KR102435507B1 - A novel benzofuran derivatives and uses thereof - Google Patents

Abstract

.The present application relates to a novel benzofuran derivative and its use, and a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the following formula (I), and a pharmaceutical for preventing or treating cancer including the same A composition is provided:
[Formula I]

.

Description

A novel benzofuran derivatives and uses thereof

The present application relates to novel benzofuran derivatives and uses thereof.

Indoleamine 2,3-dioxygenase (IDO), for example, indoleamine 2,3-dioxygenase 1 (IDO 1) is an essential amino acid L -tryptophan to N-formylkin A family of heme-containing enzymes that catalyze the breakdown to N-formylkynurenine. The IDO 1 is known to be involved in the initial and rate-limiting steps in the degradation of tryptophan.

The IDO 1 is known as one of the central regulators involved in the immune response in various physiological and pathological environments. In particular, overexpression of IDO 1 has been reported in various tumors including glioma, melanoma, lung cancer, ovarian cancer, and colorectal cancer. is considered to be possible. In fact, the results that the prognosis and survival rate of cancer patients overexpressing IDO 1 are poor support these facts. Therefore, as a target for the prevention or treatment of cancer, many studies on IDO 1 are currently in progress.

Immune anticancer drugs are anticancer drugs that overcome the side effects of existing anticancer drugs. The immuno-cancer agent can enhance the healing power of the cancer site while promoting the activation of the immune function in the abnormal human immune function seen in cancer patients. However, there is a limitation in that these immuno-cancer drugs are effective only in a limited patient group when treated alone, and resistance may be induced in some patient groups. According to the report, in the microenvironment of the tumor, not only PD-L1 but also IDO expression increase and Treg infiltration were observed together, and the tumor-induced IDO accompanying the immunotherapy is crucial for the antitumor effect of the immunotherapy. It has been reported that it may act as a barrier factor. Therefore, the combined use of the immune anticancer agent and the IDO inhibitor can produce excellent synergy. In addition, inhibition of the IDO pathway lowers the incidence of resistance to immune anticancer drugs, and has no side effects as an immune check point, thereby demonstrating high safety.

Under this technical background, various studies for the development of cancer therapeutics targeting IDO 1 are being actively conducted (Korean Patent Application Laid-Open No. 10-2016-0146807), but the situation is still insufficient.

One aspect is to provide a novel benzofuran derivative exhibiting inhibitory activity against indoleamine 2,3-dioxygenase 1.

Another aspect is to provide a pharmaceutical composition for preventing or treating cancer comprising the benzofuran derivative as an active ingredient.

Another aspect is to provide a pharmaceutical use of the benzofuran derivative for the prevention or treatment of cancer.

Other objects and advantages of the present application will become more apparent from the following detailed description in conjunction with the appended claims and drawings. Content not described in this specification will be omitted because it can be sufficiently recognized and inferred by those skilled in the technical field or similar technical field of the present application.

Each description and embodiment disclosed in this application may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. In addition, it cannot be seen that the scope of the present application is limited by the detailed description described below.

One aspect provides a compound of formula (I), a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[Formula I]

Another aspect provides a pharmaceutical composition for preventing or treating cancer comprising the compound of Formula I, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound of Formula I, solvate, stereoisomer, or pharmaceutically acceptable salt thereof according to one aspect effectively inhibits the enzymatic activity of indoleamine 2,3-dioxygenase 1, thereby treating cancer, for example, It can be applied as a combination preparation with an immuno-cancer agent or the like.

Accordingly, the compound of Formula I, solvate, stereoisomer, or pharmaceutically acceptable salt thereof according to an aspect may be utilized as an active ingredient in a pharmaceutical composition for preventing or treating cancer.

Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples.

One aspect provides a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the following formula (I):

[Formula I]

In the above formula (I),

n is 0 or 1;

R ₁ is hydrogen, phenyl, or -W-(CH) _m -X, or fuses with carbon a in the benzofuran ring to form, together with the atoms to which they are attached, a 6 membered aryl ring, where W is -(CH ₂ ) )-, or -(CH ₂ O)-, m is 0 or 1, and X is a hydroxyl group, a C ₁ -C ₅ alkyl group, a C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl group, or C _{3 -} a C ₈ cycloalkyl group;

Cy is a C ₃ -C ₁₀ aryl, C ₄ -C ₁₀ heteroaryl, or C ₃ -C ₈ cycloalkyl group;

R ₂ and R ₃ are independently hydrogen, halogen, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₅ an alkoxy group; and

R ₄ is hydrogen, halogen, phenyl, or -Y-(CH ₂ ) ₁ -Z, wherein Y is -O-, -(CH ₂ )-, -(CH ₂ O)-, -(CO) -, or -(CONH)-, l is 0 or 1, Z is a C ₁ -C ₅ alkyl group, a C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl group, a C ₃ -C ₈ cycloalkyl group, phenyl, or a C ₃ -C ₈ heterocycloalkyl group substituted with a C ₁ -C ₅ alkyl group.

As used herein, the term “halogen” may be F, Cl, Br, or I.

As used herein, the term “alkyl,” unless otherwise stated, refers to a straight-chain, or branched, hydrocarbon residue, which may be substituted or unsubstituted. The alkyl group may include, without limitation, all possible isomers thereof such as, for example, methyl, ethyl, propyl, butyl, pentyl, or isopropyl, isobutyl, and t-butyl.

As used herein, the term “alkenyl” refers to an alkyl group containing one or more double bonds, which may be substituted or unsubstituted, unless otherwise stated. The alkenyl group may be, for example, prop-1-ene, but-1-ene, but-2-ene, 3-methylbut-1-ene, pent-1-ene, etc., all possible Isomers may include without limitation.

As used herein, the term "alkynyl" refers to an alkyl group containing one or more triple bonds, which may be substituted or unsubstituted, unless otherwise stated. The alkynyl group may be, for example, prop-1-yne, but-1-yne, pent-1-yne, and the like, and may include all possible isomers thereof without limitation.

As used herein, the term "cycloalkyl" refers to saturated monocyclic and polycyclic hydrocarbon rings generally having the specified number of carbon atoms, including rings, which may be substituted or unsubstituted, which may be substituted or unsubstituted, unless otherwise indicated. it means. The cycloalkyl group may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

As used herein, the term "heterocycloalkyl" refers to a monocyclic substituted or unsubstituted containing one or more heteroatoms selected from B, N, O, S, P(=O), Si and P, unless otherwise stated. which may be cyclic alkyl. The heterocycloalkyl group may be, for example, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuryl, or a group similar thereto.

As used herein, the term "haloalkyl" is meant to include monohaloalkyl and polyhaloalkyl, which may be substituted or unsubstituted, unless otherwise stated. The terms halogen and alkyl are as described above.

As used herein, the term "alkoxy" refers to a straight-chain, or branched, hydrocarbon moiety linked by oxygen, which may be substituted or unsubstituted, unless otherwise indicated. The alkoxy may include, without limitation, all possible isomers thereof such as, for example, methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.

As used herein, the term “aryl” refers to an aromatic group that may be substituted or unsubstituted, and includes, for example, C ₃ -C ₁₀ aryl, C ₃ -C ₈ aryl, or C ₃ -C ₆ aryl, unless otherwise indicated. and alternating (resonance) double bonds between adjacent carbon atoms or suitable heteroatoms. For example, it may include, without limitation, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, or all possible isomers thereof.

As used herein, the term "heteroaryl" is, unless otherwise stated, monocyclic or bicyclic or more containing one or more heteroatoms selected from B, N, O, S, P(=O), Si and P, substituted or an aromatic group, which may be unsubstituted.

In this specification, the numerical range indicated using the term "to" refers to a range including the numerical values described before and after the term "to" as the lower limit and the upper limit, respectively.

As used herein, the term “solvate” may refer to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor may be solvents that are volatile, non-toxic, and/or suitable for administration to humans.

As used herein, the term "stereoisomer" may mean a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but optically or sterically different, and specifically, a diastereomer, enantiomer, geometric isomer, or It may be a conformational isomer.

As used herein, the term "derivative" refers to a compound obtained by substituting a part of the structure of the compound with another atom or group of atoms.

In addition, the compound can be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid, for example, the salt is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malic acid ronic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methane It may be a salt derived from sulfonic acid, benzenesulfonic acid, toluenesulfonic acid, or the like.

A pharmaceutically acceptable salt of the compound is prepared by dissolving the compound of formula (I) in a water-miscible organic solvent, for example, acetone, methanol, ethanol, or acetonitrile, and adding an excess of organic acid or an aqueous solution of an inorganic acid followed by precipitation. Or it can be prepared by crystallization. Subsequently, after evaporating the solvent or excess acid from this mixture, it can be dried to obtain an addition salt, or it can be prepared by suction filtration of the precipitated salt.

In one embodiment, R ₁ is hydrogen, phenyl, or -W-(CH) _m -X, or fuses with carbon a in the benzofuran ring to form, together with the atoms to which they are attached, a 6 membered aryl ring, wherein W is -(CH ₂ )-, or -(CH ₂ O)-, m is 0 or 1, and X may be a hydroxy group, a C ₁ -C ₃ alkyl group, or a C ₃ -C ₅ cycloalkyl group.

In one embodiment, Cy is a C ₆ -C ₈ aryl, C ₄ -C ₆ heteroaryl, or C ₃ -C ₈ cycloalkyl group; In the above C ₆ -C ₈ aryl, R ₂ and R ₃ are independently hydrogen, halogen, C ₁ -C ₃ alkyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₃ alkoxy group; and R ₄ is hydrogen, halogen, phenyl, or -Y-(CH ₂ ) ₁ -Z, wherein Y is -O-, -(CH ₂ )-, -(CH ₂ O)-, -(CO )-, or -(CONH)-, l is 0 or 1, and Z is C ₄ - substituted with a C ₁ -C ₃ alkyl group, C ₄ -C ₆ cycloalkyl group, phenyl, or C ₁ -C ₃ alkyl group. It may be a C ₆ heterocycloalkyl group.

In one embodiment, Cy is phenyl, thiophenyl, furanyl, cyclopropyl, or cyclobutyl, cyclopentanyl; In the above phenyl, R ₂ and R ₃ are independently hydrogen, halogen, C ₁ -C ₃ alkyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₃ alkoxy group; and R ₄ is hydrogen, halogen, phenyl, or -Y-(CH ₂ ) ₁ -Z, wherein Y is -O-, -(CH ₂ )-, -(CH ₂ O)-, -(CO )-, or -(CONH)-, l is 0 or 1, Z is piperidine substituted with a C ₁ -C ₃ alkyl group, a C ₄ -C ₆ cycloalkyl group, phenyl, or a C ₁ -C ₃ alkyl group. -1-day.

In one embodiment, n is 0 or 1; R ₁ is hydrogen, phenyl, or -W-(CH) _m -X, or fuses with carbon a in the benzofuran ring to form, together with the atoms to which they are attached, a 6 membered aryl ring, where W is -(CH ₂ ) )-, or -(CH ₂ O)-, m is 0 or 1, and X is a hydroxy group, a C ₁ -C ₃ alkyl group, or a C ₃ -C ₅ cycloalkyl group; Cy is C ₆ -C ₈ aryl, C ₄ -C ₆ heteroaryl containing O or S atoms, or C ₃ -C ₈ cycloalkyl group; In the above C ₆ -C ₈ aryl, R ₂ and R ₃ are independently hydrogen, halogen, C ₁ -C ₃ alkyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₃ alkoxy group; and R ₄ is hydrogen, halogen, phenyl, or -Y-(CH ₂ ) ₁ -Z, wherein Y is -O-, -(CH ₂ )-, -(CH ₂ O)-, -(CO )-, or -(CONH)-, l is 0 or 1, Z is piperidine substituted with a C ₁ -C ₃ alkyl group, a C ₄ -C ₆ cycloalkyl group, phenyl, or a C ₁ -C ₃ alkyl group. -1-day.

In one embodiment, the compound of Formula I may be selected from the group consisting of the following compounds:

N -(3-bromophenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N- (4-chloro-3-fluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N- (3-chloro-4-fluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N -(4-chlorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N- (3,4-difluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N -(3-fluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N -(3-chlorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N' -hydroxy- N -phenylbenzofuran-5-carboximidamide;

N- (3-bromo-4-fluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N' -hydroxy- N- (2,4,5-trifluorophenyl)benzofuran-5-carboximidamide;

N- (4-fluoro-3-(trifluoromethyl)phenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N- (3,4- dimethylphenyl )-N'-hydroxybenzofuran-5-carboximidamide;

N' -hydroxy- N- (3-(trifluoromethyl)phenyl)benzofuran-5-carboximidamide;

N -(3-acetylphenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N- (cyclohexylmethyl)-3-( N' -hydroxybenzofuran-5-carboximidoamido)benzamide;

N -( [ 1,1'-biphenyl]-3-yl)-N'-hydroxybenzofuran-5-carboximidamide;

N -benzyl-3-( N' -hydroxybenzofuran-5-carboximimidamido)benzamide;

N' -hydroxy- N- (3-(4-methylpiperidine-1-carbonyl)phenyl)benzofuran-5-carboximidamide;

N- (3-benzylphenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N' -hydroxy- N- (3-phenoxyphenyl)benzofuran-5-carboximidamide;

N- (3-butoxyphenyl)-N' - hydroxybenzofuran-5-carboximidamide;

N' -hydroxy- N- (3-(phenoxymethyl)phenyl)benzofuran-5-carboximidamide;

N -(3-chlorobenzyl)-N' - hydroxybenzofuran-5-carboximidamide;

N -benzyl- N' -hydroxybenzofuran-5-carboximidamide;

N- (3-chloro-4-fluorobenzyl)-N' - hydroxybenzofuran-5-carboximidamide;

N' -hydroxy- N- (thiophen-2-ylmethyl)benzofuran-5-carboximidamide;

N- (furan-2-ylmethyl)-N' - hydroxybenzofuran-5-carboximidamide;

N -(cyclopropylmethyl)-N' - hydroxybenzofuran-5-carboximidamide;

N -cyclobutyl- N' -hydroxybenzofuran-5-carboximidamide;

N -cyclopentyl- N' -hydroxybenzofuran-5-carboximidamide;

N -(3-bromophenyl)-N' - hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide;

N -(3-chlorophenyl) -N' -hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide;

N- (3-fluorophenyl)-N' - hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide;

N- (3-bromophenyl)-N' - hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide;

N -(3-chlorophenyl) -N' -hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide;

N- (3-fluorophenyl)-N' - hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide;

N- (3-bromophenyl)-2-((cyclopropylmethoxy)methyl)-N′ - hydroxybenzofuran-5-carboximidamide;

N- (3-fluorophenyl)-2-((cyclopropylmethoxy)methyl)-N' - hydroxybenzofuran-5-carboximidamide;

2-((cyclopropylmethoxy)methyl) -N′-hydroxy-N- ( 3-(trifluoromethyl)phenyl)benzofuran-5-carboximidamide;

N- (3-bromophenyl)-N' - hydroxy-2-phenylbenzofuran-5-carboximidamide;

N -(3-chlorophenyl)-N' - hydroxy-2-phenylbenzofuran-5-carboximidamide;

N- (3-fluorophenyl)-N' - hydroxy-2-phenylbenzofuran-5-carboximidamide;

N- (3-bromophenyl)-N′-hydroxydibenzo [ b , d ]furan-2-carboximidamide;

N- (3-chlorophenyl)-N′-hydroxydibenzo [ b , d ]furan-2-carboximidamide;

N- (3-bromo-4-fluorophenyl)-N′-hydroxydibenzo [ b , d ]furan-2-carboximidamide;

N- (3,5-dimethoxyphenyl)-N'-hydroxydibenzo [ b , d ]furan-2-carboximidamide;

N- (3-chloro-4-fluorophenyl)-N'-hydroxydibenzo [ b , d ]furan-2-carboximidamide; and

N -(3-chlorobenzyl)-N'-hydroxydibenzo [ b,d]furan-2-carboximidamide.

Hereinafter, a method for preparing the compound represented by Formula I will be described in detail.

The compound can be prepared by using a chemical transformation well known to those skilled in the art of organic/pharmaceutical chemistry according to the method representatively shown in Scheme 1 or 2 below.

[Scheme 1]

Reagents and reaction conditions: (a) NEt ₃ , NH ₂ OH.HCl, CH ₂ Cl ₂ , rt, 16 h; (b) NCS, DMF, 50° C., 3 h; (c) primary amine, THF, rt, 16 h.

If described in more detail with reference to Scheme 1, oxime, a key substituent, can be obtained from the substituted benzofuran-carboxaldehyde (1). Hemiaminal can be formed through nucleophilic addition reaction with hydroxylamine from the starting material aldehyde. Thereafter, dehydration may be continuously performed to form an oxime. By adding hydroxylamine and triethylamine to benzofuran-carboxaldehyde (1) in CH ₂ Cl ₂ and stirring at room temperature for 16 hours, oxime (2) can be obtained in a high yield of over 90%. N-hydroxycarboximidoyl chloride (3) can be obtained by electrophilic addition using N-chlorosuccinimide (NCS) in Oxime (2). Since the yield is not good when heated to a high temperature in DMF during chlorination, chlorination can be performed by heating to 50°C through temperature control. In consideration of the instability of N-hydroxycarboximidoyl chloride (3), the synthesis may proceed after purification. Then, N-hydroxybenzofuran-5-carboximidamide (4) can be obtained through addition-elimination reaction of N-hydroxycarboximidoyl chloride (3) with primary amine having various substituents and THF stirring at room temperature for 16 hours.

[Scheme 2]

Reagents and reaction conditions: (a) I ₂ , MeOH, 20% NH ₄ OH, rt, 2 h; (b) propargyl alcohol, Pd(dppf)Cl ₂ , DIPA, CuI, toluene/THF (2:1), 100° C., 10 h; (c) i) MeI, NaH, DMF, rt, 1 h ii) TBSCl, imidazole, , DMF, rt, 30 min iii) (chloromethyl)cyclopropane, NaH, DMF, rt, 12 h; (d) DIBAL-H, CH ₂ Cl ₂ , -10°C, 30 min; (e) NEt ₃ , NH ₂ OH.HCl, CH ₂ Cl ₂ , rt, 3 h; (f) NCS, DMF, 50° C., 3 h; (g) primary amine, THF, rt, 16 h; (h) TBAF, THF, rt, 1 h.

If described in more detail with reference to Scheme 2, 4-hydroxy-3-iodobenzonitrile (2) can be obtained through mono-iodination by adding NH ₃ aqueous solution and iodine to 4-cyanophenol (1) in MeOH. From 4-hydroxy-3-iodobenzonitrile (2), acetylene is generated through Sonogashira coupling with propargyl alcohol, and 2-(hydroxymethyl)benzofuran-5-carbonitrile (3) having a benzofuran backbone can be obtained through cyclization. . After that, 2-(hydroxymethyl)benzofuran-5-carbonitrile (3) can be synthesized by TBS protection through TBSCl on DMF. Alternatively, after deprotonation using sodium hydride, ether compound (4) can be synthesized using (chloromethyl)cyclorpropane or MeI. After reducing the nitrile group to aldehyde by stirring compound (4) over DIBAL-H and CH ₂ Cl ₂ at -10℃ for 30 minutes, it reacts with hydroxylamine in the same manner as in Scheme 1 to obtain oxime (6). . Thereafter, compound (7) can be synthesized by chlorination using N-chlorosuccinimide (NCS), and compound (8) can be synthesized through a substitution reaction using primary amines having various substituents. Thereafter, in the case of TBS-protected alcohol (9), deprotection may be performed with TBAF (Tetrabutylammonium fluoride) on THF to proceed with the reaction with primary alcohol (10).

Another aspect provides a pharmaceutical composition for preventing or treating cancer, comprising the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by Formula I as an active ingredient.

As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptom of the disease, condition or disorder, i.e., inhibiting the disease, condition or disorder. , preventing further development of the pathology and/or symptom, or ameliorating the disease, e.g., ameliorating the disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptom of the disease, condition or disorder, i.e. , to reversing pathology and/or symptoms, such as reducing disease severity.

As used herein, the term "preventing" or "prevention" refers to preventing a disease, e.g., a disease in an individual who may be predisposed to the disease, condition or disorder but has not yet experienced or exhibited the pathology or signs of the disease. , to prevent a condition or disorder.

As used herein, the term "subject" refers to a subject in need of treatment for a disease, and more specifically, a human or non-human primate, a mouse, a dog, a cat, a horse, and a mammal such as a cow. means

"Cancer", a disease to be prevented or treated by the pharmaceutical composition, refers to an aggressive characteristic in which cells divide and grow ignoring the normal growth limit, an invasive characteristic that penetrates into surrounding tissues, and other in vivo characteristics. It is a generic term for diseases caused by cells with metastatic properties that spread to sites. Examples of the cancer include lung cancer, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, gastrointestinal cancer, liver cancer, leukemia, lymphoma, melanoma tumor, multiple myeloma, Ewing's sarcoma, osteosarcoma, colorectal cancer, cholangiocarcinoma, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, or thyroid cancer.

According to one embodiment, the pharmaceutical composition comprising the compound represented by Formula I, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient is the enzymatic activity of indoleamine 2,3-dioxygenase 1. By inhibiting it, it can be used to treat cancer.

In one embodiment, the pharmaceutical composition may include conventional pharmaceutically acceptable carriers, excipients or additives. The pharmaceutical composition may be formulated according to a conventional method, and various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc. or parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration can be manufactured with

When the pharmaceutical composition is prepared in the form of an oral dosage form, examples of additives or carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, stearic acid calcium, gelatin, talc, surfactant, suspending agent, emulsifying agent, diluent, and the like. When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additive or carrier includes water, saline, aqueous glucose solution, similar sugar solution, alcohol, glycol, ether (eg, polyethylene glycol 400), oil, fatty acid, fatty acid ester , glycerides, surfactants, suspending agents, emulsifiers, and the like.

The dosage of the pharmaceutical composition is an amount effective for treatment or prevention of an individual or patient, and may be administered orally or parenterally as desired. When administered parenterally, it is administered in an amount of 1000 mg, more specifically, 0.1 to 300 mg, 0.01 to 100 mg, more specifically, 0.1 to 50 mg per 1 kg of body weight per day based on the active ingredient. If possible, it can be administered in 1 to several divided doses. The dose to be administered to a specific individual or patient should be determined in light of several related factors, such as the patient's weight, age, sex, health status, diet, administration time, administration method, and disease severity, and may be appropriately adjusted or decreased by an expert. It should be understood that the above dosage is not intended to limit the scope of the present invention in any way. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian may start a dose of a compound of the invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. can increase

In one embodiment, the pharmaceutical composition includes within its scope a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds according to one embodiment, alone or in combination with a pharmaceutical carrier. Optionally, a compound according to one embodiment may be administered alone, in combination with a compound according to another embodiment, or concurrently, separately or sequentially with one or more other therapeutic agents, such as an anticancer agent or other pharmaceutically active substance. have. The anti-cancer agent includes, for example, an anti-cancer agent, an anti-angiogenesis agent, an anti-inflammatory agent, and an immunosuppressive agent, for example, CTLA-4, PD-1, PD-L1, etc. It may be an immune anticancer agent including an immune checkpoint inhibitor.

Also within the scope of the present invention are other combination therapies involving IDO inhibitors, as is known in the art. See, for example, International Publication No. WO2015006520, the entire contents of which may be incorporated by reference for the purposes or claims cited herein.

Another aspect is a method for preventing or treating cancer comprising administering to an individual the compound represented by Formula I, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same; pharmaceutical use of the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the above formula (I) for the prevention or treatment of cancer; And it provides a pharmaceutical use of the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the formula (I) for the preparation of a therapeutic agent for cancer.

[Example]

[Example]

Example 1: N -(3-bromophenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

Step 1) Preparation of benzofuran-5-carbaldehyde oxime

After dissolving benzofuran-5-carboaldehyde (S1,4.7g) in CH ₂ Cl ₂ (300 mL), NH ₂ OH·HCl (5.4 g) and NEt ₃ (13.4 mL) were added thereto, and then at room temperature for 3 hours. stirred in. After confirming the reaction progress through TLC, H ₂ O was added thereto, and the product was separated into an organic layer by working-up twice with EtOAc. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, benzofuran-5-carbaldehyde oxime (S2, 4.6 g) was obtained under EtOAc/Hexane conditions through silica chromatography.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 2) N -Preparation of hydroxybenzofuran-5-carbimidol chloride

The compound of step 1 (S2, 0.3 g) was dissolved in DMF (10 mL), N-chlorosuccinimide (0.27 g) was added thereto, and the mixture was stirred at 50° C. for 3 hours. After confirming the progress of the reaction through TLC, it was concentrated under reduced pressure and N -hydroxybenzofuran-5-carbimidol chloride (S3, 0.1 g) was obtained under EtOAc/Hexane conditions through silica chromatography.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 3) N -(3-bromophenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The compound of step 2 (S3, 0.1 g) was dissolved in THF (10 mL), 3-bromoaniline (0.3 mL) was added thereto, and the mixture was stirred at room temperature for 16 hours. After confirming the reaction progress through TLC, it was concentrated under reduced pressure and N -(3-bromophenyl)-N′-hydroxybenzofuran-5-carboximidamide (1, 0.01 g) in EtOAc/Hexane conditions through silica chromatography . ) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Example 2: N -(4-chloro-3-fluorophenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 4-chloro-3-fluoroaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 1.8, 8.6 Hz, 1H), 7.10 (t, J = 8.4 Hz, 1H), 6.79 (dd, J = 0.6, 2.2 Hz, 1H), 6.47 (dd, J = 2.4, 10.4 Hz, 1H), 6.43 (m, 1H).

Example 3: N -(3-chloro-4-fluorophenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-chloro-4-fluoroaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.60 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 1.8, 8.6 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H), 6.99 (dd, J = 0.8, 2.0 Hz, 1H) ), 6.89 (dd, J = 2.8, 6.4 Hz, 1H), 6.49 (m, 1H).

Example 4: N -(4-chlorophenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 4-chloroaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.35 ( dd, J = 1.6, 8.4 Hz, 1H), 7.07 (dd, J = 2.0, 6.8 Hz, 2H), 6.78 (dd, J = 0.8, 2.0 Hz, 1H), 6.62 (dd, J = 2.0, 6.8 Hz) , 2H).

Example 5: N -(3,4-difluorophenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed except that 3,4-difluoroaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 1.8, 8.6 Hz, 1H), 7.23 (s, 1H), 6.90 (ddd, J = 5.0, 15.1 Hz, 1H), 6.62 (dd, J = 2.0, 6.8 Hz, 2H), 6.53 (m, 1H) ), 6.43 (m, 1H).

Example 6: N -(3-fluorophenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-fluoroaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 1.2 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.48 (s, 1H), 7.47 (d, J = 0.8 Hz, 1H), 7.38 (dd, J = 1.8, 8.6 Hz, 1H), 7.31 (s, 1H), 7.05 (ddd, J = 4.3, 13.2 Hz, 1H), 6.78 (dd, J = 1.0, 2.2 Hz, 1H) ), 6.62 (m, 1H), 6.46 (m, 1H), 6.38 (ddd, J = 2.3, 10.7 Hz, 1H).

Example 7: N -(3-chlorophenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-chloroaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, MeOD) δ 7.68 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.23 (dd, J ) = 2.0, 8.8 Hz, 1H), 6.87 (dd, J = 8.0, 8.0 Hz, 1H), 6.72 (m, 2H), 6.63 (dd, J = 2.0, 2.0 Hz, 1H), 6.43 (ddd, J = 1.2, 2.4, 8.4 Hz, 1H).

Example 8: N' -Hydroxy- N -Preparation of phenylbenzofuran-5-carboximidamide

The same process as in Example 1 was performed except that aniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 8.32 (s, 1H), 8.010 (s, 1H), 8.005 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H) ), 7.31 (dd, J = 1.2, 8.4 Hz, 1H), 7.03 (dd, J = 7.6, 7.6 Hz, 2H), 6.97 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 7.6, 7.6 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H).

Example 9: N -(3-bromo-4-fluorophenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-bromo-4-fluoroaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.64 (s, 1H), 8.09 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.63 (d, J ) = 8.4 Hz, 1H), 7.38 (dd, J = 2.0, 8.8 Hz, 1H), 7.08-7.12 (m, 2H), 7.05 (dd, J = 0.8, 2.0 Hz, 1H), 6.57-6.60 (m, 1H).

Example 10: N' -Hydroxy- N Preparation of -(2,4,5-trifluorophenyl)benzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 2,4,5-trifluoroaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, MeOD) δ 7.68 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.22 (dd, J ) = 2.0, 8.8 Hz, 1H), 6.91-7.00 (m, 1H), 6.74 (m, 1H), 6.49 (ddd, J = 8.0, 8.0, 16.0 Hz, 1H).

Example 11: N -(4-fluoro-3-(trifluoromethyl)phenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 4-fluoro-3-(trifluoromethyl)aniline was used instead of 3-bromoaniline in step 3) of Example 1).

¹ H NMR (400 MHz, MeOD) δ 7.69 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.22 (d, J ) = 1.6, 8.4 Hz, 1H), 6.86-6.92 (m, 2H), 6.74-6.79 (m, 2H).

Example 12: N -(3,4-dimethylphenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3,4-dimethyl aniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.39 (s, 1H), 8.06 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 1.6, 8.4 Hz, 1H), 6.96 (q, J = 1.1 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.24 (dd, J = 2.4, 8.0 Hz, 1H), 2.03 (s, 3H), 2.01 (s, 3H).

Example 13: N' -Hydroxy- N Preparation of -(3-(trifluoromethyl)phenyl)benzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-(trifluoromethyl)aniline was used instead of 3-bromoaniline in step 3) of Example 1).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.79 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 1.6, 8.4 Hz, 1H), 7.23 (dd, J = 7.6, 7.6 Hz, 1H), 7.03-7.06 (m, 2H), 6.98 (dd, J = 0.8, 2.4 Hz, 1H), 6.79-6.81 (m, 1H).

Example 14: N -(3-acetylphenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-acetylaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.62 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.33-7.35 (m, 2H), 7.30 (m, 1H), 7.17 (dd, J = 8.0, 8.0 Hz, 1H), 6.97 (m, 1H), 6.84 (dd, J = 1.6, 8.0 Hz, 1H), 2.35 (s, 3H).

Example 15: N -(Cyclohexylmethyl)-3-( N' -Preparation of hydroxybenzofuran-5-carboximidomido)benzamide

The same procedure as in Example 1 was performed, except that 3-amino-N-(cyclohexyl methyl)benzamide was used instead of 3-bromoaniline in step 3) of Example 1).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.68 (brs, 1H), 8.68 (brs, 1H), 8.19 (dd, J = 5.6, 5.6 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H) ), 7.71 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.22-7.26 (m, 2H), 7.10 (dd, J = 8.0, 8.0 Hz, 1H), 6.97 (dd, J = 0.8, 2.0 Hz, 1H), 6.76 (m, 1H), 2.99 (dd, J = 6.4, 6.4 Hz, 2H), 1.59-1.66 (m, 5H), 1.42-1.47 (m, 1H) ), 1.06-1.20 (m, 3H), 0.81-0.87 (m, 2H).

Example 16: N -([1,1'-biphenyl]-3-yl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-phenylaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.68 (brs, 1H), 8.68 (brs, 1H), 8.19 (dd, J = 5.6, 5.6 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H) ), 7.71 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.22-7.26 (m, 2H), 7.10 (dd, J = 8.0, 8.0 Hz, 1H), 6.97 (dd, J = 0.8, 2.0 Hz, 1H), 6.76 (m, 1H), 2.99 (dd, J = 6.4, 6.4 Hz, 2H), 1.59-1.66 (m, 5H), 1.42-1.47 (m, 1H) ), 1.06-1.20 (m, 3H), 0.81-0.87 (m, 2H).

Example 17: N -benzyl-3-( N' -Preparation of hydroxybenzofuran-5-carboximidomido)benzamide

The same process as in Example 1 was performed, except that 3-amino-N-benzylamide was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 8.83 (dd, J = 6.0, 6.0 Hz, 1H), 8.49 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H) ), 7.70 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.20-7.36 (m, 8H), 7.09-7.13 (m, 1H), 6.96-6.97 (m, 1H), 6.72-6.74 (m, 1H), 4.37-4.44 (m, 2H), 3.17 (d, J = 5.2 Hz, 1H).

Example 18: N' -Hydroxy- N Preparation of -(3-(4-methylpiperidine-1-carbonyl)phenyl)benzofuran-5-carboximidamide

The same process as in Example 1, except that (3-aminophenyl)(4-methylpiperidin-1-yl)methanone was used instead of 3-bromoaniline in step 3) of Example 1 was performed.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.55 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 2.0, 8.8 Hz, 1H), 7.15 (dd, J = 7.6, 7.6 Hz, 1H), 6.97 (dd, J = 0.8, 2.4 Hz) , 1H), 6.86-6.88 (m, 1H), 6.72-6.74 (m, 1H), 6.42 (dd, J = 1.6, 1.6 Hz, 1H), 4.26 (m, 1H), 3.17 (dd, J = 5.2) Hz, 1H), 1.39-1.57 (m, 2H), 1.04-1.06 (m, 1H), 0.47 (m, 1H).

Example 19: N -(3-benzylphenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed except that aniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.47 (s, 1H), 8.29 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.26-7.28 (m, 1H), 7.26 (dd, J = 1.6, 8.8 Hz, 1H), 7.03-7.07 (m, 3H), 6.96-7.00 (m, 2H), 6.81-6.83 (m, 2H), 6.60-6.64 (m, 2H), 6.41 (s, 1H), 3.63 (s, 2H).

Example 20: N' -Hydroxy- N Preparation of -(3-phenoxyphenyl)benzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-phenoxyaniline was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.57 (s, 1H), 8.49 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.28 (m, 1H), 7.06-7.13 (m, 3H), 6.97-7.01 (m, 2H), 6.67-6.69 (m, 2H), 6.55-6.58 ( m, 1H), 6.41-6.43 (m, 1H), 6.10 (dd, J = 2.0, 2.0 Hz, 1H).

Example 21: N -(3-butoxyphenyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-butoxybenzeneamine was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 8.29 (s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 1.6, 8.4 Hz, 1H), 6.97 (dd, J = 0.8, 2.4 Hz, 1H), 6.90 (dd, J = 8.0, 8.0 Hz) , 1H), 6.30-6.32 (m, 1H), 6.19-6.23 (m, 2H), 3.66 (dd, J = 6.4, 6.4 Hz, 1H), 1.45-1.52 (m, 2H), 1.23-1.31 (m) , 2H), 0.82 (dd, J = 7.2, 7.2 Hz, 1H).

Example 22: N' -Hydroxy- N Preparation of -(3-(phenoxymethyl)phenyl)benzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that 3-(phenoxymethyl)benzeneamine was used instead of 3-bromoaniline in step 3) of Example 1).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 8.39 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.30-7.33 (m, 1H), 7.20-7.24 (m, 2H), 7.02-7.05 (m, 1H), 6.97 (dd, J = 0.8, 2.0 Hz, 1H), 6.88-6.90 (m, 1H), 6.79-6.83 (m, 4H), 6.57-6.59 (m, 1H).

Example 23: N -(3-chlorobenzyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that (3-chlorophenyl)methanamine was used instead of 3-bromoaniline in step 3) of Example 1).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.57-7.61 (m, 2H), 7.22-7.29 (m, 3H), 7.18 (brs, 1H), 7.02 (m, 1H), 6.97 (m, 1H), 6.49 (dd, J = 6.0, 6.0 Hz, 1H).

Example 24: N -benzyl- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that phenylmethanamine was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.64 (m, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.11-7.33 (m, 4H), 6.97 (dd, J = 1.2, 2.4 Hz, 1H), 6.32 (dd, J = 6.8, 6.8 Hz, 1H), 4.17 (d, J = 7.2 Hz, 1H).

Example 25: N -(3-chloro-4-fluorobenzyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that (3-chloro-4-fluorophenyl)methanamine was used instead of 3-bromoaniline in step 3) of Example 1).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.58-7.60 (m, 2H), 7.23-7.31 (m, 3H), 7.06 (ddd, J = 2.0, 4.8, 8.4 Hz, 1H), 6.98 (m, 1H), 6.52 (dd, J = 7.2, 7.2 Hz, 1H).

Example 26: N' -Hydroxy- N Preparation of -(thiophen-2-ylmethyl)benzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that thiophen-2-ylmethanamine was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.85 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.60 (d, J = 8.5) Hz, 1H), 7.43 (dd, J = 4.9, 2.9 Hz, 1H), 7.33 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (dt, J = 2.9, 1.3 Hz, 1H), 7.07 - 6.97 (m, 1H), 6.91 (dd, J = 4.9, 1.4 Hz, 1H), 6.22 (d, J = 7.1 Hz, 1H), 4.15 (d, J = 6.9 Hz, 2H).

Example 27: N -(furan-2-ylmethyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that furan-2-ylmethanamine was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (d, J = 1.2 Hz, 1H), 8.04 (t, J = 1.9 Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.50 (dd, J = 1.9, 0.9 Hz, 1H), 7.36 (dd, J = 8.5, 1.7 Hz, 1H), 7.00 (dd, J = 2.3, 1.0 Hz, 1H), 6.33 (dt, J = 3.1, 1.7 Hz, 1H), 6.15 (s, 1H), 6.12 - 5.99 (m, 1H), 4.14 (d, J = 6.8 Hz, 2H).

Example 28: N -(Cyclopropylmethyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that cyclopropylmethanamine was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.71 (d, J = 2.7 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.61 ( dt, J = 8.5, 0.9 Hz, 1H), 7.34 (dd, J = 8.5, 1.8 Hz, 1H), 7.00 (dd, J = 2.2, 1.0 Hz, 1H), 2.79 (t, J = 6.6 Hz, 2H) ), 0.86 - 0.73 (m, 1H), 0.37 - 0.24 (m, 2H), 0.07 - 0.06 (m, 2H).

Example 29: N -Cyclobutyl- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed, except that cyclobutylmethanamine was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.68 - 7.55 (m, 2H), 7.29 (dd, J = 8.5, 1.8 Hz) , 1H), 7.01 (dd, J = 2.2, 0.9 Hz, 1H), 5.92 (d, J = 9.4 Hz, 1H), 3.68 - 3.46 (m, 1H), 1.99 (ddqd, J = 20.0, 11.4, 8.7) , 2.4 Hz, 4H), 1.63 - 1.41 (m, 1H), 1.32 (qt, J = 10.5, 8.2 Hz, 1H).

Example 30: N -Cyclopentyl- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 1 was performed except that cyclopentylmethanamine was used instead of 3-bromoaniline in step 3) of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.76 (s, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.62 (dd, J = 8.5) , 0.9 Hz, 1H), 7.37 (dd, J = 8.5, 1.7 Hz, 1H), 7.01 (dt, J = 1.9, 0.9 Hz, 1H), 5.45 (d, J = 9.9 Hz, 1H), 3.53 (dt) , J = 9.9, 6.6 Hz, 1H), 1.70 - 1.52 (m, 4H), 1.49 - 1.29 (m, 4H).

Example 31: N -(3-bromophenyl)- N' -Preparation of hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide

Step 1) Preparation of 4-hydroxy-3-iodobenzonitrile

4-hydroxybenzonitrile (S4, 9.0 g) was added to a solution of MeOH (189 mL) and 20% NH ₄ OH (189 mL). I ₂ (23.9 g) dissolved in MeOH was slowly added at room temperature and stirred for 2 hours. After confirming the progress of the reaction through TLC, it was concentrated under reduced pressure, and 1N HCl was slowly added thereto. The product was separated into an organic layer by work-up twice with EtOAc, and the aq. After washing with NaHCO3 and brine, MgSO ₄ was added to the obtained organic layer, and an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 4-hydroxy-3-iodobenzonitrile (S5, 1.25 g) was obtained through silica chromatography under CH ₂ Cl ₂ /MeOH conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 2) Preparation of 2-(hydroxymethyl)benzofuran-5-carbonitrile

After dissolving the compound of step 1 (S5, 6.5g) in toluene/THF (2:1, 88mL), Pd(dppf)Cl ₂ (194mg), CuI (50mg), DIPA (13.3mL), propargyl alcohol (1.69) mL) was added. Thereafter, the solution was warmed at 100° C. for 12 hours. After confirming the reaction progress through TLC, 10% citric acid was added. Thereafter, this was worked-up twice with CH ₂ Cl ₂ to separate the product into an organic layer, washed with 10% NaOH and brine, and then MgSO ₄ was added to the obtained organic layer to obtain an organic layer through a filter. After concentration under reduced pressure, 2-(hydroxymethyl)benzofuran-5-carbonitrile (S6, 2.7 g) was obtained under CH ₂ Cl ₂ /ether conditions through silica chromatography.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 3) Preparation of 2-(methoxymethyl)benzofuran-5-carbonitrile

After dissolving the compound of step 2 (S6, 0.7 g) in DMF (14 mL), sodium hydride 60% dispersion in mineral oil (0.32 g), MeI (0.75 mL) was added at 0° C. and stirred at room temperature for 1 hour. . After confirming the reaction progress through TLC, aq. NH4Cl was added. After that, it was worked-up twice with EtOAc to separate the product into an organic layer and aq. After washing with NH4Cl and brine, MgSO ₄ was added to the obtained organic layer, and an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 2-(methoxymethyl)benzofuran-5-carbonitrile (S7, 0.2g) was obtained through silica chromatography under EtOAc/Hexane conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 4) Preparation of 2-(methoxymethyl)benzofuran-5-carboaldehyde

The compound of step 3 (S7, 0.75 g) was dissolved in CH ₂ Cl ₂ (40 mL), DIBAL-H (1.0 M solution in hexane, 8 mL) was added at -10°C and stirred for 30 minutes. After confirming the reaction progress through TLC, 10% citric acid was added, and then the product was separated into an organic layer by working-up twice with CH ₂ Cl ₂ . Then, after washing it with brine, MgSO ₄ was added to the obtained organic layer, and an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 2-(methoxymethyl)benzofuran-5-carboaldehyde (S8, 0.18g) was obtained through silica chromatography under CH ₂ Cl ₂ /EtOAc conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 5) Preparation of 2-(methoxymethyl)benzofuran-5-carboaldehyde oxime

The compound of step 3 (S8, 0.8 g) was dissolved in CH ₂ Cl ₂ (20 mL), NH ₂ OH·HCl (0.7 g) and NEt ₃ (1.8 mL) were added thereto and stirred at room temperature for 12 hours. did. After confirming the progress of the reaction through TLC, H ₂ O was added and the product was separated into an organic layer by working-up twice with EtOAc. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 2-(methoxymethyl)benzofuran-5-carboaldehyde oxime (S9, 0.6g) was obtained in EtOAc/Hexane through silica chromatography.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 6) N -Preparation of hydroxy-2-(methoxymethyl)benzofuran-5-carboimidol chloride

The compound of step 5 (S9, 0.59 g) was dissolved in DMF (10 mL), N-chlorosuccinimide (0.42 g) was added, and the mixture was stirred at 50° C. for 3 hours. After confirming the reaction progress through TLC, it was concentrated under reduced pressure and N -hydroxy-2-(methoxymethyl)benzofuran-5-carboimidol chloride (S10, 0.26g) was obtained in EtOAc/Hexane through silica chromatography. .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 7) N -(3-bromophenyl)- N' -Preparation of hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide

The compound of step 6 (S10, 0.1 g) was dissolved in THF (10 mL), 3-bromoaniline (0.2 mL) was added thereto, and the mixture was stirred at room temperature for 16 hours. After confirming the progress of the reaction through TLC, it was concentrated under reduced pressure and N -(3-bromophenyl)-N′-hydroxy-2-(methoxymethyl)benzofuran-5-carrine under EtOAc/Hexane conditions through silica chromatography . Voximidamide (32, 0.04 g) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.62 (s, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 7.02 (dd, J = 8.4, 8.4 Hz, 1H), 6.93 (s, 1H), 6.77-6.78 (m, 2H), 6.46-6.48 (m, 1H), 4.53 (s, 2H), 3.34 (s, 3H).

Example 32: N -(3-chlorophenyl)- N' -Preparation of hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide

The same process as in Example 32 was performed, except that 3-bromoaniline was used instead of 3-bromoaniline in step 7) of Example 31.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.61 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.98 (m, 4H), 6.49-6.51 (m, 1H), 4.53 (s, 2H), 3.34 (s, 2H).

Example 33: N -(3-fluorophenyl)- N' -Preparation of hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide

The same process as in Example 31 was performed, except that 3-fluoroaniline was used instead of 3-bromoaniline in step 7) of Example 31.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.61 (s, 1H), 7.68 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.33 (dd, J ) = 2.0, 8.8 Hz, 1H), 7.00-7.06 (m, 1H), 6.92 (s, 1H), 6.39-6.57 (m, 3H), 4.53 (s, 2H), 3.34 (s, 3H).

Example 34: N -(3-bromophenyl)- N' -Preparation of hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide

Step 1) Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-carbonitrile

After dissolving 2-(hydroxymethyl)benzofuran-5-carbonitrile (S6, 0.6g) in DMF (7mL), tert-butyldimethylsilyl chloride (0.8g) and imidazole (0.72g) were added thereto. It was stirred at room temperature for hours. After confirming the reaction progress through TLC, aq. NH ₄ Cl was added. After that, it was worked-up twice with EtOAc to separate the product into an organic layer and aq. After washing with NH ₄ Cl and brine, MgSO ₄ was added to the obtained organic layer, and an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-carbonitrile (S11, 0.92g) was obtained through silica chromatography under EtOAc/Hexane conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 2) Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-carboaldehyde

After dissolving the compound of step 1 in CH ₂ Cl ₂ (32 mL), it was placed in DIBAL-H (1.0 M solution in hexane, 4 mL) at -10°C and stirred for 1 hour. After confirming the reaction progress through TLC, 10% citric acid was added thereto, and then work-up was performed twice with CH ₂ Cl ₂ to separate the product into an organic layer and washed with brine. Then, after adding MgSO ₄ to the organic layer, an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-carboaldehyde (S12, 0.83g) was obtained through silica chromatography under CH ₂ Cl ₂ /EtOAc conditions. obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 3) Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-carboaldehyde oxime

The compound of step 2 (S12, 1.2 g) was dissolved in CH ₂ Cl ₂ (21 mL), NH ₂ OH·HCl (0.86 g) and NEt ₃ (2.3 mL) were added thereto and stirred at room temperature for 12 hours. did. After confirming the reaction progress through TLC, H ₂ O was added thereto, and the product was separated into an organic layer by working-up twice with EtOAc. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-carboaldehyde oxime (S13, 1.2g) was obtained through silica chromatography under EtOAc/Hexane conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 4) 2-(((tert-butyldimethylsilyl)oxy)methyl)- N -Preparation of hydroxybenzofuran-5-carboimidol chloride

The compound of step 3 (S13, 1.2 g) was dissolved in DMF (8 mL), N-chlorosuccinimide (0.58 g) was added thereto, and the mixture was stirred at 50° C. for 2 hours. After confirming the reaction progress through TLC, it was concentrated under reduced pressure and 2-(((tert-butyldimethylsilyl)oxy)methyl) -N -hydroxybenzofuran-5-carboimi through silica chromatography under EtOAc/Hexane conditions. A stone (S14, 0.54 g) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 5) N -(3-Bromophenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The compound of step 4 (S14, 0.1 g) was dissolved in THF (5 mL), 3-bromoaniline (0.16 mL) was added thereto, and the mixture was stirred at room temperature for 16 hours. After confirming the reaction progress through TLC, it was concentrated under reduced pressure and N -(3-bromophenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl) -N' through silica chromatography under EtOAc/Hexane conditions. -Hydroxybenzofuran-5-carboximidamide (S15, 0.01 g) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.62 (s, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 7.02 (dd, J = 8.4, 8.4 Hz, 1H), 6.93 (s, 1H), 6.77-6.78 (m, 2H), 6.46-6.48 (m, 1H), 4.53 (s, 2H), 3.34 (s, 3H).

Step 6) N -(3-bromophenyl)- N' -Preparation of hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide

The compound of step 5 (S15, 0.01 g) was dissolved in THF (1 mL), tetrabutylammonium fluoride solution (1.0 M in THF, 0.3 mL) was added thereto, and stirred at room temperature for 30 minutes. After confirming the reaction progress through TLC, aq. NH ₄ Cl was added. Then, it was worked-up twice with EtOAc to separate the product into an organic layer, washed with brine, and then MgSO4 was added to the obtained organic layer to obtain an organic layer through a filter. After the organic layer was concentrated under reduced pressure, N -(3-bromophenyl)-N' - hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide (35, 0.005 g) was obtained.

¹ H NMR (400 MHz, MeOD) δ 7.34 (m, 1H), 7.32-7.34 (m, 1H), 7.21 (dd, J = 1.6, 8.4 Hz, 1H), 6.78-6.87 (m, 3H), 6.61 ( m, 1H), 6.48 (ddd, J = 1.2, 2.0, 7.6 Hz, 1H), 4.57 (s, 2H).

Example 35: N -(3-chlorophenyl)- N' -Preparation of hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide

The same process as in Example 34 was performed, except that 3-chloroaniline was used instead of 3-bromoaniline in step 5) of Example 34.

¹ H NMR (400 MHz, MeOD) δ 7.55 (d, J = 1.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 1.6, 8.4 Hz, 1H), 6.88-6.94 (m, 1H), 6.61 (s, 1H), 6.44 (ddd, J = 2.4, 8.4, 8.4 Hz, 1H), 6.36 (dd, J = 1.6, 8.0 Hz, 1H), 6.28 (ddd, J = 2.0) , 2.0, 10.8 Hz, 1H), 4.57 (s, 2H).

Example 36: N -(3-fluorophenyl)- N' -Preparation of hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide

The same process as in Example 34 was performed, except that 3-fluoroaniline was used instead of 3-bromoaniline in step 5) of Example 34.

¹ H NMR (400 MHz, MeOD) δ 7.59 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.25 (dd, J = 2.0, 8.8 Hz, 1H), 6.93 (dd , J = 8.0, 8.0 Hz, 1H), 6.76 (dd, J = 1.2, 8.0 Hz, 1H), 6.66-6.67 (m, 2H), 6.49 (dd, J = 1.2, 8.0 Hz, 1H), 4.61 ( s, 2H).

Example 37: N -(3-Bromophenyl)-2-((cyclopropylmethoxy)methyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

Step 1) Preparation of 2-((cyclopropylmethoxy)methyl)benzofuran-5-carbonitrile

After dissolving 2-(hydroxymethyl)benzofuran-5-carbonitrile (S6, 0.5g) in DMF (6mL), sodium hydride 60% dispersion in mineral oil (0.28g), (chloromethyl)cyclopropane ( 0.4 mL) and stirred at room temperature for 13 hours. After confirming the reaction progress through TLC, aq. NH ₄ Cl was added. After that, it was worked-up twice with EtOAc to separate the product into an organic layer and aq. After washing with NH ₄ Cl and brine, MgSO ₄ was added to the obtained organic layer, and an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, ) 2-((cyclopropylmethoxy)methyl)benzofuran-5-carbonitrile (S16, 0.28g) was obtained through silica chromatography under EtOAc/Hexane conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 2) Preparation of 2-((cyclopropylmethoxy)methyl)benzofuran-5-carboaldehyde

The compound of step 1 (S16, 0.46g) was dissolved in CH ₂ Cl ₂ (20 mL), DIBAL-H (1.0 M solution in hexane, 3 mL) was added at 0° C. and stirred for 1 hour. After confirming the reaction progress through TLC, 10% citric acid was added thereto, and then work-up was performed twice with CH ₂ Cl ₂ to separate the product into an organic layer and washed with brine. Thereafter, MgSO ₄ was added to the obtained organic layer, and an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 2-((cyclopropylmethoxy)methyl)benzofuran-5-carboaldehyde (S17, 0.4 g) was obtained through silica chromatography under CH ₂ Cl ₂ /EtOAc conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 3) Preparation of 2-((cyclopropylmethoxy)methyl)benzofuran-5-carboaldehyde oxime

The compound of step 2 (S17, 0.4 g) was dissolved in CH ₂ Cl ₂ (9 mL), and then NH ₂ OH·HCl (0.36 g) and NEt ₃ (1 mL) were added thereto and at room temperature for 12 hours. stirred. After confirming the reaction progress through TLC, H ₂ O was added thereto, and the product was separated into an organic layer by working-up twice with EtOAc. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, the product 2-((cyclopropylmethoxy)methyl)benzofuran-5-carboaldehyde oxime (S18, 0.37g) was obtained through silica chromatography under CH ₂ Cl ₂ /EtOAc conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 4) N -(3-Bromophenyl)-2-((cyclopropylmethoxy)methyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The compound of step 3 (S18, 0.43 g) was dissolved in CH ₂ Cl ₂ (35 mL), and then NaOCl (11 mL) and NEt ₃ (0.49 mL) were added thereto at 0° C. and stirred for 30 minutes. After confirming the reaction progress through TLC, H ₂ O was added thereto, and the product was separated into an organic layer by working-up twice with EtOAc. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. Thereafter, the organic layer was concentrated under reduced pressure and the following reaction was performed without further purification. After the reaction mixture was dissolved in THF (5 mL), 3-bromoaniline (1.0 mL) was added thereto, and the mixture was stirred at room temperature for 16 hours. After confirming the reaction progress through TLC, it was concentrated under reduced pressure and N -(3-bromophenyl) _-2 -((cyclopropylmethoxy)methyl) -N' _- hydro Roxybenzofuran-5-carboximidamide (38, 0.25 g) was obtained.

¹ H NMR (400 MHz, MeOD) δ 7.65 (dd, J = 1.7, 0.7 Hz, 1H), 7.43 (dt, J = 8.6, 0.8 Hz, 1H), 7.32 (dd, J = 8.6, 1.8 Hz, 1H) , 7.00 - 6.84 (m, 4H), 6.77 (d, J = 0.9 Hz, 1H), 6.57 (ddd, J = 7.8, 2.2, 1.2 Hz, 1H), 4.66 - 4.58 (m, 3H), 3.39 (d , J = 6.9 Hz, 2H), 1.11 - 1.02 (m, 1H), 0.56 - 0.48 (m, 2H), 0.20 (dt, J = 5.9, 4.4 Hz, 2H).

Example 38: N -(3-fluorophenyl)-2-((cyclopropylmethoxy)methyl)- N' -Preparation of hydroxybenzofuran-5-carboximidamide

The same process as in Example 37 was performed, except that 3-fluoroaniline was used instead of 3-bromoaniline in step 4) of Example 37.

¹ H NMR (400 MHz, MeOD) δ 7.67 (d, J = 1.7 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.34 (dd, J = 8.6, 1.8 Hz, 1H), 7.02 (td) , J = 8.2, 6.6 Hz, 1H), 6.78 (s, 1H), 6.55 (td, J = 8.3, 2.5 Hz, 1H), 6.50 - 6.36 (m, 2H), 4.63 (s, 2H), 3.40 ( d, J = 6.9 Hz, 2H), 1.07 (tt, J = 8.9, 3.8 Hz, 1H), 0.88 (d, J = 6.5 Hz, 1H), 0.56 - 0.50 (m, 2H), 0.22 (dt, J ) = 6.2, 4.4 Hz, 2H).

Example 39: 2-((cyclopropylmethoxy)methyl)- N' -Hydroxy- N Preparation of -(3-(trifluoromethyl)phenyl)benzofuran-5-carboximidamide

The same process as in Example 37 was performed, except that 3-trifluoromethylaniline was used instead of 3-bromoaniline in step 4) of Example 37.

¹ H NMR (400 MHz, MeOD) δ 7.67 (d, J = 1.7 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.33 (dd, J = 8.6, 1.8 Hz, 1H), 7.20 (t) , J = 7.9 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.88 - 6.83 (m, 1H), 6.78 (s, 1H), 4.63 (s, 2H), 3.39 (d, J = 6.9 Hz, 2H), 1.11 - 1.02 (m, 1H), 0.56 - 0.50 (m, 2H), 0.21 (dt, J = 6.2, 4.6 Hz, 2H).

Example 40: N -(3-bromophenyl)- N' -Preparation of hydroxy-2-phenylbenzofuran-5-carboximidamide

Step 1) Preparation of 2-phenylbenzofuran-5-carbonitrile

After dissolving 4-hydroxy-3-iodobenzonitrile (S5, 0.1 g) in toluene/THF (2:1, 1.4 mL), Pd(dppf)Cl ₂ (3mg), CuI (0.8mg), DIPA (0.2 mL), phenyl acetylene (0.05 mL) was added. The solution was warmed at 100° C. for 12 hours. After confirming the reaction progress through TLC, 10% citric acid was added thereto, and the product was separated into an organic layer by work-up twice with CH ₂ Cl ₂ and washed with 10% NaOH and brine. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 2-phenylbenzofuran-5-carbonitrile (S19, 0.07 g) was obtained through silica chromatography under CH ₂ Cl ₂ /ether conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 2) Preparation of 2-phenylbenzofuran-5-carboaldehyde

The compound of step 2 (S19, 0.07g) was dissolved in CH ₂ Cl ₂ (4 mL), DIBAL-H (1.0 M solution in hexane, 0.5 mL) was added at 0° C. and stirred for 30 minutes. After confirming the reaction progress through TLC, 10% citric acid was added thereto, and then work-up was performed twice with CH ₂ Cl ₂ to separate the product into an organic layer and washed with brine. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, 2-phenylbenzofuran-5-carboaldehyde (S20, 0.06 g) was obtained through silica chromatography under CH ₂ Cl ₂ /ether conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 3) Preparation of 2-((cyclopropylmethoxy)methyl)benzofuran-5-carboaldehyde oxime

The compound of step 3 (S20, 0.2 g) was dissolved in CH ₂ Cl ₂ (5 mL), NH ₂ OH·HCl (0.15 g) and NEt ₃ (0.4 mL) were added thereto and stirred at room temperature for 4 hours. did. After confirming the reaction progress through TLC, H ₂ O was added thereto, and the product was separated into an organic layer by working-up twice with EtOAc. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, the product 2-((cyclopropylmethoxy)methyl)benzofuran-5-carboaldehyde oxime (S21, 0.08g) was obtained through silica chromatography under EtOAc/Hexane conditions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 4) N -(3-bromophenyl)- N' -Preparation of hydroxy-2-phenylbenzofuran-5-carboximidamide

The compound of step 4 (S21, 0.08 g) was dissolved in CH ₂ Cl ₂ (8 mL), and then NaOCl (3 mL) and NEt ₃ (0.1 mL) were added thereto at 0° C. and stirred for 1 hour. After confirming the progress of the reaction through TLC, H ₂ O was added thereto, and work-up was performed twice with CH ₂ Cl ₂ to separate the product into an organic layer. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. The organic layer was concentrated under reduced pressure and the next reaction was carried out without further purification. The reaction mixture was dissolved in THF (5 mL), 3-bromoaniline (1.0 mL) was added thereto, and the mixture was stirred at room temperature for 24 hours. After confirming the reaction progress through TLC, it was concentrated under reduced pressure and N -(3-bromophenyl)-N′-hydroxy-2-phenylbenzofuran-5-carboximide under CH ₂ Cl/EtOAc conditions through silica chromatography . The amide (41, 0.02 g) was obtained.

¹ H NMR (400 MHz, MeOD) δ 7.96 - 7.86 (m, 2H), 7.71 (dd, J = 1.8, 0.7 Hz, 1H), 7.56 - 7.44 (m, 3H), 7.43 - 7.34 (m, 2H), 7.22 (d, J = 1.0 Hz, 1H), 7.04 - 6.89 (m, 3H), 6.62 (ddd, J = 7.7, 2.2, 1.3 Hz, 1H).

Example 41: N -(3-chlorophenyl)- N' -Preparation of hydroxy-2-phenylbenzofuran-5-carboximidamide

The same process as in Example 40 was performed, except that 3-chloroaniline was used instead of 3-bromoaniline in step 4) of Example 40.

¹ H NMR (400 MHz, MeOD) δ 7.96 - 7.87 (m, 2H), 7.71 (dd, J = 1.8, 0.7 Hz, 1H), 7.57 - 7.43 (m, 3H), 7.45 - 7.32 (m, 2H), 7.21 (d, J = 0.9 Hz, 1H), 7.02 (t, J = 8.1 Hz, 1H), 6.85 (ddd, J = 7.9, 2.1, 0.9 Hz, 1H), 6.80 (t, J = 2.1 Hz, 1H) ), 6.58 (ddd, J = 8.1, 2.2, 0.9 Hz, 1H).

Example 42: N -(3-fluorophenyl)- N' -Preparation of hydroxy-2-phenylbenzofuran-5-carboximidamide

The same process as in Example 40 was performed, except that 3-fluoroaniline was used instead of 3-bromoaniline in step 4) of Example 40.

¹ H NMR (400 MHz, MeOD) δ 7.94 - 7.87 (m, 2H), 7.72 (d, J = 1.4 Hz, 1H), 7.55 - 7.44 (m, 3H), 7.44 - 7.33 (m, 2H), 7.21 ( s, 1H), 7.05 (dt, J = 8.8, 7.4 Hz, 1H), 6.58 (td, J = 8.6, 2.5 Hz, 1H), 6.53 - 6.42 (m, 2H).

Example 43: N -(3-bromophenyl)- N' -Hydroxydibenzo[ b , d ] Preparation of furan-2-carboximidamide

Step 1) Preparation of dibenzo[b,d]furan-2-carboaldehyde oxime

After dissolving dibenzo[b,d]furan-2-carboaldehyde (S22, 1.0g) in MeOH (50mL), NH ₂ OH (1.4mL) and NEt ₃ (3.2mL) were added thereto, and 75℃ for 3 hours stirred in. After confirming the progress of the reaction through TLC, it was concentrated under reduced pressure, H ₂ O was added thereto, and the product was separated into an organic layer by working-up twice with EtOAc. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. After the organic layer was concentrated under reduced pressure, dibenzo[b,d]furan-2-carboaldehyde oxime (S23, 1.2 g) was obtained under EtOAc/Hexane conditions through silica chromatography.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 2) N -Preparation of hydroxydibenzo[b,d]furan-2-carbimidol chloride

The compound of step 1 (S23, 1.2 g) was dissolved in DMF (10 mL), N-chlorosuccinimide (0.83 g) was added thereto, and the mixture was stirred at 50° C. for 2 hours. After confirming the reaction progress through TLC, H ₂ O was added thereto, and the product was separated into an organic layer by working-up twice with EtOAc. After adding MgSO ₄ to the obtained organic layer, an organic layer was obtained through a filter. The obtained compound N -hydroxydibenzo[b,d]furan-2-carbimidol chloride (S24, quant.) was subjected to the following reaction without purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.89-6.99 (m, 4H), 6.49-6.51 (m, 1H).

Step 3) N -(3-bromophenyl)- N' -Hydroxydibenzo[ b , d ] Preparation of furan-2-carboximidamide

The compound of step 2 (S24, 0.2 g) was dissolved in THF (5 mL), 3-bromoaniline (0.09 mL) was added thereto, and the mixture was stirred at room temperature for 16 hours. After confirming the progress of the reaction through TLC, it was concentrated under reduced pressure and the product N -(3-bromophenyl)-N'-hydroxydibenzo [ b , d ]furan-2-car through silica chromatography under EtOAc/Hexane conditions. Voximidamide (44, 0.01 g) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.69 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.67-7.73 (m, 2H), 7.49-7.57 (m, 2H), 7.41 (dd, J = 7.2, 7.2 Hz, 1H), 6.89-6.98 (m, 3H), 6.53 (d, J = 8.4 Hz, 1H).

Example 44: N -(3-chlorophenyl)- N' -Hydroxydibenzo[ b , d ] Preparation of furan-2-carboximidamide

The same process as in Example 43 was performed, except that 3-chloroaniline was used instead of 3-bromoaniline in step 3) of Example 43.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.71 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 7.2 Hz, 1H), 7.68-7.74 (m, 2H), 7.50-7.57 (m, 2H), 7.39-7.43 (m, 1H), 7.02 (dd, J = 8.0, 8.0 Hz, 1H), 6.77-6.83 (m, 2H), 6.51 (dd, J = 2.0, 8.4 Hz, 1H).

Example 45: N -(3-bromo-4-fluorophenyl)- N' -Hydroxydibenzo[ b , d ] Preparation of furan-2-carboximidamide

The same process as in Example 43 was performed, except that 3-bromo-4-fluoroaniline was used instead of 3-bromoaniline in step 3) of Example 43.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 8.67 (s, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.67-7.74 (m, 2H), 7.53-7.57 (m, 1H), 7.49 (dd, J = 1.6, 8.4 Hz, 1H), 7.41 (dd, J = 7.2, 7.2 Hz, 1H), 7.02-7.08 ( m, 2H), 6.54-6.58 (m, 1H).

Example 46: N -(3,5-dimethoxyphenyl)- N' -Hydroxydibenzo[ b , d ] Preparation of furan-2-carboximidamide

The same process as in Example 43 was performed, except that 3,5-dimethoxyaniline was used instead of 3-bromoaniline in step 3) of Example 43.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H), 8.35 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.67-7.73 (m, 2H), 7.52-7.57 (m, 1H), 7.49 (dd, J = 2.0, 8.8 Hz, 1H), 7.39-7.43 (m, 1H), 5.92 (dd, J = 2.0, 2.0) Hz, 1H), 5.86 (m, 2H), 3.47 (s, 6H).

Example 47: N -(3-chloro-4-fluorophenyl)- N' -Hydroxydibenzo[ b , d ] Preparation of furan-2-carboximidamide

The same process as in Example 43 was performed, except that 3-chloro-4-fluoroaniline was used instead of 3-bromoaniline in step 3) of Example 43.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 8.68 (s, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.67-7.73 (m, 2H), 7.53-7.57 (m, 1H), 7.48 (dd, J = 1.6, 8.4 Hz, 1H), 7.39-7.43 (m, 1H), 7.07 (dd, J = 8.8, 8.8) Hz, 1H), 6.93 (d, J = 2.8, 6.4 Hz, 1H), 6.50-6.54 (m, 1H).

Example 48: N -(3-chlorobenzyl)- N' -Hydroxydibenzo[ b , d ] Preparation of furan-2-carboximidamide

The same process as in Example 43 was performed, except that (3-chlorophenyl)methanamine was used instead of 3-bromoaniline in step 3) of Example 43.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (s, 1H), 8.16 (dd, J = 0.8, 7.6 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.68-7.73 (m) , 2H), 7.53-7.57 (m, 1H), 7.40-7.46 (m, 2H), 7.21-7.29 (m, 3H), 7.03-7.05 (m, 1H), 6.59 (dd, J = 7.2, 7.2 Hz) , 1H), 4.22 (d, J = 7.2 Hz, 1H).

[Test Example]

Test Example 1. Confirmation of enzyme activity inhibitory effect on indoleamine-2,3-dioxygenase 1 (IDO 1)

(1.1) Recombinant human IDO 1 enzyme activity inhibitory effect evaluation

Final concentrations of 100 μg/ml catalase, 20 mM ascorbic acid, and 10 μM methylene blue were prepared in assay buffer (100 mM KPO4, 0.01% Triton X-100) and dispensed into 96-well microplates. The compounds of the above examples were prepared in assay buffer according to the final treatment concentrations of 10 μM, 30 μM, and 100 μM (1.5% DMSO), and then were dispensed into the 96-well microplate. Recombinant human IDO 1 (BPS bioscience, Cat #: 71182) was prepared to have a final concentration of 1.5 μg/ml in assay buffer, and pre-incubation was started at 25° C. for 30 minutes. Both dilution and dispensing of rhIDO were performed on ice. The group reacted without adding an enzyme was set to be included as a blank control. Then, the final concentration of 100 μM L-tryptophan was added and incubated at 25° C. for 90 minutes to initiate the enzymatic reaction. The reaction was stopped by adding 20 μl 30% TCA (Trichloroacetic acid), and incubated at 65° C. for 15 minutes. Then, after centrifugation at 3,000 x g for 10 minutes, 100 μl of the supernatant was transferred to a new 96 well plate. Then, the same amount (100 μl) of Ehrlich's reagent (2% p-dimethylaminobenzaldehyde dissolved in acetic acid) as the supernatant was added and reacted for 5 minutes. Then, the color development level was evaluated by measuring the absorbance in a microplate reader 480 nm, and IC ₅₀ was calculated based on this.

(1.2) Measurement of the inhibitory effect of IDO 1 enzyme activity in HeLa cells

The uterine cancer cell line HeLa (KCLB No.10002) was maintained at 37° C., 5% CO ₂ condition in DMEM (SH30243.01, Hyclone) supplemented with 10% FBS and 1% Pen/Strep. In order to measure the IDO enzyme activity inhibitory effect of the compounds of the above example, the cell line was plated in a 96-well cell culture plate with a cell number of 1.5 x 10 ⁴ cells, and 50 ng/ml IFN-γ was added thereto for 24 hours. 24 hours later, DMEM (SH30284.01, Hyclone) was replaced with a culture medium containing 10% FBS and 1% Pen/Strep, and the final treatment concentrations were 10 μM, 30 μM, 100 μM (1.5% DMSO). ), and then incubated for 24 hours. Then, 100 μl of the culture supernatant from each well of the tissue culture plate was transferred to a 96 well plate, and 20 μl of 30% TCA (Trichloroacetic acid) was added and incubated at 65° C. for 15 minutes. Then, after centrifugation at 3,000 x g for 10 minutes, 100 μl of the supernatant was transferred to a new 96-well plate. Then, the same amount (100 μl) of the supernatant and Ehrlich's reagent (2% p-dimethylaminobenzaldehyde dissolved in acetic acid) was added and reacted for 5 minutes. Then, the color development level was evaluated by measuring the absorbance in a microplate reader 480 nm, and IC ₅₀ was calculated based on this.

(1.3) Test results

The IDO 1 enzyme activity inhibitory effect of the compounds prepared in Examples 1 to 48 was evaluated, and the results are shown in Table 1 below.

Example IDO (IC ₅₀ , μM) Example IDO (IC ₅₀ , μM) Enzyme Hela cell Enzyme Hela cell One A A 25 C C 2 C C 26 C C 3 B A 27 C C 4 C C 28 C C 5 C C 29 C C 6 C C 30 C C 7 A A 31 A A 8 C C 32 A A 9 A A 33 B B 10 B C 34 A A 11 A A 35 B B 12 C C 36 A A 13 A A 37 A B 14 C C 38 A B 15 C C 39 A C 16 C C 40 A B 17 C C 41 A C 18 C C 42 C C 19 C C 43 A C 20 C C 44 A B 21 C C 45 A C 22 C C 46 C C 23 C B 47 B C 24 C C 48 B C

On the other hand, the classification range of the IC ₅₀ result in Table 1 is as follows.

- Classification range A: IC ₅₀ ≤3uM

- Classification range B: 3uM < IC ₅₀ ≤10 uM

- Classification range C: IC ₅₀ > 10 uM

As shown in Table 1, the compounds of Examples 1 to 48 exhibited excellent inhibitory activity against the IDO 1 enzyme.

The foregoing description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (11)

A compound of formula (I), a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof:
[Formula I]

In the above formula (I),
n is 0 or 1;
R ₁ is hydrogen, phenyl, or -W-(CH) _m -X, or fuses with carbon a in the benzofuran ring to form, together with the atoms to which they are attached, a 6 membered aryl ring, where W is -(CH ₂ ) )-, or -(CH ₂ O)-, m is 0 or 1, and X is a hydroxyl group, a C ₁ -C ₅ alkyl group, a C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl group, or C _{3 -} a C ₈ cycloalkyl group;
Cy is a C ₃ -C ₁₀ aryl, C ₄ -C ₁₀ heteroaryl, or C ₃ -C ₈ cycloalkyl group;
R ₂ and R ₃ are independently hydrogen, halogen, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₅ an alkoxy group; and
R ₄ is hydrogen, halogen, phenyl, or -Y-(CH ₂ ) ₁ -Z, wherein Y is -O-, -(CH ₂ )-, -(CH ₂ O)-, -(CO) -, or -(CONH)-, l is 0 or 1, Z is a C ₁ -C ₅ alkyl group, a C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl group, a C ₃ -C ₈ cycloalkyl group, phenyl, or a C ₃ -C ₈ heterocycloalkyl group substituted with a C ₁ -C ₅ alkyl group. The method according to claim 1,
R ₁ is hydrogen, phenyl, or -W-(CH) _m -X, or fuses with carbon a in the benzofuran ring to form, together with the atoms to which they are attached, a 6 membered aryl ring, where W is -(CH ₂ ) )-, or -(CH ₂ O)-, m is 0 or 1, and X is a hydroxy group, a C ₁ -C ₃ alkyl group, or a C ₃ -C ₅ cycloalkyl group, a compound of formula I, a solvate , a stereoisomer or a pharmaceutically acceptable salt thereof. The method according to claim 1,
Cy is a C ₆ -C ₈ aryl, C ₄ -C ₆ heteroaryl, or C ₃ -C ₈ cycloalkyl group;
In the above C ₆ -C ₈ aryl, R ₂ and R ₃ are independently hydrogen, halogen, C ₁ -C ₃ alkyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₃ alkoxy group; and
R ₄ is hydrogen, halogen, phenyl, or -Y-(CH ₂ ) ₁ -Z, wherein Y is -O-, -(CH ₂ )-, -(CH ₂ O)-, -(CO) -, or -(CONH)-, l is 0 or 1, Z is C _{4 -C substituted with a C 1 -C 3 alkyl group, a C 4 -C 6 cycloalkyl group} , phenyl, or a C ₁ -C ₃ alkyl group. A compound of formula (I), a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, which is a ₆ heterocycloalkyl group. 4. The method of claim 3,
Cy is phenyl, thiophenyl, furanyl, cyclopropyl, or cyclobutyl, cyclopentanyl;
In the above phenyl, R ₂ and R ₃ are independently hydrogen, halogen, C ₁ -C ₃ alkyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₃ alkoxy group; and
R ₄ is hydrogen, halogen, phenyl, or -Y-(CH ₂ ) ₁ -Z, wherein Y is -O-, -(CH ₂ )-, -(CH ₂ O)-, -(CO) -, or -(CONH)-, l is 0 or 1, Z is piperidine substituted with a C ₁ -C ₃ alkyl group, a C ₄ -C ₆ cycloalkyl group, phenyl, or a C ₁ -C ₃ alkyl group- 1-yl, wherein the compound of formula (I), solvate, stereoisomer or pharmaceutically acceptable salt thereof. The method according to claim 1,
n is 0 or 1;
R ₁ is hydrogen, phenyl, or -W-(CH) _m -X, or fuses with carbon a in the benzofuran ring to form, together with the atoms to which they are attached, a 6 membered aryl ring, where W is -(CH ₂ ) )-, or -(CH ₂ O)-, m is 0 or 1, and X is a hydroxy group, a C ₁ -C ₃ alkyl group, or a C ₃ -C ₅ cycloalkyl group;
Cy is C ₆ -C ₈ aryl, C ₄ -C ₆ heteroaryl containing O or S atoms, or C ₃ -C ₈ cycloalkyl group;
In the above C ₆ -C ₈ aryl, R ₂ and R ₃ are independently hydrogen, halogen, C ₁ -C ₃ alkyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₃ alkoxy group; and
R ₄ is hydrogen, halogen, phenyl, or -Y-(CH ₂ ) ₁ -Z, wherein Y is -O-, -(CH ₂ )-, -(CH ₂ O)-, -(CO) -, or -(CONH)-, l is 0 or 1, Z is piperidine substituted with a C ₁ -C ₃ alkyl group, a C ₄ -C ₆ cycloalkyl group, phenyl, or a C ₁ -C ₃ alkyl group- 1-yl, wherein the compound of formula (I), solvate, stereoisomer or pharmaceutically acceptable salt thereof. The compound of formula (I), solvate, stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of:
N -(3-bromophenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N- (4-chloro-3-fluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N- (3-chloro-4-fluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N -(4-chlorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N- (3,4-difluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N -(3-fluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N -(3-chlorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N' -hydroxy- N -phenylbenzofuran-5-carboximidamide;
N- (3-bromo-4-fluorophenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N' -hydroxy- N- (2,4,5-trifluorophenyl)benzofuran-5-carboximidamide;
N- (4-fluoro-3-(trifluoromethyl)phenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N- (3,4- dimethylphenyl )-N'-hydroxybenzofuran-5-carboximidamide;
N' -hydroxy- N- (3-(trifluoromethyl)phenyl)benzofuran-5-carboximidamide;
N -(3-acetylphenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N- (cyclohexylmethyl)-3-( N' -hydroxybenzofuran-5-carboximidoamido)benzamide;
N -( [ 1,1'-biphenyl]-3-yl)-N'-hydroxybenzofuran-5-carboximidamide;
N -benzyl-3-( N' -hydroxybenzofuran-5-carboximimidamido)benzamide;
N' -hydroxy- N- (3-(4-methylpiperidine-1-carbonyl)phenyl)benzofuran-5-carboximidamide;
N- (3-benzylphenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N' -hydroxy- N- (3-phenoxyphenyl)benzofuran-5-carboximidamide;
N- (3-butoxyphenyl)-N' - hydroxybenzofuran-5-carboximidamide;
N' -hydroxy- N- (3-(phenoxymethyl)phenyl)benzofuran-5-carboximidamide;
N -(3-chlorobenzyl)-N' - hydroxybenzofuran-5-carboximidamide;
N -benzyl- N' -hydroxybenzofuran-5-carboximidamide;
N- (3-chloro-4-fluorobenzyl)-N' - hydroxybenzofuran-5-carboximidamide;
N' -hydroxy- N- (thiophen-2-ylmethyl)benzofuran-5-carboximidamide;
N- (furan-2-ylmethyl)-N' - hydroxybenzofuran-5-carboximidamide;
N -(cyclopropylmethyl)-N' - hydroxybenzofuran-5-carboximidamide;
N -cyclobutyl- N' -hydroxybenzofuran-5-carboximidamide;
N -cyclopentyl- N' -hydroxybenzofuran-5-carboximidamide;
N -(3-bromophenyl)-N' - hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide;
N -(3-chlorophenyl) -N' -hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide;
N- (3-fluorophenyl)-N' - hydroxy-2-(methoxymethyl)benzofuran-5-carboximidamide;
N- (3-bromophenyl)-N' - hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide;
N -(3-chlorophenyl) -N' -hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide;
N- (3-fluorophenyl)-N' - hydroxy-2-(hydroxymethyl)benzofuran-5-carboximidamide;
N- (3-bromophenyl)-2-((cyclopropylmethoxy)methyl)-N′ - hydroxybenzofuran-5-carboximidamide;
N- (3-fluorophenyl)-2-((cyclopropylmethoxy)methyl)-N' - hydroxybenzofuran-5-carboximidamide;
2-((cyclopropylmethoxy)methyl) -N′-hydroxy-N- ( 3-(trifluoromethyl)phenyl)benzofuran-5-carboximidamide;
N- (3-bromophenyl)-N' - hydroxy-2-phenylbenzofuran-5-carboximidamide;
N -(3-chlorophenyl)-N' - hydroxy-2-phenylbenzofuran-5-carboximidamide;
N- (3-fluorophenyl)-N' - hydroxy-2-phenylbenzofuran-5-carboximidamide;
N- (3-bromophenyl)-N′-hydroxydibenzo [ b , d ]furan-2-carboximidamide;
N- (3-chlorophenyl)-N′-hydroxydibenzo [ b , d ]furan-2-carboximidamide;
N- (3-bromo-4-fluorophenyl)-N′-hydroxydibenzo [ b , d ]furan-2-carboximidamide;
N- (3,5-dimethoxyphenyl)-N'-hydroxydibenzo [ b , d ]furan-2-carboximidamide;
N- (3-chloro-4-fluorophenyl)-N'-hydroxydibenzo [ b , d ]furan-2-carboximidamide; and
N -(3-chlorobenzyl)-N'-hydroxydibenzo [ b , d ]furan-2-carboximidamide. A pharmaceutical composition for the prevention or treatment of cancer, comprising the compound of any one of claims 1 to 6, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of claim 7, wherein the composition exhibits inhibitory activity against indoleamine-2,3-dioxygenase 1 (Indoleamine 2,3-dioxygenase 1: IDO 1). The method according to claim 7, wherein the cancer is lung cancer, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, gastrointestinal cancer, liver cancer, leukemia, lymphoma, melanoma Tumor, multiple myeloma, Ewing's sarcoma, osteosarcoma, colorectal cancer, cholangiocarcinoma, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, or thyroid cancer, the pharmaceutical composition. The pharmaceutical composition according to claim 7, wherein the composition is administered in combination with other anticancer agents simultaneously, separately, or sequentially. The pharmaceutical composition according to claim 7, wherein the composition is formulated in a pharmaceutically acceptable form including tablets, pills, powders, capsules, syrups, emulsions or microemulsions.