C of benzoyloxy group, naphthoyloxy group, etc.) 6-10 (aryl-carbonyl-oxy group), carboxyl group, alkoxycarbonyl group (e.g., C of methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl, etc.) 1-6 (alkoxy-carbonyl group), aralkyloxycarbonyl group (e.g., C of benzyloxycarbonyl group, etc.) 7-11 (aralkyloxycarbonyl group), carbamoyl group, halogenoalkyl group (e.g., mono-, di- or tri-halogeno-C of chloromethyl group, dichloromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, etc.) 1-4 (alkyl group), oxo group, amidino group, imino group, amino group, alkylamino group (e.g., mono-C of methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, etc.) 1-4(alkylamino group), dialkylamino group (e.g., di-C such as dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, methylethylamino group, etc.) 1-4 (alkylamino group), alkoxycarbonylamino group (e.g., C such as methoxycarbonylamino group, isopropoxycarbonylamino group, tert-butoxycarbonylamino group, etc.) 1-6 (alkoxycarbonylamino group), cyclic amino group (a 3- to 6-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atom and one nitrogen atom, e.g., aziridinyl group, azetidinyl group, pyrrolidinyl group, pyrrolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, imidazolidinyl group, piperidyl group, morpholinyl group, dihydropyridyl group, pyridyl group, N-methylpiperazinyl group, N-ethylpiperazinyl group, etc.), alkylenedioxy group (e.g., C such as methylenedioxy group, ethylenedioxy group, etc.) 1-3 (alkylenedioxy group), hydroxy group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, monoalkylsulfamoyl group (e.g., mono-C such as N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.) 1-6 (alkylsulfamoyl group), dialkylsulfamoyl group (e.g., di-C such as N,N-dimethylsulfamoyl group, N,N-diethylsulfamoyl group, N,N-dipropylsulfamoyl group, N,N-dibutylsulfamoyl group, etc.) 1-6 (alkylsulfamoyl group), alkylthio group (e.g., C such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, sec-butylthio group, tert-butylthio group, etc.) 1-6 (alkylthio group), arylthio group (e.g., C such as phenylthio group, naphthylthio group, etc.) 6-10 (arylthio group), alkylsulfinyl group (e.g., C such as methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, butylsulfinyl group, etc.) 1-6an alkylsulfinyl group), an alkylsulfonyl group (e.g., a C such as a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, etc.) 1-6 alkylsulfonyl group), or an arylsulfonyl group (e.g., a C such as a phenylsulfonyl group, a naphthylsulfonyl group, etc.) 6-10 arylsulfonyl group).

[0033] In the present invention, "optionally having a substituent" means having or not having the above-mentioned substituent. When having a substituent, two or more substituents can be had, and they may be the same or different substituents. In the compound of the present invention, when "optionally having a substituent", the number of substituents is preferably 0 to 3, more preferably 0. As the "substituent", a substituent having 0 to 12 carbon atoms is preferable, and more preferably, a substituent having 0 to 6 carbon atoms is good. Further, as the "substituent", a substitution having 1 to 10 atoms is preferable, and such substituents include, but are not limited to, for example, a halogen atom, a methyl group, an ethyl group, a vinyl group, a methoxy group, an ethoxy group, an acetyl group, a carboxyl group, a methoxycarbonyl group, a chloromethyl group, an amino group, a methylamino group, a hydroxy group, a sulfo group, a methylthio group, etc.

[0034] Ring A in the above formula (I) is, as described above, an optionally substituted monocyclic or polycyclic aromatic ring or heterocyclic ring, but it is preferably an optionally substituted polycyclic aromatic ring or heterocyclic ring. More preferably, ring A is preferably a group represented by the following formula (VI).

[0035]

Chemical formula

[0036] In formula (VI), A1, A2, and A3 each independently represent a carbon atom or a nitrogen atom, and ring K represents a monocyclic or polycyclic aromatic ring, heterocyclic ring, or cyclic hydrocarbon which may have a substituent.

[0037] Examples of the group represented by formula (VI) include, but are not limited to, groups having the following structures.

[0038]

Chemical formula

[0039] As the group represented by formula (VI), a group in which A1, A2, and A3 are all carbon atoms is preferable. Further, as the group represented by formula (VI), a group in which ring K is a monocyclic or polycyclic aromatic ring which may have a substituent is preferable. More preferably, a naphthyl group is used as the group represented by formula (VI).

[0040] 1-1-3. Regarding R1 In the above formula (I), R1 represents a group represented by any one of formulas (II) to (V). The group represented by formula (II) is a group having the following structure.

[0041]

Chemical formula

[0042] In formula (II), ring B represents a monocyclic heterocyclic ring which may have a substituent, and rings C and D each independently represent a monocyclic or polycyclic aromatic ring, heterocyclic ring, or cyclic hydrocarbon which may have a substituent. Rings B, C, and D form a fused ring. N in ring B represents a nitrogen atom, and ring B is connected to Y via the nitrogen atom. When Y is a single bond, ring B will be connected to a carbonyl group (-CO-) via the nitrogen atom.

[0043] Examples of the group represented by the formula (II) include, but are not limited to, groups having the following structures.

[0044]

Chemical formula

[0045] Ring C and ring D are preferably monocyclic aromatic rings or heterocyclic rings which may have substituents, and more preferably, both are monocyclic aromatic rings which may have substituents. In these cases, the group represented by the formula (II) is a heterocyclic ring having three rings. Also, the group represented by the formula (II) is preferably a carbazolyl group which may have substituents.

[0046] The group represented by the formula (III) is a group having the following structure.

[0047]

Chemical formula

[0048] In the formula (III), ring E represents a monocyclic heterocyclic ring which may have substituents, and ring F represents a monocyclic or polycyclic aromatic ring, heterocyclic ring or cycloalkane which may have substituents. Ring E and ring F form a fused ring. N in ring E represents a nitrogen atom, and ring E is linked to Y through the nitrogen atom. When Y is a single bond, ring E is linked to a carbonyl group (-CO-) through the nitrogen atom.

[0049] Examples of the group represented by the formula (III) include, but are not limited to, groups having the following structures.

[0050]

Chemical formula

[0051] Ring F is preferably a monocyclic aromatic ring or a heterocyclic ring which may have a substituent, and more preferably a monocyclic aromatic ring which may have a substituent. In these cases, the group represented by formula (III) is a heterocyclic ring having two rings.

[0052] The group represented by formula (IV) is a group having the following structure.

[0053]

Chemical formula

[0054] In formula (IV), ring G and ring H each represent a monocyclic or polycyclic aromatic ring or heterocyclic ring which may have a substituent.

[0055] Examples of the group represented by formula (IV) include, but are not limited to, groups having the following structures.

[0056]

Chemical formula

[0057] In formula (IV), ring G and ring H are preferably a monocyclic aromatic ring or heterocyclic ring which may have a substituent. Preferred as the group represented by formula (IV) is a diphenylamino group which may have a substituent.

[0058] The group represented by formula (V) is a group having the following structure.

[0059]

Chemical formula

[0060] In formula (V), ring I represents a monocyclic aromatic ring or heterocyclic ring which may have a substituent, and ring J represents a monocyclic or polycyclic aromatic ring, heterocyclic ring or cyclic hydrocarbon which may have a substituent. Ring I and ring J form a fused ring. In formula (V), R6 represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent.

[0061] In the present invention, the "hydrocarbon group" means a group of a compound composed of carbon atoms and hydrogen atoms, and although not limited thereto, for example, it can be an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group, an aromatic hydrocarbon group, and preferably those having 1 to 16 carbon atoms. Specific examples include, but are not limited to, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group and the like. Here, examples of the "alkyl group" include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group and the like. Examples of the "alkenyl group" include a vinyl group, a 1-propenyl group, an allyl group, an isopropenyl group, a butenyl group, an isobutenyl group and the like. Examples of the "alkynyl group" include an ethynyl group, a propargyl group, a 1-propynyl group and the like. Examples of the "cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like. Examples of the "aryl group" include a phenyl group, an indenyl group, a naphthyl group, a fluorenyl group, an anthryl group, a biphenylenyl group, a phenanthrenyl group, an as-indacenyl group, an s-indacenyl group, an acenaphthylenyl group, a phenalenyl group, a fluoranthenyl group, a pyrenyl group, a naphthacenyl group, a hexacenyl group and the like.

[0062] In the present invention, the "heterocyclic group" refers to a group of a cyclic compound composed of a carbon atom and an atom other than carbon. The "heterocyclic group" is not limited to these, but for example, it can be a 5- to 14-membered ring containing one or two selected from nitrogen, oxygen, and sulfur atoms other than carbon atoms as 1 to 4 heteroatoms, and can be a monocyclic to pentacyclic heterocyclic group. Specific examples include, but are not limited to, for example, as a 5-membered ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen atoms other than carbon atoms, 2- or 3-thienyl group, 2- or 3-furyl group, 1-, 2- or 3-pyrrolyl group, 1-, 2- or 3-pyrrolidinyl group, 2-, 4- or 5-oxazolyl group, 3-, 4- or 5-isoxazolyl group, 2-, 4- or 5-thiazolyl group, 3-, 4- or 5-isothiazolyl group, 3-, 4- or 5-pyrazolyl group, 2-, 3- or 4-pyrazolidinyl group, 2-, 4- or 5-imidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, 1H- or 2H-tetrazolyl group, etc. can be mentioned. Also, as a 6-membered ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen atoms other than carbon atoms, it is not limited to these, but for example, 2-, 3- or 4-pyridyl group, N-oxide-2-, 3- or 4-pyridyl group, 2-, 4- or 5-pyrimidinyl group, N-oxide-2-, 4- or 5-pyrimidinyl group, thiomorpholinyl group, morpholinyl group, piperidino group, 2-, 3- or 4-piperidyl group, thiopyranyl group, 1,4-oxazinyl group, 1,4-thiazinyl group, 1,3-thiazinyl group, piperazinyl group, triazinyl group, 3- or 4-pyridazinyl group, pyrazinyl group, N-oxide-3- or 4-pyridazinyl group, etc. can be mentioned.In addition, as the bicyclic to tetracyclic condensed ring group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms, although not limited thereto, for example, indolyl group, benzofuryl group, benzothiazolyl group, benzoxazolyl group, xanthenyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, quinolizinyl group, 1,8-naphthyridinyl group, dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, perimidinyl group, phenazinyl group, chromanyl group, phenothiazinyl group, phenoxazinyl group, 7H-pyrazino[2,3-c]carbazolyl group and the like can be mentioned.

[0063] Examples of the group represented by formula (V) include, but are not limited to, groups having the following structures.

[0064]

Chemical formula

[0065] In formula (V), ring J is preferably a monocyclic aromatic ring or heterocyclic ring which may have a substituent. Further, R6 is preferably a hydrogen atom.

[0066] The groups represented by the above formulas (II) to (V) all have two or more rings and are groups characterized by being linked to Y via a nitrogen atom. In the present invention, from the viewpoint of the activity of the compound, among the groups represented by formulas (II) to (V), it is preferable to use a compound having a group represented by formula (II) or formula (IV), and more preferably, it is good to use a compound having a group represented by formula (II).

[0067] 1-1-4. Regarding R2 to R5, In the above formula (I), R2 represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or an amino group which may have a substituent. In the present invention, the "amino group which may have a substituent" is a primary amino group, a secondary amino group, or a tertiary amino group. As the secondary amino group, an amino group having one substituent can be used, and although not limited thereto, for example, an alkylamino group, an arylamino group, an alkoxycarbonylamino group, etc. can be used. Further, as the tertiary amino group, an amino group having two identical or different substituents can be used, and although not limited thereto, for example, a dialkylamino group, a diarylamino group, etc. can be used.

[0068] In the present invention, from the viewpoint of the activity of the compound, it is preferable to use a compound in which R2 is a hydrogen atom or a methyl group, and particularly, it is preferable to use a compound in which R2 is a hydrogen atom and the -CO2R2 group is a carboxyl group (-CO2H). However, even when R2 is a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or an amino group which may have a substituent and the activity is low, it can be easily substituted with a hydrogen atom by hydrolysis to become a carboxyl group, and the activity may increase. Therefore, such a compound can also be used as a prodrug.

[0069] In the formula (I), R3 represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. Further, R4 represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. In the present invention, from the viewpoint of the activity of the compound, it is preferable to use a compound in which R3 and R4 are hydrogen atoms. Such a compound can be represented by the following general formula (VII).

[0070]

Chemical formula

[0071] In formula (VII), ring A, R1, R2, R5, X and Y are the same as those in formula (I) above.

[0072] In formula (I) above, R5 represents the same or different 0 to 3 substituents linked to the benzene ring. Here, "different" includes the case where only one of the three substituents is different. In the present invention, it is preferable to use a compound in which R5 is 0, that is, a compound having hydrogen atoms at the 2nd, 4th, and 6th positions of the benzene ring.

[0073] 1-1-5. Regarding X and Y In formula (I) above, X represents a single bond, an alkylene group having 1 or 2 carbon atoms, an -O- group, a -CH2-O- group, a -CH2-NH-CO- group, or a -CH2-NH-CO-O-CH2- group. In the present invention, from the viewpoint of the activity of the compound, it is preferable to use a compound in which X is a single bond, a -CH2-O- group, or a -CH2-NH-CO- group, and more preferably, it is good to use a compound in which X is a single bond.

[0074] In formula (I) above, Y represents a single bond or an alkylene group having 1 or 2 carbon atoms. In the present invention, from the viewpoint of the activity of the compound, it is preferable to use a compound in which Y is a single bond or an alkylene group having 1 carbon atom (methylene group), and more preferably, it is good to use a compound in which Y is a single bond. Here, "single bond" indicates a state where the groups on both sides of X (or Y) are directly linked without passing through a linking group.

[0075] In the present invention, from the viewpoint of the activity of the compound, in the compound represented by formula (I), it is preferable that R3 and R4 are hydrogen atoms, and more preferably, X and Y are single bonds. Such a compound can be represented by the following general formula (VIII).

[0076]

Chemical formula

[0077] In formula (VIII), ring A, R1, R2, and R5 are the same as those in the aforementioned formula (I).

[0078] 1-2. Salts of the compound The salts of the compound of the present invention can be salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with acidic or basic amino acids, etc. When the compound of the present invention represented by formula (I) has an acidic functional group, it can form salts with inorganic bases, organic bases, and basic amino acids. Also, when the compound of the present invention represented by formula (I) has a basic functional group, it can form salts with inorganic acids, organic acids, and acidic amino acids.

[0079] Examples of the salts with inorganic bases include, but are not limited to, sodium salts, potassium salts, ammonium salts, etc. Examples of the salts with organic bases include, but are not limited to, salts with trimethylamine, ethanolamine, cyclohexylamine, etc. Examples of the salts with inorganic acids include, but are not limited to, salts with hydrochloric acid, phosphoric acid, etc. Examples of the salts with organic acids include, but are not limited to, salts with acetic acid, phthalic acid, fumaric acid, oxalic acid, etc. Examples of the salts with acidic amino acids include, but are not limited to, salts with aspartic acid, glutamic acid, etc., and examples of the salts with basic amino acids include salts with arginine, lysine, etc.

[0080] 1-3. Methods for producing the compound The compound of the present invention can be synthesized, for example, using diaminobenzoic acid ester as a raw material according to the scheme shown in the following reaction formula (A), although it is not limited thereto.

[0081]

Chemical formula

[0082] In Reaction Scheme (A), ring A, R1 to R5, X and Y are the same as those in the formula (I). Further, W and Z each independently represent a halogen atom or a hydroxyl group. In Reaction Scheme (A), the reaction of (1) is a reaction in which one amine of the diaminobenzoic acid ester is reacted with (Boc)2O (di-tert-butyl dicarbonate) in the presence of a base to effect Boc protection of the amine. Next, the reaction of (2) is a reaction in which the unreacted other amine of the diaminobenzoic acid ester is reacted with an acyl halide or a carboxylic acid having R1 and Y to link a group having R1 and Y by an amide bond. The reaction of (3) is a reaction in which the Boc group is eliminated under acidic conditions to effect deprotection. And the reaction of (4) is a reaction in which the deprotected amine is reacted with an acyl halide or a carboxylic acid having ring A and X to link a group having ring A and X by an amide bond.

[0083] The compound obtained by Reaction Scheme (A) is a compound represented by the formula (I), but when R2 is not a hydrogen atom, it is also possible to further eliminate R2 under basic conditions to obtain a carboxylic acid in which the portion of R2 is substituted with a hydrogen atom. Also, when R2 is not a hydrogen atom, R2 may be eliminated after the reaction of (3) and then the reaction of (4) may be carried out to obtain a carboxylic acid compound.

[0084] As a method for synthesizing the compound of the present invention using a diaminobenzoic acid ester as a raw material, it is also possible to synthesize by a scheme represented by the following Reaction Scheme (B).

[0085]

Chemical formula

[0086] In Reaction Scheme (B), ring A, R1 to R5, X and Y are the same as those in the formula (I). Further, W and Z each independently represent a halogen atom or a hydroxyl group. In reaction formula (B), the reaction of (1) is the same as the reaction of (1) in the reaction formula (A), and it is a reaction in which one amine of the diaminobenzoic acid ester is reacted with (Boc)₂O (di-tert-butyl dicarbonate) in the presence of a base to carry out Boc protection of the amine. Next, the reaction of (5) is a reaction in which an acyl halide or carboxylic acid having ring A and X is reacted with the unreacted other amine of the diaminobenzoic acid ester to link a group having ring A and X by an amide bond. The reaction of (6) is a reaction in which the Boc group is eliminated under acidic conditions to carry out deprotection. And the reaction of (7) is a reaction in which an acyl halide or carboxylic acid having R₁ and Y is reacted with the deprotected amine to link a group having R₁ and Y by an amide bond. Reaction (A) first links a group having R₁ and Y, while reaction (B) first links a group having ring A and X, and the two reactions are different in this regard.

[0087] The compound obtained by reaction formula (B) is a compound represented by formula (I). However, when R₂ is not a hydrogen atom, it is also possible to further eliminate R₂ under basic conditions to obtain a carboxylic acid compound in which the R₂ moiety is substituted with a hydrogen atom. Also, when R₂ is not a hydrogen atom, R₂ may be eliminated after the reaction of (6), and then the reaction of (7) may be carried out to obtain a carboxylic acid compound.

[0088] The reaction formulas (A) and (B) involve protection and deprotection with a Boc group, but it is also possible to carry out the reaction without Boc protection. For example, it can be synthesized by the scheme shown in the following reaction formula (C).

[0089]

Chemical formula

[0090] In reaction formula (C), ring A, R₁ to R₅, X and Y represent the same ones as those in the above formula (I). Also, W and Z each independently represent a halogen atom or a hydroxyl group. In reaction formula (C), the reaction of (8) is a reaction in which an acyl halide or carboxylic acid having R1 and Y is reacted with one amine of the diaminobenzoic acid ester, and a group having R1 and Y is linked by an amide bond. The reaction of (9) is a reaction in which an acyl halide or carboxylic acid having ring A and X is reacted with the unreacted other amine of the diaminobenzoic acid ester, and a group having ring A and X is linked by an amide bond.

[0091] Reaction formula (C) is a synthetic method for first linking a group having R1 and Y in the same way as the above reaction formula (A). Although the purity is lowered by not performing protection with a Boc group, it is possible to synthesize with a sufficiently high purity by examining the reaction conditions.

[0092] The compound obtained by reaction formula (C) is a compound represented by formula (I). When R2 is not a hydrogen atom, further, R2 can be eliminated under basic conditions to obtain a carboxylic acid in which the portion of R2 is substituted with a hydrogen atom. Also, when R2 is not a hydrogen atom, R2 may be eliminated after the reaction of (8), and then the reaction of (9) may be carried out to obtain a carboxylic acid compound.

[0093] 2. Pin1 inhibitor Pin1 is a kind of peptidyl-prolyl cis-trans isomerase (PPIase) that catalyzes the cis / trans conformational change of proline in proteins, and is an enzyme that specifically acts on proline located next to phosphorylated serine or threonine to change the conformational structure. The Pin1 inhibitor of the present invention is a compound that inhibits the function of this Pin1, and the compound represented by formula (I) described in the above 1. or a salt thereof can be used as a Pin1 inhibitor.

[0094] In the present invention, "inhibiting the function of Pin1" means inhibiting the isomerase activity (racemase activity) of Pin1 and / or inhibiting the activity of Pin1 to bind to or interact with other proteins such as IRS-1. The activity of the Pin1 inhibitor of the present invention to inhibit the function of Pin1 is not limited to these, but for example, by an assay using cells, by using the phosphorylation of AMPK (AMP-activated protein kinase) as an index (see Yusuke Nakatsu et al., Journal of Biological Chemistry, 2015, Vol.290, No.40, pp.24255-24266), the activity of the Pin1 inhibitor of the present invention to inhibit the function of Pin1 can be measured. It can also be measured by an assay without using cells (cell-free), for example, by detecting the isomerase activity of Pin1 using a peptide as a substrate by the change in absorbance (see B. Janowskie et al., Analytical Biochemistry, 1997, Vol.252, Issue 2, pp.299-307), or by coupling with a protease and detecting the degradation of the substrate (see Hailong Zhao et al., Bioorganic & Medicinal Chemistry, 2016, Vol.24, pp.5911-5920), the activity of the Pin1 inhibitor of the present invention to inhibit the function of Pin1 can also be measured. Alternatively, by detecting the binding of the Pin1 inhibitor of the present invention to Pin1 that competes with the peptide serving as the substrate (see Shuo Wei et al., Nature Medicine, 2015, Vol.21, No.5, pp.457-466, online methods), the activity of the Pin1 inhibitor of the present invention to inhibit the function of Pin1 can also be measured.

[0095] 3. Pharmaceutical Composition The pharmaceutical composition of the present invention is a composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The structure of the compound represented by formula (I) is as described in the above 1-1. The pharmaceutical composition of the present invention can treat or prevent various diseases by inhibiting the function of Pin1 as one of the mechanisms of action.

[0096] Examples of pharmaceutically acceptable salts of the compound represented by formula (I) include, but are not limited to, sodium salts, potassium salts, ammonium salts, etc. when the compound has an acidic functional group. Also, when the compound has a basic functional group, salts with, for example, hydrochloric acid, phosphoric acid, acetic acid, phthalic acid, fumaric acid, oxalic acid, etc. can be formed.

[0097] The pharmaceutical composition of the present invention can be obtained by mixing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, and can be, for example, but not limited to, tablets, granules, capsules, powders, liquids, injections, suppositories, patches, eye drops, inhalants.

[0098] As the pharmaceutically acceptable carrier used in the pharmaceutical composition of the present invention, various inorganic or organic carrier substances can be used. When the pharmaceutical composition is made into a solid preparation such as tablets or granules, excipients, lubricants, binders, disintegrants, etc. can be used, and when it is made into a liquid preparation such as a liquid or an injection, solvents, solubilizing agents, suspending agents, buffering agents, etc. can be used. Also, additives such as antioxidants, preservatives, coloring agents, etc. can be used as necessary.

[0099] Examples of excipients include, but are not limited to, lactose, D-mannitol, starch, etc., examples of lubricants include magnesium stearate, talc, etc., examples of binders include crystalline cellulose, gelatin, etc., and examples of disintegrants include carboxymethyl cellulose, etc. In addition, as the solvent, for example, distilled water, alcohol, propylene glycol, etc. can be used. As the dissolution aid, for example, polyethylene glycol, ethanol, etc. can be used. As the suspending agent, for example, stearyltriethanolamine, sodium lauryl sulfate, etc. can be used. As the buffer, for example, phosphate, acetate, etc. can be used.

[0100] 4. Therapeutic and prophylactic agents for inflammatory diseases The therapeutic or prophylactic agent for inflammatory diseases of the present invention contains a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. The structure of the compound represented by formula (I) is as described in the above 1-1., and for its pharmaceutically acceptable salt, it is as described in the above 3. In the present invention, an inflammatory disease is a disease that causes damage to tissues due to the continuation of inflammation, and includes non-alcoholic steatohepatitis, inflammatory bowel disease, and pulmonary fibrosis.

[0101] In the present invention, "non-alcoholic steatohepatitis" is also called NASH (Non-Alcoholic SteatoHepatitis), and among non-alcoholic fatty liver diseases in which fat deposition similar to alcoholic hepatitis is observed despite no history of alcohol intake sufficient to cause liver damage, it refers to those accompanied by inflammation of liver tissue. Non-alcoholic steatohepatitis is known to cause liver cirrhosis in which hepatocytes die and are replaced by fibrous tissue. In the present invention, "inflammatory bowel disease" is a general term for diseases that cause chronic inflammation and ulcers in the mucosa of the large intestine and small intestine. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease as typical diseases. Ulcerative colitis is a disease in which chronic inflammation occurs in the large intestine and ulcers form, and Crohn's disease is a disease in which inflammatory lesions such as ulcers and swellings occur in any part of the gastrointestinal tract. When inflammatory bowel disease causes stenosis due to intestinal fibrosis, surgery is inevitable. In the present invention, "pulmonary fibrosis" is a disease in which chronic inflammation occurs in lung tissue, the inflamed tissue becomes fibrotic and hardened, and the expansion and contraction of the lungs are hindered.

[0102] The therapeutic or prophylactic agent for inflammatory diseases of the present invention contains, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, thereby reducing the symptoms of inflammatory diseases such as non-alcoholic steatohepatitis (NASH), inflammatory bowel disease, and pulmonary fibrosis, or having an effect of preventing the occurrence of inflammatory diseases. Such medicinal effects are considered to be based on the mechanism of action in which the compound represented by formula (I) or a pharmaceutically acceptable salt thereof inhibits the function of Pin1. Regarding the therapeutic effect on both non-alcoholic steatohepatitis (NASH) and inflammatory bowel disease by the mechanism of action of inhibiting the function of Pin1, it has also been demonstrated in Patent Document 5 (International Publication WO2018 / 101329).

[0103] The compound represented by formula (I) contained as an active ingredient in the therapeutic or prophylactic agent for inflammatory diseases of the present invention can have a wide variety of chemical structures in ring A, R1 to R5, X, and Y. Therefore, it is possible to change the chemical structure of the therapeutic or prophylactic agent for inflammatory diseases of the present invention so that the absorbability, distribution, degradability, ease of excretion, etc. of the drug are suitable.

[0104] The therapeutic or prophylactic agent for inflammatory diseases of the present invention can be administered as a therapeutic or prophylactic agent not only to patients diagnosed with inflammatory diseases such as non-alcoholic steatohepatitis, inflammatory bowel disease, and pulmonary fibrosis, but also to patients who may have these diseases or patients who are at risk of developing them.

[0105] The therapeutic or prophylactic agent for inflammatory diseases of the present invention can be formulated into various dosage forms by mixing with a pharmaceutically acceptable carrier as described in 3. above. When used as a therapeutic or prophylactic agent for non-alcoholic steatohepatitis, although it is not necessarily limited to these dosage forms, for example, it can be orally administered as tablets, granules, capsules, powders, liquids, etc. Also, from the viewpoint of directly acting on the liver to reduce side effects, it can also be directly administered to the liver through a tube or the like as an injection. When used as a therapeutic or prophylactic agent for inflammatory bowel disease, although it is not necessarily limited to these dosage forms, from the viewpoint of directly acting on the intestine, it is preferably in the form of tablets, granules, capsules, powders, liquids, or suppositories. When used as a therapeutic or prophylactic agent for pulmonary fibrosis, although it is not necessarily limited to these dosage forms, from the viewpoint of directly acting on the lungs, it is preferably in the form of inhalants, etc.

[0106] The therapeutic or prophylactic agent for inflammatory diseases of the present invention is preferably administered at 0.01 to 100 mg, more preferably 0.1 to 10 mg, per 1 kg of the patient's body weight per day, in terms of the active ingredient.

[0107] The therapeutic or prophylactic agent for inflammatory diseases of the present invention may contain, in addition to the compound of the present invention or its pharmaceutically acceptable salt, the active ingredient of at least one or more drugs selected from drugs classified as therapeutic or prophylactic agents for inflammatory diseases. Such active ingredients are not necessarily limited to these, but for example, as the active ingredient of a therapeutic agent for non-alcoholic steatohepatitis, vitamin E, obeticholic acid (6-ethyl-chenodeoxycholic acid), elafibranor, selonsertib, saroglitazar, lanifibranor, semaglutide, pemafibrate, etc., which are in the clinical trial stage at the time of this application, can be used. Also, as the active ingredient of a therapeutic agent for inflammatory bowel disease, 5-aminolevulinic acid, sulfasalazine, etc. can be used.

[0108] The therapeutic or prophylactic agent for inflammatory diseases of the present invention can also be used in combination with at least one or more drugs selected from drugs classified as therapeutic or prophylactic agents for inflammatory diseases.

[0109] 5. Therapeutic and prophylactic agents for fatty liver disease The therapeutic or prophylactic agent for fatty liver disease of the present invention contains, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The structure of the compound represented by formula (I) is as described in the above 1-1., and for its pharmaceutically acceptable salt, it is as described in the above 3.

[0110] In the present invention, "fatty liver disease" is also referred to as "fatty liver" and is a pathological condition in which neutral fat accumulates excessively in the liver. Fatty liver disease includes alcoholic fatty liver and non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease (NAFLD) is a pathological condition belonging to the metabolic syndrome in which fat deposition similar to alcoholic fatty liver is observed despite no history of alcohol intake sufficient to cause liver damage. Non-alcoholic fatty liver disease (NAFLD) includes simple fatty liver, which is a mild pathological condition, and non-alcoholic steatohepatitis (NASH), which is a severe pathological condition accompanied by inflammation of liver tissue.

[0111] The compound serving as the active ingredient in the present invention inhibits the function of Pin1 as its mechanism of action and can suppress fat accumulation, so it can be used as a therapeutic or prophylactic agent for fatty liver disease. The therapeutic or prophylactic agent for fatty liver disease of the present invention can be administered as a therapeutic or prophylactic agent not only to patients diagnosed with fatty liver disease but also to patients who may have fatty liver disease or patients at risk of developing fatty liver disease. In addition, since the therapeutic or prophylactic agent for fatty liver disease of the present invention suppresses liver inflammation, it can be preferably used for the treatment or prevention of non-alcoholic steatohepatitis (NASH) in particular.

[0112] The compound represented by formula (I) contained as an active ingredient in the therapeutic or prophylactic agent for fatty liver disease of the present invention can have a wide variety of chemical structures in ring A, R1 to R5, X and Y. Therefore, the therapeutic or prophylactic agent for fatty liver disease of the present invention can change the chemical structure so that the absorbability, distribution, degradability, ease of excretion, etc. of the drug are suitable.

[0113] The therapeutic or prophylactic agent for fatty liver disease of the present invention can be administered as a therapeutic or prophylactic agent not only to patients diagnosed with fatty liver disease, but also to patients who may have these diseases and patients who may develop these diseases.

[0114] The therapeutic or prophylactic agent for fatty liver disease of the present invention can be formulated into various dosage forms by mixing with a pharmaceutically acceptable carrier as described in 3. above. For example, it can be orally administered as tablets, granules, capsules, powders, liquids, etc. Also, from the viewpoint of directly acting on the liver to reduce side effects, it can be directly administered to the liver by a tube or the like as an injection.

[0115] The therapeutic or prophylactic agent for fatty liver disease of the present invention is preferably administered at 0.01 to 100 mg, more preferably 0.1 to 10 mg, per kg of the patient's body weight per day, in terms of its active ingredient.

[0116] The therapeutic or prophylactic agent for fatty liver disease of the present invention may contain, in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof, the active ingredient of at least one or more drugs selected from drugs classified as therapeutic or prophylactic agents for fatty liver disease. Such active ingredients include, but are not limited to, for example, vitamin E which is an active ingredient of a therapeutic agent for non-alcoholic steatohepatitis, obeticholic acid (6-ethyl-chenodeoxycholic acid), elafibranor, selonsertib, saroglitazar, lanifibranor, semaglutide, pemafibrate, etc. which are in the clinical trial stage at the time of filing this application.

[0117] The therapeutic or prophylactic agent for fatty liver disease of the present invention can also be used in combination with at least one drug selected from drugs classified as therapeutic or prophylactic agents for fatty liver disease.

[0118] 6. Therapeutic or prophylactic agent for obesity The therapeutic or prophylactic agent for obesity of the present invention contains, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The structure of the compound represented by formula (I) is as described in the above 1-1., and for its pharmaceutically acceptable salt, it is as described in the above 3. The therapeutic or prophylactic agent for obesity of the present invention has the effect of treating obesity or preventing the onset of obesity by suppressing fat accumulation. Such drug efficacy is considered to be based on the mechanism of action in which the compound represented by formula (I) or a pharmaceutically acceptable salt thereof inhibits the function of Pin1.

[0119] In the present invention, "obesity" is a disease in which fat accumulates excessively in the viscera or under the skin, and it can be diagnosed from the fat area in abdominal CT scans, etc. The therapeutic or prophylactic agent for obesity of the present invention can be administered as a therapeutic or prophylactic agent not only to patients diagnosed with obesity but also to patients who may be obese or patients at risk of developing obesity.

[0120] The compound represented by formula (I) contained as an active ingredient in the therapeutic or prophylactic agent for obesity of the present invention can have a wide variety of chemical structures in ring A, R1~R5, X and Y. Therefore, it is possible to change the chemical structure of the therapeutic or prophylactic agent for obesity of the present invention so that the absorbability, distribution, degradability, ease of excretion, etc. of the drug are suitable.

[0121] The therapeutic or prophylactic agent for obesity of the present invention can be formulated into various dosage forms by mixing with a pharmaceutically acceptable carrier as described in 3. above. For example, it can be orally administered as tablets, granules, capsules, powders, liquids, etc. The therapeutic or prophylactic agent for obesity of the present invention is preferably administered at 0.01 to 100 mg, more preferably 0.1 to 10 mg, per kg of the patient's body weight per day, in terms of its active ingredient.

[0122] In addition to the compound of the present invention or its pharmaceutically acceptable salt, the therapeutic or prophylactic agent for obesity of the present invention may contain the active ingredient of at least one drug selected from drugs classified as therapeutic or prophylactic agents for obesity. Examples of such active ingredients include, but are not limited to, mazindol, cetilistat, sibutramine, orlistat, lorcaserin, Qsymia, etc. The therapeutic or prophylactic agent for obesity of the present invention can also be used in combination with at least one drug selected from drugs classified as therapeutic or prophylactic agents for obesity. The therapeutic or prophylactic agent for obesity of the present invention may also be used in combination with diet therapy, exercise therapy, behavior therapy, etc. used for the treatment or prevention of obesity.

[0123] 7. Therapeutic or prophylactic agent for viral diseases The therapeutic or prophylactic agent for viral diseases (including COVID-19) of the present invention contains, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The structure of the compound represented by formula (I) is as described in 1-1. above, and for its pharmaceutically acceptable salt, it is as described in 3. above.

[0124] The "viral disease" which is the disease to which the therapeutic or prophylactic agent of the present invention is applied is a disease caused by a virus, and includes, for example, coronavirus infections caused by coronaviruses. Coronaviruses that infect humans are alpha coronaviruses (HCoV-229E, HCoV-NL63) and beta coronaviruses (MERS-CoV, SARS-CoV, SARS-CoV-2, HCoV-OC43, HCoV-HKU1). HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 are the causes of common colds and are mostly mild, but can sometimes cause high fevers. SARS-CoV is thought to have originated when a bat coronavirus infected humans and caused severe pneumonia. MERS-CoV is a virus that causes cold-like symptoms in dromedary camels and is thought to cause severe pneumonia if it infects humans across species barriers. The infection (COVID-19) caused by SARS-CoV-2 mainly spreads through human-to-human infection via droplets in the air scattered by the coughs and sneezes of infected individuals. COVID-19 is characterized by fever, respiratory symptoms, headache, fatigue, etc., and may also cause olfactory and gustatory disorders. The therapeutic or prophylactic agent of the present invention is particularly preferably applied to coronavirus infections caused by beta coronaviruses, and among them, it is preferably applied to coronavirus infections (COVID-19) caused by SARS-CoV-2.

[0125] The compound that serves as the active ingredient in the present invention inhibits the function of Pin1 as its mechanism of action and can suppress the growth of viruses. Therefore, it can be used as a therapeutic or prophylactic agent for viral diseases. The therapeutic or prophylactic agent for viral diseases of the present invention can be administered as a therapeutic or prophylactic agent not only to patients diagnosed with viral diseases but also to patients who may have viral diseases or patients at risk of developing viral diseases. In addition, since the therapeutic or prophylactic agent for viral diseases of the present invention suppresses the growth of the SARS-CoV-2 virus, it can be particularly preferably used for the treatment or prevention of coronavirus infections caused by SARS-CoV-2. That is, in the present invention, a method for treating COVID-19 can be provided, which includes administering a therapeutically effective amount of a Pin1 inhibitor or a pharmaceutically acceptable salt thereof that functions as a therapeutic or prophylactic agent for viral diseases to a subject in need thereof, such as a COVID-19 patient.

[0126] The therapeutic or prophylactic agent for viral diseases of the present invention can be made into a pharmaceutical composition by mixing the compound serving as the active ingredient or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. For example, but not limited to these, it can be made into tablets, granules, capsules, powders, liquids, injections, suppositories, patches, eye drops, inhalants. As a preferred dosage form, for example, it may be orally administered as tablets, granules, capsules, powders, liquids, etc., or may be administered via the lungs as an inhalant.

[0127] As the pharmaceutically acceptable carrier that can be used in the therapeutic or prophylactic agent for viral diseases of the present invention, various inorganic or organic carrier substances can be used. When the pharmaceutical composition is made into a solid preparation such as tablets or granules, excipients, lubricants, binders, disintegrants, etc. can be used. When it is made into a liquid preparation such as a liquid or an injection, solvents, solubilizing agents, suspending agents, buffering agents, etc. can be used. In addition, additives such as antioxidants, preservatives, coloring agents, etc. can also be used as necessary.

[0128] Although not limited thereto, for example, lactose, D-mannitol, starch, etc. can be used as excipients, magnesium stearate, talc, etc. can be used as lubricants, crystalline cellulose, gelatin, etc. can be used as binders, and carboxymethyl cellulose, etc. can be used as disintegrants. Further, for example, distilled water, alcohol, propylene glycol, etc. can be used as solvents, polyethylene glycol, ethanol, etc. can be used as solubilizing agents, stearyl triethanolamine, sodium lauryl sulfate, etc. can be used as suspending agents, and phosphates, acetates, etc. can be used as buffers.

[0129] The therapeutic or prophylactic agent for viral diseases of the present invention is preferably administered, for example, at 0.01 to 100 mg, more preferably 0.1 to 10 mg, per 1 kg of the patient's body weight per day, in terms of the active ingredient.

[0130] In addition to the compound of the present invention or a pharmaceutically acceptable salt thereof, the therapeutic or prophylactic agent for coronavirus diseases of the present invention may contain the active ingredient of at least one or more agents selected from agents classified as therapeutic or prophylactic agents for coronavirus diseases. Such active ingredients include, but are not limited to, for example, remdesivir, favipiravir, chloroquine, hydroxychloroquine, nafamostat, interferon, etc. Further, the therapeutic or prophylactic agent for viral diseases of the present invention can be used in combination with a therapeutic or prophylactic agent for other viral diseases.

[0131] Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

Examples

[0132] (Synthesis of compound) (Example 1-1) Synthesis of intermediate Various intermediates (H-675, H-676, H-677, H-608, H-720, H-721, H-722, H-724, H-725, H-814, H-816) used for synthesizing the compounds of the present invention were synthesized.

[0133] (Synthesis of H-675) Triethylamine (5.48 g, 7.52 mL, 54 mmol) was added to a mixed solution of methyl 3,5-diaminobenzoate (3.0 g, 18.0 mmol) in dioxane (60 mL) and water (30 mL), and the mixture was cooled to 0 °C. At the same temperature, (Boc)2O (4.32 g, 19.7 mmol) was added, and the mixture was stirred at the same temperature for 1 hour and then further stirred at room temperature for 20 hours. Dioxane was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate, 8:1), and H-675 was obtained as a white powder (3.78 g, 14.2 mmol, 79%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-675 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 1.45 (9H, s), 3.76 (3H, s), 5.33 (2H,s),6.80 (1H, t, J = 1.8 Hz), 6.95 (1H, bs), 7.25 (1H,bs), 9.26 (1H, s); HRESIMS calcd for C 13 H 18 N2O4Na [M+Na] + 289.1164, found289.1160. The confirmed chemical structure of H-675 is as follows.

[0134]

Chemical formula

[0135] (Synthesis of H-676) To a solution of H-675 (5.0 g, 18.7 mmol) in THF (60 mL) was added pyridine (2.2 g, 2.3 mL, 28.2 mmol) and 9H-carbazole-9-carbonyl chloride (5.15 g, 22.4 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hours. After adding a saturated aqueous ammonium chloride solution to the mixture, THF was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain H-676 as a white powder (8.12 g, 17.6 mmol, 95%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-676 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 1.48 (9H, s), 3.86 (3H, s), 7.38 (2H, t, J = 7.8 Hz), 7.53 (2H, t, J = 8.2 Hz), 7.88 (1H, t, J = 1.8 Hz), 7.92 (2H, d, J = 8.2 Hz), 7.99 (1H, t, J = 1.9 Hz), 8.17 (1H, t, J = 1.9 Hz), 8.22 (2H, d, J = 7.8 Hz), 9.72 (1H, s), 10.76 (1H, s); HRESIMS calcd for C 26 H 25 N3O5Na [M+Na] + 482.1692, found 482.1684. The confirmed chemical structure of H-676 is as follows.

[0136]

Chemical Structure

[0137] (Synthesis of H-677) To a solution of H-676 (8.0 g, 17.4 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (10 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. The volatile solvent was distilled off under reduced pressure, and the residue was neutralized by adding 1M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain H-677 as a white powder (5.93 g, 16.5 mmol, 95%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-677 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 3.81 (3H, s), 5.56 (2H, bs), 7.00 (1H,t, J = 1.8 Hz), 7.22 (1H, t, J =1.8 Hz), 7.37 (2H, t, J = 7.8 Hz), 7.48 (1H, t,J = 1.8 Hz), 7.52 (2H, t, J =8.2 Hz), 7.89 (2H, d, J = 8.2 Hz), 8.22 (2H, d, J= 7.8 Hz), 10.50 (1H, s); HRESIMS calcd for C 21 H 17 N3O3Na [M+Na] + 382.1168, found382.1161. The confirmed chemical structure of H-677 is as follows.

[0138]

Chemical Structure

[0139] (Synthesis of H-608) To a solution of H-675 (100 mg, 0.375 mmol) in dichloromethane (15 mL) were added pyridine (45 mg, 0.45 mL, 0.563 mmol) and 2-naphthoyl chloride (85 mg, 0.45 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hours. After adding saturated aqueous ammonium chloride solution to the mixture, it was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane (10 mL) and trifluoroacetic acid (5 mL) were added to the residue at room temperature, and the mixture was stirred at the same temperature for 3 hours. After distilling off dichloromethane under reduced pressure, 1 M aqueous sodium hydroxide solution was added to the residue to adjust the pH to 8 - 9, and then it was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain H-608 as a flesh-colored powder (114 mg, 0.356 mmol, 95%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-608 are as follows. 1 H NMR (400 MHz, DMSO-d6) δ 3.81 (3H, s), 5.46 (2H, bs), 6.97 (1H, t, J = 1.8 Hz), 7.44 (1H, t, J = 1.8 Hz), 7.57 (1H, t, J = 1.8 Hz), 7.59 - 7.66 (2H, m), 7.98 - 8.08 (4H, m), 8.57 (1H, bs), 10.32 (1H, s); HRESIMS calcd for C 19 H 16 N2O3Na [M + Na] + 343.1059, found 343.1052. The confirmed chemical structure of H-608 is as follows.

[0140]

Chemical Structure

[0141] (Synthesis of H-720) To a solution of H-675 (1.45 g, 5.44 mmol) in THF (50 mL) were added carbazole acetic acid (1.47 g, 6.5 mmol), EDCI (2.08 g, 10.1 mmol) and DMAP (130 mg, 1.1 mmol) at room temperature, and the mixture was stirred overnight at the same temperature. After THF was distilled off under reduced pressure, water was added to the residue 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 obtain H-720 as a white powder (2.27 g, 4.79 mmol, 88%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-720 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 1.46 (9H, s), 3.79 (3H, s), 5.26 (2H,s),7.21 (2H, t, J = 7.8 Hz), 7.44 (2H, t, J = 7.3 Hz), 7.57 (2H, d, J =8.2 Hz),7.77 (1H, t, J = 1.8 Hz), 7.95 (1H, t, J = 1.8 Hz), 8.04 (1H, t, J =1.8 Hz),8.16 (2H, d, J = 7.8 Hz), 9.64 (1H, s), 10.70 (1H, s); HRESIMScalcdfor C 27 H 27 N3O5Na [M+Na] + 496.1848, found496.1847. The confirmed chemical structure of H-720 is as follows.

[0142]

Chemical Structure

[0143] (Synthesis of H-721) To a solution of H-720 (35 mg, 0.074 mmol) in THF (3 mL) and methanol (1 mL), an aqueous lithium hydroxide solution (1 M, 2 mL, 2 mmol) was added at room temperature, and the mixture was stirred overnight at the same temperature. 1 M hydrochloric acid was added to the mixture for neutralization, 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 obtain H-721 as a pale red powder (26.7 mg, 0.058 mmol, 78%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-721 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 1.46 (9H, s), 5.26 (2H, s), 7.21 (2H, t, J = 7.8 Hz), 7.44 (2H, t, J = 7.3 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.72 (1H, bs), 7.89 (1H, bs), 8.05 (1H, bs), 8.16 (2H, d, J = 7.8 Hz), 9.59 (1H, s), 10.66 (1H, s); HRESIMS calcd for C 26 H 25 N3O5Na [M+Na] + 482.1692, found 482.1686. The confirmed chemical structure of H-721 is as follows.

[0144]

Chemical Structure

[0145] (Synthesis of H-722) To a solution of H-721 (160 mg, 0.279 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (3 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. After cooling the reaction mixture to 0 °C, the pH was adjusted to 8 - 9 using 1M aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain H-720 as a white powder (98.6 mg, 0.264 mmol, 95%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-722 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 3.75 (3H, s), 5.22 (2H, bs), 5.44(2H,bs), 6.90 (1H, t, J = 1.8 Hz), 7.09 (1 H, t, J = 1.8 Hz), 7.21 (2H, t, J=7.7 Hz), 7.38 (1H, bs), 7.43 (2H, t, J = 7.7 Hz), 7.56(2H, d, J = 8.2 Hz),8.16 (2H, d,J = 7.8 Hz), 10.42 (1H, bs); HRESIMS calcd for C 22 H 19 N3O3Na [M+Na] + 396.1324, found396.1315. The confirmed chemical structure of H-722 is as follows.

[0146]

Chemical Structure

[0147] (Synthesis of H-724) To a solution of H-675 (1.0 g, 3.76 mmol) in THF (20 mL), pyridine (450 mg, 0.45 mL, 3.44 mmol) and diphenylcarbamoyl chloride (1.3 g, 5.63 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 17 hours. After adding saturated aqueous ammonium chloride solution to the mixture, it was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain H-724 as a pale red powder (1.59 g, 3.44 mmol, 92%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-724 are as follows. 1 H NMR (400 MHz, DMSO-d6) δ 1.45 (9H, s), 3.79 (3H, s), 7.17 - 7.25 (6H, m), 7.34 - 7.40 (4H, m), 7.64 (1H, t, J = 1.8 Hz), 7.73 (1H, t, J = 1.8 Hz), 7.94 (1H, t, J = 1.8 Hz), 8.71 (1H, s), 9.51 (1H, s); HRESIMS calcd for C 26 H 27 N3O5Na [M+Na] + 484.1848, found 484.1848. The confirmed chemical structure of H-724 is as follows.

[0148]

Chemical Structure

[0149] (Synthesis of H-725) To a solution of H-724 (1.4 g, 3.03 mmol) in dioxane (30 mL) was added concentrated hydrochloric acid (10 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. After the solvent was distilled off under reduced pressure, water was added 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 obtain H-725 as a white powder (970 mg, 2.44 mmol, 80%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-725 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 3.80 (3H, s), 7.18 - 7.26 (7H, m), 7.38(4H, t, J = 8.2 Hz), 7.52 (1H, bs), 7.71 (1H, bs), 8.73; HRESIMS calcd for C 21 H 19 N3O3Cl [M+Cl] - 396.1115, found 396.1106. The confirmed chemical structure of H-725 is as follows.

[0150]

Chemical Structure

[0151] (Synthesis of H-814) To a solution of H-675 (615 mg, 2.31 mmol) in dichloromethane (40 mL) were added N,N-diphenylglycine (525 mg, 2.31 mmol), EDCI (1.32 g, 6.93 mmol), and DMAP (56.4 mg, 0.46 mmol) at room temperature, and the mixture was stirred at the same temperature overnight. Water was added to the mixture and it was extracted with dichloromethane. The organic layer was washed with water, saturated sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain H-814 as a skin-colored powder (1.01 g, 2.12 mmol, 92%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-814 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 1.46 (9H, s), 3.81 (3H, s), 4.54 (2H,s),6.93 (2H, t, J = 7.3 Hz), 7.02 (4H, d, J = 7.8 Hz), 7.26 (4H, t, J =7.8 Hz),7.74 (1H, bs), 7.96 (1H, bs), 8.01 (1H, bs), 9.62 (1H, bs), 10.34 (1H,bs);HRESIMS calcd for C 27 H 29 N3O5Na [M+Na] + 498.2005, found498.2004. The confirmed chemical structure of H-814 is as follows.

[0152]

Chemical formula

[0153] (Synthesis of H-816) To a solution of H-814 (1.0 g, 2.10 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. After evaporating the volatile substances under reduced pressure, the pH was adjusted to 8 - 9 using 1M aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain H-816 as a pale yellow powder (720 mg, 1.92 mmol, 90%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-816 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.77 (3H, s), 4.50 (2H, s), 5.42(2H,bs), 6.88 (1H, bs), 6.92 (2H, t, J = 7.3 Hz), 7.02(4H, d, J = 7.8 Hz), 7.13(1H, bs), 7.25 (4H, t, J = 7.8 Hz), 7.36 (1H, bs), 10.04 (1H, bs); HRESIMS calcdfor C 22 H 21 N3O3Na [M+Na] + 398.1481, found 398.1474. The chemical structure of confirmed H-816 is as follows.

[0154] [Chemical formula] H-816

[0155] (Example 1-2) Synthesis of H-591 To a solution of H-677 (50 mg, 0.139 mmol) synthesized in Example 1-1 in dichloromethane (3 mL) were added 2-naphthoyl chloride (32 mg, 0.167 mmol) and pyridine (16 mg, 0.17 mL, 0.209 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain H-591 as a white powder (70 mg, 0.136 mmol, 97%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-591 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.91 (3H, s), 7.39 (2H, t, J = 7.8 Hz),7.54 (2H, t, J =7.3 Hz), 7.60-7.69 (2H, m), 7.93-8.12 (6H, m), 8.13 (1H, t,J = 1.8 Hz), 8.24 (2H, d, J = 7.8 Hz), 8.30 (1H, bs),8.63(1H, bs), 8.65 (1H, bs), 10.75 (1H, s), 10.87 (1H, s); HRESIMS calcd for C 32 H 23 N3O4Na [M+Na] + 536.1586, found 536.1588. The confirmed chemical structure of H-591 is as follows.

[0156] [Chemical formula] H-591

[0157] (Examples 1-3) Synthesis of H-594 To a solution of H-591 (40 mg, 0.078 mmol) synthesized in Examples 1-2 in methanol (1 mL) and THF (2 mL), an aqueous sodium hydroxide solution (1M, 1 mL, 1 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 17 hours. 1M hydrochloric acid was added to the mixture for neutralization, 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 obtain H-594 as a pale yellow powder (25 mg, 0.05 mmol, 64%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-594 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 7.39 (2H, t, J = 7.8 Hz), 7.54 (2H, t, J = 7.3 Hz), 7.60 - 7.68 (2H, m), 7.96 (2H, d, J = 8.7 Hz), 7.99 - 8.12 (5H, m), 8.24 (2H, d, J = 7.8 Hz), 8.26 (1H, bs), 8.60 (1H, bs), 8.64 (1H, bs), 10.71 (1H, s), 10.83 (1H, s); HRESIMS calcd for C 31 H 21 N3O4Na [M+Na] + 522.1430, found 522.1428. The chemical structure of confirmed H-594 is as follows.

[0158] [Chemical formula] H-594

[0159] (Examples 1-4) Synthesis of H-679 To a solution of H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 in THF (5 mL) were added benzoic acid (62 mg, 0.51 mmol), EDCI (240 mg, 1.26 mmol) and DMAP (10 mg, 0.08 mmol) at room temperature, and the mixture was stirred at the same temperature for 16 h. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain H-679 as a gray powder (175 mg, 0.378 mmol, 89%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-679 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.90 (3H, s), 7.39 (2H, t, J = 7.8 Hz), 7.50 - 7.64 (5H, m), 7.95 (2H, d, J = 8.7 Hz), 8.01 (2H, d, J = 8.2 Hz), 8.11 (1H, bs), 8.24 (2H, d, J = 7.8 Hz), 8.26 (1H, bs), 8.58 (1H, bs), 10.59 (1H, s), 10.86 (1H, s); HRESIMS calcd for C 28 H 21 N3O4Na [M+Na] + 486.1430, found 486.1425. The confirmed chemical structure of H-679 is as follows.

[0160] [Chemical formula] H-679

[0161] (Examples 1 - 5) Synthesis of H-681 To a solution of H-679 (100 mg, 0.163 mmol) synthesized in Examples 1 - 4 in THF (3 mL) and methanol (1 mL), an aqueous lithium hydroxide solution (1M, 2 mL, 2 mmol) was added at room temperature, and the mixture was stirred overnight at the same temperature. 1M hydrochloric acid was added to the mixture for neutralization, 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 obtain H-681 as a light gray powder (85 mg, 0.189 mmol, 88%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-681 are as follows. 11H NMR (400 MHz, DMSOd6) δ 7.39 (2H, t, J= 7.3 Hz), 7.50-7.64 (5H,m), 7.95 (2H, d, J = 8.2Hz), 8.01 (2H, d, J = 8.2 Hz), 8.07 (1H, bs), 8.21(1H,bs), 8.23 (2H, d, J = 7.8 Hz), 8.55 (1H, t, J = 1.8 Hz), 10.54 (1H, s), 10.81(1H, s); HRESIMS calcdfor C 27 H 19 N3O4Na [M+Na] + 472.1273, found472.1267. The confirmed chemical structure of H-681 is as follows.

[0162] [Chemical formula] H-681

[0163] (Example 1-6) Synthesis of H-680 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and nicotinic acid (62 mg, 0.51 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-680 as a flesh-colored powder (120 mg, 0.258 mmol, 61%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-680 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.90 (3H, s), 7.39 (2H, t, J = 7.8 Hz),7.54 (2H, t, J =8.2 Hz), 7.58 (1H, dd, J = 7.8, 4.6 Hz), 7.95 (2H, d,J = 8.2 Hz), 8.13 (1H, bs), 8.24 (2H, d, J = 7.8 Hz),8.26(1H, bs), 8.34 (1H, dt, J = 7.8, 1.8 Hz), 8.57 (1H, t,J= 1.8 Hz), 8.77 (1H, dd, J = 4.6, 1.8 Hz), 9.15 (1H, d,J= 1.8 Hz), 10.77 (1H, s), 10.87 (1H, s); HRESIMS calcdfor C 27 H 20 N4O4Na [M+Na] + 487.1382, found 487.1378. The chemical structure of confirmed H-680 is as follows.

[0164] [Chemical formula] H-680

[0165] (Example 1-7) Synthesis of H-682 For H-680 (70 mg, 0.15 mmol) synthesized in Examples 1-6, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-682 as a brown powder (48.3 mg, 0.107 mmol, 71%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-682 are as follows. 11H NMR (400 MHz, DMSOd6) δ 7.39 (2H, t, J= 7.8 Hz), 7.54 (2H, t, J= 8.2 Hz), 7.58 (1H, dd, J =7.8, 4.6 Hz), 7.95 (2H, d, J = 8.2 Hz), 8.09 (1H,bs),8.22 (1H, bs), 8.24 (2H, d, J = 7.8 Hz), 8.34 (1H, dt,J= 7.8, 1.8 Hz), 8.55 (1H, bs), 8.77 (1H, dd, J = 4.6, 1.8 Hz), 9.14 (1H, d, J =1.8 Hz), 10.73 (1H, s), 10.83 (1H, s); HRESIMS calcdforC 26 H 18 N4O4Na [M+Na] + 473.1226, found 473.1224. The confirmed chemical structure of H-682 is as follows.

[0166] [Chemical Structure Diagram] H-682

[0167] (Example 1-8) Synthesis of H-684 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and quinolinic acid (90 mg, 0.51 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-684 as a flesh-colored powder (168 mg, 0.33 mmol, 79%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-684 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.92 (3H, s), 7.40 (2H, t, J = 7.3 Hz), 7.55 (2H, t, J = 8.2 Hz), 7.77 (1H, t, J = 7.3 Hz), 7.93 (1H, t, J = 7.3 Hz), 7.98 (2H, d, J = 8.7 Hz), 8.13 (1H, d, J = 7.8 Hz), 8.17 (1H, bs), 8.24 (2H, d, J = 7.8 Hz), 8.25 (1H, d, J = 8.7 Hz), 8.29 (1H, d, J = 8.2 Hz), 8.42 (1H, bs), 8.65 (1H, d, J = 8.6 Hz), 8.71 (1H, t, J = 2.3 Hz), 10.88 (1H, s), 11.10 (1H, s); HRESIMS calcd for C 31 H 22 N4O4Na [M+Na] + 537.1539, found 537.1535. The confirmed chemical structure of H-684 is as follows.

[0168] [Chemical formula] H-684

[0169] (Example 1-9) Synthesis of H-688 For H-684 (90 mg, 0.17 mmol) synthesized in Examples 1-8, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681, and H-688 was obtained as a flesh-colored powder (70 mg, 0.14 mmol, 82%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-688 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 7.39 (2H, t, J = 7.8 Hz), 7.55 (2H, t, J = 8.2 Hz), 7.77 (1H, t, J = 7.5 Hz), 7.93 (1H, t, J = 7.3 Hz), 7.97 (2H, d, J = 8.2 Hz), 8.12 (1H, bs), 8.13 (1H, d, J = 7.8 Hz), 8.20 - 8.31 (4H, m), 8.37 (1H, bs), 8.65 (1H, d, J = 8.2 Hz), 8.68 (1H, t, J = 1.8 Hz), 10.85 (1H, s), 11.05 (1H, s); HRESIMS calcd for C 30 H 20 N4O4Na [M+Na] + 523.1382, found 523.1384. The confirmed chemical structure of H-688 is as follows.

[0170] [Chemical formula] H-688

[0171] (Example 1-10) Synthesis of H-685 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and 2-quinoxalinecarboxylic acid (90 mg, 0.51 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-685 as a gray powder (185 mg, 0.36 mmol, 85%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-685 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.92 (3H, s), 7.40 (2H, t, J = 7.4 Hz),7.55 (2H, t, J =8.2 Hz), 7.98 (2H, d, J = 8.2 Hz), 8.01-8.06 (2H, m),8.17 (1H,bs), 8.22-8.26 (3H, m), 8.30-8.35 (1H, m), 8.42 (1H, bs), 8.72 (1H, t, J = 1.8Hz), 9.57 (1H, s), 10.90 (1H, s), 11.21 (1H, s);HRESIMS calcdfor C 30 H 21 N5O4Na [M+Na] + 538.1491, found538.1492. The confirmed chemical structure of H-685 is as follows.

[0172] [Chemical formula] H-685

[0173] (Example 1-11) Synthesis of H-686 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and 1,4-benzodioxane-6-carboxylic acid (90 mg, 0.51 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-686 as a white powder (159 mg, 0.31 mmol, 73%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-686 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.89 (3H, s), 4.28 - 4.34 (4H, m), 7.00 (1H, d, J = 8.2 Hz), 7.39 (2H, t, J = 7.4 Hz), 7.50 - 7.60 (4H, m), 7.94 (2H, d, J = 8.2 Hz), 8.09 (1H, bs), 8.21 - 8.25 (3H, m), 8.56 (1H, t, J = 1.8 Hz), 10.38 (1H, s), 10.83 (1H, s); HRESIMS calcd for C 30 H 23 N3O6Na [M+Na] + 544.1485, found 544.1487. The confirmed chemical structure of H-686 is as follows.

[0174]

Chemical Structure

[0175] (Example 1-12) Synthesis of H-692 For H-686 (80 mg, 0.17 mmol) synthesized in Example 1-11, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681, and H-692 was obtained as a white powder (56.2 mg, 0.11 mmol, 72%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-692 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 4.27 - 4.34 (4H, m), 7.00 (1H, d, J = 8.2 Hz), 7.38 (2H, t, J = 7.4 Hz), 7.50 - 7.60 (4H, m), 7.94 (2H, d, J = 8.7 Hz), 8.05 (1H, bs), 8.19 (1H, bs), 8.23 (2H, d, J = 7.7 Hz), 8.53 (1H, bs), 10.34 (1H, s), 10.79 (1H, s); HRESIMS calcd for C 29 H 21 N3O6Na [M+Na] + 530.1328, found 530.1324. The chemical structure of the confirmed H-692 is as follows.

[0176]

Chemical formula

[0177] (Example 1-13) Synthesis of H-687 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and 4-acetamidobenzoic acid (90 mg, 0.50 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-687 as an off-white powder (152 mg, 0.29 mmol, 69%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-687 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 2.08 (3H, s), 3.89 (3H, s), 7.39 (2H, t, J = 7.8 Hz), 7.54 (2H, t, J = 8.2 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.95 (2H, d, J = 8.2 Hz), 7.97 (2H, d, J = 8.7 Hz), 8.10 (1H, t, J = 1.8 Hz), 8.23 (2H, d, J = 7.8 Hz), 8.24 (1H, bs), 8.56 (1H, t, J = 1.8 Hz), 10.24 (1H, s), 10.44 (1H, s), 10.84 (1H, s); HRESIMS calcd for C 30 H 24 N4O5Na [M+Na] + 543.1644, found 543.1647. The chemical structure of confirmed H-687 is as follows.

[0178] [Chemical formula] H-687

[0179] (Example 1-14) Synthesis of H-694 For H-687 (65 mg, 0.124 mmol) synthesized in Example 1-13, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-694 as an off-white powder (47.2 mg, 0.093 mmol, 75%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-694 are as follows. 11H NMR (400 MHz, DMSOd6) δ 2.08 (3H, s), 7.38 (2H, t, J = 7.8 Hz), 7.54 (2H, t, J = 8.2 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.95 (2H, d, J = 8.2 Hz), 7.97 (2H, d, J = 8.7 Hz), 8.06 (1H, bs), 8.20 (1H, bs), 8.23 (2H, d, J = 7.8 Hz), 8.53 (1H, t, J = 1.8 Hz), 10.23 (1H, s), 10.40 (1H, s), 10.80 (1H, s); HRESIMS calcd for C 29 H 22 N4O5Na [M+Na] + 529.1488, found 529.1487. The confirmed chemical structure of H-694 is as follows.

[0180]

Chemical formula

[0181] (Example 1-15) Synthesis of H-690 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and piperonylic acid (85 mg, 0.50 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-690 as a light gray powder (148 mg, 0.29 mmol, 70%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-690 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.89 (3H, s), 6.14 (2H, s), 7.07 (1H, d, J = 8.2 Hz), 7.39 (2H, t, J = 7.3 Hz), 7.54 (2H, t, J = 8.2 Hz), 7.57 (1H, d, J = 1.8 Hz), 7.63 (1H, dd, J = 8.2, 1.4 Hz), 7.95 (2H, d, J = 8.2 Hz), 8.10 (1H, bs), 8.21 - 8.25 (3H, m), 8.56 (1H, t, J = 1.8 Hz), 10.38 (1H, s), 10.83 (1H, s); HRESIMS calcd for C 29 H 21 N3O6Na [M+Na]+ + 530.1328, found 530.1325. The confirmed chemical structure of H-690 is as follows.

[0182] [Chemical formula] H-690

[0183] (Example 1-16) Synthesis of H-695 For H-690 (70 mg, 0.137 mmol) synthesized in Example 1-15, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-695 as a light gray powder (51.8 mg, 0.105 mmol, 77%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-695 are as follows. 11H NMR (400 MHz, DMSOd6) δ 6.13 (2H, s), 7.07 (1H, d, J = 7.8 Hz),7.38 (2H, t, J =7.8 Hz), 7.53 (2H, t, J = 8.2 Hz), 7.57 (1H, d, J = 1.8 Hz),7.63 (1H, dd, J = 8.2, 1.3 Hz), 7.94 (2H, d, J = 8.2 Hz), 8.06 (1H, bs), 8.19(1H, bs), 8.23 (2H, d, J = 7.3 Hz), 8.53 (1H, t,J =1.8 Hz), 10.35 (1H, s), 10.80 (1H, s); HRESIMS calcdfor C 28 H 19 N3O6Na [M+Na] + 516.1172, found 516.1170. The chemical structure of confirmed H-695 is as follows.

[0184] [Chemical Structure] H-695

[0185] (Example 1-17) Synthesis of H-696 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and 4-acetoxybenzoic acid (90 mg, 0.50 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-696 as a white powder (85 mg, 0.162 mmol, 38%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-696 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 2.31 (3H, s), 3.89 (3H, s), 7.31 (2H, d, J = 8.2 Hz), 7.39 (2H, t, J = 7.3 Hz), 7.54 (2H, t, J = 8.2 Hz), 7.95 (2H, d, J = 8.2 Hz), 8.05 (2H, d, J = 8.2 Hz), 8.12 (1H, bs), 8.21 - 8.25 (3H, m), 8.57 (1H, bs), 10.60 (1H, s), 10.85 (1H, s); HRESIMS calcd for C 30 H 23 N3O6Na [M+Na] + 544.1485, found 544.1486. The chemical structure of the confirmed H-696 is as follows.

[0186] [Chemical formula] H-696

[0187] (Example 1-18) Synthesis of H-697 For H-696 (40 mg, 0.077 mmol) synthesized in Example 1-17, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-697 as a white powder (28.9 mg, 0.062 mmol, 81%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-697 are as follows. 11H NMR (400 MHz, DMSOd6) δ 6.87 (2H, d, J = 8.2 Hz), 7.38 (2H, t, J = 7.4 Hz), 7.54 (2H, t, J = 8.2 Hz), 7.90 (2H, d, J = 8.7 Hz), 7.94 (2H, d, J = 8.2 Hz), 8.03 (1H, bs), 8.18(1H, bs), 8.23 (2H, d, J = 7.8 Hz), 8.51 (1H,bs),10.15 (1H, bs), 10.27 (1H, s), 10.77 (1H, s); HRESIMS calcdfor C 27 H 19 N3O5Na [M+Na] + 488.1222, found 488.1219. The chemical structure of confirmed H-697 is as follows.

[0188] [Chemical formula] H-697

[0189] (Example 1-19) Synthesis of H-699 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and pyrazinecarboxylic acid (65 mg, 0.50 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-699 as a white powder (89 mg, 0.191 mmol, 45%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-699 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.90 (3H, s), 7.39 (2H, t, J = 7.4 Hz), 7.54 (2H, t, J = 7.3 Hz), 7.96 (2H, d, J = 8.7 Hz), 8.15 (1H, t, J = 1.8 Hz), 8.23 (2H, d, J = 7.8 Hz), 8.36 (1H, t, J = 1.4 Hz), 8.63 (1H, t, J = 1.8 Hz), 8.83 (1H, dd, J = 2.3, 1.4 Hz), 8.94 (1H, d, J = 2.3 Hz), 9.31 (1H, d, J = 1.4 Hz), 10.87 (1H, s), 11.09 (1H, s); HRESIMS calcd for C 26 H 19 N5O4Na [M+Na]+ + 488.1335, found 488.1334. The chemical structure of confirmed H-699 is as follows.

[0190]

Chemical formula

[0191] (Example 1-20) Synthesis of H-700 To H-699 (65 mg, 0.14 mmol) synthesized in Example 1-19, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-700 as a white powder (42 mg, 0.093 mmol, 66%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-700 are as follows. 11H NMR (400 MHz, DMSOd6) δ 7.39 (2H, t, J = 7.4 Hz), 7.54 (2H, t, J = 8.2 Hz), 7.96 (2H, d, J = 8.2 Hz), 8.11 (1H, t, J = 1.8 Hz), 8.23 (2H, d, J = 7.4 Hz), 8.30 (1H, t, J = 1.8 Hz), 8.60 (1H, t, J = 1.8 Hz), 8.83 (1H, dd, J = 2.3, 1.4 Hz), 8.94 (1H, d, J = 2.3 Hz), 9.31 (1H, d, J = 1.3 Hz), 10.83 (1H, s), 11.03 (1H, s); HRESIMS calcd for C 25 H 17 N5O4Na [M+Na] + 474.1178, found 474.1173. The chemical structure of the confirmed H-700 is as follows.

[0192]

Chemical Structure

[0193] (Example 1-21) Synthesis of H-728 To a solution of H-725 (150 mg, 0.377 mmol) synthesized in Example 1-1 in THF (3 mL) were added 2-naphthoic acid (78 mg, 0.452 mmol), EDCI (215 mg, 1.13 mmol), triethylamine (58 mg, 0.8 mL, 0.57 mmol) and DMAP (10 mg, 0.08 mmol) at room temperature, and the mixture was stirred at the same temperature overnight. Water was added to the 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 obtain H-728 as an off-white powder (126 mg, 0.244 mmol, 65%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-728 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.84 (3H, s), 7.21 - 7.27 (6H, m), 7.36 - 7.42 (4H, m), 7.59 - 7.67 (2H,m), 7.89 (1H, bs), 7.98 - 8.10 (5H, m), 8.33 (1H, bs), 8.60 (1H,bs), 8.78 (1H,bs), 10.55 (1H, bs); HRESIMS calcd for C 32 H 25 N3O4Na [M+Na] + 538.1743, found 538.1743. The chemical structure of confirmed H - 728 is as follows.

[0194]

Chemical Structure

[0195] (Example 1 - 22) Synthesis of H - 732 For H - 728 (80 mg, 0.155 mmol) synthesized in Example 1 - 21, a hydrolysis reaction was carried out in the same manner as the synthesis of H - 681, and H - 732 was obtained as a white powder (58 mg, 0.115 mmol, 75%). The results of NMR measurement spectra and mass spectrometry by HR - ESI - MS for H - 732 are as follows. 1 1H NMR (400 MHz, DMSOd6) δ 7.21 - 7.27 (6H, m), 7.36 - 7.42 (4H,m),7.59 - 7.67 (2H, m), 7.84 (1H, t, J = 1.8 Hz), 7.98 - 8.08(5H, m), 8.30 (1H, t,J = 1.8 Hz), 8.59 (1H, bs), 8.74(1H, bs), 10.53 (1H, bs); HRESIMS calcd for C 31 H 23 N3O4Na [M+Na] +524.1586, found 524.1587. The confirmed chemical structure of H-732 is as follows.

[0196] [Chemical formula] H-732

[0197] (Example 1-23) Synthesis of H-729 Using H-725 (150 mg, 0.377 mmol) synthesized in Example 1-1 and quinolinic acid (78 mg, 0.452 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-728, and H-729 was obtained as an off-white powder (158 mg, 0.306 mmol, 81%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-729 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 3.85 (3H, s), 7.15 - 7.27 (6H,m),7.34 - 7.43 (4H, m), 7.75 (1H, ddd, J = 8.2, 6.8,1.4 Hz), 7.88 - 7.93 (2H, m),8.11 (1H, d, J = 7.3 Hz), 8.21 (1H, d,J = 8.2 Hz), 8.23 - 8.27 (2H, m), 8.38 (1H, t, J = 1.8Hz),8.63 (1H, d, J = 8.3 Hz), 8.80 (1H, bs), 10.87 (1H, bs);HRESIMS calcd for C 31 H 24 N4O4Na [M+Na] + 539.1695, found539.1698. The confirmed chemical structure of H-729 is as follows.

[0198] [Chemical formula] H-729

[0199] (Example 1-24) Synthesis of H-733 For H-729 (80 mg, 0.154 mmol) synthesized in Examples 1-23, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681, and H-733 was obtained as a white powder (63 mg, 0.125 mmol, 81%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-733 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 7.15 - 7.27 (6H, m), 7.34 - 7.43 (4H,m),7.75 (1H, ddd, J = 8.2, 6.8, 1.4 Hz), 7.87 (1H, t,J =1.8 Hz), 7.91 (1H, ddd, J = 8.7, 6.8, 1.4 Hz),8.11 (1H, d, J = 7.8 Hz), 8.20 (1H, t, J = 1.8 Hz), 8.21 (1H, d, J =8.2 Hz),8.25 (1H, d, J = 8.2 Hz), 8.34 (1H, t, J = 1.8 Hz), 8.63 (1H, d, J =8.3 Hz),8.75 (1H, bs), 10.82 (1H, bs); HRESIMS calcd for C 30 H 22 N4O4Na [M+Na] + 525.1539, found 525.1539. The confirmed chemical structure of H-733 is as follows.

[0200]

Chemical formula

[0201] (Example 1-25) Synthesis of H-730 Using H-725 (150 mg, 0.377 mmol) synthesized in Example 1-1 and 1,4-benzodioxane-6-carboxylic acid (81 mg, 0.425 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-728, and H-730 was obtained as a white powder (179 mg, 0.341 mmol, 90%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-730 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 3.82 (3H, s), 4.26 - 4.32 (4H, m), 6.97(1H, d, J = 8.7 Hz), 7.19 - 7.26 (6H, m), 7.36 - 7.41 (4H,m), 7.50 (1H, dd, J =8.7, 1.8 Hz), 7.54 (1H, d, J =2.3 Hz), 7.85 (1H, t, J = 1.8 Hz), 8.02 (1H, t, J= 1.8 Hz), 8.26 (1H, t, J =1.8 Hz), 8.75 (1H, bs), 10.19 (1H, bs); HRESIMS calcd for C 30 H 25 N3O6Na [M+Na] + 546.1641, found 546.1644. The confirmed chemical structure of H-730 is as follows.

[0202]

Chemical formula

[0203] (Example 1-26) Synthesis of H-734 For H-730 (80 mg, 0.152 mmol) synthesized in Example 1-25, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681, and H-734 was obtained as a white powder (65 mg, 0.128 mmol, 84%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-734 are as follows. 1 H NMR (400 MHz, DMSOd6) δ 4.26 - 4.32 (4H, m), 6.96 (1H, d, J = 8.7Hz), 7.19 - 7.26 (6H, m), 7.35 - 7.41 (4H, m), 7.50(1H, dd, J = 8.2, 2.3 Hz), 7.54(1H, d, J = 2.3 Hz),7.80 (1H, t, J = 1.8 Hz), 7.98 (1H, t,J = 1.8 Hz), 8.22 (1H, t, J = 1.8 Hz), 8.69 (1H, bs), 10.15 (1H, bs); HRESIMS calcd for C 29 H 23 N3O6Na [M+Na] + 532.1485, found 532.1481. The confirmed chemical structure of H-734 is as follows.

[0204]

Chemical formula

[0205] (Example 1-27) Synthesis of H-731 Using H-725 (150 mg, 0.377 mmol) synthesized in Example 1-1 and 2-quinoxalinecarboxylic acid (78 mg, 0.425 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-728 to obtain H-731 as a white powder (135 mg, 0.261 mmol, 69%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-731 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.85 (3H, s), 7.22 - 7.27 (6H, m), 7.37 - 7.42 (4H, m), 7.92 (1H, t, J = 1.8 Hz), 7.99 - 8.04 (2H, m), 8.20 - 8.24 (1H, m), 8.23 (1H, t, J = 1.8 Hz), 8.26 - 8.31 (1H, m), 8.40 (1H, t, J = 1.8 Hz), 8.81 (1H, s), 9.52 (1H, s), 10.98 (1H, bs); HRESIMS calcd for C 30 H 23 N5O4Na [M+Na] + 540.1648, found 540.1652. The confirmed chemical structure of H-731 is as follows.

[0206] [Chemical formula] H-731

[0207] (Example 1-28) Synthesis of H-735 To H-731 (80 mg, 0.154 mmol) synthesized in Example 1-27, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-735 as an off-white powder (53 mg, 0.105 mmol, 68%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-735 are as follows. 11H NMR (400 MHz, DMSOd6) δ 7.22 - 7.27 (6H, m), 7.36 - 7.42 (4H,m), 7.88 (1H, t, J = 1.8 Hz), 7.99 - 8.04 (2H, m), 8.18 (1H, t, J = 1.8Hz), 8.20 - 8.24 (1H, m), 8.26 - 8.31 (1H, m), 8.37 (1H, t, J = 1.8 Hz), 8.77 (1H, s), 9.52 (1H, s), 10.93 (1H, bs); HRESIMS calcd for C 29 H 21 N5O4Na [M+Na] + 526.1491, found 526.1494. The confirmed chemical structure of H - 735 is as follows.

[0208] [Chemical formula] H - 735

[0209] (Example 1 - 29) Synthesis of H - 609 To a solution of H - 608 (100 mg, 0.312 mmol) synthesized in Example 1 - 1 in THF (5 mL) was added 1 - naphtylisocyanate (69 mg, 0.373 mmol) at room temperature, and the mixture was stirred at the same temperature for 20 hours. Water was added to the 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 obtain H - 609 as a white powder (121 mg, 0.247 mmol, 79%). The results of NMR measurement spectrum and mass spectrometry by HR - ESI - MS for H - 609 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.89 (3H, s), 7.46 - 7.68 (6H, m), 7.95 (1H, d, J = 7.8 Hz), 8.00 - 8.15 (8H, m), 8.34 (1H, bs), 8.63 (1H, bs), 8.78 (1H, s), 9.43 (1H, s), 10.65 (1H, s); HRESIMS calcd for C 30 H 23 N3O4Na [M+Na] + 512.1586, found 512.1585. The confirmed chemical structure of H-609 is as follows.

[0210] [Chemical formula] H-609

[0211] (Examples 1 - 30) Synthesis of H-613 To a solution of H-609 (80 mg, 0.163 mmol) synthesized in Examples 1 - 29 in methanol (4 mL) and THF (10 mL), an aqueous sodium hydroxide solution (1 M, 2 mL, 2 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 17 hours. 1 M hydrochloric acid was added to the mixture to neutralize it, 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 obtain H-613 as a light gray powder (61.3 mg, 0.129 mmol, 79%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-613 are as follows. 11H NMR (400 MHz, DMSOd6) δ 7.48 (1H, t, J = 7.8 Hz), 7.52 - 7.68 (5H,m), 7.94 (1H, d, J = 8.2Hz), 7.99 - 8.15 (8H, m), 8.33 (1H, bs), 8.62 (1H, bs),8.77 (1H, s), 9.38 (1H,s), 10.61 (1H, s); HRESIMS calcdfor C 29 H 21 N3O4Na [M+Na] + 498.1430, found 498.1430. The chemical structure of confirmed H-613 is as follows.

[0212]

Chemical formula

[0213] (Examples 1 - 31) Synthesis of H-744 To a solution of H-722 (150 mg, 0.40 mmol) synthesized in Example 1-1 in THF (3 mL) were added 2-naphthoic acid (82 mg, 0.476 mmol), EDCI (150 mg, 0.785 mmol) and DMAP (9.8 mg, 0.08 mmol) at room temperature, and the mixture was stirred overnight at the same temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:hexane, 8:1) to obtain H-744 as a white powder (48 mg, 0.091 mmol, 23%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-744 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.84 (3H, s), 5.31 (2H, s), 7.22 (2H, t, J = 7.8 Hz), 7.45 (2H, t, J = 7.3 Hz), 7.60 (2H, d, J = 8.2 Hz), 7.58 - 7.67 (3H, m), 7.96 - 8.08 (4H, m), 8.14 - 8.18 (3H, m), 8.52 (1H, t, J = 1.8 Hz), 8.59 (1H, bs), 10.64 (1H, s), 10.83 (1H, s); HRESIMS calcd for C 33 H 25 N3O4Na [M+Na] + 550.1743, found 550.1740. The chemical structure of confirmed H-744 is as follows.

[0214] [Chemical formula] H-744

[0215] (Example 1-32) Synthesis of H-745 For H-744 (20 mg, 0.038 mmol) synthesized in Example 1-31, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-745 as a white powder (8.0 mg, 0.015 mmol, 41%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-745 are as follows. 11H NMR (400 MHz, DMSOd6) δ 5.30 (2H, s), 7.22 (2H, t, J = 7.8 Hz),7.45 (2H, t, J = 7.3 Hz),7.60 (2H, d,J = 8.2 Hz), 7.59-7.66 (3H, m), 7.96-8.10(5H, m), 8.17 (2H, d,J = 7.4 Hz), 8.48 (1H, bs), 8.59(1H, bs), 10.55 (1H, s), 10.74 (1H, s); HRESIMS calcdfor C 32 H 23 N3O4Na [M+Na] + 536.1586, found536.1589. The chemical structure of the confirmed H-745 is as follows.

[0216] [Chemical formula] H-745

[0217] (Examples 1-33) Synthesis of H-746 Using H-722 (150 mg, 0.40 mmol) synthesized in Example 1-1 and quinolinic acid (82 mg, 0.48 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-744, and the residue was purified by silica gel column chromatography (chloroform) to obtain H-746 as a white powder (30.3 mg, 0.057 mmol, 14%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-746 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.85 (3H, s), 5.31 (2H, s), 7.22 (2H, t, J= 7.8 Hz), 7.45 (2H, t, J= 7.3 Hz), 7.60 (2H, d, J = 8.2 Hz), 7.75 (1H, t, J =7.8 Hz), 7.90 (1H, t, J =8.3 Hz), 8.08 (1H, bs), 8.11 (1H, d, J = 7.8 Hz), 8.17 (2H, d, J = 7.7 Hz),8.21 (1H, d, J =8.7 Hz), 8.25 (1H, d, J = 8.2 Hz), 8.28 (1H, bs), 8.59 (1H, t,J = 1.8 Hz), 8.62 (1H, d,J = 8.7 Hz), 10.85 (1H, s),10.99 (1H, s); HRESIMS calcd for C 32 H 24 N4O4Na [M+Na] + 551.1695, found 551.1690. The confirmed chemical structure of H-746 is as follows.

[0218]

Chemical Structure

[0219] (Examples 1-34) Synthesis of H-747 To H-746 (20 mg, 0.038 mmol) synthesized in Examples 1-33, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-747 as a white powder (16 mg, 0.031 mmol, 82%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-747 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 5.31 (2H, s), 7.22 (2H, t, J = 7.8 Hz), 7.45 (2H, t, J = 7.3 Hz), 7.61 (2H, d, J = 8.2 Hz), 7.75 (1H, t, J = 8.2 Hz), 7.90 (1H, t, J = 8.3 Hz), 8.00 (1H, bs), 8.11 (1H, d, J = 8.3 Hz), 8.17 (2H, d, J = 7.8 Hz), 8.20 (1H, bs), 8.21 (1H, d, J = 8.7 Hz), 8.24 (1H, d, J = 8.2 Hz), 8.55 (1H, bs), 8.62 (1H, d, J = 8.2 Hz), 10.78 (1H, s), 10.89 (1H, s); HRESIMS calcd for C 31 H 22 N4O4Na [M+Na] + 537.1539, found 537.1541. The confirmed chemical structure of H-747 is as follows.

[0220]

Chemical formula

[0221] (Examples 1-35) Synthesis of H-748 Using H-722 (150 mg, 0.40 mmol) synthesized in Example 1-1 and 1,4-benzodioxane-6-carboxylic acid (82 mg, 0.48 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-744, and the residue was purified by silica gel column chromatography (chloroform) to obtain H-748 as a white powder (25.7 mg, 0.048 mmol, 12%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-748 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.82 (3H, s), 4.26 - 4.32 (4H, m), 5.29 (2H, s), 6.97 (1H, d, J = 8.7 Hz), 7.21 (2H, t, J = 7.3 Hz), 7.44 (2H, t, J = 7.3 Hz), 7.51 (1H, dd, J = 8.3, 2.3 Hz), 7.54 (1H, d, J = 2.3 Hz), 7.59 (2H, d, J = 8.2 Hz), 8.02 (1H, t, J = 1.8 Hz), 8.10 (1H, t, J = 1.8 Hz), 8.17 (2H, d, J = 7.8 Hz), 8.45 (1H, t, J = 1.8 Hz), 10.26 (1H, s), 10.78 (1H, s); HRESIMS calcd for C 31 H 25 N3O6Na [M+Na]+ + 558.1641, found 558.1642. The confirmed chemical structure of H-748 is as follows.

[0222]

Chemical formula

[0223] (Examples 1 - 36) Synthesis of H-749 For H-748 (20 mg, 0.037 mmol) synthesized in Examples 1 - 35, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-749 as a white powder (10 mg, 0.019 mmol, 52%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-749 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 4.26 - 4.32 (4H, m), 5.29 (2H, s), 6.96 (1H, d, J = 8.6 Hz), 7.21 (2H, t, J = 7.8 Hz), 7.44 (2H, t, J = 7.3 Hz), 7.51 (1H, dd, J = 8.2, 2.3 Hz), 7.54 (1H, d, J = 2.3 Hz), 7.59 (2H, d, J = 7.8 Hz), 7.95 (1H, bs), 8.04 (1H, bs), 8.16 (2H, d, J = 7.3 Hz), 8.42 (1H, bs), 10.20 (1H, s), 10.71 (1H, s); HRESIMS calcd for C 30 H 23 N3O6Na [M+Na]+ + 544.1485, found 544.1487. The confirmed chemical structure of H-749 is as follows.

[0224] [Chemical formula] H-749

[0225] (Examples 1 - 37) Synthesis of H-818 Using H-816 (100 mg, 0.266 mmol) synthesized in Example 1-1 and 2-naphthoic acid (55 mg, 0.32 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-818 as a white powder (136 mg, 0.256 mmol, 96%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-818 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.86 (3H, s), 4.59 (2H, s), 6.94 (2H, t, J = 7.3 Hz), 7.05 (4H, d, J = 7.8 Hz), 7.27 (4H, t, J = 7.8 Hz), 7.59 - 7.67 (2H, m), 7.98 - 8.09 (5H, m), 8.18 (1H, bs), 8.53 (1H, t, J = 1.8 Hz), 8.61 (1H, bs), 10.47 (1H, s), 10.65 (1H, s); HRESIMS calcd for C 33 H 27 N3O4Na [M+Na] + 552.1899, found 552.1898. The chemical structure of the confirmed H-818 is as follows.

[0226]

Chemical formula

[0227] (Example 1 - 38) Synthesis of H-819 For H-818 (60 mg, 0.113 mmol) synthesized in Example 1 - 37, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-819 as a white powder (54 mg, 0.104 mmol, 92%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-819 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 4.59 (2H, s), 6.94 (2H, t, J = 7.3 Hz), 7.06 (4H, d, J = 7.8 Hz), 7.27 (4H, t, J = 7.8 Hz), 7.59 - 7.68 (2H, m), 7.97 - 8.09 (5H, m), 8.15 (1H, bs), 8.51 (1H, bs), 8.61 (1H, bs), 10.42 (1H, s), 10.61 (1H, s); HRESIMS calcd for C 32 H 25 N3O4Na [M+Na] + 538.1743, found 538.1742. The chemical structure of confirmed H-819 is as follows.

[0228]

Chemical Structure

[0229] (Examples 1 - 39) Synthesis of H-820 Using H-816 (100 mg, 0.266 mmol) synthesized in Example 1-1 and quinolinic acid (55 mg, 0.32 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-820 as a yellow powder (126 mg, 0.238 mmol, 89%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-820 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.87 (3H, s), 4.60 (2H, s), 6.94 (2H, t, J = 7.3 Hz), 7.06 (4H, d, J = 7.8 Hz), 7.27 (4H, t, J = 7.8 Hz), 7.76 (1H, t, J = 7.3 Hz), 7.91 (1H, t, J = 7.3 Hz), 8.08 (1H, bs), 8.12 (1H, d, J = 8.3 Hz), 8.22 (1H, d, J = 8.7 Hz), 8.27 (1H, d, J = 8.2 Hz), 8.28 (1H, bs), 8.59 (1H, bs), 8.63 (1H, d, J = 8.7 Hz), 10.49 (1H, bs), 11.00 (1H, bs); HRESIMS calcd for C 32 H 26 N4O4Na [M+Na] + 553.1852, found 553.1852. The chemical structure of the confirmed H-820 is as follows.

[0230] [Chemical formula] H-820

[0231] (Example 1-40) Synthesis of H-821 For H-820 (60 mg, 0.113 mmol) synthesized in Example 1-39, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-821 as a white powder (53 mg, 0.103 mmol, 91%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-821 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 4.59 (2H, s), 6.94 (2H, t, J = 7.3 Hz), 7.06 (4H, d, J = 7.8 Hz), 7.27 (4H, t, J = 7.8 Hz), 7.76 (1H, t, J = 7.3 Hz), 7.91 (1H, t, J = 7.3 Hz), 8.02 (1H, bs), 8.12 (1H, d, J = 8.3 Hz), 8.22 (1H, d, J = 8.7 Hz), 8.23 (1H, bs), 8.26 (1H, d, J = 8.2 Hz), 8.56 (1H, bs), 8.63 (1H, d, J = 8.7 Hz), 10.44 (1H, bs), 10.94 (1H, bs); HRESIMS calcd for C 31 H 24 N4O4Na [M+Na] + 539.1695, found 539.1697. The chemical structure of confirmed H-821 is as follows.

[0232] [Chemical formula] H-821

[0233] (Example 1-41) Synthesis of H-822 Using H-816 (100 mg, 0.266 mmol) synthesized in Example 1-1 and 1,4-benzodioxane-6-carboxylic acid (58 mg, 0.32 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-822 as a white powder (124 mg, 0.231 mmol, 87%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-822 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.84 (3H, s), 4.26 - 4.33 (4H, m), 4.57 (2H, s), 6.93 (2H, t, J = 7.3 Hz), 6.97 (1H, d, J = 8.2 Hz), 7.04 (4H, d, J = 7.8 Hz), 7.26 (4H, t, J = 7.8 Hz), 7.52 (1H, dd, J = 8.3, 1.8 Hz), 7.55 (1H, d, J = 1.8 Hz), 8.00 (1H, bs), 8.11 (1H, bs), 8.44 (1H, t, J = 1.8 Hz), 10.27 (1H, bs), 10.43 (1H, bs); HRESIMS calcd for C 31 H 27 N3O6Na [M+Na]+ + 560.1798, found 560.1797. The confirmed chemical structure of H-822 is as follows.

[0234] [Chemical Structure] H-822

[0235] (Example 1-42) Synthesis of H-823 For H-822 (60 mg, 0.112 mmol) synthesized in Example 1-41, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-823 as a white powder (45 mg, 0.087 mmol, 77%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-823 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 4.26 - 4.33 (4H, m), 4.56 (2H, s), 6.93 (2H, t, J = 7.3 Hz), 6.97 (1H, d, J = 8.2 Hz), 7.04 (4H, d, J = 7.8 Hz), 7.26 (4H, t, J = 7.8 Hz), 7.51 (1H, dd, J = 8.3, 1.8 Hz), 7.55 (1H, d, J = 1.8 Hz), 7.94 (1H, bs), 8.06 (1H, bs), 8.41 (1H, bs), 10.22 (1H, bs), 10.36 (1H, bs); HRESI MS calcd for C 30 H 25 N3O6Na [M+Na] + 546.1641, found 546.1646. The chemical structure of confirmed H-823 is as follows.

[0236] [Chemical formula] H-823

[0237] (Example 1-43) Synthesis of H-824 Using H-816 (100 mg, 0.266 mmol) synthesized in Example 1-1 and benzoic acid (39 mg, 0.32 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-824 as a white powder (127 mg, 0.263 mmol, 99%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-824 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.85 (3H, s), 4.58 (2H, s), 6.93 (2H, t, J = 7.3 Hz), 7.04 (4H, d, J = 7.8 Hz), 7.26 (4H, t, J = 7.8 Hz), 7.52 (2H, t, J = 7.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.97 (2H, t, J = 7.3 Hz), 8.03 (1H, bs), 8.13 (1H, bs), 8.46 (1H, bs), 10.44 (1H, bs), 10.47 (1H, bs); HRESIMS calcd for C 29 H 25 N3O4Na [M+Na] + 502.1743, found 502.1740. The chemical structure of confirmed H-824 is as follows.

[0238] [Chemical formula] H-824

[0239] (Example 1-44) Synthesis of H-825 For H-824 (60 mg, 0.112 mmol) synthesized in Example 1-43, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-825 as a white powder (52 mg, 0.112 mmol, 90%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-825 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 4.57 (2H, s), 6.93 (2H, t, J = 7.3 Hz), 7.04 (4H, d, J = 7.8 Hz), 7.26 (4H, t, J = 7.8 Hz), 7.52 (2H, t, J = 7.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.97 (2H, t, J = 7.3 Hz), 7.97 (1H, bs), 8.08 (1H, bs), 8.44 (1H, bs), 10.38 (1H, bs), 10.42 (1H, bs); HRESIMS calcd for C 28 H 23 N3O4Na [M+Na] + 488.1586, found 488.1582. The confirmed chemical structure of H-825 is as follows.

[0240]

Chem.

[0241] (Example 1-45) Synthesis of H-758 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and phenoxyacetic acid (76 mg, 0.50 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-758 as a white powder (170 mg, 0.346 mmol, 83%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-758 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.87 (3H, s), 4.74 (2H, s), 6.94 - 7.02 (3H, m), 7.32 (2H, dd, J = 8.7, 7.3 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.53 (2H, t, J = 7.3 Hz), 7.93 (2H, d, J = 8.2 Hz), 8.08 (1H, bs), 8.12 (1H, bs), 8.23 (2H, d, J = 7.3 Hz), 8.37 (1H, bs), 10.46 (1H, bs), 10.83 (1H, bs); HRESIMS calcd for C 29 H 23 N3O5Na [M+Na]+ + 516.1535, found 516.1530. The confirmed chemical structure of H-758 is as follows.

[0242]

Chem.

[0243] (Examples 1 - 46) Synthesis of H-759 For H-758 (80.0 mg, 0.16 mmol) synthesized in Examples 1 - 45, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-759 as a white powder (60.0 mg, 0.13 mmol, 77%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-759 are as follows. 11H NMR (400 MHz, DMSOd6) δ 4.73 (2H, s), 6.94 - 7.02 (3H, m), 7.31(2H, dd, J = 8.7, 7.3 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.53 (2H, t, J = 7.3Hz), 7.93 (2H, d, J = 8.2 Hz), 8.03 (1H, bs), 8.07 (1H, bs), 8.23 (2H, d, J = 7.3Hz), 8.34 (1H, bs), 10.40 (1H, bs), 10.78(1H, bs); HRESIMS calcd for C 28 H 21 N3O5Na [M+Na] + 502.1379, found 502.1375. The confirmed chemical structure of H-759 is as follows.

[0244]

Chemical Structure

[0245] (Example 1 - 47) Synthesis of H-760 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1 - 1 and 2-naphthyloxyacetic acid (102 mg, 0.50 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-760 as a white powder (225 mg, 0.41 mmol, 99%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-760 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.87 (3H, s), 4.87 (2H, s), 7.30 - 7.41 (5H, m), 7.46 (1H, t, J = 7.3 Hz), 7.52 (2H, t, J = 7.3 Hz), 7.78 - 7.90 (3H, m), 7.93 (2H, d, J = 8.2 Hz), 8.09 (1H, t, J = 1.8 Hz), 8.14 (1H, t, J = 1.8 Hz), 8.23 (2H, d, J = 7.3 Hz), 8.40 (1H, t, J = 1.8 Hz), 10.52 (1H, bs), 10.83 (1H, bs); HRESIMS calcd for C 33 H 25 N3O5Na [M+Na]+ + 566.1692, found 566.1691. The chemical structure of confirmed H-760 is as follows.

[0246]

Chemical Structure

[0247] (Example 1-48) Synthesis of H-761 For H-760 (100 mg, 0.18 mmol) synthesized in Example 1-47, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-761 as a white powder (53.0 mg, 0.10 mmol, 56%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-761 are as follows. 11H NMR (400 MHz, DMSOd6) δ 4.86 (2H, s), 7.30 - 7.40 (5H, m), 7.46(1H, t, J = 7.3 Hz), 7.52 (2H, t, J = 7.3 Hz), 7.78 - 7.90 (3H, m), 7.93 (2H, d, J = 8.2Hz), 8.04 (1H, bs), 8.08 (1H, bs), 8.22(2H, d, J = 7.3 Hz), 8.37 (1H, bs), 10.45 (1H, bs), 10.78 (1H, bs); HRESIMS calcd for C 32 H 23 N3O5Na [M+Na] + 552.1535, found 552.1535. The confirmed chemical structure of H-761 is as follows.

[0248] [Chemical formula] H-761

[0249] (Examples 1 - 49) Synthesis of H-762 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and 2-pyridyloxyacetic acid (76.6 mg, 0.50 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679, and H-762 was obtained as an off-white powder (42.0 mg, 0.085 mmol, 21%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-762 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.87 (3H, s), 4.77 (2H, s), 6.25 (1H, td, J = 6.9, 1.3 Hz), 6.40 (1H, d, J = 9.1 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.46 (1H, ddd, J = 9.2, 6.8, 1.8 Hz), 7.53 (2H, t, J = 7.3 Hz), 7.68 (1H, dd, J = 6.4, 1.8 Hz), 7.93 (2H, d, J = 8.2 Hz), 8.06 (1H, bs), 8.09 (1H, bs), 8.23 (2H, d, J = 7.8 Hz), 8.30 (1H, bs), 10.73 (1H, bs), 10.83 (1H, bs); HRESIMS calcd for C 28 H 22 N4O5Na [M+Na]+ + 517.1488, found 517.1490. The chemical structure of the confirmed H-762 is as follows.

[0250]

Chemical formula

[0251] (Examples 1-50) Synthesis of H-763 For H-762 (55.0 mg, 0.11 mmol) synthesized in Examples 1-49, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-763 as a white powder (37.0 mg, 0.077 mmol, 70%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-763 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 4.76 (2H, s), 6.22 - 6.28 (1H, m), 6.40 (1H, d, J = 9.1 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.46 (1H, ddd, J = 9.2, 6.8, 1.8 Hz), 7.53 (2H, t, J = 7.3 Hz), 7.68 (1H, bd, J = 6.9 Hz), 7.93 (2H, d, J = 8.2 Hz), 8.02 (1H, bs), 8.03 (1H, bs), 8.22 (2H, d, J = 7.8 Hz), 8.30 (1H, bs), 10.65 (1H, bs), 10.78 (1H, bs); HRESIMS calcd for C 27 H 20 N4O5Na [M+Na] + 503.1331, found 503.1331. The confirmed chemical structure of H-763 is as follows.

[0252] [Chemical Structure] H-763

[0253] (Example 1 - 51) Synthesis of H-764 Using H-677 (100 mg, 0.278 mmol) synthesized in Example 1 - 1 and 2 - quinolinyl oxyacetic acid (85 mg, 0.417 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679 to obtain H-764 as a white powder (146 mg, 0.268 mmol, 97%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-764 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.86 (3H, s), 5.18 (2H, s), 6.67 (1H, d, J = 9.1 Hz), 7.26 (1H, t, J = 7.3 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.46 - 7.62 (4H, m), 7.75 (1H, d, J = 7.8 Hz), 7.92 (2H, d, J = 8.2 Hz), 7.99 (1H, d, J = 9.3 Hz), 8.06 (1H, bs), 8.09 (1H, bs), 8.22 (2H, d, J = 7.8 Hz), 8.32 (1H, bs), 10.81 (2H, bs); HRESIMS calcd for C 32 H 24 N4O5Na [M+Na]+ + 567.1644, found 567.1642. The chemical structure of confirmed H-764 is as follows.

[0254] [Chemical formula] H-764

[0255] (Example 1-52) Synthesis of H-765 For H-764 (80 mg, 0.144 mmol) synthesized in Example 1-51, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-765 as a white powder (57.3 mg, 0.108 mmol, 75%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-765 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 5.17 (2H, s), 6.66 (1H, d, J = 9.6 Hz), 7.26 (1H, t, J = 7.3 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.46 - 7.54 (3H, m), 7.59 (1H, t, J = 7.3 Hz), 7.75 (1H, d, J = 7.8 Hz), 7.91 (2H, d, J = 8.2 Hz), 7.99 (1H, d, J = 9.6 Hz), 8.01 (1H, bs), 8.02 (1H, bs), 8.22 (2H, d, J = 7.8 Hz), 8.30 (1H, bs), 10.76 (1H, bs), 10.77 (1H, bs); HRESIMS calcd for C 31 H 22 N4O5Na [M+Na] + 553.1488, found 553.1492. The confirmed chemical structure of H-765 is as follows.

[0256] [Chemical formula] H-765

[0257] (Example 1 - 53) Synthesis of H-766 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1 - 1 and hippuric acid (90.2 mg, 0.50 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679, and H-766 was obtained as an off-white powder (96.0 mg, 0.18 mmol, 44%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-766 are as follows. 11H NMR (400 MHz, DMSO-d6) δ 3.87 (3H, s), 4.08 (2H, d, J = 5.9 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.46 - 7.57 (5H, m), 7.88 - 7.94 (4H, m), 8.06 (1H, t, J = 1.8 Hz), 8.09 (1H, t, J = 1.8 Hz), 8.22 (2H, d, J = 7.8 Hz), 8.33 (1H, t, J = 1.8 Hz), 8.88 (1H, t, J = 5.9 Hz), 10.41 (1H, bs), 10.82 (1H, bs); HRESIMS calcd for C 30 H 24 N4O5Na [M+Na]+ + 543.1644, found 543.1644. The confirmed chemical structure of H-766 is as follows.

[0258] [Chemical formula] H-766

[0259] (Example 1-54) Synthesis of H-767 To H-766 (50.0 mg, 0.096 mmol) synthesized in Example 1-53, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681, and H-767 was obtained as an off-white powder (33.0 mg, 0.065 mmol, 67%). The results of NMR measurement spectra and mass spectrometry by HR-ESI-MS for H-767 are as follows. 11H NMR (400 MHz, DMSOd6) δ 4.08 (2H, d, J = 5.9 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.46 - 7.57 (5H, m), 7.88 - 7.94 (4H, m), 8.02 (1H, t, J = 1.8 Hz), 8.05 (1H, t, J = 1.8 Hz), 8.22 (2H, d, J = 7.8 Hz), 8.32 (1H, t, J = 1.8 Hz), 8.88 (1H, t, J = 5.9 Hz), 10.37 (1H, bs), 10.78 (1H, bs); HRESIMS calcd for C 29 H 22 N4O5Na [M+Na] + 529.1488, found 529.1492. The confirmed chemical structure of H-767 is as follows.

[0260]

Chemical formula

[0261] (Example 1-55) Synthesis of H-768 Using H-677 (150 mg, 0.42 mmol) synthesized in Example 1-1 and N-carbobenzoxy glycine (105 mg, 0.50 mmol), a dehydration condensation reaction was carried out in the same manner as the synthesis of H-679, and H-768 was obtained as an off-white powder (227 mg, 0.41 mmol, 99%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-768 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.83 (2H, d, J = 6.0 Hz), 3.87 (3H, s), 5.05 (2H, s), 7.29 - 7.41 (7H, m), 7.53 (2H, t, J = 8.2 Hz), 7.60 (1H, t, J = 5.9 Hz), 7.93 (2H, d, J = 8.2 Hz), 8.06 (1H, t, J = 1.8 Hz), 8.07 (1H, t, J = 1.8 Hz), 8.23 (2H, d, J = 7.8 Hz), 8.31 (1H, t, J = 1.8 Hz), 10.33 (1H, bs), 10.82 (1H, bs); HRESIMS calcd for C 31 H 26 N4O6Na [M+Na] + 573.1750, found 573.1757. The confirmed chemical structure of H-768 is as follows.

[0262]

Chemical formula

[0263] (Examples 1 - 56) Synthesis of H-769 For H-768 (100 mg, 0.18 mmol) synthesized in Examples 1 - 55, a hydrolysis reaction was carried out in the same manner as the synthesis of H-681 to obtain H-769 as an off-white powder (12.0 mg, 0.022 mmol, 12%). The results of NMR measurement spectrum and mass spectrometry by HR-ESI-MS for H-769 are as follows. 11H NMR (400 MHz, DMSOd6) δ 3.83 (2H, d, J = 6.4 Hz), 5.05 (2H, s), 7.28 - 7.40 (7H, m), 7.53 (2H, t, J = 8.2 Hz), 7.58 (1H, t, J = 6.4 Hz), 7.92 (2H, d, J = 8.2 Hz), 7.98 (2H, bs), 8.23 (2H, d, J = 7.8 Hz), 8.27(1H, bs), 10.22 (1H, bs), 10.73 (1H, bs); HRESIMS calcd for C 30 H 24 N4O6Na [M+Na] + 559.1594, found 559.1597. The chemical structure of confirmed H-769 is as follows.

[0264]

Chem.

Example

[0265] (Evaluation of the activity of inhibiting Pin1) To evaluate the activity of the compound synthesized in Example 1 to inhibit the function of Pin1, the degree of phosphorylation of AMPK (AMP-activated protein kinase), which has been shown to be suppressed from phosphorylation by Pin1, was used as an index according to the method previously developed by the present inventors (Yusuke Nakatsu et al., Journal of Biological Chemistry, 2015, Vol.290, No.40, pp.24255 - 24266), and an assay using cells was performed. Briefly, 293T cells were seeded on a collagen-coated 24-well plate. After 48 hours, each compound (50 μM) synthesized in the example was added and left standing in an incubator for 30 minutes. Then, 10 mM 2-DG was added, and after 1 hour, the samples were collected with a buffer containing mercaptoethanol and SDS. ​ According to the conventional method, after performing SDS-PAGE and blotting, blocking was carried out with 3% BSA for 1 hour. Then, pAMPK antibody (Cell signaling 1:2000, diluted with Can get signal solution1: Toyobo) was used as the primary antibody, and HRP-linked anti-rabbit IgG (GE healthcare 1:4000, diluted with Can get signal solution2: Toyobo) was used as the secondary antibody, and they were each reacted at room temperature for 1 hour and detected. The activity of inhibiting the function of Pin1 was evaluated as follows by comparing with the degree of inhibition by C1 ((R)-2-(5-(4-methoxyphenyl)-2-methylfuran-3-carboxamido)-3-(naphthalene-6-yl)propanoic acid), a known Pin1 inhibitor. (+++): Promotes phosphorylation of AMPK more strongly than C1. (++): Promotes phosphorylation of AMPK to the same extent as C1. (+): Promotes phosphorylation of AMPK, but is weaker than C1. (-): Almost no promotion of AMPK phosphorylation is observed.

[0266] As a method for measuring the activity of inhibiting the function of Pin1, since there is also an assay for measuring peptidylprolyl isomerase activity without using cells (cell-free), for some of the compounds synthesized in Example 1, a cell-free assay was performed based on the method of Janowski et al. (Analytical Biochemistry, 1997, Vol. 252, Issue 2, pp. 299-307). Briefly described, the assay buffer (containing 35 mM HEPES pH 7.8, 50 μM DTT and 0.0025% NP40) was equilibrated to 10 degrees in a quartz cell equipped with a stirring function. A compound (10 μM) dissolved in DMSO was added to this solution, and the UV spectrum in this state was measured. Then Pin1 (final concentration 5 nM) was added. The reaction was initiated by adding a substrate peptide (Suc-Ala-Glu-Pro-Phe-pNA) (final concentration 60 μM) dissolved in a solution of 0.5 M LiCl in trifluoroethanol. The change in absorbance at 330 nm after the start of the reaction was measured for 5 minutes. The reaction curve was fitted to a first-order decay model to calculate the reaction rate. The background rate was subtracted to obtain the catalytic reaction rate. The inhibition rate (%) was calculated from the catalytic reaction rates with and without the compound. The higher the inhibition rate, the higher the activity of inhibiting the function of Pin1.

[0267] Regarding the activity of inhibiting the function of Pin1, the results of cell-based assays and cell-free assays are tabulated as follows.

[0268] [Table 1]

[0269] [Table 2]

[0270] [Table 3]

[0271] [Table 4]

[0272] [Table 5]

[0273]

Table 6

[0274]

Table 7

[0275]

Table 8

[0276]

Table 9

[0277]

Table 10

[0278]

Table 11

[0279]

Table 12

[0280]

Table 13

[0281]

Table 14

Example

[0282] (NASH Treatment Experiment) (Example 3-1) To test the therapeutic effect of the compound of the present invention on non-alcoholic steatohepatitis (NASH), an animal experiment was conducted using NASH model mice. NASH model mice (hereinafter referred to as "NASH mice") were prepared by feeding 8-week-old male individuals of mice for animal experiments with a high-fat, high-cholesterol, palm oil-containing diet (HFD) for 8 weeks. During the 8-week HFD intake period, an animal experiment was conducted by dividing the mice into two groups: a group orally administered with the compound (H-686) of the present invention at 5 mg / Kg / day three times a week, and a group not administered with anything. In addition, to serve as control mice, 8-week-old male individuals of mice for animal experiments were fed a normal diet for 8 weeks. The results of measuring the body weights and liver weights of these mice are shown in FIGS. 1(A) and 1(B), respectively. The results of measuring the blood AST (GOT) concentration and blood ALT (GPT) concentration are shown in FIGS. 2(A) and 2(B), respectively. And the results of measuring the mRNA expression levels of Col1a1 (type I collagen α1 chain) and Col1a2 (type I collagen α2 chain) are shown in FIGS. 3(A) and 3(B), respectively.

[0283] FIG. 1(A) is a graph showing the results of measuring the body weights of mice. Each bar graph shows the measurement results of control mice, mice fed with HFD, and mice fed with HFD and H-686 from left to right. FIG. 1(B) is a graph showing the results of measuring the liver weights of mice. Each bar graph shows the measurement results of control mice, mice fed with HFD, and mice fed with HFD and H-686 from left to right. As shown in Fig. 1(A), in the mice fed with HFD, the body weight increased, but when H-686 was administered, the increase in body weight was suppressed. Also, regarding the liver weight, as shown in Fig. 1(B), in the mice fed with HFD, fat accumulated in the liver and the liver weight increased, but when H-686 was administered, the increase in liver weight was significantly suppressed.

[0284] Fig. 2(A) is a graph showing the results of measuring the concentration (IU / ml) of AST (GOT) in the blood. Each bar graph shows the measurement results of control mice, mice fed with HFD, and mice fed with HFD and H-686 from left to right. Fig. 2(B) is a graph showing the results of measuring the concentration (IU / ml) of ALT (GPT) in the blood. Each bar graph shows the measurement results of control mice, mice fed with HFD, and mice fed with HFD and H-686 from left to right. As shown in Fig. 2(A), in the mice fed with HFD, the numerical value of AST indicating liver inflammation increased, but when H-686 was administered, the numerical value of AST decreased and suppression of liver inflammation was observed. Also, regarding ALT, as shown in Fig. 2(B), in the mice fed with HFD, the numerical value of ALT indicating liver inflammation increased, but when H-686 was administered, the numerical value of ALT decreased and suppression of liver inflammation was observed.

[0285] Fig. 3(A) is a graph showing the results of measuring the expression level of Col1a1 (type I collagen α1 chain) mRNA. Each bar graph shows the measurement results of control mice, mice fed with HFD, and mice fed with HFD and H-686 from left to right. The measured values show the ratio when the expression level in the control is set to 1. Fig. 3(B) is a graph showing the results of measuring the expression level of Col1a2 (type I collagen α2 chain) mRNA. Each bar graph shows the measurement results of control mice, mice fed with HFD, and mice fed with HFD and H-686 from left to right. The measured values show the ratio when the expression level in the control is set to 1. As shown in Fig. 3(A), in mice fed with HFD, the expression level of Col1a1 (type I collagen α1 chain) involved in liver tissue fibrosis increased, but when H-686 was administered, the expression level of Col1a1 was suppressed. Also, for Col1a2 (type I collagen α2 chain), as shown in Fig. 3(B), the expression level increased in mice fed with HFD, but when H-686 was administered, suppression of the expression level was observed.

[0286] (Example 3-2) Next, Fig. 4 shows the results of microscopic observation of liver tissue sections of control mice, mice fed with HFD, and mice fed with HFD and H-686. Fig. 4(A) is a photograph showing the observation result of the liver tissue of control mice, Fig. 4(B) is a photograph showing the observation result of the liver tissue of mice fed with HFD, and Fig. 4(C) is a photograph showing the observation result of the liver tissue of mice fed with HFD and H-686. As shown in Fig. 4(A), no fat accumulation was observed in the liver tissue of control mice, but as shown in Figs. 4(B) and (C), fat accumulation was observed in the liver tissue of mice fed with HFD. And, as is clear from the comparison between Figs. 4(B) and 4(C), even in mice fed with HFD, fat accumulation was suppressed by administering H-686.

Example

[0287] (SARS-CoV-2 Growth Inhibition Experiment) (Examples 4-1 to 4-8) Table 15 shows the results of the confirmation test for the inhibitory effect on SARS-CoV-2 proliferation. In the confirmation test, a Pin1 inhibitor was added to VeroE6 / TMPRSS2 cells at a final concentration of 20 μM. After 2 hours, the cells were infected with SARS-CoV-2 at a multiplicity of infection (MOI) of 10. After 8 hours of infection, cell lysates were collected, and intracellular SARS-CoV-2 nucleocapsid, Pin1, and actin as an internal standard protein were detected by Western blotting. The inhibition rate was calculated as the ratio of the band area when the Pin1 inhibitor was added, with the band area in the same system without the addition of the Pin1 inhibitor set as 0% inhibition rate. When the band area was 0 (when no band was observed), the inhibition rate was 100%.

[0288]

Table 15

[0289] Furthermore, for the Pin1 inhibitor H-688 (Example 4-4) with a high inhibition rate in Table 15, the inhibitory effect on SARS-CoV-2 proliferation was confirmed when the addition amounts were 5 μM and 10 μM. To VeroE6 / TMPRSS2 cells at 1×10 5 cells / well, a Pin1 inhibitor was added to a final concentration of 5 or 10 μM. After 2 hours, the cells were infected with SARS-CoV-2 at a multiplicity of infection (MOI) of 10. After 8 hours of infection, cell lysates were collected, and intracellular SARS-CoV-2 nucleocapsid and actin as an internal standard protein were detected by Western blotting. Figure 5 shows the results of adding the Pin1 inhibitor H-688.

Industrial Applicability

[0290] The compound or its salt of the present invention, the Pin1 inhibitor, the pharmaceutical composition, the therapeutic or prophylactic agent for inflammatory diseases, the therapeutic or prophylactic agent for fatty liver diseases, the therapeutic or prophylactic agent for obesity, and the therapeutic or prophylactic agent for COVID-19 are all useful in the pharmaceutical industry.

Claims

1. Formula (I) 【Chemical 1】 (In the formula, ring A represents a naphthalene ring, benzene ring, pyridine ring, quinoline ring, quinoxaline ring, benzodioxane ring, benzodioxole ring, or pyrazine ring which may have a substituent, R １ represents a carbazolyl group, a diphenylamino group, or a naphthylamino group which may have a substituent, and the nitrogen atom of R1 is bonded to Y, R ２ represents a hydrogen atom or a hydrocarbon group which may have a substituent, R ３ represents a hydrogen atom, R ４ represents a hydrogen atom, R ５ represents the same or different 0 to 3 substituents linked to the benzene ring, X represents a single bond, an alkylene group having 1 or 2 carbon atoms, an -O- group, -CH ２ -O- group, -CH ２ -NH-CO- group or -CH ２ -NH-CO-O-CH ２ - group, and Y represents a single bond or an alkylene group having 1 or 2 carbon atoms.) A compound represented by the formula or a salt thereof.

2. The compound or a salt thereof according to claim 1, wherein the ring A is a naphthalene ring, quinoline ring, quinoxaline ring, benzodioxane ring, or benzodioxole ring which may have a substituent.

3. Said R １ The compound or a salt thereof according to claim 1 or 2, wherein R is a carbazolyl group.

4. The aforementioned R ２ The compound or its salt according to any one of claims 1 to 3, wherein R is a hydrogen atom.

5. The compound or a salt thereof according to any one of claims 1 to 4, wherein X is a single bond.

6. The compound or a salt thereof according to any one of claims 1 to 5, wherein Y is a single bond.

7. A Pin1 inhibitor comprising the compound or a salt thereof according to any one of claims 1 to 6.

8. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

9. A therapeutic or prophylactic agent for inflammatory diseases, containing the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 as an active ingredient.

10. A therapeutic or prophylactic agent for inflammatory diseases, which is a combination of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 and an active ingredient of at least one drug selected from drugs classified as therapeutic or prophylactic agents for inflammatory diseases.

11. The therapeutic or prophylactic agent for inflammatory diseases according to claim 9, which is used to treat or prevent inflammatory diseases in combination with at least one drug selected from drugs classified as therapeutic or prophylactic agents for inflammatory diseases.

12. The therapeutic or prophylactic agent for inflammatory diseases according to any one of claims 9 to 11, wherein the inflammatory disease is non-alcoholic steatohepatitis, inflammatory bowel disease or pulmonary fibrosis.

13. A therapeutic or prophylactic agent for fatty liver diseases, containing the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 as an active ingredient.

14. A therapeutic or prophylactic agent for fatty liver diseases, which is a combination of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 and an active ingredient of at least one drug selected from drugs classified as therapeutic or prophylactic agents for fatty liver diseases.

15. A therapeutic or prophylactic agent for fatty liver disease according to claim 13, for treating or preventing fatty liver disease in combination with at least one agent selected from agents classified as therapeutic or prophylactic agents for fatty liver disease.

16. A therapeutic or prophylactic agent for obesity, containing as an active ingredient a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

17. A therapeutic or prophylactic agent for obesity, comprising a combination of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and an active ingredient of at least one agent selected from agents classified as therapeutic or prophylactic agents for obesity.

18. A therapeutic or prophylactic agent for obesity according to claim 16, for treating or preventing obesity in combination with at least one agent selected from agents classified as therapeutic or prophylactic agents for obesity.

19. A therapeutic or prophylactic agent for COVID-19, containing as an active ingredient a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

20. A therapeutic or prophylactic agent for COVID-19, comprising a combination of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and an active ingredient of at least one agent selected from agents classified as therapeutic or prophylactic agents for coronaviruses.

21. A therapeutic or prophylactic agent for COVID-19 according to claim 19, for treating or preventing COVID-19 in combination with at least one agent selected from agents classified as therapeutic or prophylactic agents for coronaviruses.

Images