WO2023229099A1 - Benzofuranyl hydroxyphenyl methanone oxime derivative and uses thereof - Google Patents

Abstract

Provided in the present invention is a novel benzofuranyl hydroxyphenyl methanone oxime derivative compound as an HSP47 inhibitor, hydrates thereof, solvates thereof, or pharmaceutically acceptable salts thereof. It was confirmed that the benzofuranyl hydroxyphenyl methanone oxime derivative compound of the present invention exhibits excellent activity as an HSP47 inhibitor by effectively inhibiting the HSP47 protein, which is a therapeutic target specific for fibrosis inhibition treatment, and has excellent efficacy in inhibiting collagen production in respective tissue cells, and thus may be used for the prevention or treatment of HSP47-related diseases. Accordingly, the novel benzofuranyl hydroxyphenyl methanone oxime derivative compound of the present invention may be effectively used for the prevention or treatment of HSP47-related diseases in the medical and pharmaceutical fields.

Description

Benzofuranyl hydroxyphenyl methanone oxime derivatives and uses thereof

The present invention relates to benzofuranyl hydroxyphenyl methanone oxime derivatives, and more particularly to benzofuranyl hydroxyphenyl methanone oxime derivatives and their use in inhibiting HSP47.

HSP47 (Heat shock protein 47) protein is a protein present in the endoplasmic reticulum induced by stress and acts as a chaperon protein for the formation of the three-dimensional structure of collagen and extracellular secretion. HSP47 has been reported to have increased expression in fibrosis of various tissues, such as liver cirrhosis, pulmonary fibrosis, keloid, hypertrophic scar, and glomerulosclerosis. According to the literature, it has been reported that inhibiting the HSP47 protein inhibits collagen secretion in cells that produce collagen. In addition, it has been reported that inhibition of HSP47 protein induces apoptosis of cells producing collagen (Ito S et. al ., 2017). These results show that inhibition of HSP47 protein is an effective and specific therapeutic target for fibrosis inhibition treatment.

Fibrosis or fibrosis refers to the abnormal accumulation of collagen following damage or inflammation that changes the structure and function of various tissues. Regardless of where fibrosis occurs, most etiologies of fibrosis involve excessive accumulation of collagen that replaces normal tissue. Progressive fibrosis in the liver, lung, or skin is a disease with high unmet medical need for which there is no specific treatment to date.

HSP47 has also been reported to be expressed in cancer cells, and it has been reported that increased expression of HSP47 facilitates the metastasis of many cancer cells and increases mortality. It has also been reported that cancer progression is suppressed when HSP47 expression is suppressed through genetic methods (Parveen A et. al., 2020).

The problem to be solved by the present invention is to recognize that there is a close relationship between HSP47 and excessive accumulation of collagen, and to provide an HSP47 inhibitory substance that has therapeutic efficacy against diseases such as fibrosis and cancer by inhibiting the HSP47 protein.

In addition, the problem of the present invention is to provide a pharmaceutical composition for preventing or treating HSP47-related diseases containing the benzofuranyl hydroxyphenyl methanone oxime derivative compound as an active ingredient.

In addition, the problem of the present invention is to provide a method for preventing or treating HSP47-related diseases using the benzofuranyl hydroxyphenyl methanone oxime derivative compound.

In addition, the problem of the present invention is to provide a use of the benzofuranyl hydroxyphenyl methanone oxime derivative compound for the prevention or treatment of HSP47-related diseases.

In addition, the problem of the present invention is to provide a method for producing the benzofuranyl hydroxyphenyl methanone oxime derivative compound.

The problem to be solved by the present invention is not limited to the problems mentioned above, and other technical problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.

In order to solve the above problem, according to one aspect of the present invention, a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided. .

<Formula I>

In the above equation,

R ¹ is hydrogen, C ₁ -C ₆ straight or branched chain alkyl, or halogen,

R ² is hydrogen, C ₁ -C ₆ straight or branched chain alkyl, halogen, or SO ₂ NR ^a R ^b ,

At this time, R ^a and R ^b are independently hydrogen, C ₁ -C ₆ straight or branched chain alkyl, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ cycloalkyl substitution. is C ₁ -C ₃ alkyl, or

R ^a and R ^b are linked to each other to form a 4- to 7-membered heterocycloalkyl containing 0 to 2 heteroatoms with N connected to SO ₂ , wherein C forming the heterocycloalkyl is O. Substituted or not substituted,

R ³ is hydrogen or halogen,

R ⁴ and R ⁵ are independently halogen,

R ⁶ is hydrogen or C ₁ -C ₆ straight or branched chain alkyl.

According to another aspect of the present invention, a treatment for HSP47-related diseases comprising a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutical compositions for prophylaxis or treatment are provided.

According to another aspect of the present invention, prevention or treatment of HSP47-related diseases using the benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by Formula I, its hydrate, its solvate, or its pharmaceutically acceptable salt. A method is provided.

According to another aspect of the present invention, the use of the benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), its hydrate, its solvate or its pharmaceutically acceptable salt for the prevention or treatment of HSP47-related diseases. provided.

According to another aspect of the present invention, a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. A pharmaceutical composition comprising a is provided.

According to another aspect of the present invention, a method for producing a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by Formula I is provided.

The novel benzofuranyl hydroxyphenyl methanone oxime derivative compound of the present invention was confirmed to exhibit excellent activity as an HSP47 inhibitor by effectively inhibiting HSP47 protein, a specific therapeutic target for fibrosis inhibition treatment, lung epithelial cells, and hepatic stellate cells. , it was confirmed to have excellent efficacy in suppressing collagen production in skin cells, and it was found that it can be used for the prevention or treatment of HSP47-related diseases.

Therefore, the novel benzofuranyl hydroxyphenyl methanone oxime derivative compound of the present invention can be usefully used in the prevention or treatment of HSP47-related diseases in the medical and pharmaceutical fields.

The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the configuration of the invention described in the description or claims of the present invention.

The present invention provides a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

<Formula Ⅰ>

In the above equation,

R ¹ is hydrogen, C ₁ -C ₆ straight or branched chain alkyl, or halogen,

R ² is hydrogen, C ₁ -C ₆ straight or branched chain alkyl, halogen, or SO ₂ NR ^a R ^b ,

At this time, R ^a and R ^b are independently hydrogen, C ₁ -C ₆ straight or branched chain alkyl, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ cycloalkyl substitution. is C ₁ -C ₃ alkyl, or

R ^a and R ^b are linked to each other to form a 4- to 7-membered heterocycloalkyl containing 0 to 2 heteroatoms with N connected to SO ₂ , wherein C forming the heterocycloalkyl is O. Substituted or not substituted,

R ³ is hydrogen or halogen,

R ⁴ and R ⁵ are independently halogen,

R ⁶ is hydrogen or C ₁ -C ₆ straight or branched chain alkyl.

In one embodiment, R ¹ may be hydrogen, methyl, or Cl.

In one embodiment, R ² is hydrogen, methyl, Cl, or SO ₂ NR ^a R ^b , where R ^a and R ^b are independently hydrogen, methyl, ethyl, propyl, hydroxyethyl, cyclopropyl, or It may be cyclopropylmethyl, or R ^a and R ^b may include N linked to SO ₂ to form azetidinyl, pyrrolidinyl, morpholino, or piperazinone.

In one embodiment, R ³ may be hydrogen, Cl, or Br.

In one embodiment, R ⁴ and R ⁵ may independently be Br or I.

In one embodiment, R ⁶ may be hydrogen or methyl.

Specific examples of benzofuranyl hydroxyphenyl methanone oxime derivative compounds according to the present invention are as follows:

[1] (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone oxime,

[2] (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone O-methyl oxime,

[3] (6-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime,

[4] (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-methylbenzofuran-3-yl)methanone oxime,

[5] (7-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime,

[6] (7-bromo-2-ethylbenbofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime,

[7] (2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime,

[8] (6-chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime,

[9] (5-chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime,

[10] (2-ethyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime,

[11] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide,

[12] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-methylbenzofuran-6-sulfonamide,

[13] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N,N-dimethylbenzofuran-6-sulfonamide,

[14] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-N,N,2-triethylbenzofuran-6-sulfonamide,

[15] (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(morpholinosulfonyl)benzofuran-3-yl)methanone oxime,

[16] N-cyclopropyl-3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide,

[17] N-(cyclopropylmethyl)-3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide,

[18] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-(2-hydroxyethyl)benzofuran-6-sulfonamide,

[19] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N,N-dipropylbenzofuran-6-sulfonamide,

[20] (6-(azetidin-1-ylsulfonyl)-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime,

[21] (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(pyrrolidin-1-ylsulfonyl)benzofuran-3-yl)methanone oxime,

[22] 4-((3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-yl)sulfonyl)piperazine-2 -on,

[23] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-N,2-diethylbenzofuran-6-sulfonamide, and

[24] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-propylbenzofuran-6-sulfonamide.

When defining compounds of formula I throughout this specification, the following definitions apply unless otherwise specified.

The term “alkyl” refers to a straight or branched chain saturated hydrocarbon, preferably C ₁ -C ₁₀ alkyl. For example, the alkyl is methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, tert -butyl, n -pentyl, iso -pentyl, n -hexyl, 3-methylhexyl, 2, It includes, but is not limited to, 2-dimethylpentyl, 2,3-dimethylpentyl, n -heptyl, n -octyl, n -nonyl, and n -decyl.

The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term “heteroatom” means N, O or S.

The term “heterocycloalkyl” refers to a non-aromatic carbocyclic ring containing one or more heteroatoms such as nitrogen, oxygen or sulfur within the cycloalkyl.

The compound represented by Formula I according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility, so the above prodrug, Hydrates, solvates and pharmaceutically acceptable salts are also within the scope of the present invention.

The term “prodrug” refers to a substance that is transformed in vivo into the parent drug. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioactive by oral administration, whereas the parent drug may not be. A prodrug may also have improved solubility in a pharmaceutical composition than the parent drug. For example, prodrugs may be in vivo hydrolyzable esters of compounds according to the invention and pharmaceutically acceptable salts thereof. Another example of a prodrug may be a short peptide (polyamino acid) in which the peptide is linked to an acid group that is metabolically converted to reveal the active site.

The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt.

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

The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. These isomers include both structural isomers such as tautomers, and stereoisomers such as R or S isomers and geometric isomers (trans, cis) having an asymmetric carbon center. All these isomers and mixtures thereof are also included within the scope of the present invention.

The term “pharmaceutically acceptable salt” refers to a salt form of a compound that does not cause significant irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, etc. Organic carboxylic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed by sulfonic acids and the like are included. For example, pharmaceutically acceptable carboxylic acid salts include metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N- Organic salts such as methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine are included. The compound of formula I according to the present invention can also be converted into its salt by conventional methods.

In addition, the present invention provides a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the following formula (I), comprising the step of reacting the ketone compound of the formula (I-1) with hydroxylamine (H ₂ NO-R ⁶ ) hydrochloride. Provides a manufacturing method.

<Formula Ⅰ-1>

<Formula Ⅰ>

In the above formula, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are the same as those of Chemical Formula I above.

This step is a step of condensing the ketone compound of Formula I-1 with hydroxylamine (H ₂ NO-R ⁶ ) hydrochloride to convert the ketone group contained in the ketone compound of Formula I-1 into an oxime group (Synthetic Method A )am. The solvent used at this time may be an organic solvent used in the ketone-oxime condensation reaction, for example, ethanol may be used, but is not limited thereto.

In the ketone compound of Formula I-1, the compound in which R ² is SO ₂ NR ^a R ^b is an amine compound (HNR ^a R ^b ) containing the desired substituent, a compound containing a -SO ₂ Cl group (Compound A), and By reacting, ketone compound B containing the desired substituent (when R ² is SO ₂ NR ^a R ^b in Chemical Formula I-1) can be obtained. Afterwards, the oxime derivative of Formula I can be obtained by condensation of ketone compound B with hydroxylamine (H ₂ NO-R ⁶ ) hydrochloride.

Schemes 1 to 24 of the Examples are exemplified as methods for preparing the compound of Formula I of the present invention, and the preparation methods of Schemes 1 to 24 do not limit the method of preparing the compound of Formula I according to the present invention. It is obvious that the preparation methods of Schemes 1 to 24 are merely examples and can be easily modified by those skilled in the art depending on the specific substituent.

The present invention also provides a method for preventing or treating HSP47-related diseases, comprising as an active ingredient a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. Provides a pharmaceutical composition for use.

The present invention also provides a method of administering a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a patient in need thereof, Provides a method of treating or preventing HSP47-related diseases.

The present invention also provides the use of the benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), its hydrate, its solvate, or its pharmaceutically acceptable salt for the prevention or treatment of HSP47-related diseases.

In one embodiment, the HSP47-related disease may be fibrosis or cancer. In particular, the fibrosis may be one or more selected from the group consisting of cirrhosis, pulmonary fibrosis, keloid, hypertrophic scar, and renal fibrosis (glomerulosclerosis), and the cancer may include breast cancer, colon cancer, and cancer-related cancer. It may be one or more selected from the group consisting of fibrosis.

The present invention also provides a pharmaceutical composition comprising a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. provides.

The additive may include a pharmaceutically acceptable carrier or diluent, and can be used in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, topical preparations, suppositories, and sterilization products according to conventional methods. It can be formulated in the form of an injectable solution.

The pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, and microcrystalline. Contains cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It also includes diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, or lactose. ), gelatin, etc., and may include lubricants such as magnesium stearate and talc. Oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc., and may include diluents such as water and liquid paraffin, humectants, sweeteners, fragrances, and preservatives. Parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, and vegetable oils such as olive oil. Includes injectable esters such as oil and ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.

The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, degree of disease, form of the active ingredient, route and period of administration, and can be appropriately adjusted depending on the patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.01 to 100 mg/kg, and the administration may be administered once a day or in divided doses. Additionally, the pharmaceutical composition of the present invention may contain the active ingredient at a weight percentage of 0.001 to 90% based on the total weight of the composition.

The pharmaceutical composition of the present invention is administered to mammals such as rats, mice, livestock, and humans by various routes, for example, orally, through the skin, abdominal cavity, rectum, or intravenously, into muscle, subcutaneously, intrauterine dura, or intracerebroventricularly. It can be administered by injection.

Hereinafter, the present invention will be described in more detail through synthesis examples, examples, and experimental examples. However, the following synthesis examples, examples, and experimental examples are for illustrating the present invention, and the scope of the present invention is not limited thereto.

Synthesis Example 1. General method of ketone → oxime conversion (Synthesis Method A [Method A])

<Synthesis Formula 1>

After dissolving the ketone compound synthesized by a known method in ethanol (50 volumes), hydroxylamine hydrochloride and (10 equivalents) caustic soda aqueous solution (1N aqueous solution, 5 equivalents) were added and refluxed and stirred for 3 to 5 hours. After completion of the reaction, the reaction solution was concentrated, water (100 volumes) was added, and then extracted with ethyl acetate (50 volumes x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain the target compound.

Example 1. (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone oxime

[(3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone oxime]

<Scheme 1>

^1H NMR (400 MHz, DMSO-d ₆ ) d.9.72 (s, 1H), 7.57 (s, 2H), 7.32 (ddd, J = 8.8, 7.4, 1.8 Hz, 1H), 7.16 (dd, J = 7.5, 1.7 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.92 (td, J = 7.4, 1.2 Hz, 1H), 2.47 (q, J = 7.5 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₇ H ₁₄ Br ₂ NO ₃ ] ⁺ (M+H) ⁺ : 437.9, observed: 437.9.

Example 2. (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone O-methyl oxime

[(3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone O-methyl oxime]

<Scheme 2>

In Example 1, O-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride, and the target compound was obtained by treatment according to the synthesis method (Method A).

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.46 (s, 1H), 7.60 (d, J = 13.7 Hz, 3H), 7.29 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.18 ( t, J = 7.4 Hz, 1H), 7.12 - 7.03 (m, 1H), 3.95 (d, J = 3.1 Hz, 3H), 2.59 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₈ H ₁₆ Br ₂ NO ₃ ] ⁺ (M+H) ⁺ : 451.9, observed: 451.7

Example 3. (6-Chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime

[(6-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime]

<Scheme 3>

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.59 (s, 1H), 10.31 (s, 1H), 7.57 (s, 2H), 7.23 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.1, 2.1 Hz, 1H), 2.51 - 2.44 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₇ H ₁₃ Br ₂ ClNO ₃ ] ⁺ (M+H) ⁺ : 471.9, observed: 471.8

Example 4. (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-methylbenzofuran-3-yl)methanone oxime

[(3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-methylbenzofuran-3-yl)methanone oxime]

<Scheme 4>

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.52 (s, 1H), 9.60 (s, 1H), 7.60 (s, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.74 (dd, J = 7.9, 1.7 Hz, 1H), 2.47 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.06 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₈ H ₁₆ Br ₂ NO ₃ ] ⁺ (M+H) ⁺ : 451.9, observed: 451.9.

Example 5. (7-Chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime

[(7-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime]

<Scheme 5>

^1H NMR (400 MHz, DMSO-d ₆ ) d 9.58 (s, 1H), 7.52 (d, J = 9.4 Hz, 3H), 7.18 (dd, J = 7.6, 1.7 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 2.47 (d, J = 7.5 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₇ H ₁₃ Br ₂ ClNO ₃ ] ⁺ (M+H) ⁺ : 471.9, observed: 471.8.

Example 6. (7-Bromo-2-ethylbenbofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime

[(7-bromo-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime]

<Scheme 6>

MS (ESI, LR) Calculated for [C ₁₇ H ₁₃ Br ₃ NO ₃ ] ⁺ (M+H) ⁺ : 515.8, observed: 515.9.

Example 7. (2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime

[(2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime]

<Scheme 7>

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.02 (s, 1H), 9.69 (s, 1H), 7.78 (s, 2H), 7.31 (ddd, J = 8.9, 7.4, 1.8 Hz, 1H), 7.14 (dd, J = 7.6, 1.8 Hz, 1H), 7.00 (dd, J = 8.3, 1.2 Hz, 1H), 6.91 (td, J = 7.4, 1.2 Hz, 1H), 2.47 (d, J = 7.6 Hz) , 2H), 1.06 (t, J = 7.6 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₇ H ₁₄ I ₂ NO ₃ ] ⁺ (M+H) ⁺ : 533.9, observed: 533.8.

Example 8. (6-Chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime

[(6-chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime]

<Scheme 8>

MS (ESI, LR) Calculated for [C ₁₇ H ₁₃ ClI ₂ NO ₃ ] ⁺ (M+H) ⁺ : 567.9, observed: 567.7.

Example 9. (5-Chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime

[(5-chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime]

<Scheme 9>

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.05 (s, 1H), 7.78 (s, 2H), 7.36 (dd, J = 8.7, 2.7 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 2.49 (d, J = 7.3 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₇ H ₁₃ ClI ₂ NO ₃ ] ⁺ (M+H) ⁺ : 567.9, observed: 567.7.

Example 10. (2-ethyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime

[(2-ethyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime]

<Scheme 10>

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.03 (s, 1H), 9.44 (s, 1H), 7.81 (d, J = 4.6 Hz, 2H), 7.15 - 7.07 (m, 1H), 6.95 ( d, J = 2.2 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 2.50 - 2.42 (m, 2H), 2.22 (s, 2H), 1.07 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₈ H ₁₆ I ₂ NO ₃ ] ⁺ (M+H) ⁺ : 547.9, observed: 547.8.

Synthesis Example 2. General method for synthesizing sulfonamino-oxime compounds

<Synthetic formula 2>

Step 1) / Step 2) (Synthesis Method B [Method B])

Compound A ( compound A ) synthesized by a known method ( Nat. Struct. Mol. Biol. 2004 , 11 , 730-737) was dissolved in N,N-dimethylformamide (20 volumes) and then 4 equivalents of the corresponding amine were added. It was stirred at room temperature for 2-4 hours. After completion of the reaction, 6 equivalents of sodium ethanethiolate (NaSEt) was added to the reaction solution and stirred at room temperature for 4-6 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (20 volumes) was added and the reaction solution was concentrated. Water (50 volumes) was added to the concentrate and extracted with ethyl acetate (50 volumes ) was obtained.

Step 3 (Synthesis Method A [Method A])

Compound B was treated using method A to obtain the target compound C.

Example 11. 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide

[3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide]

<Scheme 11>

Compound 11-1

Compound A was reacted using method B to obtain intermediate compound 11-1 .

^1H NMR (400 MHz, DMSO-d ₆ ) d 8.06 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 5.2 Hz, 2H), 7.77 (ddd, J = 8.3, 3.2, 1.6 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 2.86 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₇ H ₁₄ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 501.9, observed: 501.9.

Compound 11

Compound 11-1 was treated using Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.61 (s, 1H), 10.47 (s, 1H), 7.58 (s, 2H), 7.46 - 7.44 (m, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 8.0, 1.8 Hz, 1H), 2.48 - 2,43 (m, 2H), 1.10 - 1.04 (m, 3H).

MS (ESI, LR) Calculated for [C ₁₇ H ₁₅ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 516.9, observed: 516.8.

Example 12. 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-methylbenzofuran-6-sulfonamide

[3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-methylbenzofuran-6-sulfonamide]

<Scheme 12>

Compound 12-1

Compound A was reacted using method B to obtain intermediate compound 12-1 .

^1H NMR (400 MHz, DMSO-d ₆ ) d 8.03 (d, J = 1.5 Hz, 1H), 7.97 (d, J = 5.2 Hz, 2H), 7.71 (dd, J = 8.3, 1.6 Hz, 1H) , 7.66 (d, J = 8.3 Hz, 1H), 2.84 (q, J = 7.5 Hz, 2H), 2.43 (d, J = 5.0 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₈ H ₁₆ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 515.9, observed: 515.7.

Compound 12

Compound 12-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.62 (s, 1H), 10.53 (s, 1H), 7.53 (d, J = 4.2 Hz, 3H), 7.44 (d, J = 7.9 Hz, 1H) , 7.41 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 7.9, 1.8 Hz, 1H), 2.58 - 2.52 (m, 2H), 2.45 (d, J = 5.1 Hz, 3H), 1.12 - 1.05 (m, 3H).

MS (ESI, LR) Calculated for [C ₁₈ H ₁₇ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 530.9, observed: 530.8.

Example 13. 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N,N-dimethylbenzofuran-6-sulfonamide

[3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N,N-dimethylbenzofuran-6-sulfonamide]

<Scheme 13>

Compound 13-1

Compound A was reacted using method B to obtain intermediate compound 13-1 .

MS (ESI, LR) Calculated for [C ₁₇ H ₁₅ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 516.9, observed: 516.8.

Compound 13

Compound 13-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.60 (s, 1H), 7.48 (d, J = 6.5 Hz, 3H), 7.34 (d, J = 1.8 Hz, 1H), 7.27 (dd, J = 7.9, 1.8 Hz, 1H), 2.65 (s, 6H), 2.55 (q, J = 7.5 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₉ H ₁₉ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 544.9, observed: 544.6.

Example 14. 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-N,N,2-triethylbenzofuran-6-sulfonamide

[3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-N,N,2-triethylbenzofuran-6-sulfonamide]

<Scheme 14>

Compound 14-1

Compound A was reacted using method B to obtain intermediate compound 14-1 .

MS (ESI, LR) Calculated for [C ₂₁ H ₂₂ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 558.0, observed: 558.0.

Compound 14

Compound 14-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.62 (s, 1H), 10.53 (s, 1H), 7.51 (s, 2H), 7.43 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.0, 1.8 Hz, 1H), 3.22 (q, J = 7.1 Hz, 4H), 2.54 (d, J = 7.5 Hz, 2H), 1.13 - 0.98 ( m, 9H).

MS (ESI, LR) Calculated for [C ₂₁ H ₂₃ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 573.0, observed: 572.9.

Example 15. (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(morpholinosulfonyl)benzofuran-3-yl)methanone oxime

[(3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(morpholinosulfonyl)benzofuran-3-yl)methanone oxime]

<Scheme 15>

Compound 15-1

Compound A was reacted using method B to obtain intermediate compound 15-1 .

^1H NMR (400 MHz, DMSO-d ₆ ) d 8.06 (d, J = 1.5 Hz, 1H), 7.96 (s, 2H), 7.74 (d, J = 8.3 Hz, 1H), 7.66 (dd, J = 8.4, 1.6 Hz, 1H), 3.67 - 3.59 (m, 5H), 2.90 (t, J = 4.7 Hz, 4H), 2.84 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₂₁ H ₁₉ Br ₂ NNaO ₆ S] ⁺ (M+Na) ⁺ : 593.9, observed: 594.0.

Compound 15

Compound 15-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.65 (s, 2H), 7.53 - 7.48 (m, 3H), 7.33 (d, J = 1.8 Hz, 1H), 7.27 (dd, J = 7.9, 1.9 Hz, 1H), 3.73 - 3.60 (m, 4H), 2.92 (dd, J = 6.0, 3.4 Hz, 4H), 2.56 (q, J = 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H) ).

MS (ESI, LR) Calculated for [C ₂₁ H ₂₁ Br ₂ N ₂ O ₆ S] ⁺ (M+H) ⁺ : 585.9, observed: 586.8.

Example 16. N-Cyclopropyl-3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide

[N-cyclopropyl-3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide]

<Scheme 16>

Compound 16-1

Compound A was reacted using method B to obtain intermediate compound 16-1 .

MS (ESI, LR) Calculated for [C ₂₀ H ₁₈ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 541.9, observed: 541.4.

Compound 16

Compound 16-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.62 (s, 1H), 10.52 (s, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.54 (s, 2H), 7.47 - 7.42 ( m, 2H), 7.33 (dd, J = 7.9, 1.8 Hz, 1H), 2.54 (t, J = 7.5 Hz, 2H), 2.16 (tt, J = 6.8, 3.4 Hz, 1H), 1.07 (t, J) = 7.5 Hz, 3H), 0.52 (td, J = 7.0, 4.7 Hz, 2H), 0.41 (q, J = 3.4 Hz, 2H).

MS (ESI, LR) Calculated for [C ₂₀ H ₁₉ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 556.9, observed: 556.6.

Example 17. N-(Cyclopropylmethyl)-3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide

[N-(cyclopropylmethyl)-3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide]

<Scheme 17>

Compound 17-1

Compound A was reacted using method B to obtain intermediate compound 17-1 .

MS (ESI, LR) Calculated for [C ₂₁ H ₂₀ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 555.9, observed: 556.0.

Compound 17

Compound 17-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 10.40 (s, 2H), 7.74 (t, J = 5.9 Hz, 1H), 7.44 (s, 2H), 7.35 - 7.29 (m, 2H), 7.24 ( dd, J = 7.9, 1.8 Hz, 1H), 2.61 (t, J = 6.4 Hz, 2H), 2.44 (d, J = 7.5 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H), 0.80 - 0.65 (m, 1H), 0.33 - 0.20 (m, 2H), 0.05 - 0.01 (m, 2H).

MS (ESI, LR) Calculated for [C ₂₁ H ₂₂ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 570.9, observed: 571.1.

Example 18. 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-(2-hydroxyethyl)benzofuran-6-sulfonamide

[3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-(2-hydroxyethyl)benzofuran-6-sulfonamide]

<Scheme 18>

Compound 18-1

Compound A was reacted using method B to obtain intermediate compound 18-1 .

^1H NMR (400 MHz, DMSO-d ₆ ) d 8.06 (d, J = 1.7 Hz, 1H), 7.97 (s, 2H), 7.74 (dd, J = 8.2, 1.6 Hz, 1H), 7.70 - 7.64 ( m, 2H), 3.37 (t, J = 6.3 Hz, 2H), 2.88 - 2.76 (m, 4H), 1.29 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₉ H ₁₈ Br ₂ NO ₆ S] ⁺ (M+H) ⁺ : 545.9, observed: 545.8.

Compound 18

Compound 18-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.59 (s, 1H), 10.51 (s, 1H), 7.69 (t, J = 6.0 Hz, 1H), 7.53 (s, 2H), 7.45 - 7.39 ( m, 2H), 7.33 (dd, J = 7.9, 1.8 Hz, 1H), 4.71 (s, 1H), 3.40 (q, J = 5.8 Hz, 2H), 2.83 (q, J = 6.3 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 1.08 (t, J = 7.6 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₉ H ₁₉ Br ₂ N ₂ O ₆ S] ⁺ (M+H) ⁺ : 560.9, observed: 560.8.

Example 19. 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N,N-dipropylbenzofuran-6-sulfonamide

[3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N,N-dipropylbenzofuran-6-sulfonamide]

<Scheme 19>

Compound 19-1

Compound A was reacted using method B to obtain intermediate compound 19-1 .

^1H NMR (400 MHz, DMSO-d ₆ ) d 8.07 (d, J = 1.6 Hz, 1H), 7.86 (s, 2H), 7.70 (dd, J = 8.3, 1.6 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 3.09 - 3.02 (m, 4H), 2.84 (q, J = 7.5 Hz, 2H), 1.47 (p, J = 7.4 Hz, 4H), 1.29 (t, J = 7.5 Hz, 3H), 0.82 (t, J = 7.3 Hz, 6H).

MS (ESI, LR) Calculated for [C ₂₃ H ₂₆ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 586.0, observed: 586.1

Compound 19

Compound 19-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.62 (s, 1H), 10.53 (s, 1H), 7.53 (s, 2H), 7.43 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 7.9, 1.8 Hz, 1H), 3.15 - 3.02 (m, 4H), 2.58 - 2.52 (m, 2H), 1.50 (h, J = 7.4 Hz, 4H) ), 1.07 (t, J = 7.6 Hz, 3H), 0.83 (t, J = 7.3 Hz, 6H).

MS (ESI, LR) Calculated for [C ₂₃ H ₂₇ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 601.0, observed: 600.9.

Example 20. (6-(azetidin-1-ylsulfonyl)-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime

[(6-(azetidin-1-ylsulfonyl)-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime]

<Scheme 20>

Compound 20-1

Compound A was reacted using method B to obtain intermediate compound 20-1 .

^1H NMR (400 MHz, DMSO-d ₆ ) d 8.11 (d, J = 1.5 Hz, 1H), 8.00 (s, 2H), 7.78 (d, J = 8.2 Hz, 1H), 7.73 (dd, J = 8.3, 1.5 Hz, 1H), 3.70 (t, J = 7.6 Hz, 4H), 2.85 (q, J = 7.5 Hz, 2H), 1.96 (dq, J = 16.1, 8.0 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₂₀ H ₁₈ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 541.9, observed: 541.5.

Compound 20

Compound 20-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.67 (s, 1H), 7.58 - 7.49 (m, 3H), 7.40 (d, J = 1.8 Hz, 1H), 7.33 (dd, J = 7.9, 1.8 Hz, 1H), 3.72 (t, J = 7.6 Hz, 4H), 2.56 (q, J = 7.4 Hz, 2H), 2.04 (p, J = 7.6 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H).

MS (ESI, LR) Calculated for [C ₂₀ H ₁₉ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 556.9, observed: 556.9.

Example 21. (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(pyrrolidin-1-ylsulfonyl)benzofuran-3-yl)methanone oxime

[(3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(pyrrolidin-1-ylsulfonyl)benzofuran-3-yl)methanone oxime]

<Scheme 21>

Compound 21-1

Compound A was reacted using method B to obtain intermediate compound 21-1 .

^1H NMR (400 MHz, DMSO-d ₆ ) d 8.08 (d, J = 1.5 Hz, 1H), 7.90 (s, 2H), 7.73 (dd, J = 8.2, 1.5 Hz, 1H), 7.71 - 7.65 ( m, 1H), 3.19 (d, J = 6.5 Hz, 4H), 2.83 (q, J = 7.5 Hz, 2H), 1.64 (td, J = 8.4, 4.9 Hz, 4H), 1.29 (t, J = 7.5) Hz, 3H).

MS (ESI, LR) Calculated for [C ₂₁ H ₂₀ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 555.9, observed: 555.8.

Compound 21

Compound 21-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.58 (d, J = 11.2 Hz, 1H), 7.50 (s, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.33 (dd, J = 7.9, 1.8 Hz, 1H), 3.19 (q, J = 4.7 Hz, 4H), 2.58 - 2.51 (m, 2H), 1.69 (dq, J = 9.9, 5.0 Hz, 4H), 1.07 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₂₁ H ₂₁ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 570.9, observed: 571.3.

Example 22. 4-((3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-yl)sulfonyl)piperazine- 2-on

[4-((3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-yl)sulfonyl)piperazin-2-one]

<Scheme 22>

Compound 22-1

Compound A was reacted using method B to obtain intermediate compound 22-1 .

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.17 (s, 1H), 8.04 (s, 1H), 7.98 (s, 2H), 7.73 (s, 1H), 3.55 (s, 2H), 3.25 - 3.16 (m, 4H), 2.84 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H).

MS (ESI, LR) Calculated for [C ₂₁ H ₁₈ Br ₂ N ₂ NaO ₆ S] ⁺ (M+Na) ⁺ : 606.9, observed: 607.0.

Compound 22

Compound 22-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) 10.68 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.48 (s, 2H), 7.38 (d, J = 1.8 Hz, 1H), 7.34 (dd, J = 7.9, 1.8 Hz, 1H), 3.51 (s, 2H), 3.27 - 3.13 (m, 4H), 2.60 - 2.53 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H) .

MS (ESI, LR) Calculated for [C ₂₁ H ₂₀ Br ₂ N ₃ O ₆ S] ⁺ (M+H) ⁺ : 599.9, observed: 599.9.

Example 23. 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-N,2-diethylbenzofuran-6-sulfonamide

[3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-N,2-diethylbenzofuran-6-sulfonamide]

<Scheme 23>

Compound 23-1

Compound A was reacted using method B to obtain intermediate compound 23-1 .

^1H NMR (400 MHz, DMSO-d ₆ ) d 8.04 (d, J = 1.5 Hz, 1H), 7.97 (s, 2H), 7.73 (dd, J = 8.3, 1.6 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.63 (t, J = 5.7 Hz, 1H), 2.93 - 2.73 (m, 4H), 1.29 (t, J = 7.5 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₉ H ₁₈ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 529.9, observed: 530.0.

Compound 23

Compound 23-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.62 (s, 1H), 10.51 (s, 1H), 7.64 (t, J = 5.7 Hz, 1H), 7.53 (s, 2H), 7.45 - 7.40 ( m, 2H), 7.32 (dd, J = 7.9, 1.8 Hz, 1H), 2.84 (qd, J = 7.2, 5.6 Hz, 2H), 2.57 - 2.51 (m, 2H), 1.07 (t, J = 7.5 Hz) , 3H), 1.00 (t, J = 7.2 Hz, 3H).

MS (ESI, LR) Calculated for [C ₁₉ H ₁₉ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 544.9, observed: 544.8.

Example 24. 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-propylbenzofuran-6-sulfonamide

[3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-propylbenzofuran-6-sulfonamide]

<Scheme 24>

Compound 24-1

Compound A was reacted using method B to obtain intermediate compound 24-1 .

^1H NMR (400 MHz, DMSO-d ₆ ) d 8.04 (d, J = 1.6 Hz, 1H), 7.97 (s, 2H), 7.73 (dd, J = 8.2, 1.6 Hz, 1H), 7.68 - 7.62 ( m, 2H), 2.84 (q, J = 7.5 Hz, 2H), 2.72 (td, J = 7.1, 5.9 Hz, 2H), 1.38 (h, J = 7.3 Hz, 2H), 1.29 (t, J = 7.5) Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H).

MS (ESI, LR) Calculated for [C ₂₀ H ₂₀ Br ₂ NO ₅ S] ⁺ (M+H) ⁺ : 543.9, observed: 544.6.

Compound 24

Compound 24-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.

^1H NMR (400 MHz, DMSO-d ₆ ) d 10.51 (s, 1H), 7.67 (t, J = 5.9 Hz, 1H), 7.53 (s, 2H), 7.45 - 7.39 (m, 2H), 7.32 ( dd, J = 8.0, 1.7 Hz, 1H), 2.75 (td, J = 7.2, 5.8 Hz, 2H), 2.55 (d, J = 7.5 Hz, 2H), 1.40 (h, J = 7.3 Hz, 2H), 1.07 (t, J = 7.6 Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H).

MS (ESI, LR) Calculated for [C ₂₀ H ₂₁ Br ₂ N ₂ O ₅ S] ⁺ (M+H) ⁺ : 558.9, observed: 558.4.

Experimental Example 1. HSP47 activity evaluation

Fibrils were formed by adding 180 ul of PBS (phosphate-buffered saline, pH 7.4) solution to 20 ul of collagen solution (UK) dissolved in an acidic solution, and this was measured at a wavelength of 340 nm. HSP47 activity was evaluated as the degree to which fibril formation was inhibited by adding HSP47 protein (GenScript US) at a concentration of 9.45 μg/ml. Test substances were included at concentrations of 100 μM to 1 μM, and the degree of HSP47 inhibition was expressed as a percentage.

Table 1 below lists the results of inhibition of HSP47 protein function.

Experimental Example 2. Sirius red assay

After culturing lung epithelial cells (A549 cells), liver stellate LX-2 cells (Elabscience, CH), or skin KEL FIB (ATCC, US) cells in a 24-well tissue culture plate for 18 hours, TGF-beta After treatment with 10 ng/ml, the cells were incubated with the test substance for 24 hours. The cells were washed with PBS, fixed with Bouin's solution, and washed twice using distillation. After staining the fixed cells with Sirius red for 2 hours, changes in cell shape were observed, washed with HCl 0.01 N solution, and Sirius red bound to collagen was extracted with NaOH 0.1 N solution. and then quantified at a wavelength of 570 nm. The collagen production inhibition efficacy of each test substance is expressed as a percentage in Table 1 below.

test substance HSP47% inhibition at 100 uM HSP47 inhibition
Active EC ₅₀ (uM) A549 cell fibrosis inhibition EC ₅₀ (uM) LX-2 cell fibrosis inhibition EC ₅₀ (uM) One 26.18 - - - 2 0 - - - 3 68.32 68.86 - - 4 64.72 95.1 - 11.59 5 53.3 - - - 6 31.48 - - - 7 115.9 29.59 10.4 - 8 30.45 - 9.29 - 9 53.03 47.08 - - 10 43.03 - 5.32 - 11 9.95 151.8 - - 12 75.12 81.2 - - 13 84.43 141.7 9.25 - 14 79.46 38.04 - - 15 87.49 50.04 - - 16 87.49 58.44 - - 17 119.5 40.2 - - 18 53.27 123.9 - - 19 15.95 - - - 20 88.92 - - - 21 89.96 - - - 22 54.95 - - - 23 82.05 - - - 24 89.45 - - -

The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive. For example, each component described as unitary may be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.

The scope of the present invention is indicated by the claims described below, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.

Claims (13)

Benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the following formula (Ⅰ), its hydrate, its solvate, or its pharmaceutically acceptable salt: <Formula Ⅰ>

In the above equation, R ¹ is hydrogen, C ₁ -C ₆ straight or branched chain alkyl, or halogen, R ² is hydrogen, C ₁ -C ₆ straight or branched chain alkyl, halogen, or SO ₂ NR ^a R ^b , At this time, R ^a and R ^b are independently hydrogen, C ₁ -C ₆ straight or branched chain alkyl, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ cycloalkyl substitution. is C ₁ -C ₃ alkyl, or R ^a and R ^b are linked to each other to form a 4- to 7-membered heterocycloalkyl containing 0 to 2 heteroatoms with N connected to SO ₂ , wherein C forming the heterocycloalkyl is O. Substituted or not substituted, R ³ is hydrogen or halogen, R ⁴ and R ⁵ are independently halogen, R ⁶ is hydrogen or C ₁ -C ₆ straight or branched chain alkyl. The benzofuranyl hydroxyphenyl methanone oxime derivative compound according to claim 1, wherein R ¹ is hydrogen, methyl, or Cl, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein R ² is hydrogen, methyl, Cl, or SO ₂ NR ^a R ^b , In this case, R ^a and R ^b are independently hydrogen, methyl, ethyl, propyl, hydroxyethyl, cyclopropyl, or cyclopropylmethyl, or A benzofuranyl hydroxyphenyl methanone oxime derivative compound, characterized in that R ^a and R ^b include N linked to SO ₂ to form azetidinyl, pyrrolidinyl, morpholino, or piperazinone, a hydrate thereof , its solvate or its pharmaceutically acceptable salt. The benzofuranyl hydroxyphenyl methanone oxime derivative compound according to claim 1, wherein R ³ is hydrogen, Cl, or Br, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The benzofuranyl hydroxyphenyl methanone oxime derivative compound according to claim 1, wherein R ⁴ and R ⁵ are independently Br or I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The benzofuranyl hydroxyphenyl methanone oxime derivative compound according to claim 1, wherein R ⁶ is hydrogen or methyl, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The benzofuranyl hydroxyphenyl methanone oxime derivative according to claim 1, wherein the benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by Formula I is any one selected from the group consisting of the following compounds. Compound, hydrate thereof, solvate thereof or pharmaceutically acceptable salt thereof: [1] (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone oxime, [2] (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone O-methyl oxime, [3] (6-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime, [4] (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-methylbenzofuran-3-yl)methanone oxime, [5] (7-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime, [6] (7-bromo-2-ethylbenbofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime, [7] (2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime, [8] (6-chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime, [9] (5-chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime, [10] (2-ethyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone oxime, [11] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide, [12] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-methylbenzofuran-6-sulfonamide, [13] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N,N-dimethylbenzofuran-6-sulfonamide, [14] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-N,N,2-triethylbenzofuran-6-sulfonamide, [15] (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(morpholinosulfonyl)benzofuran-3-yl)methanone oxime, [16] N-cyclopropyl-3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide, [17] N-(cyclopropylmethyl)-3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-sulfonamide, [18] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-(2-hydroxyethyl)benzofuran-6-sulfonamide, [19] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N,N-dipropylbenzofuran-6-sulfonamide, [20] (6-(azetidin-1-ylsulfonyl)-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone oxime, [21] (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(pyrrolidin-1-ylsulfonyl)benzofuran-3-yl)methanone oxime, [22] 4-((3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethylbenzofuran-6-yl)sulfonyl)piperazine-2 -on, [23] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-N,2-diethylbenzofuran-6-sulfonamide, and [24] 3-((3,5-dibromo-4-hydroxyphenyl)(hydroxyimino)methyl)-2-ethyl-N-propylbenzofuran-6-sulfonamide. A pharmaceutical composition for preventing or treating HSP47-related diseases, comprising the derivative compound of any one of claims 1 to 7, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 8, wherein the HSP47-related disease is fibrosis or cancer. The pharmaceutical composition according to claim 9, wherein the fibrosis is at least one selected from the group consisting of liver cirrhosis, pulmonary fibrosis, keloid, hypertrophic scar, and renal fibrosis (glomerulosclerosis). The pharmaceutical composition according to claim 9, wherein the cancer is at least one selected from the group consisting of breast cancer, colon cancer, and cancer-related fibrosis. A pharmaceutical composition comprising the derivative compound of any one of claims 1 to 7, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. Method for producing a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the following formula I, comprising reacting a ketone compound of the formula I-1 with hydroxylamine (H ₂ NO-R ⁶ ) hydrochloride: <Formula Ⅰ-1>

<Formula Ⅰ>

In the above formula, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are the same as the definitions of Formula I of claim 1.