WO2023068852A1 - Benzothiophene-1,1-dioxide derivative compound as stat3 inhibitor, and use thereof - Google Patents

Benzothiophene-1,1-dioxide derivative compound as stat3 inhibitor, and use thereof Download PDF

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WO2023068852A1
WO2023068852A1 PCT/KR2022/016069 KR2022016069W WO2023068852A1 WO 2023068852 A1 WO2023068852 A1 WO 2023068852A1 KR 2022016069 W KR2022016069 W KR 2022016069W WO 2023068852 A1 WO2023068852 A1 WO 2023068852A1
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cancer
dioxidobenzo
thiophen
acetamide
acrylamide
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French (fr)
Korean (ko)
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심태진
김지훈
이준호
이민범
박영환
임재성
노준기
최누리
이혜원
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주식회사 프롬바이오
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/64—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • One object of the present invention is to provide a benzothiophene-1,1-dioxide derivative compound exhibiting STAT3 inhibitory activity and a method for preparing the same.
  • A is a 6-membered ring ⁇ wherein at least one H of the 6-membered ring is -H, -C 1-4 alkyl, -C 1-4 cyanoalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NR 1 R 2 , -OR 3 , halo, cycloalkyl, or heterocycloalkyl, or two adjacent substituents are linked together to form 6 can form a fused ring together with the original ring ⁇ ;
  • Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, -NR 1 R 2 , -OR 3 , or halo;
  • Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, or halo;
  • R A and R B are each independently -H or -C 1-4 alkyl
  • R 1 and R 2 are each independently -H or -C 1-4 alkyl
  • R 3 is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl.
  • the compound represented by Formula 1 may be a compound represented by Formula 3 below:
  • Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, -NR 1 R 2 , -OR 3 , or halo;
  • R 1 and R 2 are each independently -H or -C 1-4 alkyl
  • R 3 is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl;
  • the compound represented by Formula 1 may be selected from the group consisting of the following compounds. However, it is not limited thereto.
  • alkyl may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon in which they are bonded, unless otherwise specified.
  • C 1-4 alkyl may mean an alkyl containing 1 to 4 carbon atoms.
  • Non-cyclic alkyl may include, for example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc. Not limited to this.
  • Cyclic alkyl may be used interchangeably with "cycloalkyl” herein, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as examples. It doesn't work.
  • alkoxy can mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above.
  • C 1-4 alkoxy may mean C 1-4 alkyl-containing alkoxy, that is, -(OC 1-4 alkyl), and as an example, alkoxy is methoxy. ), ethoxy, n -propoxy, isopropoxy , n -butoxy, isobutoxy, sec - butoxy ), or tert -butoxy ( tert -butoxy), etc., but is not limited thereto.
  • halo can be F, Cl, Br, or I.
  • haloalkyl can mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo as defined herein.
  • haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n -butyl independently substituted with one or more halogens such as F, Cl, Br, or I .
  • aminoalkyl may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R").
  • R' and R" are each independently hydrogen , And C 1-4 It may be selected from the group consisting of alkyl, and the selected R' and R" may each independently be substituted or unsubstituted.
  • hydroxyalkyl may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH).
  • cyanoalkyl may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).
  • heterocycloalkyl may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated.
  • unsaturated it may be referred to as a heterocycloalkene.
  • a heterocycloalkyl can be a single ring or multiple rings such as spiro rings, bridged rings or fused rings.
  • heterocycloalkyl may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring
  • heterocycloalkyl includes pyrrolidine, piperidine, Dazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H )- Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, Thiophyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]hept
  • arene may mean an aromatic hydrocarbon ring.
  • Arenes can be monocyclic arenes or polycyclic arenes.
  • the number of ring carbon atoms of the arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less.
  • examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, terbenzene, quarterbenzene, quincbenzene, sexybenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like. Not limited.
  • aryl a residue obtained by removing one hydrogen atom from the above "arene" is referred to as "aryl".
  • heteroene may be an aromatic ring containing one or more of O, N, P, Si, and S as heterogeneous elements.
  • the number of ring carbon atoms of the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less.
  • Heteroarenes may be monocyclic heteroarenes or polycyclic heteroarenes.
  • Polycyclic heteroarenes may have, for example, a bicyclic or tricyclic structure.
  • heteroarenes examples include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, triazine, acridyl, pyridazine, pyrazine, and quinoline.
  • the term "enantiomer” means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included in the scope of the present invention.
  • the solid bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid bond representing the absolute configuration of the stereogenic center. or Wedge Dotted Combination can include
  • the compound of Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt".
  • a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt is a concentration that has a relatively non-toxic and harmless effective effect on patients, and any of the compounds represented by Formula 1 do not reduce the beneficial effects of the compound represented by Formula 1 by side effects caused by the salt. means any organic acid or inorganic acid addition salt of
  • Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used. However, it is not limited to these.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable for preparing a sodium, potassium, or calcium salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compounds of Formula 1 above.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group
  • other pharmaceutically acceptable salts of an amino group include hydrobromides, sulfates, hydrogen sulfates, phosphates, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p -toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a salt known to.
  • the present invention provides a use of a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 of the present invention exhibits inhibitory activity against STAT3, treatment of STAT3-related diseases, particularly cancer, fibrotic diseases, or autoimmune diseases Or it can be useful for prevention.
  • STAT3 is known to be involved in cancer, fibrotic disease, or autoimmune disease by acting as a transcription factor and regulating the expression of various genes, inhibiting STAT3 activity prevents cancer, fibrotic disease, inflammatory disease, or autoimmune disease or can be treated.
  • the cancer includes all "cancers” that can exhibit therapeutic or preventive effects due to inhibition of STAT3 activity, and may be solid cancers or hematological cancers.
  • cancers may be solid cancers or hematological cancers.
  • pseudomyxoma intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, head and neck cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal
  • the fibrotic disease refers to any disease caused by fibrosis or inflammation and damage caused by an inducing substance, and liver fibrosis (eg, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH)) ), pulmonary fibrosis, diabetic fibrosis, cardiac fibrosis, renal fibrosis, scleroderma, skeletal muscle fibrosis, intestinal fibrosis, pancreatic fibrosis, articular fibrosis, myelofibrosis, myocardial fibrosis, dermal fibrosis, elastic fibrosis, retroperitoneal fibrosis, cystic fibrosis, uterine fibrosis , And may be one or more selected from the group consisting of cellular fibrosis, but is not limited thereto.
  • liver fibrosis eg, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH)
  • the inflammatory disease or autoimmune disease refers to any disease caused by direct or indirect causes of an immune response to a diseased subject's own antigen, and includes psoriasis, atopic dermatitis, pneumonia, lymphadenitis, rheumatoid arthritis, and immune thrombocytopenia.
  • the pharmaceutical composition of the present invention may further contain at least one active ingredient in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the step of administering a therapeutically effective amount of the compound represented by Formula 1, its optical isomer, or its pharmaceutically acceptable salt to a subject in need thereof It provides a method for treating or preventing a STAT3-related disease, particularly cancer, fibrotic disease, or autoimmune disease, including.
  • the subject may be a mammal including a human.
  • therapeutically effective amount used in the present invention refers to an amount of the compound represented by Formula 1 effective for the treatment or prevention of STAT3-related diseases.
  • therapeutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type and severity of the subject, age, sex, type of disease, It may be determined according to the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, or may be administered sequentially or simultaneously with a commercially available therapeutic agent. And it can be single or multiple administrations. It is important to administer the amount that can obtain the maximum effect with the minimum amount without side effects in consideration of all the above factors, and can be easily determined by those skilled in the art.
  • the dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used even at a dose determined or higher.
  • the present invention is a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutical thereof for use in the preparation of a medicament for use in the treatment or prevention of STAT3-related diseases
  • Uses of the generally acceptable salts are provided.
  • the compound represented by Formula 1 for the preparation of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may be prepared as a combined preparation with other active agents to have a synergistic action of the active ingredients.
  • Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.
  • embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
  • "include” a certain component throughout the specification means that other components may be further included without excluding other components unless otherwise stated.
  • novel benzothiophene-1,1-dioxide derivative compounds of the present invention bind to the SH2 domain of STAT3 and show excellent STAT3-selective inhibitory activity, they can be very useful for preventing or treating STAT3-related diseases.
  • Figure 1 shows the effect of inhibiting the transcriptional activity of STAT3 induced by IL-6 of Example compounds.
  • Step 1a Preparation of Compound S1
  • step 1 The reaction of step 1 was carried out according to Scheme 1 and recrystallized from CH 2 Cl 2 / n -hexane (1:20) to obtain the title compound as a pale yellow solid (173.0 mg, 87%).
  • Example 22 N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-fluorophenyl)acrylamide ⁇ N-(1,1-Dioxidobenzo[ b Preparation of ]thiophen-6-yl)-2-(4-fluorophenyl)acrylamide ⁇
  • Example 28 2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide ⁇ 2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b Preparation of ]thiophen-6-yl)acrylamide ⁇
  • Example 33 N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acrylamide ⁇ N-(1,1-dioxidobenzo[ b Preparation of ]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acetamide ⁇
  • Example 37 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide ⁇ 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ b Preparation of ]thiophen-6-yl)acetamide ⁇
  • step 1 The reaction of step 1 was carried out according to Scheme 1 and purified by recrystallization with EtOAc and n -hexane to obtain the title compound as a yellow solid (359.6 mg, 97%).
  • Example 38 N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(2-fluorophenyl)acetamide ⁇ N-(1,1-dioxidobenzo[ b Preparation of ]thiophen-6-yl)-2-(2-fluorophenyl)acetamide ⁇
  • Example 39 2-(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)-N-(1,1-dioxidobenzo[ b ]thiophene-6-yl)acetamide ⁇ 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(1,1-dioxidobenzo[ b Preparation of ]thiophen-6-yl)acetamide ⁇
  • step 1 The reaction of step 1 was carried out according to Scheme 1 and purified by recrystallization with MeOH to obtain the title compound as a pale yellow solid (113.4 mg, 29%).
  • Example 40 2-(3,4-dimethylphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide ⁇ 2-(3,4-dimethylphenyl)-N-(1,1-dioxidobenzo[ b Preparation of ]thiophen-6-yl)acetamide ⁇
  • Example 41 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide ⁇ 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ b Preparation of ]thiophen-6-yl)acrylamide ⁇
  • Example 42 N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(2-fluorophenyl)acrylamide ⁇ N-(1,1-dioxidobenzo[ b Preparation of ]thiophen-6-yl)-2-(2-fluorophenyl)acrylamide ⁇
  • Stat3 Luciferase Reporter HEK293 Stable Cell Line (Cat# SL-0071-NP) containing the STAT3 reporter gene was purchased from Signosis and 10% FBS (Thermo fisher scientific, Cat# 26140-079), It was cultured in DMEM High Glucose (Thermo fisher scientific, Cat# 11995-073) medium supplemented with 1% penicillin/streptomycin (Thermo fisher scientific, Cat# 15140-122), and hygromycin was added at 100 ⁇ g/ml By treatment with a concentration of luciferase (luciferase) to obtain a stable expression clone (clone).
  • FBS Thermo fisher scientific, Cat# 26140-079
  • DMEM High Glucose Thermo fisher scientific, Cat# 11995-073
  • penicillin/streptomycin Thermo fisher scientific, Cat# 15140-122
  • hygromycin was added at 100

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Abstract

The present invention pertains to a benzothiophene-1,1-dioxide derivative compound having STAT3 inhibitory activity, and a use thereof. The benzothiophene-1,1-dioxide derivative compounds according to the present invention bind to SH2 domains of STAT3 and exhibit excellent STAT3-selective inhibitory activities, and can thus be very useful for preventing or treating STAT3-related diseases.

Description

STAT3 저해제로서 벤조싸이오펜-1,1-다이옥사이드 유도체 화합물 및 이의 용도Benzothiophene-1,1-dioxide derivative compounds and their uses as STAT3 inhibitors
본 발명은 STAT3 저해 활성을 갖는 벤조싸이오펜-1,1-다이옥사이드 유도체 화합물 및 이의 용도에 관한 것이다.The present invention relates to a benzothiophene-1,1-dioxide derivative compound having STAT3 inhibitory activity and a use thereof.
STAT3(signal transducer and activator of transcription 3)는 STAT 단백질 패밀리 중 하나이며, 여러 사이토카인 및 성장인자들의 작용을 매개하는 신호전달 중간체로 알려져 있다. STAT3는 외부 신호를 핵 내에 전달하는 전사 인자(transcription factor)로 작용하여 다양한 하위 유전자들의 발현을 조절한다. 예를 들어, IL-6가 IL-6 수용체에 결합하면, gp-130 수용체가 유인되어 IL-6/IL-6α 수용체/gp-130 복합체를 형성하고, 이때 세포질 내의 JAK 키나아제들(JAK1, JAK2, JAK3 및 Tyk2)이 gp-130 수용체의 세포질 부분으로 유인되어 활성화된다. 그 다음, 세포질에 존재하는 STAT3 단백질이 수용체로 유인되면서 JAK 키나아제에 의해 인산화된다. 인산화된 STAT3(p-STAT3) 단백질은 다른 STAT 단백질과 동종이합체(homo-dimer) 또는 이종이합체(hetero-dimer)를 형성하고, 핵내 DNA와 결합하여 세포의 성장(proliferation)과 분화(differentiation) 등에 관여하는 광범위한 유전자들의 발현을 유도한다.STAT3 (signal transducer and activator of transcription 3) is a member of the STAT protein family and is known as a signal transduction intermediate that mediates the action of various cytokines and growth factors. STAT3 acts as a transcription factor that transmits external signals into the nucleus and regulates the expression of various subgenes. For example, when IL-6 binds to the IL-6 receptor, the gp-130 receptor is attracted to form an IL-6/IL-6α receptor/gp-130 complex, at which time JAK kinases (JAK1, JAK2) in the cytoplasm , JAK3 and Tyk2) are attracted to the cytoplasmic portion of the gp-130 receptor and activated. Then, STAT3 protein present in the cytoplasm is attracted to the receptor and phosphorylated by JAK kinase. Phosphorylated STAT3 (p-STAT3) protein forms homo-dimers or hetero-dimers with other STAT proteins, binds to DNA in the nucleus, and plays a role in cell growth and differentiation. It induces the expression of a wide range of involved genes.
STAT3는 매우 다양한 질환들과 연관되어 있음이 보고되고 있다. 특히 IL-6에 의해 유도되는 신호전달체계와 염증성 질환, 자가면역질환 또는 섬유화 질환에 대한 관련성은 잘 알려져 있는 사실이다(Cell, Akira et al., 1994, 76(2): 253). 구체적으로, STAT3는 IL-6에 의해 활성화되어 류마티스 관절염(Rheumatology, Pia Isomaki et al., 2015, 54(6): 1103), 건선(Int J Mol Sci., Enzo Calautti et al., 2018, 19(1): 171) 등 자가면역질환의 발병과 밀접한 연관이 있는 것으로 보고되었으며, 섬유화(O'Reilly, Steven, et al., 2014, 289(14): 9952-9960) 질환과도 밀접한 연관이 있는 것으로 알려지고 있다. 또한, 최근 임상 연구 결과에 따르면, 전립선암, 위암, 유방암, 폐암, 췌장암, 신장암, 자궁암, 난소암, 두경부암 등의 고형암 및 급성/만성 백혈병, 다발성 골수종 등의 혈액암 환자에서 STAT3 단백질이 지속적으로 활성화되는 것으로 보고되었으며(Cancer Res., Masuda et al., 2002, 62(12): 3351; Blood, Mustafa Benekli et al., 2002, 99(1): 252; Int J Oncol., Yuichi Yakata et al., 2007, 30(2): 437), 다양한 암 세포주에서 STAT3 억제에 의한 세포사멸이 확인되어 매우 유망한 항암 타겟으로 여겨지고 있다.It has been reported that STAT3 is associated with a wide variety of diseases. Particularly, the relationship between the signal transduction system induced by IL-6 and inflammatory diseases, autoimmune diseases, or fibrotic diseases is well known (Cell, Akira et al., 1994, 76(2): 253). Specifically, STAT3 is activated by IL-6 to prevent rheumatoid arthritis (Rheumatology, Pia Isomaki et al., 2015, 54(6): 1103), psoriasis (Int J Mol Sci., Enzo Calautti et al., 2018, 19 (1): 171) has been reported to be closely related to the onset of autoimmune diseases, and it is also closely related to fibrosis (O'Reilly, Steven, et al., 2014, 289(14): 9952-9960) disease. It is known that there are In addition, according to the results of recent clinical studies, STAT3 protein is found in patients with solid cancers such as prostate cancer, stomach cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, uterine cancer, ovarian cancer, head and neck cancer, and blood cancer patients such as acute/chronic leukemia and multiple myeloma. It has been reported to be continuously activated (Cancer Res., Masuda et al., 2002, 62(12): 3351; Blood, Mustafa Benekli et al., 2002, 99(1): 252; Int J Oncol., Yuichi Yakata et al., 2007, 30(2): 437), apoptosis by STAT3 inhibition was confirmed in various cancer cell lines, and it is considered a very promising anti-cancer target.
따라서, STAT3 활성을 선택적으로 억제함으로써 STAT3 관련 질환의 치료에 유용하게 활용될 수 있는 신규 화합물에 대한 미충족된 수요가 증대되고 있다.Therefore, there is an increasing unmet need for novel compounds that can be usefully utilized for the treatment of STAT3-related diseases by selectively inhibiting STAT3 activity.
본 발명의 하나의 목적은, STAT3 억제 활성을 나타내는 벤조싸이오펜-1,1-다이옥사이드 유도체 화합물 및 이의 제조방법을 제공하는 것이다.One object of the present invention is to provide a benzothiophene-1,1-dioxide derivative compound exhibiting STAT3 inhibitory activity and a method for preparing the same.
본 발명의 다른 하나의 목적은, 본 발명에 따른 벤조싸이오펜-1,1-다이옥사이드 유도체의 의약용도를 제공하는 것이다.Another object of the present invention is to provide a medicinal use of the benzothiophene-1,1-dioxide derivative according to the present invention.
상기 목적을 달성하기 위하여, 본 발명자들이 연구 노력한 결과, 아래에서 언급하는 화학식 1로 표시되는 벤조티오펜-1,1-다이옥사이드 유도체 화합물들이 STAT3 활성을 저해하는 것을 확인함으로써 본 발명을 완성하였다.In order to achieve the above object, as a result of research efforts by the present inventors, the present invention was completed by confirming that benzothiophene-1,1-dioxide derivative compounds represented by Formula 1 below inhibit STAT3 activity.
벤조싸이오펜-1,1-다이옥사이드 유도체 화합물Benzothiophene-1,1-dioxide derivative compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2022016069-appb-img-000001
Figure PCTKR2022016069-appb-img-000001
상기 화학식 1에서,In Formula 1,
L은 -CH2- 또는 -C(=CRARB)-이고;L is -CH 2 - or -C(=CR A R B )-;
RA 및 RB는 각각 독립적으로 -H 또는 -C1-4알킬이고;R A and R B are each independently -H or -C 1-4 alkyl;
A는 6원 고리이고 {여기서, 상기 6원 고리의 하나 이상의 H는 -H, -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 할로, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있고, 또는 인접한 2개의 치환기들은 서로 연결되어 6원 고리와 함께 융합 고리를 형성할 수 있음};A is a 6-membered ring {wherein at least one H of the 6-membered ring is -H, -C 1-4 alkyl, -C 1-4 cyanoalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NR 1 R 2 , -OR 3 , halo, cycloalkyl, or heterocycloalkyl, or two adjacent substituents are linked together to form 6 can form a fused ring together with the original ring};
Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, -NR1R2, -OR3, 또는 할로이고;Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, -NR 1 R 2 , -OR 3 , or halo;
R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 and R 2 are each independently -H or -C 1-4 alkyl;
R3는 -H, -C1-4알킬, -C1-4할로알킬, 또는 -페닐이다.R 3 is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1 may be in the following ranges:
L은 -CH2- 또는 -C(=CRARB)-이고;L is -CH 2 - or -C(=CR A R B )-;
RA 및 RB는 각각 독립적으로 -H 또는 -C1-4알킬이고;R A and R B are each independently -H or -C 1-4 alkyl;
A는 6원 고리이고 {여기서, 상기 6원 고리의 하나 이상의 H는 -H, -C1-4알킬, -C1-4할로알킬, -OR3, 또는 할로로 치환될 수 있고, 또는 인접한 2개의 치환기들은 서로 연결되어 6원 고리와 함께 융합 고리를 형성할 수 있음};A is a 6-membered ring {wherein at least one H of the 6-membered ring may be substituted with -H, -C 1-4 alkyl, -C 1-4 haloalkyl, -OR 3 , or halo, or adjacent two substituents can be linked together to form a fused ring with a 6-membered ring};
Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, 또는 할로이고; Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, or halo;
R3는 -C1-4알킬, -C1-4할로알킬, 또는 -페닐이다.R 3 is -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl.
또한, 본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물은 하기 화학식 2로 표시되는 화합물일 수 있다:Further, according to an embodiment of the present invention, the compound represented by Formula 1 may be a compound represented by Formula 2 below:
[화학식 2][Formula 2]
Figure PCTKR2022016069-appb-img-000002
Figure PCTKR2022016069-appb-img-000002
상기 화학식 2에서,In Formula 2,
RA 및 RB는 각각 독립적으로 -H 또는 -C1-4알킬이고;R A and R B are each independently -H or -C 1-4 alkyl;
A는 6원 고리이고 {여기서, 상기 6원 고리의 하나 이상의 H는 -H, -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 할로로 치환될 수 있고, 또는 인접한 2개의 치환기들은 서로 연결되어 6원 고리와 함께 융합 고리를 형성할 수 있음};A is a 6-membered ring {wherein at least one H of the 6-membered ring is -H, -C 1-4 alkyl, -C 1-4 cyanoalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NR 1 R 2 , -OR 3 , or halo, or two adjacent substituents are linked together to form a fused ring with a six-membered ring. can form};
Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, -NR1R2, -OR3, 또는 할로이고; Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, -NR 1 R 2 , -OR 3 , or halo;
R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 and R 2 are each independently -H or -C 1-4 alkyl;
R3는 -H, -C1-4알킬, -C1-4할로알킬, 또는 -페닐이다.R 3 is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl.
또한, 본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물은 하기 화학식 3로 표시되는 화합물일 수 있다:Further, according to an embodiment of the present invention, the compound represented by Formula 1 may be a compound represented by Formula 3 below:
[화학식 3][Formula 3]
Figure PCTKR2022016069-appb-img-000003
Figure PCTKR2022016069-appb-img-000003
상기 화학식 3에서,In Formula 3,
RA 및 RB는 각각 독립적으로 -H 또는 -C1-4알킬이고;R A and R B are each independently -H or -C 1-4 alkyl;
A는 6원 고리이고 {여기서, 상기 6원 고리의 하나 이상의 H는 -H, -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 할로로 치환될 수 있고, 또는 인접한 2개의 치환기는 서로 연결되어 6원 고리와 함께 융합 고리를 형성할 수 있음};A is a 6-membered ring {wherein at least one H of the 6-membered ring is -H, -C 1-4 alkyl, -C 1-4 cyanoalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NR 1 R 2 , -OR 3 , or halo, or two adjacent substituents are linked together to form a fused ring with a six-membered ring. can form};
Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, -NR1R2, -OR3, 또는 할로이고; Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, -NR 1 R 2 , -OR 3 , or halo;
R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 and R 2 are each independently -H or -C 1-4 alkyl;
R3는 -H, -C1-4알킬, -C1-4할로알킬, 또는 -페닐인;R 3 is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl;
또한, 본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물이 하기 화합물로 이루어진 군으로부터 선택된 것일 수 있다. 다만, 이에 제한되지 않는다.In addition, according to an embodiment of the present invention, the compound represented by Formula 1 may be selected from the group consisting of the following compounds. However, it is not limited thereto.
(1) 2-(4-클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(1) 2-(4-chlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(2) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-플루오로페닐)아세트아마이드;(2) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-fluorophenyl)acetamide;
(3) 2-(벤조[d][1,3]다이옥솔-5-일)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(3) 2-(benzo[ d ][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(4) 2-(벤조[d][1,3]다이옥솔-5-일)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(4) 2-(benzo[ d ][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(5) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-메톡시페닐)아크릴아마이드;(5) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-methoxyphenyl)acrylamide;
(6) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-메톡시페닐)아세트아마이드;(6) N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(4-methoxyphenyl)acetamide;
(7) 2-(3,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(7) 2-(3,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(8) 2-(3,4-다이플루오로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(8) 2-(3,4-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(9) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-(트라이플루오로메톡시)페닐)아세트아마이드;(9) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide;
(10) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(p-톨릴)아크릴아마이드;(10) N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(p-tolyl)acrylamide;
(11) 2-(4-(터트-부틸)페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(11) 2-(4-(tert-butyl)phenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(12) 2-(4-(터트-부틸)페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(12) 2-(4-(tert-butyl)phenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(13) 2-(3,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(13) 2-(3,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(14) 2-(3,4-다이플루오로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(14) 2-(3,4-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(15) 2-(4-클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(15) 2-(4-chlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(16) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-(트라이플루오로메틸)페닐)아세트아마이드;(16) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acetamide;
(17) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(나프탈렌-2-일)아세트아마이드;(17) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(naphthalen-2-yl)acetamide;
(18) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(나프탈렌-2-일)아크릴아마이드.(18) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(naphthalen-2-yl)acrylamide.
(19) 2-(3,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(19) 2-(3,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(20) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-(트라이플루오로메톡시)페닐)아크릴아마이드;(20) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acrylamide;
(21) 2-(3,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(21) 2-(3,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(22) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-플루오로페닐)아크릴아마이드;(22) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-fluorophenyl)acrylamide;
(23) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-(트라이플루오로메틸)페닐)아크릴아마이드; (23) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acrylamide;
(24) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(p-톨릴)아세트아마이드;(24) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(p-tolyl)acetamide;
(25) 2-(2,3-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(25) 2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(26) 2-(2,3-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; (26) 2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(27) 2-(2,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(27) 2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(28) 2-(2,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마아드;(28) 2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(29) 2-(2,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; (29) 2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(30) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(3-플루오로페닐)아세트아마이드;(30) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(3-fluorophenyl)acetamide;
(31) 2-(2,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(31) 2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(32) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(3-플루오로페닐)아크릴아마이드; (32) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(3-fluorophenyl)acrylamide;
(33) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(3,4,5-트라이메톡시페닐)아크릴아마이드;(33) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acrylamide;
(34) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-페녹시페닐)아세트아마이드; (34) N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(4-phenoxyphenyl)acetamide;
(35) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-페녹시페닐)아크릴아마이드; (35) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-phenoxyphenyl)acrylamide;
(36) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(3,4,5-트라이메톡시페닐)아크릴아마이드;(36) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acrylamide;
(37) 2-(3,5-다이플루오로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(37) 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(38) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(2-플루오로페닐)아세트아마이드;(38) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(2-fluorophenyl)acetamide;
(39) 2-(2,3-다이하이드로벤조[b][1,4]다이옥신-6-일)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-yl)아세트아마이드; (39) 2-(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide ;
(40) 2-(3,4-다이메틸페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; (40) 2-(3,4-dimethylphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(41) 2-(3,5-다이플루오로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(41) 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
(42) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(2-플루오로페닐)아크릴아마이드;(42) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(2-fluorophenyl)acrylamide;
(43) 2-(2,3-다이하이드로벤조퓨란-5-일)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; (43) 2-(2,3-dihydrobenzofuran-5-yl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
(44) 2-사이클로헥실-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; 및(44) 2-cyclohexyl-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide; and
(45) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-몰폴리노아세트아마이드.(45) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-morpholinoacetamide.
본 발명에 있어서, "알킬"은, 다른 기재가 없는 한, 직쇄 또는 분지쇄의 비고리형, 고리형 또는 이들이 결합된 포화 탄화수소를 의미할 수 있다. 예를 들어, "C1-4알킬"은 탄소 원자를 1 내지 4 개 포함하는 알킬을 의미할 수 있다. 비고리형 알킬은, 일 예로서, 메틸, 에틸, n-프로필, n-부틸, 아이소프로필, 2 급(sec)-부틸, 아이소부틸, 또는 3 급(tert)-부틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 고리형 알킬은 본 명세서에서 "사이클로알킬"과 교환적으로 사용될 수 있으며, 일 예로서, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 또는 사이클로옥틸 등을 포함할 수 있으나, 이에 제한되지 않는다.In the present invention, "alkyl" may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon in which they are bonded, unless otherwise specified. For example, "C 1-4 alkyl" may mean an alkyl containing 1 to 4 carbon atoms. Non-cyclic alkyl may include, for example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc. Not limited to this. Cyclic alkyl may be used interchangeably with "cycloalkyl" herein, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as examples. It doesn't work.
본 발명에 있어서, "알콕시"는 알킬 에터기로 -(O-알킬)을 의미할 수 있고, 여기서, 알킬은 상기에서 정의된 바와 같다. 예를 들어, "C1-4의 알콕시"는 C1-4의 알킬을 함유하는 알콕시, 즉, -(O-C1-4알킬)을 의미할 수 있으며, 일 예로서, 알콕시는 메톡시(methoxy), 에톡시(ethoxy), n-프로폭시(n-propoxy), 아이소프로폭시(isopropoxy), n-부톡시(n-butoxy), 아이소부톡시(isobutoxy), sec-부톡시(sec-butoxy), 또는 tert-부톡시(tert-butoxy) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "alkoxy" can mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above. For example, "C 1-4 alkoxy" may mean C 1-4 alkyl-containing alkoxy, that is, -(OC 1-4 alkyl), and as an example, alkoxy is methoxy. ), ethoxy, n -propoxy, isopropoxy , n -butoxy, isobutoxy, sec - butoxy ), or tert -butoxy ( tert -butoxy), etc., but is not limited thereto.
본 발명에 있어서, "할로"는 F, Cl, Br, 또는 I일 수 있다.In the present invention, "halo" can be F, Cl, Br, or I.
본 발명에 있어서, "할로알킬"은 본원에 정의된 바와 같은 하나 이상의 할로로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 상기 할로알킬의 예로는 하나 이상의 할로겐, 예를 들어 F, Cl, Br, 또는 I로 독립적으로 치환된 메틸, 에틸, 프로필, 아이소프로필, 아이소부틸 또는 n-부틸을 포함하나, 이에 한정되는 것은 아니다.For purposes of this invention, "haloalkyl" can mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo as defined herein. Examples of such haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n -butyl independently substituted with one or more halogens such as F, Cl, Br, or I .
본 발명에 있어서, "아미노알킬"은 아미노(NR'R")로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 여기서, R' 및 R"은 각각 독립적으로 수소, 및 C1-4알킬로 이루어진 군으로부터 선택될 수 있으며, 상기 선택된 R'및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다.In the present invention, "aminoalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R"). Here, R' and R" are each independently hydrogen , And C 1-4 It may be selected from the group consisting of alkyl, and the selected R' and R" may each independently be substituted or unsubstituted.
본 발명에 있어서, "하이드록시알킬"은 하이드록시(OH)로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다.In the present invention, "hydroxyalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH).
본 발명에 있어서, "시아노알킬"은 시아노(CN)로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다.In the present invention, "cyanoalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).
본 발명에 있어서, "헤테로사이클로알킬"은 고리를 형성하는 원자로 N, O 및 S로부터 선택된 1 내지 5 개의 헤테로 원자를 함유하는 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 헤테로사이클로알켄으로 지칭될 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬은 단일 고리이거나, 스파이로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리와 같은 다중 고리일 수 있다. 또한, "3 내지 12원 헤테로사이클로알킬"은 고리를 형성하는 원자를 3 내지 12 개 포함하는 헤테로사이클로알킬을 의미할 수 있으며, 일 예로서, 헤테로사이클로알킬은 피롤리딘, 피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이미드, 피페리딘, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥산, 모르폴린, 싸이오모르폴린, 싸이오모르폴린-S-옥사이드, 싸이오모르폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 싸이오오피란, 피론, 테트라하이드로퓨란, 테트라하이드로싸이오펜, 퀴누클리딘, 트로판, 2-아자스파이로[3.3]헵탄, (1R,5S)-3-아자바이사이클로[3.2.1]옥탄, (1s,4s)-2-아자바이사이클로[2.2.2]옥탄, 또는 (1R,4R)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, a heterocycloalkyl can be a single ring or multiple rings such as spiro rings, bridged rings or fused rings. In addition, "3- to 12-membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring, and as an example, heterocycloalkyl includes pyrrolidine, piperidine, Dazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H )- Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, Thiophyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1 R ,5 S )-3-azabicyclo[3.2.1] octane, (1 s ,4 s )-2-azabicyclo[2.2.2]octane, or (1 R ,4 R )-2-oxa-5-azabicyclo[2.2.2]octane, and the like. It may be, but is not limited thereto.
본 발명에 있어서, "아렌"은 방향족 탄화수소 고리를 의미할 수 있다. 아렌은 단환식 아렌 또는 다환식 아렌일 수 있다. 아렌의 고리 형성 탄소수는 5 이상 30 이하, 5 이상 20 이하, 또는 5 이상 15 이하일 수 있다. 아렌의 예로는 벤젠, 나프탈렌, 플루오렌, 안트라센, 페난트렌, 터벤젠, 쿼터벤젠, 퀸크벤젠, 섹시벤젠, 트라이페닐렌, 피렌, 벤조 플루오란텐, 크리센 등을 예시할 수 있지만, 이들에 한정되지 않는다. 본 명세서에서 상기 "아렌"에서 수소 원자 하나를 제거한 잔기를 "아릴"로 지칭한다.In the present invention, "arene" may mean an aromatic hydrocarbon ring. Arenes can be monocyclic arenes or polycyclic arenes. The number of ring carbon atoms of the arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, terbenzene, quarterbenzene, quincbenzene, sexybenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like. Not limited. In the present specification, a residue obtained by removing one hydrogen atom from the above "arene" is referred to as "aryl".
본 발명에 있어서, "헤테로아렌"은 이종 원소로 O, N, P, Si, 및 S 중 1 개 이상을 포함하는 방향족 고리일 수 있다. 헤테로아렌의 고리 형성 탄소수는 2 이상 30 이하 또는 2 이상 20 이하일 수 있다. 헤테로아렌은 단환식 헤테로아렌 또는 다환식 헤테로아렌일 수 있다. 다환식 헤테로아렌은 예를 들어, 2 환 또는 3 환 구조를 갖는 것일 수 있다. 헤테로아렌의 예로는 싸이오펜, 퓨린, 피롤, 피라졸, 이미다졸, 싸이아졸, 옥사졸, 아이소싸이아졸, 옥사다이아졸, 트라이아졸, 피리딘, 트라이아진, 아크리딜, 피리다진, 피라진, 퀴놀린, 퀴나졸린, 퀴녹살린, 페녹사진, 프탈라진, 피리미딘, 피리도 피리미딘, 피리도 피라진, 피라지노 피라진, 아이소퀴놀린, 인돌, 카바졸, 이미다조피리다진, 이미다조피리딘, 이미다조피리미딘, 피라졸로피리미딘, 이미다조피라진, 피라졸로피리딘, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸, 벤조옥사졸, 벤조이미다졸, 벤조싸이아졸, 벤조카바졸, 벤조싸이오펜, 다이벤조싸이오펜, 싸이에노싸이오펜, 벤조퓨란, 페난트롤린, 아이소옥사졸, 옥사다이아졸, 싸이아다이아졸, 벤조싸이아졸, 테트라졸, 페노싸이아진, 다이벤조실롤, 다이벤조퓨란 등이 있으나, 이들에 한정되지 않는다. 본 명세서에서 상기 "헤테로아렌"에서 수소 원자 하나를 제거한 잔기를 "헤테로아릴"로 지칭한다.In the present invention, "heteroarene" may be an aromatic ring containing one or more of O, N, P, Si, and S as heterogeneous elements. The number of ring carbon atoms of the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. Heteroarenes may be monocyclic heteroarenes or polycyclic heteroarenes. Polycyclic heteroarenes may have, for example, a bicyclic or tricyclic structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, triazine, acridyl, pyridazine, pyrazine, and quinoline. , quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyrido pyrimidine, pyrido pyrazine, pyrazino pyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazophy Rimidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzooxazole, benzoimidazole, benzothiazole, benzocarbazole , benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosyl rolls, dibenzofurans, etc., but are not limited thereto. In the present specification, a residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as "heteroaryl".
본 발명에 있어서, 용어 "광학 이성질체(enantiomer)"는 동일한 화학식 또는 분자식을 가지지만 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 각각의 광학 이성질체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다. 다른 설명이 없는 한, 비대칭 탄소 원자와 연결되는 실선 결합 (-)은 입체 중심의 절대적 배열을 나타내는 쐐기형 실선 결합
Figure PCTKR2022016069-appb-img-000004
또는 쐐기형 점선 결합
Figure PCTKR2022016069-appb-img-000005
을 포함할 수 있다.In the present invention, the term "enantiomer" means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included in the scope of the present invention. Unless otherwise specified, the solid bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid bond representing the absolute configuration of the stereogenic center.
Figure PCTKR2022016069-appb-img-000004
or Wedge Dotted Combination
Figure PCTKR2022016069-appb-img-000005
can include
본 발명의 화학식 1의 화합물은 "약학적으로 허용가능한 염"의 형태로 존재할 수 있다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기산 또는 무기산 부가염을 의미한다.The compound of Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt". As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" of the present invention is a concentration that has a relatively non-toxic and harmless effective effect on patients, and any of the compounds represented by Formula 1 do not reduce the beneficial effects of the compound represented by Formula 1 by side effects caused by the salt. means any organic acid or inorganic acid addition salt of
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토나이트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 또는 질산 등을 사용할 수 있고 유기산으로는 메테인설폰산, p-톨루엔설폰산, 아세트산, 트라이플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 또는 아이오딘화수소산(hydroiodic acid) 등을 사용할 수 있다. 다만, 이들에 제한되지 않는다.At this time, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used. However, it is not limited to these.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable for preparing a sodium, potassium, or calcium salt, but is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
본 발명의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 하이드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 하이드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메테인설포네이트(메실레이트), 및 p-톨루엔설포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the present invention, unless otherwise indicated, include salts of acidic or basic groups that may be present in the compounds of Formula 1 above. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromides, sulfates, hydrogen sulfates, phosphates, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p -toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a salt known to.
벤조싸이오펜-1,1-다이옥사이드 유도체 화합물의 용도Uses of benzothiophene-1,1-dioxide derivative compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염의 용도를 제공한다.The present invention provides a use of a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2022016069-appb-img-000006
Figure PCTKR2022016069-appb-img-000006
상기 화학식 1은 위에서 정의한 바와 같다.Formula 1 is as defined above.
본 발명의 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 STAT3에 대하여 억제 활성을 나타내므로, STAT3 관련 질환, 특히, 암, 섬유화 질환, 또는 자가면역질환의 치료 또는 예방에 유용하게 사용될 수 있다. STAT3는 전사 인자로 작용하여 다양한 유전자들의 발현을 조절함으로써 암, 섬유화 질환, 또는 자가면역질환 등에 관여하는 것으로 알려져 있으므로, STAT3 활성을 억제함으로써 암, 섬유화 질환, 염증성 질환, 또는 자가면역질환 등을 예방 또는 치료할 수 있다.Since the compound represented by Formula 1 of the present invention, its optical isomer, or its pharmaceutically acceptable salt exhibits inhibitory activity against STAT3, treatment of STAT3-related diseases, particularly cancer, fibrotic diseases, or autoimmune diseases Or it can be useful for prevention. Since STAT3 is known to be involved in cancer, fibrotic disease, or autoimmune disease by acting as a transcription factor and regulating the expression of various genes, inhibiting STAT3 activity prevents cancer, fibrotic disease, inflammatory disease, or autoimmune disease or can be treated.
본 발명에 있어서, 상기 암은 STAT3 활성 억제로 인해 치료 또는 예방 효능을 나타낼 수 있는 모든　암을 포함하며, 고형암　또는 혈액암일 수 있다. 예컨대, 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 두경부암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인 것일 수 있으나, 이에 제한되지 않는다. 또한, 상기　암은 원발성　암뿐 아니라 전이성　암도 포함한다.In the present invention, the cancer includes all "cancers" that can exhibit therapeutic or preventive effects due to inhibition of STAT3 activity, and may be solid cancers or hematological cancers. For example, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, head and neck cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla cancer, bladder cancer, Peritoneal cancer, parathyroid cancer, adrenal cancer, rhinosinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart Cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal interstitial cancer , Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, villus disease of pregnancy, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinum cancer, rectal cancer, rectal carcinoid carcinoma, vaginal cancer, spinal cord cancer, Acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, larynx cancer, pleural cancer, hematological cancer, And it may be one or more selected from the group consisting of thymic cancer, but is not limited thereto. In addition, the above "cancer" includes not only primary "cancer" but also metastatic "cancer".
본 발명에 있어서, 상기 섬유화 질환은 섬유화 유발질환이나, 유발물질에 의해 염증 및 손상으로 나타나는 모든 질환을 말하며, 간 섬유증(예를 들어, 비알코올성 지방간질환(NAFLD), 비알코올성 지방간염(NASH)), 폐 섬유증, 당뇨성 섬유증, 심장 섬유증, 신장 섬유증, 경피증, 골격근 섬유증, 장 섬유증, 췌장 섬유증, 관절 섬유증, 골수 섬유증, 심근 섬유증, 진피 섬유증, 탄력 섬유증, 후복막 섬유증, 낭성 섬유증, 자궁 섬유증, 및 세포성 섬유증으로 이루어진 군으로부터 선택되는 1종 이상인 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the fibrotic disease refers to any disease caused by fibrosis or inflammation and damage caused by an inducing substance, and liver fibrosis (eg, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH)) ), pulmonary fibrosis, diabetic fibrosis, cardiac fibrosis, renal fibrosis, scleroderma, skeletal muscle fibrosis, intestinal fibrosis, pancreatic fibrosis, articular fibrosis, myelofibrosis, myocardial fibrosis, dermal fibrosis, elastic fibrosis, retroperitoneal fibrosis, cystic fibrosis, uterine fibrosis , And may be one or more selected from the group consisting of cellular fibrosis, but is not limited thereto.
본 발명에 있어서, 상기 염증성 질환 또는 자가면역질환은 병적인 개체의 자체 항원에 대한 면역 반응이 직간접적 원인으로 나타나는 모든 질환을 말하며, 건선, 아토피 피부염, 폐렴, 임파선염, 류마티스 관절염, 면역 혈소판감소증, 천식, 크론병, 다발성 경화증, 중증 근무력증, 갑상선염, 포도막염, 하시모토 갑상선염, 원발성 점액수종, 갑상샘 중독증, 악성 빈혈, 자가 면역 위축 위염, 애디슨 질환, 조기 폐경, 남성 불임증, 제1형 당뇨병, 굿파스처 증후군, 보통 천포창, 유천포창, 교감성 안염, 수정체성 포도막염, 자가면역 용혈성 빈혈, 특발성 백혈구 감소, 원발성 담관 경화증, 만성 활동성 간염, 만성 폐쇄성 폐질환, 잠재성 간경변증, 궤양성 대장염, 쇼그렌 증후군, 경피증, 베게너 육아종증, 다발근육염, 피 부근육염, 원판상루푸스 또는 전신홍반루푸스일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the inflammatory disease or autoimmune disease refers to any disease caused by direct or indirect causes of an immune response to a diseased subject's own antigen, and includes psoriasis, atopic dermatitis, pneumonia, lymphadenitis, rheumatoid arthritis, and immune thrombocytopenia. , asthma, Crohn's disease, multiple sclerosis, myasthenia gravis, thyroiditis, uveitis, Hashimoto's thyroiditis, primary myxedema, thyrotoxicosis, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, early menopause, male infertility, type 1 diabetes, Goodpas Cheer syndrome, pemphigus common, pemphigoid, sympathetic ophthalmitis, phacosomal uveitis, autoimmune hemolytic anemia, idiopathic leukopenia, primary biliary sclerosis, chronic active hepatitis, chronic obstructive pulmonary disease, latent cirrhosis, ulcerative colitis, Sjogren's syndrome, It may be, but is not limited to, scleroderma, Wegener's granulomatosis, polymyositis, paracutaneous myositis, discoid lupus, or systemic lupus erythematosus.
본 발명의 상기 약학적 조성물은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 유효성분을 1 종 이상을 더 포함할 수 있다.The pharmaceutical composition of the present invention may further contain at least one active ingredient in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
또한 본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상 (subject)에게 투여하는 단계를 포함하는, STAT3 관련 질환, 특히 암, 섬유화 질환, 또는 자가면역질환을 치료 또는 예방하는 방법을 제공한다. 상기 대상 (subject)은 인간을 포함하는 포유류일 수 있다.In addition, according to one embodiment of the present invention, the step of administering a therapeutically effective amount of the compound represented by Formula 1, its optical isomer, or its pharmaceutically acceptable salt to a subject in need thereof It provides a method for treating or preventing a STAT3-related disease, particularly cancer, fibrotic disease, or autoimmune disease, including. The subject may be a mammal including a human.
본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 STAT3 관련 질환의 치료 또는 예방에 유효한 상기 화학식 1로 표시되는 화합물의 양을 나타낸다. 구체적으로, "치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 투여 용량은, 환자의 상태, 연령, 성별 및 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다.The term "therapeutically effective amount" used in the present invention refers to an amount of the compound represented by Formula 1 effective for the treatment or prevention of STAT3-related diseases. Specifically, "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type and severity of the subject, age, sex, type of disease, It may be determined according to the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, or may be administered sequentially or simultaneously with a commercially available therapeutic agent. And it can be single or multiple administrations. It is important to administer the amount that can obtain the maximum effect with the minimum amount without side effects in consideration of all the above factors, and can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used even at a dose determined or higher.
또한 본 발명의 일 구체예에 따르면, 본 발명은 STAT3 관련 질환의 치료 또는 예방에 사용하기 위한 약제 (medicament)의 제조에 사용하기 위한, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도 (use)를 제공한다. 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다.In addition, according to one embodiment of the present invention, the present invention is a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutical thereof for use in the preparation of a medicament for use in the treatment or prevention of STAT3-related diseases Uses of the generally acceptable salts are provided. The compound represented by Formula 1 for the preparation of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may be prepared as a combined preparation with other active agents to have a synergistic action of the active ingredients.
본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the use, composition, and treatment method of the present invention are equally applied unless contradictory to each other.
본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. Furthermore, "include" a certain component throughout the specification means that other components may be further included without excluding other components unless otherwise stated.
본 발명의 신규 벤조싸이오펜-1,1-다이옥사이드 유도체 화합물들은 STAT3의 SH2 도메인에 결합하여 우수한 STAT3 선택적 저해 활성을 나타내므로, STAT3 관련 질환의 예방 또는 치료를 위해 매우 유용하게 사용될 수 있다.Since the novel benzothiophene-1,1-dioxide derivative compounds of the present invention bind to the SH2 domain of STAT3 and show excellent STAT3-selective inhibitory activity, they can be very useful for preventing or treating STAT3-related diseases.
도 1은 실시예 화합물들의 IL-6에 의해 유도되는 STAT3의 전사활성 억제 효과를 나타낸 것이다.Figure 1 shows the effect of inhibiting the transcriptional activity of STAT3 induced by IL-6 of Example compounds.
이하, 실시예 및 실험예를 통하여 본 발명의 구성 및 효과를 더욱 상세히 설명하고자 한다. 이들 실시예 및 실험예는 오로지 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들 실시예 및 실험예에 의해 제한되는 것은 아니다.Hereinafter, the configuration and effects of the present invention will be described in more detail through examples and experimental examples. These Examples and Experimental Examples are only for exemplifying the present invention, but the scope of the present invention is not limited by these Examples and Experimental Examples.
제조방법manufacturing method
본 발명의 화합물은 아래 반응식 1에 도시된 반응에 따라 제조될 수 있다.Compounds of the present invention can be prepared according to the reaction shown in Scheme 1 below.
[반응식 1][Scheme 1]
Figure PCTKR2022016069-appb-img-000007
Figure PCTKR2022016069-appb-img-000007
단계 1a: 화합물 S1의 제조Step 1a: Preparation of Compound S1
2-아릴아세트산 또는 2-헤테로아릴아세트산(1.5 당량)이 교반된 CH2Cl2 용액에, 0 ℃에서 옥살릴 클로라이드(3.0 당량) 및 DMF 1 방울을 가하였다. 2 시간 후, 반응 혼합물을 진공 하에서 농축하였다. 0.5 시간 후, 조(crude) 산 염화물(acid chloride)을 CH2Cl2에 용해시킨 다음, 6-아미노벤조[b]싸이오펜 유도체(1.0 당량) 및 Et3N(2.0 당량)을 가하였다. 주위 온도에서 14 시간 동안 교반한 후, 반응 혼합물을 NH4Cl 포화 수용액으로 퀜칭한 다음, CH2Cl2로 추출하였다. 결합된 유기층들을 MgSO4로 건조시키고 진공 하에서 농축하였다. 잔류물을 실리카겔에서 플래쉬 칼럼 크로마토그래피로 정제하거나 재결정으로 수득하였다.To a stirred CH 2 Cl 2 solution of 2-arylacetic acid or 2-heteroarylacetic acid (1.5 equiv.), oxalyl chloride (3.0 equiv.) and 1 drop of DMF were added at 0 °C. After 2 hours, the reaction mixture was concentrated under vacuum. After 0.5 hour, crude acid chloride was dissolved in CH 2 Cl 2 , and then 6-aminobenzo[ b ]thiophene derivative (1.0 equiv.) and Et 3 N (2.0 equiv.) were added. After stirring at ambient temperature for 14 hours, the reaction mixture was quenched with saturated aqueous NH 4 Cl solution and then extracted with CH 2 Cl 2 . The combined organic layers were dried over MgSO 4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel or obtained by recrystallization.
단계 1b: 화합물 S1의 제조Step 1b: Preparation of Compound S1
2-아릴아세트산 또는 2-헤테로아릴아세트산(1.5 당량)이 교반된 DMF 용액에, 주위 온도에서 6-아미노벤조[b]싸이오펜 유도체(1.0 당량), EDC·HCl(3.0 당량), HOBt·H2O(1.5 당량), DMAP(0.1 당량) 및 DIPEA(1.5 당량)를 가하였다. 같은 온도에서 6 시간 동안 교반한 후, 반응 혼합물을 H2O로 퀜칭한 다음, EtOAc로 추출하였다. 연결된 유기층들을 Na2SO4로 건조시키고 진공 하에서 농축하였다. 잔류물을 실리카겔에서 플래쉬 칼럼 크로마토그래피로 정제하거나 재결정으로 수득하였다.2-Arylacetic acid or 2-heteroarylacetic acid (1.5 equiv.) was added to a stirred DMF solution, 6-aminobenzo[ b ]thiophene derivative (1.0 equiv.), EDC HCl (3.0 equiv.), HOBt H at ambient temperature. 2 O (1.5 equiv), DMAP (0.1 equiv) and DIPEA (1.5 equiv) were added. After stirring at the same temperature for 6 h, the reaction mixture was quenched with H 2 O and then extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel or obtained by recrystallization.
단계 2: 화합물 S3의 제조Step 2: Preparation of Compound S3
단계 1a 또는 단계 1b에서 제조된 2-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드 유도체(1.0 당량)가 교반된 DMF 용액에, 파라포름알데하이드(10.0 당량) 및 포타슘 카보네이트(2.2 당량)를 가하였다. 80 ℃에서 6 시간 동안 격렬히 교반한 후, 반응 혼합물을 brine으로 퀜칭한 다음, EtOAc로 추출하였다. 연결된 유기층들을 Na2SO4로 건조시키고 진공 하에서 농축하였다. 잔류물을 실리카겔에서 플래쉬 칼럼 크로마토그래피로 정제하였다.2- N- (1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide derivative (1.0 equivalent) prepared in step 1a or step 1b was added to a stirred DMF solution, and paraformaldehyde (10.0 equivalent) ) and potassium carbonate (2.2 eq) were added. After vigorous stirring at 80 °C for 6 hours, the reaction mixture was quenched with brine and then extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel.
실시예 1: 2-(4-클로로페닐)-N-(1,1-다이옥시도벤조[Example 1: 2-(4-chlorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(4-Chlorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acetamide {2-(4-Chlorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000008
Figure PCTKR2022016069-appb-img-000008
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 2 : 3)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(132.4 mg, 99 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 2:3) to obtain the title compound as a yellow solid (132.4 mg, 99%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.68 (s, 1H), 8.12 (s, 1H), 7.71 (dd, 1H, J = 8.3, 1.8 Hz), 7.57 (dd, 1H, J = 6.9, 0.5 Hz), 7.53 (d, 1H, J = 8.2 Hz), 7.39 (d, 2H, J = 8.6 Hz), 7.35 (d, 2H, J = 8.6 Hz), 7.26 (d, 1H, J = 6.9 Hz), 3.71 (s, 2H). 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.68 (s, 1H), 8.12 (s, 1H), 7.71 (dd, 1H, J = 8.3, 1.8 Hz), 7.57 (dd, 1H, J = 6.9 , 0.5 Hz), 7.53 (d, 1H, J = 8.2 Hz), 7.39 (d, 2H, J = 8.6 Hz), 7.35 (d, 2H, J = 8.6 Hz), 7.26 (d, 1H, J = 6.9 Hz), 3.71 (s, 2H).
실시예 2: N-(1,1-다이옥시도벤조[Example 2: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(4-플루오로페닐)아세트아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(4-fluorophenyl)acetamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(4-fluorophenyl)acetamide}의 제조Preparation of ]thiophen-6-yl)-2-(4-fluorophenyl)acetamide}
Figure PCTKR2022016069-appb-img-000009
Figure PCTKR2022016069-appb-img-000009
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(29.6 mg, 24 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a yellow solid (29.6 mg, 24%).
1H NMR (CDCl3, 500 MHz) δ 7.87 (dd, 1H, J = 8.2, 1.3 Hz), 7.82 (s, 1H), 7.69 (s, 1H), 7.29 (dd, 2H, J = 8.3, 5.5 Hz), 7.25 (d, 1H, J = 4.7 Hz), 7.17 (d, 1H, J = 6.9 Hz), 7.07 (d, 1H, J = 8.6 Hz), 7.06 (m, 2H), 6.63 (d, 1H, J = 6.9 Hz), 3.70 (s, 2H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.87 (dd, 1H, J = 8.2, 1.3 Hz), 7.82 (s, 1H), 7.69 (s, 1H), 7.29 (dd, 2H, J = 8.3, 5.5 Hz), 7.25 (d, 1H, J = 4.7 Hz), 7.17 (d, 1H, J = 6.9 Hz), 7.07 (d, 1H, J = 8.6 Hz), 7.06 (m, 2H), 6.63 (d, 1H, J = 6.9 Hz), 3.70 (s, 2H).
실시예 3: 2-(벤조[Example 3: 2-(benzo[ dd ][1,3]다이옥솔-5-일)-N-(1,1-다이옥시도벤조[][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(Benzo[]thiophen-6-yl)acetamide {2-(Benzo[ dd ][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000010
Figure PCTKR2022016069-appb-img-000010
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 3 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(82.0 mg, 62 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 3:1) to obtain the title compound as a yellow solid (82.0 mg, 62%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.59 (s, 1H), 8.12 (s, 1H), 7.72 (d, 1H, J = 8.3 Hz), 7.57 (d, 1H, J = 6.9 Hz), 7.53 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.8 Hz), 6.91 (s, 1H), 6.86 (d, 1H, J =7.9 Hz), 6.79 (d, 1H, J = 7.9 Hz), 5.98 (s, 2H), 3.60 (s, 2H). 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.59 (s, 1H), 8.12 (s, 1H), 7.72 (d, 1H, J = 8.3 Hz), 7.57 (d, 1H, J = 6.9 Hz) , 7.53 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.8 Hz), 6.91 (s, 1H), 6.86 (d, 1H, J = 7.9 Hz), 6.79 (d, 1H, J = 7.9 Hz), 5.98 (s, 2H), 3.60 (s, 2H).
실시예 4: 2-(벤조[Example 4: 2-(benzo[ dd ][1,3]다이옥솔-5-일)-N-(1,1-다이옥시도벤조[][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마이드 {2-(Benzo[]thiophen-6-yl)acrylamide {2-(Benzo[ dd ][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000011
Figure PCTKR2022016069-appb-img-000011
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 2 : 1)로 정제하여 노란색 오일로 표제 화합물을 수득하였다(18.2 mg, 32 %).The reaction of steps 1 and 2 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 2:1) to obtain the title compound as a yellow oil (18.2 mg, 32%).
1H NMR (CDCl3, 500 MHz) δ 7.95 (d, 1H, J = 8.2 Hz), 7.78 (s, 2H), 7.30 (d, 1H, J = 8.3 Hz), 7.17 (d, 1H, J = 6.6 Hz), 6.89 (m, 1H), 6.89 (s, 1H), 6.86 (d, 1H, J = 8.0 Hz), 6.64 (d, 1H, J = 6.9 Hz), 6.22 (s, 1H), 6.03 (s, 2H), 5.70 (s, 1H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.95 (d, 1H, J = 8.2 Hz), 7.78 (s, 2H), 7.30 (d, 1H, J = 8.3 Hz), 7.17 (d, 1H, J = 6.6 Hz), 6.89 (m, 1H), 6.89 (s, 1H), 6.86 (d, 1H, J = 8.0 Hz), 6.64 (d, 1H, J = 6.9 Hz), 6.22 (s, 1H), 6.03 (s, 2H), 5.70 (s, 1H).
실시예 5: N-(1,1-다이옥시도벤조[Example 5: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(4-메톡시페닐)아크릴아마이드 {N-(1,1-Dioxidobenzo[b]thiophen-6-yl)-2-(4-methoxyphenyl)acrylamide}의 제조Preparation of ]thiophen-6-yl)-2-(4-methoxyphenyl)acrylamide {N-(1,1-Dioxidobenzo[b]thiophen-6-yl)-2-(4-methoxyphenyl)acrylamide}
Figure PCTKR2022016069-appb-img-000012
Figure PCTKR2022016069-appb-img-000012
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 2 : 3)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(10.7 mg, 22 %).The reaction of steps 1 and 2 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 2:3) to obtain the title compound as a yellow solid (10.7 mg, 22%).
1H NMR (CD3OD, 500 MHz) δ 8.19 (s, 1H), 7.87 (d, 1H, J = 8.2 Hz), 7.47 (d, 1H, J = 8.3 Hz), 7.44 (d, 2H, J = 8.2 Hz), 7.42 (m, 1H), 6.95 (d, 2H, J = 8.6 Hz), 6.92 (d, 1H, J = 6.9 Hz), 5.84 (s, 1H), 5.73 (s, 1H), 3.82 (s, 3H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.19 (s, 1H), 7.87 (d, 1H, J = 8.2 Hz), 7.47 (d, 1H, J = 8.3 Hz), 7.44 (d, 2H, J = 8.2 Hz), 7.42 (m, 1H), 6.95 (d, 2H, J = 8.6 Hz), 6.92 (d, 1H, J = 6.9 Hz), 5.84 (s, 1H), 5.73 (s, 1H), 3.82 (s, 3H).
실시예 6: N-(1,1-다이옥시도벤조[Example 6: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(4-메톡시페닐)아세트아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(4-methoxyphenyl)acetamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(4-methoxyphenyl)acetamide}의 제조Preparation of ]thiophen-6-yl)-2-(4-methoxyphenyl)acetamide}
Figure PCTKR2022016069-appb-img-000013
Figure PCTKR2022016069-appb-img-000013
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산/CH2Cl2 = 1 : 1 : 3)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(61.5 mg, 34 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane/CH 2 Cl 2 = 1 : 1 : 3) to obtain the title compound as a yellow solid (61.5 mg, 34 %).
1H NMR (DMSO-d 6, 500 MHz) δ 10.61 (s, 1H), 8.13 (s, 1H), 7.72 (d, 1H, J = 8.2 Hz), 7.57 (d, 1H, J = 6.9 Hz), 7.52 (d, 1H, J = 8.2 Hz), 7.25 (m, 3H), 6.89 (d, 2H, J = 8.3 Hz), 3.73 (s, 3H), 3.62 (s, 2H). 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.61 (s, 1H), 8.13 (s, 1H), 7.72 (d, 1H, J = 8.2 Hz), 7.57 (d, 1H, J = 6.9 Hz) , 7.52 (d, 1H, J = 8.2 Hz), 7.25 (m, 3H), 6.89 (d, 2H, J = 8.3 Hz), 3.73 (s, 3H), 3.62 (s, 2H).
실시예 7: 2-(3,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[Example 7: 2-(3,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(3,4-Dimethoxyphenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acetamide {2-(3,4-Dimethoxyphenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000014
Figure PCTKR2022016069-appb-img-000014
반응식 1에 따라 단계 1의 반응을 진행하고, CH2Cl2/n-헥산(1 : 20)로 재결정화하여 연한 노란색 고체로 표제 화합물을 수득하였다(173.0 mg, 87 %).The reaction of step 1 was carried out according to Scheme 1 and recrystallized from CH 2 Cl 2 / n -hexane (1:20) to obtain the title compound as a pale yellow solid (173.0 mg, 87%).
1H NMR (CDCl3, 500 MHz) δ 7.83 (d, 1H, J = 8.2 Hz), 7.73 (s, 1H), 7.70 (s, 1H), 7.25 (d, 1H, J = 7.7 Hz), 7.16 (d, 1H, J = 6.8 Hz), 6.89 (d, 1H, J = 8.1 Hz), 6.86 (d, 1H, J = 8.6 Hz), 6.83 (s, 1H), 6.62 (d, 1H, J = 6.8 Hz), 3.89 (s, 3H), 3.88 (s, 3H), 3.69 (s, 2H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.83 (d, 1H, J = 8.2 Hz), 7.73 (s, 1H), 7.70 (s, 1H), 7.25 (d, 1H, J = 7.7 Hz), 7.16 (d, 1H, J = 6.8 Hz), 6.89 (d, 1H, J = 8.1 Hz), 6.86 (d, 1H, J = 8.6 Hz), 6.83 (s, 1H), 6.62 (d, 1H, J = 8.6 Hz) 6.8 Hz), 3.89 (s, 3H), 3.88 (s, 3H), 3.69 (s, 2H).
실시예 8: 2-(3,4-다이플루오로페닐)-N-(1,1-다이옥시도벤조[Example 8: 2-(3,4-difluorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마이드 {2-(3,4-Difluorophenyl)-N-(1,1-dioxidobenzo[b]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide {2-(3,4-Difluorophenyl)-N-(1,1-dioxidobenzo[b]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000015
Figure PCTKR2022016069-appb-img-000015
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 3 : 1)로 정제하여 연한 녹색 오일로 표제 화합물을 수득하였다(12.0 mg, 22 %).The reaction of steps 1 and 2 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 3:1) to obtain the title compound as a pale green oil (12.0 mg, 22%).
1H NMR (CDCl3, 500 MHz) δ 7.92 (d, 1H, J = 7.9 Hz), 7.85 (s, 1H), 7.67 (s, 1H), 7.34 (d, 1H, J = 8.2 Hz), 7.30 (d, 1H, J = 9.1 Hz), 7.24 (m, 1H), 7.19 (m, 2H), 6.66 (d, 1H, J = 6.8 Hz), 6.23 (s, 1H), 5.82 (s, 1H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.92 (d, 1H, J = 7.9 Hz), 7.85 (s, 1H), 7.67 (s, 1H), 7.34 (d, 1H, J = 8.2 Hz), 7.30 (d, 1H, J = 9.1 Hz), 7.24 (m, 1H), 7.19 (m, 2H), 6.66 (d, 1H, J = 6.8 Hz), 6.23 (s, 1H), 5.82 (s, 1H) .
실시예 9: N-(1,1-다이옥시도벤조[Example 9: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(4-(트라이플루오로메톡시)페닐)아세트아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide}의 제조Preparation of ]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide}
Figure PCTKR2022016069-appb-img-000016
Figure PCTKR2022016069-appb-img-000016
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 30)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(140.7 mg, 33 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:30) to obtain the title compound as a yellow solid (140.7 mg, 33%).
1H NMR (CDCl3, 500 MHz) δ 7.92 (m, 2H), 7.70 (s, 1H), 7.36 (d, 2H, J = 8.6 Hz), 7.27 (d, 1H, J = 8.3 Hz), 7.22 (d, 1H, J = 8.1 Hz), 7.19 (d, 1H, J = 7.0 Hz), 6.64 (d, 1H, J = 6.9 Hz), 3.73 (s, 2H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.92 (m, 2H), 7.70 (s, 1H), 7.36 (d, 2H, J = 8.6 Hz), 7.27 (d, 1H, J = 8.3 Hz), 7.22 (d, 1H, J = 8.1 Hz), 7.19 (d, 1H, J = 7.0 Hz), 6.64 (d, 1H, J = 6.9 Hz), 3.73 (s, 2H).
실시예 10: N-(1,1-다이옥시도벤조[Example 10: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(p-톨릴)아크릴아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(p-tolyl)acrylamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(p-tolyl)acrylamide}의 제조Preparation of ]thiophen-6-yl)-2-(p-tolyl)acrylamide}
Figure PCTKR2022016069-appb-img-000017
Figure PCTKR2022016069-appb-img-000017
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 연한 오렌지색 고체로 표제 화합물을 수득하였다(13.7 mg, 21 %).Steps 1 and 2 were carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a pale orange solid (13.7 mg, 21%).
1H NMR (CDCl3, 500 MHz) δ 7.94 (dd, 1H, J = 8.2, 1.6 Hz), 7.75 (s, 1H), 7.64 (s, 1H), 7.30 (m, 3H), 7.26 (m, 2H), 7.17 (d, 1H, J = 6.8 Hz), 6.64 (d, 1H, J = 6.9 Hz), 6.32 (s, 1H), 5.74 (s, 1H), 2.42 (s, 3H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.94 (dd, 1H, J = 8.2, 1.6 Hz), 7.75 (s, 1H), 7.64 (s, 1H), 7.30 (m, 3H), 7.26 (m, 2H), 7.17 (d, 1H, J = 6.8 Hz), 6.64 (d, 1H, J = 6.9 Hz), 6.32 (s, 1H), 5.74 (s, 1H), 2.42 (s, 3H).
실시예 11: 2-(4-(터트-부틸)페닐)-N-(1,1-다이옥시도벤조[Example 11: 2-(4-(tert-butyl)phenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(4-(]thiophen-6-yl)acetamide {2-(4-( terttert -Butyl)phenyl)-N-(1,1-dioxidobenzo[-Butyl)phenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000018
Figure PCTKR2022016069-appb-img-000018
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산/CH2Cl2 = 1 : 1 : 3)로 정제하여 아이보리색 고체로 표제 화합물을 수득하였다(115.3 mg, 59 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane/CH 2 Cl 2 = 1 : 1 : 3) to obtain the title compound as an ivory solid (115.3 mg, 59%).
1H NMR (CDCl3, 500 MHz) δ 7.88 (dd, 1H, J = 8.2, 1.7 Hz), 7.63 (s, 1H), 7.52 (s, 1H), 7.43 (d, 2H, J = 8.2 Hz), 7.26 (m, 3H), 7.16 (d, 1H, J = 6.9 Hz), 6.62 (d, 1H, J = 6.9 Hz), 3.73 (s, 2H), 1.34 (s, 9H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.88 (dd, 1H, J = 8.2, 1.7 Hz), 7.63 (s, 1H), 7.52 (s, 1H), 7.43 (d, 2H, J = 8.2 Hz) , 7.26 (m, 3H), 7.16 (d, 1H, J = 6.9 Hz), 6.62 (d, 1H, J = 6.9 Hz), 3.73 (s, 2H), 1.34 (s, 9H).
실시예 12: 2-(4-(터트-부틸)페닐)-N-(1,1-다이옥시도벤조[Example 12: 2-(4-(tert-butyl)phenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마이드 {2-(4-(]thiophen-6-yl)acrylamide {2-(4-( terttert -Butyl)phenyl)-N-(1,1-dioxidobenzo[-Butyl)phenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000019
Figure PCTKR2022016069-appb-img-000019
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다(29.8 mg, 34 %).Steps 1 and 2 were carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a pale yellow solid (29.8 mg, 34%).
1H NMR (CDCl3, 500 MHz) δ 7.98 (dd, 1H, J = 8.3, 1.8 Hz), 7.74 (s, 1H), 7.68 (s, 1H), 7.47 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.4 Hz), 7.31 (d, 1H, J = 8.3 Hz), 7.17 (dd, 1H, J = 6.9, 0.7 Hz), 6.64 (d, 1H, J = 6.9 Hz), 6.32 (d, 1H, J = 0.6 Hz), 5.76 (d, 1H, J = 0.7 Hz), 1.37 (s, 9H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.98 (dd, 1H, J = 8.3, 1.8 Hz), 7.74 (s, 1H), 7.68 (s, 1H), 7.47 (d, 2H, J = 8.4 Hz) , 7.35 (d, 2H, J = 8.4 Hz), 7.31 (d, 1H, J = 8.3 Hz), 7.17 (dd, 1H, J = 6.9, 0.7 Hz), 6.64 (d, 1H, J = 6.9 Hz) , 6.32 (d, 1H, J = 0.6 Hz), 5.76 (d, 1H, J = 0.7 Hz), 1.37 (s, 9H).
실시예 13: 2-(3,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[Example 13: 2-(3,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마이드 {2-(3,4-Dimethoxyphenyl)-N-(1,1-dioxidobenzo[b]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide {2-(3,4-Dimethoxyphenyl)-N-(1,1-dioxidobenzo[b]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000020
Figure PCTKR2022016069-appb-img-000020
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산/CH2Cl2 = 3 : 1 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(23.0 mg, 22 %).The reaction of steps 1 and 2 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane/CH 2 Cl 2 = 3 : 1 : 1) to obtain the title compound as a yellow solid (23.0 mg , 22%).
1H NMR (CDCl3, 500 MHz) δ 7.94 (d, 1H, J = 8.3 Hz), 7.88 (s, 1H), 7.82 (s, 1H), 7.30 (d, 1H, J = 8.3 Hz), 7.17 (d, 1H, J = 6.9 Hz), 6.97 (m, 1H), 6.91 (m, 2H), 6.63 (d, 1H, J = 6.9 Hz), 6.24 (s, 1H), 5.72 (s, 1H), 3.91 (s, 3H), 3.89 (s, 3H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.94 (d, 1H, J = 8.3 Hz), 7.88 (s, 1H), 7.82 (s, 1H), 7.30 (d, 1H, J = 8.3 Hz), 7.17 (d, 1H, J = 6.9 Hz), 6.97 (m, 1H), 6.91 (m, 2H), 6.63 (d, 1H, J = 6.9 Hz), 6.24 (s, 1H), 5.72 (s, 1H) , 3.91 (s, 3H), 3.89 (s, 3H).
실시예 14: 2-(3,4-다이플루오로페닐)-N-(1,1-다이옥시도벤조[Example 14: 2-(3,4-difluorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(3,4-Difluorophenyl)-N-(1,1-dioxidobenzo[b]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide {2-(3,4-Difluorophenyl)-N-(1,1-dioxidobenzo[b]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000021
Figure PCTKR2022016069-appb-img-000021
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산/CH2Cl2 = 1 : 1 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(64.0 mg, 35 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane/CH 2 Cl 2 = 1 : 1 : 1) to obtain the title compound as a yellow solid (64.0 mg, 35 %).
1H NMR (CD3OD, 500 MHz) δ 8.07 (s, 1H), 7.75 (dd, 1H, J = 8.2, 1.7 Hz), 7.44 (d, 1H, J = 8.2 Hz), 7.40 (d, 1H, J = 6.9 Hz), 7.28 (m, 1H), 7.22 (m, 1H), 7.15 (m, 1H), 6.90 (d, 1H, J = 6.9 Hz), 3.72 (s, 2H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.07 (s, 1H), 7.75 (dd, 1H, J = 8.2, 1.7 Hz), 7.44 (d, 1H, J = 8.2 Hz), 7.40 (d, 1H , J = 6.9 Hz), 7.28 (m, 1H), 7.22 (m, 1H), 7.15 (m, 1H), 6.90 (d, 1H, J = 6.9 Hz), 3.72 (s, 2H).
실시예 15: 2-(4-클로로페닐)-N-(1,1-다이옥시도벤조[Example 15: 2-(4-chlorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마이드 {2-(4-Chlorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acrylamide {2-(4-Chlorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000022
Figure PCTKR2022016069-appb-img-000022
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1.5)로 정제하여 무색 오일로 표제 화합물을 수득하였다(28.9 mg, 33 %).The reaction of steps 1 and 2 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1 : 1.5) to obtain the title compound as a colorless oil (28.9 mg, 33%).
1H NMR (CDCl3, 500 MHz) δ 7.90 (d, 1H, J = 8.2 Hz), 7.84 (s, 1H), 7.63 (s, 1H), 7.43 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H, J = 8.3 Hz), 7.32 (d, 1H, J = 8.2 Hz), 7.18 (d, 1H, J = 6.9 Hz), 6.65 (d, 1H, J = 6.8 Hz), 6.28 (s, 1H), 5.80 (s, 1H). 1 H NMR (CDCl 3 , 500 MHz) δ 7.90 (d, 1H, J = 8.2 Hz), 7.84 (s, 1H), 7.63 (s, 1H), 7.43 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H, J = 8.3 Hz), 7.32 (d, 1H, J = 8.2 Hz), 7.18 (d, 1H, J = 6.9 Hz), 6.65 (d, 1H, J = 6.8 Hz), 6.28 (s , 1H), 5.80 (s, 1H).
실시예 16: N-(1,1-다이옥시도벤조[Example 16: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(4-(트라이플루오로메틸)페닐)아세트아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acetamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acetamide}의 제조Preparation of ]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acetamide}
Figure PCTKR2022016069-appb-img-000023
Figure PCTKR2022016069-appb-img-000023
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 2 : 1)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다(293.5 mg, 73 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 2:1) to obtain the title compound as a pale yellow solid (293.5 mg, 73%).
1H NMR (CD3OD, 500 MHz) δ 8.08 (s, 1H), 7.75 (dd, 1H, J = 8.3, 1.9 Hz), 7.64 (d, 2H, J = 8.2 Hz), 7.54 (d, 2H, J = 8.1 Hz), 7.43 (d, 1H, J = 8.3 Hz), 7.39 (d, 1H, J = 6.9 Hz), 6.89 (d, 1H, J = 6.9 Hz), 3.83 (s, 2H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.08 (s, 1H), 7.75 (dd, 1H, J = 8.3, 1.9 Hz), 7.64 (d, 2H, J = 8.2 Hz), 7.54 (d, 2H , J = 8.1 Hz), 7.43 (d, 1H, J = 8.3 Hz), 7.39 (d, 1H, J = 6.9 Hz), 6.89 (d, 1H, J = 6.9 Hz), 3.83 (s, 2H).
실시예 17: N-(1,1-다이옥시도벤조[Example 17: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(나프탈렌-2-일)아세트아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(naphthalen-2-yl)acetamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(naphthalen-2-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)-2-(naphthalen-2-yl)acetamide}
Figure PCTKR2022016069-appb-img-000024
Figure PCTKR2022016069-appb-img-000024
반응식 1에 따라 단계 1의 반응을 진행하고, MeOH로 재결정화하여 빨간색 고체로 표제 화합물을 수득하였다(104.0 mg, 27 %).The reaction of step 1 was carried out according to Scheme 1 and recrystallized with MeOH to obtain the title compound as a red solid (104.0 mg, 27%).
1H NMR (CD3OD, 500 MHz) δ 8.10 (s, 1H), 7.83 (m, 4H), 7.78 (d, 1H, J = 8.2 Hz), 7.47 (m, 3H), 7.43 (d, 1H, J = 8.4 Hz), 7.39 (d, 1H, J = 6.9 Hz), 6.89 (d, 1H, J = 6.9 Hz), 3.90 (s, 2H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.10 (s, 1H), 7.83 (m, 4H), 7.78 (d, 1H, J = 8.2 Hz), 7.47 (m, 3H), 7.43 (d, 1H) , J = 8.4 Hz), 7.39 (d, 1H, J = 6.9 Hz), 6.89 (d, 1H, J = 6.9 Hz), 3.90 (s, 2H).
실시예 18: N-(1,1-다이옥시도벤조[Example 18: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(나프탈렌-2-일)아크릴아마이드 {N-(1,1-Dioxidobenzo[b]thiophen-6-yl)-2-(naphthalen-2-yl)acrylamide}의 제조]thiophen-6-yl)-2-(naphthalen-2-yl)acrylamide {N-(1,1-Dioxidobenzo[b]thiophen-6-yl)-2-(naphthalen-2-yl)acrylamide} manufacture of
Figure PCTKR2022016069-appb-img-000025
Figure PCTKR2022016069-appb-img-000025
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 연한 녹색 오일로 표제 화합물을 수득하였다(14.0 mg, 4 %).The reaction of steps 1 and 2 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a pale green oil (14.0 mg, 4%).
1H NMR (CD3OD, 500 MHz) δ 8.23 (s, 1H), 7.98 (s, 1H), 7.88 (m, 4H), 7.65 (d, 1H, J = 8.6 Hz), 7.49 (m, 3H), 7.43 (d, 1H, J = 6.9 Hz), 6.93 (d, 1H, J = 6.9 Hz), 6.09 (s, 1H), 5.94 (s, 1H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.23 (s, 1H), 7.98 (s, 1H), 7.88 (m, 4H), 7.65 (d, 1H, J = 8.6 Hz), 7.49 (m, 3H) ), 7.43 (d, 1H, J = 6.9 Hz), 6.93 (d, 1H, J = 6.9 Hz), 6.09 (s, 1H), 5.94 (s, 1H).
실시예 19: 2-(3,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[Example 19: 2-(3,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(3,4-Dichlorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acetamide {2-(3,4-Dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000026
Figure PCTKR2022016069-appb-img-000026
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 20)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다(95.0 mg, 47 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:20) to obtain the title compound as a pale yellow solid (95.0 mg, 47%).
1H NMR (CD3OD, 500 MHz) δ 8.07 (s, 1H), 7.76 (dd, 1H, J = 8.2, 1.5 Hz), 7.53 (s, 1H), 7.49 (d, 1H, J = 8.3 Hz), 7.44 (d, 1H, J = 8.3 Hz), 7.40 (d, 1H, J = 6.9 Hz), 7.28 (d, 1H, J = 8.2 Hz), 6.90 (d, 1H, J = 6.9 Hz), 3.73 (s, 2H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.07 (s, 1H), 7.76 (dd, 1H, J = 8.2, 1.5 Hz), 7.53 (s, 1H), 7.49 (d, 1H, J = 8.3 Hz ), 7.44 (d, 1H, J = 8.3 Hz), 7.40 (d, 1H, J = 6.9 Hz), 7.28 (d, 1H, J = 8.2 Hz), 6.90 (d, 1H, J = 6.9 Hz), 3.73 (s, 2H).
실시예 20: N-(1,1-다이옥시도벤조[Example 20: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(4-(트라이플루오로메톡시)페닐)아크릴아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acrylamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acrylamide}의 제조Preparation of ]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acrylamide}
Figure PCTKR2022016069-appb-img-000027
Figure PCTKR2022016069-appb-img-000027
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 2 : 1)로 정제하여 노란색 오일로 표제 화합물을 수득하였다(58.3 mg, 56 %).The reaction of steps 1 and 2 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 2:1) to obtain the title compound as a yellow oil (58.3 mg, 56%).
1H NMR (CD3OD, 500 MHz) δ 8.18 (s, 1H), 7.86 (dd, 1H, J = 8.2, 1.4 Hz), 7.61 (d, 2H, J = 8.7 Hz), 7.47 (d, 1H, J = 8.2 Hz), 7.42 (d, 1H, J = 6.9 Hz), 7.30 (d, 2H, J = 8.3 Hz), 6.92 (d, 1H, J = 6.9 Hz), 5.99 (s, 1H), 5.94 (s, 1H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.18 (s, 1H), 7.86 (dd, 1H, J = 8.2, 1.4 Hz), 7.61 (d, 2H, J = 8.7 Hz), 7.47 (d, 1H , J = 8.2 Hz), 7.42 (d, 1H, J = 6.9 Hz), 7.30 (d, 2H, J = 8.3 Hz), 6.92 (d, 1H, J = 6.9 Hz), 5.99 (s, 1H), 5.94 (s, 1H).
실시예 21: 2-(3,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[Example 21: 2-(3,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마이드 {2-(3,4-Dichlorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acrylamide {2-(3,4-Dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000028
Figure PCTKR2022016069-appb-img-000028
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 5 : 1)로 정제하여 연한 녹색 오일로 표제 화합물을 수득하였다(14.0 mg, 23 %).The reaction of steps 1 and 2 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 5: 1) to obtain the title compound as a pale green oil (14.0 mg, 23%).
1H NMR (CD3OD, 500 MHz) δ 8.17 (s, 1H), 7.88 (d, 1H, J = 8.3 Hz), 7.70 (s, 1H), 7.55 (d, 1H, J = 8.5 Hz), 7.48 (d, 1H, J = 8.3 Hz), 7.44 (m, 2H), 6.93 (d, 1H, J = 6.9 Hz), 6.04 (s, 1H), 5.98 (s, 1H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.17 (s, 1H), 7.88 (d, 1H, J = 8.3 Hz), 7.70 (s, 1H), 7.55 (d, 1H, J = 8.5 Hz), 7.48 (d, 1H, J = 8.3 Hz), 7.44 (m, 2H), 6.93 (d, 1H, J = 6.9 Hz), 6.04 (s, 1H), 5.98 (s, 1H).
실시예 22: N-(1,1-다이옥시도벤조[Example 22: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(4-플루오로페닐)아크릴아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(4-fluorophenyl)acrylamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(4-fluorophenyl)acrylamide}의 제조Preparation of ]thiophen-6-yl)-2-(4-fluorophenyl)acrylamide}
Figure PCTKR2022016069-appb-img-000029
Figure PCTKR2022016069-appb-img-000029
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 2 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(16.0 mg, 36 %).The reaction of steps 1 and 2 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 2:1) to obtain the title compound as a yellow solid (16.0 mg, 36%).
1H NMR (CD3OD, 500 MHz) δ 8.18 (s, 1H), 7.87 (d, 1H, J = 8.2 Hz), 7.53 (m, 2H), 7.47 (d, 1H, J = 8.3 Hz), 7.42 (d, 1H, J = 6.9 Hz), 7.13 (m, 2H), 6.92 (d, 1H, J = 6.9 Hz), 5.92 (s, 1H), 5.87 (s, 1H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.18 (s, 1H), 7.87 (d, 1H, J = 8.2 Hz), 7.53 (m, 2H), 7.47 (d, 1H, J = 8.3 Hz), 7.42 (d, 1H, J = 6.9 Hz), 7.13 (m, 2H), 6.92 (d, 1H, J = 6.9 Hz), 5.92 (s, 1H), 5.87 (s, 1H).
실시예 23: N-(1,1-다이옥시도벤조[Example 23: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(4-(트라이플루오로메틸)페닐)아크릴아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acrylamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acrylamide}의 제조Preparation of ]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acrylamide}
Figure PCTKR2022016069-appb-img-000030
Figure PCTKR2022016069-appb-img-000030
반응식 1에 따라 단계 1 및 2의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다(12.7 mg, 5 %).Steps 1 and 2 were carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a pale yellow solid (12.7 mg, 5%).
1H NMR (CD3OD, 500 MHz) δ 8.19 (s, 1H), 7.88 (d, 1H, J = 8.2 Hz), 7.71 (m, 4H), 7.49 (d, 1H, J = 8.1 Hz), 7.43 (d, 1H, J = 6.5 Hz), 6.93 (m, 1H), 6.09 (s, 1H), 6.02 (s, 1H). 1 H NMR (CD 3 OD, 500 MHz) δ 8.19 (s, 1H), 7.88 (d, 1H, J = 8.2 Hz), 7.71 (m, 4H), 7.49 (d, 1H, J = 8.1 Hz), 7.43 (d, 1H, J = 6.5 Hz), 6.93 (m, 1H), 6.09 (s, 1H), 6.02 (s, 1H).
실시예 24: N-(1,1-다이옥시도벤조[Example 24: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(p-톨릴)아세트아마이드 {N-(1,1-Dioxidobenzo[]thiophen-6-yl)-2-(p-tolyl)acetamide {N-(1,1-Dioxidobenzo[ bb ]thiophen-6-yl)-2-(p-tolyl)acetamide}의 제조Preparation of ]thiophen-6-yl)-2-(p-tolyl)acetamide}
Figure PCTKR2022016069-appb-img-000031
Figure PCTKR2022016069-appb-img-000031
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다(37.3 mg, 22 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a yellow solid (37.3 mg, 22%).
1H NMR (CDCl3, 500 MHz) δ 7.84 (dd, 1H, J = 8.3, 1.7 Hz), 7.63 (s, 1H), 7.35 (s, 1H), 7.26 (m, 1H), 7.23 (d, 2H, J = 8.1 Hz), 7.20 (d, 2H, J = 8.1 Hz), 7.15 (d, 1H, J = 6.9 Hz), 6.63 (d, 1H, J = 6.9 Hz), 3.73 (s, 2H), 2.39 (s, 3H). 1H NMR (CDCl 3 , 500 MHz) δ 7.84 (dd, 1H, J = 8.3, 1.7 Hz), 7.63 (s, 1H), 7.35 (s, 1H), 7.26 (m, 1H), 7.23 (d, 2H, J = 8.1 Hz), 7.20 (d, 2H, J = 8.1 Hz), 7.15 (d, 1H, J = 6.9 Hz), 6.63 (d, 1H, J = 6.9 Hz), 3.73 (s, 2H) , 2.39 (s, 3H).
실시예 25: 2-(2,3-다이클로로페닐)-N-(1,1-다이옥시도벤조[Example 25: 2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마이드 {2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acrylamide {2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000032
Figure PCTKR2022016069-appb-img-000032
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 노란색 폼형 고체로 표제 화합물을 수득하였다 (73.6 mg, 39 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a yellow foamy solid (73.6 mg, 39%).
1H NMR (CDCl3, 500 MHz) δ 7.89 (dd, 1H, J = 8.3, 0.4 Hz), 7.73 (m, 1H), 7.57 (dd, 1H, J = 7.2, 2.5 Hz), 7.46 (s, 1H), 7.30 (m, 3H), 7.17 (dd, 1H, J = 6.9, 1.0 Hz), 6.64 (d, 1H, J = 6.9 Hz), 6.54 (d, 1H, J = 0.9 Hz), 5.76 (d, 1H, J = 0.8 Hz); 13C NMR (CDCl3, 125 MHz) δ 163.7, 142.6, 140.4, 137.7, 137.7, 134.2, 132.3, 132.2, 131.5, 130.1, 129.9, 128.3, 127.9, 126.8, 126.1, 124.4, 113.5. 1H NMR (CDCl 3 , 500 MHz) δ 7.89 (dd, 1H, J = 8.3, 0.4 Hz), 7.73 (m, 1H), 7.57 (dd, 1H, J = 7.2, 2.5 Hz), 7.46 (s, 1H), 7.30 (m, 3H), 7.17 (dd, 1H, J = 6.9, 1.0 Hz), 6.64 (d, 1H, J = 6.9 Hz), 6.54 (d, 1H, J = 0.9 Hz), 5.76 ( d, 1H, J = 0.8 Hz); 13 C NMR (CDCl 3, 125 MHz) δ 163.7, 142.6, 140.4, 137.7, 137.7, 134.2, 132.3, 132.2, 131.5, 130.1, 129.9, 128.3, 127.9, 126.8, 121.4, 126.1, 126.1
실시예 26: 2-(2,3-다이클로로페닐)-N-(1,1-다이옥시도벤조[Example 26: 2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acetamide {2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000033
Figure PCTKR2022016069-appb-img-000033
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다 (200.6 mg, 52 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a yellow solid (200.6 mg, 52%).
1H NMR (DMSO-d 6, 400 MHz) δ 10.77 (s, 1H), 8.11 (m, 1H), 7.72 (dd, 1H, J = 8.2, 2.0 Hz), 7.58 (dd, 2H, J = 8.0, 1.5 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.44 (dd, 1H, J = 7.7, 1.6 Hz), 7.35 (t, 1H, J = 7.8 Hz), 7.27 (d, 1H, J = 6.9 Hz), 3.98 (s, 2H); 13C NMR (DMSO-d 6, 125 MHz) δ 168.4, 141.5, 137.2, 136.2, 132.8, 131.9, 131.6, 131.0, 130.0, 129.3, 128.0, 126.6, 125.5, 123.1, 111.1, 41.7. 1 H NMR (DMSO- d 6 , 400 MHz) δ 10.77 (s, 1H), 8.11 (m, 1H), 7.72 (dd, 1H, J = 8.2, 2.0 Hz), 7.58 (dd, 2H, J = 8.0 , 1.5 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.44 (dd, 1H, J = 7.7, 1.6 Hz), 7.35 (t, 1H, J = 7.8 Hz), 7.27 (d, 1H, J = 7.8 Hz ) . = 6.9 Hz), 3.98 (s, 2H); 13 C NMR (DMSO- d 6, 125 MHz) δ 168.4, 141.5, 137.2, 136.2, 132.8, 131.9, 131.6, 131.0, 130.0, 129.3, 128.0, 126.6, 125.5, 123.1, 111.1.
실시예 27: 2-(2,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[Example 27: 2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acetamide {2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000034
Figure PCTKR2022016069-appb-img-000034
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다 (360 mg, 89 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a pale yellow solid (360 mg, 89%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.74 (s, 1H), 8.11 (s, 1H), 7.72 (dd, 1H, J = 8.3, 1.8 Hz), 7.63 (d, 1H, J = 2.0 Hz), 7.58 (d, 1H, J = 6.9 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.48 (d, 1H, J = 8.3 Hz), 7.43 (dd, 1H, J = 8.3, 2.1 Hz), 7.27 (d, 1H, J = 6.9 Hz), 3.90 (s, 2H); 13C NMR (DMSO-d 6, 125 MHz ) δ 168.4, 141.5, 137.2, 134.7, 133.6, 132.8, 132.6, 132.4, 130.0, 128.5, 127.3, 126.6, 125.5, 123.1, 111.1. 1H NMR (DMSO- d 6 , 500 MHz) δ 10.74 (s, 1H), 8.11 (s, 1H), 7.72 (dd, 1H, J = 8.3, 1.8 Hz), 7.63 (d, 1H, J = 2.0 Hz), 7.58 (d, 1H, J = 6.9 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.48 (d, 1H, J = 8.3 Hz), 7.43 (dd, 1H, J = 8.3, 2.1 Hz), 7.27 (d, 1H, J = 6.9 Hz), 3.90 (s, 2H); 13 C NMR (DMSO- d 6 , 125 MHz ) δ 168.4, 141.5, 137.2, 134.7, 133.6, 132.8, 132.6, 132.4, 130.0, 128.5, 127.3, 126.6, 125.5, 123.1, 111.1.
실시예 28: 2-(2,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[Example 28: 2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마아드 {2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acrylamide {2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000035
Figure PCTKR2022016069-appb-img-000035
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다 (71.2 mg, 22 %).The reaction of step 1 was carried out according to Scheme 1 and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a pale yellow solid (71.2 mg, 22%).
1H NMR (CDCl3, 400 MHz) δ 10.56 (s, 1H), 8.14 (s, 1H), 7.92 (dd, 1H, J = 8.3, 1.9 Hz), 7.67 (d, 1H, J = 1.9 Hz), 7.60 (d, 1H, J = 6.9 Hz), 7.55 (d, 1H, J = 8.2 Hz), 7.52 (dd, 1H, J = 8.3, 2.0 Hz), 7.48 (d, 1H, J = 8.2 Hz), 7.29 (d, 1H, J = 6.9 Hz), 6.28 (s, 1H), 5.95 (s, 1H); 1H NMR (CDCl 3 , 400 MHz) δ 10.56 (s, 1H), 8.14 (s, 1H), 7.92 (dd, 1H, J = 8.3, 1.9 Hz), 7.67 (d, 1H, J = 1.9 Hz) , 7.60 (d, 1H, J = 6.9 Hz), 7.55 (d, 1H, J = 8.2 Hz), 7.52 (dd, 1H, J = 8.3, 2.0 Hz), 7.48 (d, 1H, J = 8.2 Hz) , 7.29 (d, 1H, J = 6.9 Hz), 6.28 (s, 1H), 5.95 (s, 1H);
실시예 29: 2-(2,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[Example 29: 2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acetamide {2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000036
Figure PCTKR2022016069-appb-img-000036
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 2)로 정제하여 노란색 고체로 표제 화합물을 수득하였다 (118.6 mg, 30 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:2) to obtain the title compound as a yellow solid (118.6 mg, 30%).
1H NMR (CDCl3, 500 MHz) δ 10.5 (s, 1H), 8.13(s, 1H), 7.73 (dd, 1H, J = 10.3, 2.4 Hz), 7.57 (d, 1H, J = 8.6 Hz), 7.52 (d, 1H, J = 10.2 Hz), 7.25 (d, 1H, J = 8.6 Hz), 7.12 (d, 1H, J = 1.3 Hz), 6.55 (d, 1H, J = 3 Hz), 6.49 (dd, 1H, J = 10.3, 3.1 Hz), 3.75 (s, 3H), 3.78 (s, 3H), 3.59 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 170.3, 159.7, 158.1, 141.8, 137.2, 132.9, 131.3, 129.8, 126.5, 125.1, 122.9, 115.8, 111.0, 104.5, 98.3, 55.5, 55.2. 1H NMR (CDCl 3 , 500 MHz) δ 10.5 (s, 1H), 8.13 (s, 1H), 7.73 (dd, 1H, J = 10.3, 2.4 Hz), 7.57 (d, 1H, J = 8.6 Hz) , 7.52 (d, 1H, J = 10.2 Hz), 7.25 (d, 1H, J = 8.6 Hz), 7.12 (d, 1H, J = 1.3 Hz), 6.55 (d, 1H, J = 3 Hz), 6.49 (dd, 1H, J = 10.3, 3.1 Hz), 3.75 (s, 3H), 3.78 (s, 3H), 3.59 (s, 2H); 13 C NMR (CDCl 3, 125 MHz) δ 170.3, 159.7, 158.1, 141.8, 137.2, 132.9, 131.3, 129.8, 126.5, 125.1, 122.9, 115.8, 111.0, 104.5, 55.2.3, 55.2.3,
실시예 30: N-(1,1-다이옥시도벤조[Example 30: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(3-플루오로페닐)아세트아마이드 {N-(1,1-dioxidobenzo[]thiophen-6-yl)-2-(3-fluorophenyl)acetamide {N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)-2-(3-fluorophenyl)acetamide}의 제조Preparation of ]thiophen-6-yl)-2-(3-fluorophenyl)acetamide}
Figure PCTKR2022016069-appb-img-000037
Figure PCTKR2022016069-appb-img-000037
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다 (97.7 mg, 56 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a pale yellow solid (97.7 mg, 56%).
1H NMR (DMSO-d6, 400 MHz) δ 10.69 (s, 1H), 8.13 (s, 1H), 7.73 (dd, 1H, J = 8.3, 2.0 Hz), 7.57 (d, 1H, J = 6.9 Hz), 7.53 (d, 1H, J = 8.2 Hz), 7.37 (m, 1H), 7.27 (d, 1H, J = 6.8 Hz), 7.18 (m, 2H), 7.09 (m, 1H), 3.74 (s, 2H); 13C NMR (DMSO-d6, 125 MHz) δ 169.4, 163.0, 161.1, 141.5, 138.1, 138.0, 137.2, 132.8, 130.2, 130.2, 130.0, 126.6, 125.5, 125.5, 125.4, 123.2, 116.2, 116.0, 113.6, 113.5, 111.2, 42.7. 1 H NMR (DMSO-d 6 , 400 MHz) δ 10.69 (s, 1H), 8.13 (s, 1H), 7.73 (dd, 1H, J = 8.3, 2.0 Hz), 7.57 (d, 1H, J = 6.9 Hz), 7.53 (d, 1H, J = 8.2 Hz), 7.37 (m, 1H), 7.27 (d, 1H, J = 6.8 Hz), 7.18 (m, 2H), 7.09 (m, 1H), 3.74 ( s, 2H); 13 C NMR (DMSO-d 6 , 125 MHz) δ 169.4, 163.0, 161.1, 141.5, 138.1, 138.0, 137.2, 132.8, 130.2, 130.2, 130.0, 126.6, 125.5, 125.2, 125.5, 125.4, 125.5 116.0, 113.6 , 113.5, 111.2, 42.7.
실시예 31: 2-(2,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[Example 31: 2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마이드 {2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acrylamide {2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000038
Figure PCTKR2022016069-appb-img-000038
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 노란색 오일로 표제 화합물을 수득하였다 (18.4 mg, 22 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a yellow oil (18.4 mg, 22%).
1H NMR (CDCl3, 500 MHz) δ 7.94 (dd, 1H, J = 8.1, 2.05 Hz), 7.68 (s, 1H), 7.60 (s, 1H), 7.29 (d, 1H, J = 8.25 Hz), 7.22 (d, 1H, J = 8.3 Hz), 7.17 (d, 1H, J = 7.0 Hz), 6.63 (d, 1H, J = 6.9 Hz), 6.57 (dd, 1H, J = 8.3, 2.4 Hz), 6.52 (d, 1H, J = 2.4), 6.33(d, 1H, J = 1.6 Hz), 5.63 (d, 1H, J = 1.6), 3.86 (s, 3H), 3.77(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 165.9, 162.2, 158.0, 141.9, 141.0, 137.8, 132.3, 132.0, 129.7, 126.1, 126.0, 125.3, 123.8, 118.2, 112.9, 105.6, 99.1, 56.0, 55.7. 1H NMR (CDCl 3 , 500 MHz) δ 7.94 (dd, 1H, J = 8.1, 2.05 Hz), 7.68 (s, 1H), 7.60 (s, 1H), 7.29 (d, 1H, J = 8.25 Hz) , 7.22 (d, 1H, J = 8.3 Hz), 7.17 (d, 1H, J = 7.0 Hz), 6.63 (d, 1H, J = 6.9 Hz), 6.57 (dd, 1H, J = 8.3, 2.4 Hz) , 6.52 (d, 1H, J = 2.4), 6.33 (d, 1H, J = 1.6 Hz), 5.63 (d, 1H, J = 1.6), 3.86 (s, 3H), 3.77 (s, 3H); 13 C NMR (CDCl 3, 125 MHz) δ 165.9, 162.2, 158.0, 141.9, 141.0, 137.8, 132.3, 132.0, 129.7, 126.1, 126.0, 125.3, 123.8, 118.2, 118.2, 192.9, , 55.7.
실시예 32: N-(1,1-다이옥시도벤조[Example 32: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(3-플루오로페닐)아크릴아마이드 N-(1,1-dioxidobenzo[]thiophen-6-yl)-2-(3-fluorophenyl)acrylamide N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)-2-(3-fluorophenyl)acrylamide}의 제조Preparation of ]thiophen-6-yl)-2-(3-fluorophenyl)acrylamide}
Figure PCTKR2022016069-appb-img-000039
Figure PCTKR2022016069-appb-img-000039
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 연한 녹색 고체로 표제 화합물을 수득하였다 (21.4 mg, 26 %).The reaction of step 1 was carried out according to Scheme 1 and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a pale green solid (21.4 mg, 26%).
1H NMR (DMSO-d 6, 400 MHz) δ 10.75 (s, 1H), 8.21 (s, 1H), 7.91 (dd, 1H, J = 8.2, 1.9 Hz), 7.61 (d, 1H, J = 6.9 Hz ), 7.57 (d, 1H, J = 8.2 Hz), 7.45 (m, 1H), 7.39 (m, 1H), 7.34 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 6.8 Hz), 7.21 (m, 1H), 6.14 (s, 1H), 5.93 (s, 1H); 13C NMR (DMSO-d 6, 125 MHz) δ 167.2, 163.1, 161.2, 143.4, 141.4, 138.3, 138.3, 137.1, 132.8, 130.5, 130.5, 130.2, 126.4, 125.9, 124.1, 123.3, 123.3, 120.6, 115.3, 115.1, 113.8, 113.6, 112.2. 1 H NMR (DMSO- d 6 , 400 MHz) δ 10.75 (s, 1H), 8.21 (s, 1H), 7.91 (dd, 1H, J = 8.2, 1.9 Hz), 7.61 (d, 1H, J = 6.9 Hz), 7.57 (d, 1H, J = 8.2 Hz), 7.45 (m, 1H), 7.39 (m, 1H), 7.34 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 6.8 Hz), 7.21 (m, 1H), 6.14 (s, 1H), 5.93 (s, 1H); 13 C NMR (DMSO- d 6, 125 MHz) δ 167.2, 163.1, 161.2, 143.4, 141.4, 138.3, 138.3, 137.1, 132.8, 130.5, 130.5, 130.2, 126.4, 125.3, 121.3, 121.1 20.6, 115.3 , 115.1, 113.8, 113.6, 112.2.
실시예 33: N-(1,1-다이옥시도벤조[Example 33: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(3,4,5-트라이메톡시페닐)아크릴아마이드 {N-(1,1-dioxidobenzo[]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acrylamide {N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acetamide}의 제조Preparation of ]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acetamide}
Figure PCTKR2022016069-appb-img-000040
Figure PCTKR2022016069-appb-img-000040
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다 (90.8 mg, 45 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a yellow solid (90.8 mg, 45%).
1H NMR (CDCl3, 500 MHz) δ 7.84 (dd, 1H, J = 8.2, 2.0 Hz), 7.73 (s, 1H), 7.60 (s, 1H), 7.28 (d, 1H, J = 8.4 Hz), 7.17 (d, 1H, J = 7.0 Hz), 6.65 (d, 1H, J = 6.8 Hz), 6.53 (s, 1H), 3.87 (s, 6H), 3.87 (s, 3H), 3.70(s, 1H); 13C NMR (CDCl3, 125 MHz) δ 169.4, 154.0, 140.6, 137.7, 137.7, 132.4, 129.9, 129.4, 126.4, 126.1, 123.8, 112.9, 106.5, 61.1, 56.4, 45.2. 1 H NMR (CDCl 3 , 500 MHz) δ 7.84 (dd, 1H, J = 8.2, 2.0 Hz), 7.73 (s, 1H), 7.60 (s, 1H), 7.28 (d, 1H, J = 8.4 Hz) , 7.17 (d, 1H, J = 7.0 Hz), 6.65 (d, 1H, J = 6.8 Hz), 6.53 (s, 1H), 3.87 (s, 6H), 3.87 (s, 3H), 3.70 (s, 1H); 13 C NMR (CDCl 3, 125 MHz) δ 169.4, 154.0, 140.6, 137.7, 137.7, 132.4, 129.9, 129.4, 126.4, 126.1, 123.8, 112.9, 106.5, 61.1, 56.2.4, 45.2.
실시예 34: N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-페녹시페닐)아세트아마이드 {N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(4-phenoxyphenyl)acetamide}의 제조Example 34: N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(4-phenoxyphenyl)acetamide {N-(1,1-dioxidobenzo[b]thiophen- Preparation of 6-yl)-2-(4-phenoxyphenyl)acetamide}
Figure PCTKR2022016069-appb-img-000041
Figure PCTKR2022016069-appb-img-000041
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 2)로 정제하여 녹색 고체로 표제 화합물을 수득하였다 (343 mg, 80 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:2) to obtain the title compound as a green solid (343 mg, 80%).
1H NMR (CDCl3, 500 MHz) δ 7.88 (dd, 1H, J = 8.3, 2.1 Hz), 7.69 (s, 1H), 7.64 (s, 1H), 7.35 (m, 2H), 7.27 (d, 2H, J = 2.5 Hz), 7.25 (d, 1H, J = 2.6 Hz), 7.16 (d, 1H, J = 6.9 Hz), 7.13 (t, 1H, J = 7.4 Hz), 7.03 (m, 2H), 7.00 (m, 2H), 6.63 (d, 1H, J = 6.9 Hz), 3.71 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 169.5, 157.2, 156.6, 140.6, 137.5, 132.4, 130.8, 129.9, 129.6, 128.2, 126.2, 126.0, 123.7, 123.7, 119.3, 119.2, 112.7, 77.3, 77.0, 76.8, 43.9. 1 H NMR (CDCl 3 , 500 MHz) δ 7.88 (dd, 1H, J = 8.3, 2.1 Hz), 7.69 (s, 1H), 7.64 (s, 1H), 7.35 (m, 2H), 7.27 (d, 2H, J = 2.5 Hz), 7.25 (d, 1H, J = 2.6 Hz), 7.16 (d, 1H, J = 6.9 Hz), 7.13 (t, 1H, J = 7.4 Hz), 7.03 (m, 2H) , 7.00 (m, 2H), 6.63 (d, 1H, J = 6.9 Hz), 3.71 (s, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 169.5, 157.2, 156.6, 140.6, 137.5, 132.4, 130.8, 129.9, 129.6, 128.2, 126.2, 126.0, 123.7, 123.7, 119.2, 119.3 .3, 77.0, 76.8 , 43.9.
실시예 35: N-(1,1-다이옥시도벤조[Example 35: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(4-페녹시페닐)아크릴아마이드 {N-(1,1-dioxidobenzo[]thiophen-6-yl)-2-(4-phenoxyphenyl)acrylamide {N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)-2-(4-phenoxyphenyl)acrylamide}의 제조Preparation of ]thiophen-6-yl)-2-(4-phenoxyphenyl)acrylamide}
Figure PCTKR2022016069-appb-img-000042
Figure PCTKR2022016069-appb-img-000042
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다 (52.6 mg, 20 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a yellow solid (52.6 mg, 20%).
1H NMR (CDCl3, 500 MHz) δ 7.96 (dd, 1H, J = 8.3, 2.1 Hz), 7.80 (s, 1H), 7.71 (s, 1H), 7.40 (m, 2H), 7.37 (m, 2H), 7.32 (d, 1H, J = 8.3 Hz), 7.18 (m, 1H), 7.17 (m, 1H), 7.08 (m, 2H), 7.04 (m, 2H), 6.65 (d, 1H, J = 6.9 Hz), 6.25 (s, 1H), 5.76 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 165.6, 158.6, 156.1, 143.8, 140.4, 137.7, 132.1, 130.4, 130.0, 129.9, 129.8, 126.5, 126.0, 124.2, 123.8, 123.7, 119.7, 118.6, 113.0, 77.3, 77.0, 76.8. 1 H NMR (CDCl 3 , 500 MHz) δ 7.96 (dd, 1H, J = 8.3, 2.1 Hz), 7.80 (s, 1H), 7.71 (s, 1H), 7.40 (m, 2H), 7.37 (m, 2H), 7.32 (d, 1H, J = 8.3 Hz), 7.18 (m, 1H), 7.17 (m, 1H), 7.08 (m, 2H), 7.04 (m, 2H), 6.65 (d, 1H, J = 6.9 Hz), 6.25 (s, 1H), 5.76 (s, 1H); 13 C NMR (CDCl 3 , 125 MHz) δ 165.6, 158.6, 156.1, 143.8, 140.4, 137.7, 132.1, 130.4, 130.0, 129.9, 129.8, 126.5, 126.0, 124.2, 121.7, 121.8 8.6, 113.0, 77.3 , 77.0, 76.8.
실시예 36: N-(1,1-다이옥시도벤조[Example 36: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(3,4,5-트라이메톡시페닐)아크릴아마이드 {N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acrylamide}의 제조]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acrylamide {N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(3,4 ,5-trimethoxyphenyl)acrylamide} Preparation
Figure PCTKR2022016069-appb-img-000043
Figure PCTKR2022016069-appb-img-000043
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 2 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다 (59.5 mg, 26 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 2:1) to obtain the title compound as a yellow solid (59.5 mg, 26%).
1H NMR (CDCl3, 500 MHz) δ 7.93 (dd, 1H, J = 5.2, 2.0 Hz), 7.86 (d, 1H, J = 1.8 Hz), 7.85 (s, 1H), 7.31 (d, 1H, J = 8.3 Hz), 6.65 (d, 1H, J = 6.9 Hz), 6.61 (s, 2H), 6.31 (d, 1H, J = 1.2 Hz ); 13C NMR (CDCl3, 125 MHz) δ 165.3, 153.7, 144.5, 140.6, 138.8, 137.8, 132.3, 131.7, 130.1, 126.6, 126.1, 124.6, 124.0, 113.3, 105.6, 77.4, 77.2, 76.9, 61.1, 56.4. 1 H NMR (CDCl 3 , 500 MHz) δ 7.93 (dd, 1H, J = 5.2, 2.0 Hz), 7.86 (d, 1H, J = 1.8 Hz), 7.85 (s, 1H), 7.31 (d, 1H, J = 8.3 Hz), 6.65 (d, 1H, J = 6.9 Hz), 6.61 (s, 2H), 6.31 (d, 1H, J = 1.2 Hz); 13 C NMR (CDCl 3 , 125 MHz) δ 165.3, 153.7, 144.5, 140.6, 138.8, 137.8, 132.3, 131.7, 130.1, 126.6, 126.1, 124.6, 124.0, 113.3, 77.24, 775.6 , 61.1, 56.4 .
실시예 37: 2-(3,5-다이플루오로페닐)-N-(1,1-다이옥시도벤조[Example 37: 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acetamide {2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000044
Figure PCTKR2022016069-appb-img-000044
반응식 1에 따라 단계 1의 반응을 진행하고, EtOAc 및 n-헥산에 의한 재결정화로 정제하여 노란색 고체로 표제 화합물을 수득하였다 (359.6 mg, 97 %).The reaction of step 1 was carried out according to Scheme 1 and purified by recrystallization with EtOAc and n -hexane to obtain the title compound as a yellow solid (359.6 mg, 97%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.69 (s, 1H), 8.12 (s, 1H), 7.72 (dd, 1H, J = 8.2, 1.8 Hz), 6.85 (d, 1H, J = 6.9 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.27 (d, 1H, J = 6.9 Hz), 7.13 (m, 1H), 7.08(d, 2H, J = 6.6 Hz), 3.78(s, 1H); 13C NMR (DMSO-d 6, 125 MHz) δ 168.9, 163.2, 163.1, 161.3, 161.2, 141.4, 139.7, 139.6, 139.5, 137.2, 132.8, 130.1, 126.6, 125.5, 123.2, 112.8, 112.7, 112.6, 112.6, 111.3, 102.5, 102.3, 102.1, 42.4, 40.0, 39.9, 39.7, 39.5, 39.4, 39.2, 39.0. 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.69 (s, 1H), 8.12 (s, 1H), 7.72 (dd, 1H, J = 8.2, 1.8 Hz), 6.85 (d, 1H, J = 6.9 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.27 (d, 1H, J = 6.9 Hz), 7.13 (m, 1H), 7.08 (d, 2H, J = 6.6 Hz), 3.78 (s, 1H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 168.9, 163.2, 163.1, 161.3, 161.2, 141.4, 139.7, 139.6, 139.5, 137.2, 132.8, 130.1, 126.6, 125.2, 121.2, 121.2, 121.2 112.6, 112.6 , 111.3, 102.5, 102.3, 102.1, 42.4, 40.0, 39.9, 39.7, 39.5, 39.4, 39.2, 39.0.
실시예 38: N-(1,1-다이옥시도벤조[Example 38: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(2-플루오로페닐)아세트아마이드 {N-(1,1-dioxidobenzo[]thiophen-6-yl)-2-(2-fluorophenyl)acetamide {N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)-2-(2-fluorophenyl)acetamide}의 제조Preparation of ]thiophen-6-yl)-2-(2-fluorophenyl)acetamide}
Figure PCTKR2022016069-appb-img-000045
Figure PCTKR2022016069-appb-img-000045
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 2)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다 (243.7 mg, 70 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:2) to obtain the title compound as a pale yellow solid (243.7 mg, 70%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.73 (s, 1H), 8.13 (s, 1H), 7.73 (dd, 1H, J = 8.3, 2.0 Hz), 7.58 (d, 1H, J = 6.9 Hz), 7.54 (d, 1H, J = 8.3 Hz), 7.40 (t, 1H, J = 7.8 Hz), 7.33 (m, 1H), 7.27(d, 1H, J = 6.9 Hz), 7.18 (m, 2H), 3.80 (s, 2H); 13C NMR (DMSO-d 6, 125 MHz) δ 168.9, 161.7, 159.7, 141.5, 137.2, 132.8, 132.1, 132.0, 130.0, 129.0, 129.0, 126.6, 125.4, 124.3, 124.3, 123.1, 122.5, 122.4, 115.2, 115.0, 111.2, 40.0, 39.9, 39.7, 39.5, 39.4, 39.2, 39.0, 36.4. 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.73 (s, 1H), 8.13 (s, 1H), 7.73 (dd, 1H, J = 8.3, 2.0 Hz), 7.58 (d, 1H, J = 6.9 Hz), 7.54 (d, 1H, J = 8.3 Hz), 7.40 (t, 1H, J = 7.8 Hz), 7.33 (m, 1H), 7.27 (d, 1H, J = 6.9 Hz), 7.18 (m, 2H), 3.80 (s, 2H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 168.9, 161.7, 159.7, 141.5, 137.2, 132.8, 132.1, 132.0, 130.0, 129.0, 129.0, 126.6, 125.4, 124.3, 5, 124.3, 124.3 122.4, 115.2 , 115.0, 111.2, 40.0, 39.9, 39.7, 39.5, 39.4, 39.2, 39.0, 36.4.
실시예 39: 2-(2,3-다이하이드로벤조[Example 39: 2-(2,3-dihydrobenzo[ bb ][1,4]다이옥신-6-일)-N-(1,1-다이옥시도벤조[][1,4]dioxin-6-yl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-yl)아세트아마이드 {2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(1,1-dioxidobenzo[]thiophene-6-yl)acetamide {2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000046
Figure PCTKR2022016069-appb-img-000046
반응식 1에 따라 단계 1의 반응을 진행하고, MeOH에 의한 재결정화로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다 (113.4 mg, 29 %).The reaction of step 1 was carried out according to Scheme 1 and purified by recrystallization with MeOH to obtain the title compound as a pale yellow solid (113.4 mg, 29%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.58 (s, 1H), 8.12 (s, 1H), 7.71 (dd, 1H, J = 8.3, 2.0 Hz), 7.57 (d, 1H, J = 6.9 Hz), 7.52 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.9 Hz), 6.84 (s, 1H), 6.80 (m, 1H), 6.77 (m, 1H), 4.21 (s, 4H), 3.55 (s, 2H); 13C NMR (DMSO-d 6, 125 MHz) δ 170.1, 143.1, 142.3, 141.6, 137.2, 132.8, 129.9, 128.2, 126.6, 125.4, 123.1, 121.9, 117.7, 116.9, 111.1, 64.1, 64.0. 1H NMR (DMSO- d 6, 500 MHz) δ 10.58 (s, 1H), 8.12 (s, 1H), 7.71 (dd, 1H, J = 8.3, 2.0 Hz), 7.57 (d, 1H, J = 6.9 Hz), 7.52 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.9 Hz), 6.84 (s, 1H), 6.80 (m, 1H), 6.77 (m, 1H), 4.21 ( s, 4H), 3.55 (s, 2H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 170.1, 143.1, 142.3, 141.6, 137.2, 132.8, 129.9, 128.2, 126.6, 125.4, 123.1, 121.9, 117.7, 116.1, 64.1, 111.9
실시예 40: 2-(3,4-다이메틸페닐)-N-(1,1-다이옥시도벤조[Example 40: 2-(3,4-dimethylphenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(3,4-dimethylphenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acetamide {2-(3,4-dimethylphenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000047
Figure PCTKR2022016069-appb-img-000047
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 1)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다 (92.3 mg, 26 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:1) to obtain the title compound as a pale yellow solid (92.3 mg, 26%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.60 (s, 1H), 8.13 (s, 1H), 7.72 (dd, 1H, J = 8.2, 1.5 Hz), 7.57 (d, 1H, J = 6.9 Hz), 7.35 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.9 Hz), 7.09 (s, 1H), 7.08 (d, 1H, J = 8.5 Hz), 7.04 (d, 1H, J = 7.7 Hz), 3.60 (s, 2H), 2.20 (s, 3H), 2.18 (s, 3H); 13C NMR (DMSO-d 6, 125 MHz) δ 170.2, 141.7, 137.2, 136.0, 134.5, 132.8, 132.6, 130.2, 129.9, 129.5, 126.6, 126.5, 125.3, 123.1, 111.1, 43.0, 19.4, 19.0. 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.60 (s, 1H), 8.13 (s, 1H), 7.72 (dd, 1H, J = 8.2, 1.5 Hz), 7.57 (d, 1H, J = 6.9 Hz), 7.35 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.9 Hz), 7.09 (s, 1H), 7.08 (d, 1H, J = 8.5 Hz), 7.04 (d, 1H, J = 7.7 Hz), 3.60 (s, 2H), 2.20 (s, 3H), 2.18 (s, 3H); 13 C NMR (DMSO- d 6, 125 MHz) δ 170.2, 141.7, 137.2, 136.0, 134.5, 132.8, 132.6, 130.2, 129.9, 129.5, 126.6, 126.5, 125.3, 123.1, 193.1, 1911.1 0.
실시예 41: 2-(3,5-다이플루오로페닐)-N-(1,1-다이옥시도벤조[Example 41: 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아크릴아마이드 {2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acrylamide {2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acrylamide}의 제조Preparation of ]thiophen-6-yl)acrylamide}
Figure PCTKR2022016069-appb-img-000048
Figure PCTKR2022016069-appb-img-000048
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산/CH2Cl2 = 2 : 2 : 1)로 정제하여 흰색 고체로 표제 화합물을 수득하였다 (53.9 mg, 19 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane/CH 2 Cl 2 = 2 : 2 : 1) to obtain the title compound as a white solid (53.9 mg, 19 %).
1H NMR (DMSO-d 6, 500 MHz) δ 10.75 (s, 1H), 8.21 (s, 1H), 7.90 (dd, 1H, J = 8.3, 1.5 Hz), 7.61 (d, 1H, J = 6.9 Hz), 7.57 (d, 1H, J = 8.2 Hz), 7.28 (m, 4H), 6.23 (s, 1H), 6.03 (s, 1H); 13C NMR (DMSO-d 6, 125 MHz) δ 166.6, 163.4, 163.3, 161.5, 161.3, 142.3, 141.3, 139.6, 139.5, 139.4, 137.0, 132.8, 130.2, 126.4, 125.9, 124.2, 122.3, 112.4, 110.6, 110.5, 110.4, 104.0, 103.8, 103.6. 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.75 (s, 1H), 8.21 (s, 1H), 7.90 (dd, 1H, J = 8.3, 1.5 Hz), 7.61 (d, 1H, J = 6.9 Hz), 7.57 (d, 1H, J = 8.2 Hz), 7.28 (m, 4H), 6.23 (s, 1H), 6.03 (s, 1H); 13 C NMR (DMSO- d 6, 125 MHz) δ 166.6, 163.4, 163.3, 161.5, 161.3, 142.3, 141.3, 139.6, 139.5, 139.4, 137.0, 132.8, 130.2, 126.2, 126.2, 121.9 12.4, 110.6 , 110.5, 110.4, 104.0, 103.8, 103.6.
실시예 42: N-(1,1-다이옥시도벤조[Example 42: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-(2-플루오로페닐)아크릴아마이드 {N-(1,1-dioxidobenzo[]thiophen-6-yl)-2-(2-fluorophenyl)acrylamide {N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)-2-(2-fluorophenyl)acrylamide}의 제조Preparation of ]thiophen-6-yl)-2-(2-fluorophenyl)acrylamide}
Figure PCTKR2022016069-appb-img-000049
Figure PCTKR2022016069-appb-img-000049
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 2)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다 (89.7 mg, 40 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:2) to obtain the title compound as a pale yellow solid (89.7 mg, 40%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.67 (s, 1H), 8.18 (s, 1H), 7.92 (dd, 1H, J = 8.3, 2.0 Hz), 7.60 (d, 1H), 7.56 (d, 1H), 7.49 (m, 1H), 7.44 (m, 1H), 7.28 (m, 2H), 7.22 (d, 1H, J = 8.5 Hz), 6.14 (s, 1H), 6.02 (s, 1H); 13C NMR (DMSO-d 6, 125 MHz) δ 166.6, 160.3, 158.3, 141.6, 140.2, 137.1, 132.8, 130.9, 130.9, 130.7, 130.7, 130.1, 126.5, 125.7, 125.0, 124.9, 124.7, 124.7, 123.9, 123.8, 115.6, 115.5, 112.0. 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.67 (s, 1H), 8.18 (s, 1H), 7.92 (dd, 1H, J = 8.3, 2.0 Hz), 7.60 (d, 1H), 7.56 ( d, 1H), 7.49 (m, 1H), 7.44 (m, 1H), 7.28 (m, 2H), 7.22 (d, 1H, J = 8.5 Hz), 6.14 (s, 1H), 6.02 (s, 1H) ); 13 C NMR (DMSO- d 6 , 125 MHz) δ 166.6, 160.3, 158.3, 141.6, 140.2, 137.1, 132.8, 130.9, 130.9, 130.7, 130.7, 130.1, 126.5, 125.4, 125.4, 125.4, 125.7, 125.7 124.7, 123.9 , 123.8, 115.6, 115.5, 112.0.
실시예 43: 2-(2,3-다이하이드로벤조퓨란-5-일)-N-(1,1-다이옥시도벤조[Example 43: 2-(2,3-dihydrobenzofuran-5-yl)-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-(2,3-dihydrobenzofuran-5-yl)-N-(1,1-dioxidobenzo[]thiophen-6-yl)acetamide {2-(2,3-dihydrobenzofuran-5-yl)-N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000050
Figure PCTKR2022016069-appb-img-000050
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(CH2Cl2/MeOH = 80 : 1)로 정제하여 노란색 고체로 표제 화합물을 수득하였다 (88 mg, 23 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (CH 2 Cl 2 /MeOH = 80: 1) to obtain the title compound as a yellow solid (88 mg, 23%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.59 (s, 1H), 8.13 (s, 1H), 7.72 (dd, 1H, J = 8.3, 2.0 Hz), 7.57 (d, 1H, J = 7.0 Hz), 7.52 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 8.2 Hz), 7.19 (s, 1H), 7.03 (d, 1H, J = 8.1 Hz), 6.70 (d, 1H, J = 8.1 Hz), 4.49 (t, 2H, J = 8.7 Hz), 3.59 (s, 2H), 3.15 (t, 2H, J = 8.7 Hz); 13C NMR (DMSO-d 6, 125 MHz) δ 170.4, 158.6, 141.7, 137.2, 132.8, 129.9, 128.5, 127.4, 127.0, 126.5, 125.8, 125.3, 123.0, 111.1, 108.6, 70.9, 42.7, 29.1. 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.59 (s, 1H), 8.13 (s, 1H), 7.72 (dd, 1H, J = 8.3, 2.0 Hz), 7.57 (d, 1H, J = 7.0 Hz), 7.52 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 8.2 Hz), 7.19 (s, 1H), 7.03 (d, 1H, J = 8.1 Hz), 6.70 (d, 1H, J = 8.1 Hz), 4.49 (t, 2H, J = 8.7 Hz), 3.59 (s, 2H), 3.15 (t, 2H, J = 8.7 Hz); 13 C NMR (DMSO- d 6 , 125 MHz) δ 170.4, 158.6, 141.7, 137.2, 132.8, 129.9, 128.5, 127.4, 127.0, 126.5, 125.8, 125.3, 123.0, 111.9, 270.1, 92.1, 108.1 .1.
실시예 44: 2-사이클로헥실-N-(1,1-다이옥시도벤조[Example 44: 2-cyclohexyl-N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)아세트아마이드 {2-cyclohexyl-N-(1,1-dioxidobenzo[b]thiophen-6-yl)acetamide}의 제조Preparation of ]thiophen-6-yl)acetamide {2-cyclohexyl-N-(1,1-dioxidobenzo[b]thiophen-6-yl)acetamide}
Figure PCTKR2022016069-appb-img-000051
Figure PCTKR2022016069-appb-img-000051
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 1 : 4)로 정제하여 흰색 고체로 표제 화합물을 수득하였다 (32.4 mg, 20 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 1:4) to obtain the title compound as a white solid (32.4 mg, 20%).
1H NMR (DMSO-d 6, 400 MHz) δ 10.38 (s, 1H), 8.16 (s, 1H), 7.69 (dd, 1H, J = 8.2, 1.9 Hz), 7.58 (d, 1H, J = 6.9 Hz), 7.51 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.8 Hz), 2.23 (d, 2H, J = 7.1 Hz), 1.78 (m, 1H), 1.67 (m, 4H), 1.60 (s, 1H), 1.23 (m, 2H), 1.13 (m, 1H), 0.97 (m, 2H); 13C NMR (DMSO-d 6, 125 MHz) δ 171.3, 141.7, 137.2, 132.9, 129.9, 126.5, 125.2, 122.9, 111.1, 44.3, 34.7, 32.5, 25.8, 25.6. 1 H NMR (DMSO- d 6 , 400 MHz) δ 10.38 (s, 1H), 8.16 (s, 1H), 7.69 (dd, 1H, J = 8.2, 1.9 Hz), 7.58 (d, 1H, J = 6.9 Hz), 7.51 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.8 Hz), 2.23 (d, 2H, J = 7.1 Hz), 1.78 (m, 1H), 1.67 (m, 4H), 1.60 (s, 1H), 1.23 (m, 2H), 1.13 (m, 1H), 0.97 (m, 2H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 171.3, 141.7, 137.2, 132.9, 129.9, 126.5, 125.2, 122.9, 111.1, 44.3, 34.7, 32.5, 25.8, 25.6.
실시예 45: N-(1,1-다이옥시도벤조[Example 45: N-(1,1-dioxidobenzo[ bb ]싸이오펜-6-일)-2-몰폴리노아세트아마이드 {N-(1,1-dioxidobenzo[]thiophen-6-yl)-2-morpholinoacetamide {N-(1,1-dioxidobenzo[ bb ]thiophen-6-yl)-2-morpholinoacetamide}의 제조Preparation of ]thiophen-6-yl)-2-morpholinoacetamide}
Figure PCTKR2022016069-appb-img-000052
Figure PCTKR2022016069-appb-img-000052
반응식 1에 따라 단계 1의 반응을 진행하고, 실리카겔 칼럼 크로마토그래피(EtOAc/n-헥산 = 3 : 1)로 정제하여 연한 노란색 고체로 표제 화합물을 수득하였다 (102.4 mg, 60 %).The reaction of step 1 was carried out according to Scheme 1, and purified by silica gel column chromatography (EtOAc/ n -hexane = 3:1) to obtain the title compound as a pale yellow solid (102.4 mg, 60%).
1H NMR (DMSO-d 6, 500 MHz) δ 10.20 (s, 1H), 8.17 (s, 1H), 7.85 (d, 1H, J = 8.2 Hz), 7.57 (d, 1H, J = 6.9 Hz), 7.52 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.9 Hz), 3.63 (s, 4H), 3.17 (s, 2H), 2.49 (m, 4H)); 13C NMR (DMSO-d 6, 100 MHz) δ 169.1, 141.1, 137.1, 132.9, 130.1, 126.5, 125.6, 123.6, 111.9, 66.1, 62.1, 1 H NMR (DMSO- d 6 , 500 MHz) δ 10.20 (s, 1H), 8.17 (s, 1H), 7.85 (d, 1H, J = 8.2 Hz), 7.57 (d, 1H, J = 6.9 Hz) , 7.52 (d, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 6.9 Hz), 3.63 (s, 4H), 3.17 (s, 2H), 2.49 (m, 4H)); 13 C NMR (DMSO- d 6, 100 MHz) δ 169.1, 141.1, 137.1, 132.9, 130.1, 126.5, 125.6, 123.6, 111.9, 66.1, 62.1,
실험예 1: IL-6에 의해 유도되는 STAT3의 전사활성 억제 효과 확인Experimental Example 1: Confirmation of the effect of inhibiting the transcriptional activity of STAT3 induced by IL-6
1.1. 루시퍼레이즈(Luciferase)가 도입된 형질전환 세포1.1. Transformed cells into which Luciferase was introduced
STAT3의 활성 변화를 확인하기 위해 STAT3 리포터 유전자를 포함하는 Stat3 Luciferase Reporter HEK293 Stable Cell Line(Cat# SL-0071-NP)을 Signosis로부터 구입하여 10% FBS(Thermo fisher scientific, Cat# 26140-079), 1% 페니실린/스트렙토마이신(Thermo fisher scientific, Cat# 15140-122)이 첨가된 DMEM High glucose(Thermo fisher scientific, Cat# 11995-073) 배지로 배양하였고, 하이그로마이신(hygromycin)을 100 μg/ml의 농도로 처리하여 루시퍼레이즈(luciferase)가 안정하게 발현되는 클론(clone)을 얻었다.To confirm the change in STAT3 activity, Stat3 Luciferase Reporter HEK293 Stable Cell Line (Cat# SL-0071-NP) containing the STAT3 reporter gene was purchased from Signosis and 10% FBS (Thermo fisher scientific, Cat# 26140-079), It was cultured in DMEM High Glucose (Thermo fisher scientific, Cat# 11995-073) medium supplemented with 1% penicillin/streptomycin (Thermo fisher scientific, Cat# 15140-122), and hygromycin was added at 100 μg/ml By treatment with a concentration of luciferase (luciferase) to obtain a stable expression clone (clone).
1-2. IL-6 반응성 STAT3 루시퍼라제 활성 확인1-2. Confirmation of IL-6-responsive STAT3 luciferase activity
Stat3 Luciferase Reporter HEK293 Stable Cell line을 6 well plate에 5x105 개 분주한 후 16 시간 동안 배양하였다. 본 발명의 화합물 각각을 5 μM로 30 분 동안 처리한 후, IL-6 100 ng/ml을 첨가하여 4 시간 동안 배양하였다. 각 well의 배양액을 모두 제거한 후 PBS를 이용하여 세척한 다음 150 μl의 1x Luciferase Cell Culture Lysis Reagent(Promega, Cat# E1500)를 넣고 cell lysis하여 1.7 ml tube에 옮겨 담았다. 13000 rpm, 4 ℃에서 2 분 동안 원심분리 후 상층액을 새 tube에 옮겨 담았다. 이후 96 well white plate에 각 샘플을 20 μl씩 분주한 다음, 100 μl 의 Luciferase Assay Substrate(Promega, Cat# E1500)를 첨가하고 Luminometer 기기(Molecular Devices, FlexStation III Platereader)를 사용해 luciferase의 발색 정도를 측정하였다. 실험 결과, 본 발명의 화합물들은 루시퍼라제 활성을 현저히 저해시키는 것을 확인하였다(도 1).Stat3 Luciferase Reporter HEK293 Stable Cell line was dispensed in an amount of 5x10 5 in a 6 well plate and cultured for 16 hours. After treatment for 30 minutes with 5 μM of each compound of the present invention, 100 ng/ml of IL-6 was added and cultured for 4 hours. After removing all the culture medium from each well, washing with PBS, 150 μl of 1x Luciferase Cell Culture Lysis Reagent (Promega, Cat# E1500) was added, followed by cell lysis, and transferred to a 1.7 ml tube. After centrifugation at 13000 rpm and 4 °C for 2 minutes, the supernatant was transferred to a new tube. Then, 20 μl of each sample was dispensed on a 96-well white plate, 100 μl of Luciferase Assay Substrate (Promega, Cat# E1500) was added, and the degree of color development of luciferase was measured using a luminometer device (Molecular Devices, FlexStation III Platereader) did As a result of the experiment, it was confirmed that the compounds of the present invention significantly inhibit luciferase activity (FIG. 1).
이상의 설명으로부터, 본 발명의 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention can be embodied in other specific forms without changing its technical spirit or essential features. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not limiting. The scope of the present invention should be construed as including all changes or modifications derived from the meaning and scope of the claims to be described later and equivalent concepts rather than the detailed description above are included in the scope of the present invention.

Claims (14)

  1. 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염:A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2022016069-appb-img-000053
    Figure PCTKR2022016069-appb-img-000053
    상기 화학식 1에서,In Formula 1,
    L은 -CH2- 또는 -C(=CRARB)-이고;L is -CH 2 - or -C(=CR A R B )-;
    RA 및 RB는 각각 독립적으로 -H 또는 -C1-4알킬이고;R A and R B are each independently -H or -C 1-4 alkyl;
    A는 6원 고리이고 {여기서, 상기 6원 고리의 하나 이상의 H는 -H, -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 할로, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있고, 또는 인접한 2개의 치환기들은 서로 연결되어 6원 고리와 함께 융합 고리를 형성할 수 있음};A is a 6-membered ring {wherein at least one H of the 6-membered ring is -H, -C 1-4 alkyl, -C 1-4 cyanoalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NR 1 R 2 , -OR 3 , halo, cycloalkyl, or heterocycloalkyl, or two adjacent substituents are linked together to form 6 can form a fused ring together with the original ring};
    Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, -NR1R2, -OR3, 또는 할로이고; Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, -NR 1 R 2 , -OR 3 , or halo;
    R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 and R 2 are each independently -H or -C 1-4 alkyl;
    R3는 -H, -C1-4알킬, -C1-4할로알킬, 또는 -페닐이다.R 3 is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl.
  2. 제 1 항에 있어서,According to claim 1,
    L은 -CH2- 또는 -C(=CRARB)-이고;L is -CH 2 - or -C(=CR A R B )-;
    RA 및 RB는 각각 독립적으로 -H 또는 -C1-4알킬이고;R A and R B are each independently -H or -C 1-4 alkyl;
    A는 6원 고리이고 {여기서, 상기 6원 고리의 하나 이상의 H는 -H, -C1-4알킬, -C1-4할로알킬, -OR3, 또는 할로로 치환될 수 있고, 또는 인접한 2개의 치환기들은 서로 연결되어 6원 고리와 함께 융합 고리를 형성할 수 있음};A is a 6-membered ring {wherein at least one H of the 6-membered ring may be substituted with -H, -C 1-4 alkyl, -C 1-4 haloalkyl, -OR 3 , or halo, or adjacent two substituents can be linked together to form a fused ring with a 6-membered ring};
    Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, 또는 할로이고; Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, or halo;
    R3는 -C1-4알킬, -C1-4할로알킬, 또는 -페닐인;R 3 is -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl;
    화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  3. 제 1 항에 있어서,According to claim 1,
    상기 화학식 1로 표시되는 화합물이 하기 화학식 2로 표시되는 화합물인,The compound represented by Formula 1 is a compound represented by Formula 2 below,
    [화학식 2][Formula 2]
    Figure PCTKR2022016069-appb-img-000054
    Figure PCTKR2022016069-appb-img-000054
    상기 화학식 2에서,In Formula 2,
    RA 및 RB는 각각 독립적으로 -H 또는 -C1-4알킬이고;R A and R B are each independently -H or -C 1-4 alkyl;
    A는 6원 고리이고 {여기서, 상기 6원 고리의 하나 이상의 H는 -H, -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 할로로 치환될 수 있고, 또는 인접한 2개의 치환기들은 서로 연결되어 6원 고리와 함께 융합 고리를 형성할 수 있음};A is a 6-membered ring {wherein at least one H of the 6-membered ring is -H, -C 1-4 alkyl, -C 1-4 cyanoalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NR 1 R 2 , -OR 3 , or halo, or two adjacent substituents are linked together to form a fused ring with a six-membered ring. can form};
    Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, -NR1R2, -OR3, 또는 할로이고; Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, -NR 1 R 2 , -OR 3 , or halo;
    R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 and R 2 are each independently -H or -C 1-4 alkyl;
    R3는 -H, -C1-4알킬, -C1-4할로알킬, 또는 -페닐인;R 3 is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl;
    화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  4. 제 1 항에 있어서,According to claim 1,
    상기 화학식 1로 표시되는 화합물이 하기 화학식 3로 표시되는 화합물인,The compound represented by Formula 1 is a compound represented by Formula 3 below,
    [화학식 3][Formula 3]
    Figure PCTKR2022016069-appb-img-000055
    Figure PCTKR2022016069-appb-img-000055
    상기 화학식 3에서,In Formula 3,
    RA 및 RB는 각각 독립적으로 -H 또는 -C1-4알킬이고;R A and R B are each independently -H or -C 1-4 alkyl;
    A는 6원 고리이고 {여기서, 상기 6원 고리의 하나 이상의 H는 -H, -C1-4알킬, -C1-4시아노알킬, -C1-4아미노알킬, -C1-4하이드록시알킬, -C1-4할로알킬, -CN, -NR1R2, -OR3, 또는 할로로 치환될 수 있고, 또는 인접한 2개의 치환기는 서로 연결되어 6원 고리와 함께 융합 고리를 형성할 수 있음};A is a 6-membered ring {wherein at least one H of the 6-membered ring is -H, -C 1-4 alkyl, -C 1-4 cyanoalkyl, -C 1-4 aminoalkyl, -C 1-4 hydroxyalkyl, -C 1-4 haloalkyl, -CN, -NR 1 R 2 , -OR 3 , or halo, or two adjacent substituents are linked together to form a fused ring with a six-membered ring. can form};
    Y1 및 Y2는 각각 독립적으로 -H, -C1-4알킬, -NR1R2, -OR3, 또는 할로이고; Y 1 and Y 2 are each independently -H, -C 1-4 alkyl, -NR 1 R 2 , -OR 3 , or halo;
    R1 및 R2는 각각 독립적으로 -H 또는 -C1-4알킬이고;R 1 and R 2 are each independently -H or -C 1-4 alkyl;
    R3는 -H, -C1-4알킬, -C1-4할로알킬, 또는 -페닐인;R 3 is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, or -phenyl;
    화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  5. 제 1 항에 있어서,According to claim 1,
    상기 화학식 1로 표시되는 화합물이 하기 화합물로 이루어진 군으로부터 선택된 것인, 화합물, 이의 광학 이성질체, 이의 약학적으로 허용 가능한 염:A compound, an optical isomer thereof, and a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula 1 is selected from the group consisting of the following compounds:
    (1) 2-(4-클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(1) 2-(4-chlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (2) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-플루오로페닐)아세트아마이드;(2) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-fluorophenyl)acetamide;
    (3) 2-(벤조[d][1,3]다이옥솔-5-일)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(3) 2-(benzo[ d ][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (4) 2-(벤조[d][1,3]다이옥솔-5-일)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(4) 2-(benzo[ d ][1,3]dioxol-5-yl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (5) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-메톡시페닐)아크릴아마이드;(5) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-methoxyphenyl)acrylamide;
    (6) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-메톡시페닐)아세트아마이드;(6) N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(4-methoxyphenyl)acetamide;
    (7) 2-(3,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(7) 2-(3,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (8) 2-(3,4-다이플루오로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(8) 2-(3,4-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (9) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-(트라이플루오로메톡시)페닐)아세트아마이드;(9) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide;
    (10) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(p-톨릴)아크릴아마이드;(10) N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(p-tolyl)acrylamide;
    (11) 2-(4-(터트-부틸)페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(11) 2-(4-(tert-butyl)phenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (12) 2-(4-(터트-부틸)페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(12) 2-(4-(tert-butyl)phenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (13) 2-(3,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(13) 2-(3,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (14) 2-(3,4-다이플루오로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(14) 2-(3,4-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (15) 2-(4-클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(15) 2-(4-chlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (16) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-(트라이플루오로메틸)페닐)아세트아마이드;(16) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acetamide;
    (17) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(나프탈렌-2-일)아세트아마이드;(17) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(naphthalen-2-yl)acetamide;
    (18) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(나프탈렌-2-일)아크릴아마이드.(18) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(naphthalen-2-yl)acrylamide.
    (19) 2-(3,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(19) 2-(3,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (20) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-(트라이플루오로메톡시)페닐)아크릴아마이드;(20) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-(trifluoromethoxy)phenyl)acrylamide;
    (21) 2-(3,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(21) 2-(3,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (22) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-플루오로페닐)아크릴아마이드;(22) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-fluorophenyl)acrylamide;
    (23) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-(트라이플루오로메틸)페닐)아크릴아마이드; (23) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-(trifluoromethyl)phenyl)acrylamide;
    (24) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(p-톨릴)아세트아마이드;(24) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(p-tolyl)acetamide;
    (25) 2-(2,3-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(25) 2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (26) 2-(2,3-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; (26) 2-(2,3-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (27) 2-(2,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(27) 2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (28) 2-(2,4-다이클로로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마아드;(28) 2-(2,4-dichlorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (29) 2-(2,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; (29) 2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (30) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(3-플루오로페닐)아세트아마이드; (30) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(3-fluorophenyl)acetamide;
    (31) 2-(2,4-다이메톡시페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(31) 2-(2,4-dimethoxyphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (32) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(3-플루오로페닐)아크릴아마이드; (32) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(3-fluorophenyl)acrylamide;
    (33) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(3,4,5-트라이메톡시페닐)아크릴아마이드;(33) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acrylamide;
    (34) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-페녹시페닐)아세트아마이드; (34) N-(1,1-dioxidobenzo[b]thiophen-6-yl)-2-(4-phenoxyphenyl)acetamide;
    (35) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(4-페녹시페닐)아크릴아마이드; (35) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(4-phenoxyphenyl)acrylamide;
    (36) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(3,4,5-트라이메톡시페닐)아크릴아마이드;(36) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(3,4,5-trimethoxyphenyl)acrylamide;
    (37) 2-(3,5-다이플루오로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드;(37) 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (38) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(2-플루오로페닐)아세트아마이드; (38) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(2-fluorophenyl)acetamide;
    (39) 2-(2,3-다이하이드로벤조[b][1,4]다이옥신-6-일)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-yl)아세트아마이드; (39) 2-(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide ;
    (40) 2-(3,4-다이메틸페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; (40) 2-(3,4-dimethylphenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (41) 2-(3,5-다이플루오로페닐)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아크릴아마이드;(41) 2-(3,5-difluorophenyl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acrylamide;
    (42) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-(2-플루오로페닐)아크릴아마이드; (42) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-(2-fluorophenyl)acrylamide;
    (43) 2-(2,3-다이하이드로벤조퓨란-5-일)-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; (43) 2-(2,3-dihydrobenzofuran-5-yl)-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide;
    (44) 2-사이클로헥실-N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)아세트아마이드; 및(44) 2-cyclohexyl-N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)acetamide; and
    (45) N-(1,1-다이옥시도벤조[b]싸이오펜-6-일)-2-몰폴리노아세트아마이드.(45) N-(1,1-dioxidobenzo[ b ]thiophen-6-yl)-2-morpholinoacetamide.
  6. 제 1 항 내지 제 5 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, STAT3 관련 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating STAT3-related diseases, comprising the compound according to any one of claims 1 to 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  7. 제 6 항에 있어서, According to claim 6,
    상기 STAT3 관련 질환은 암, 섬유화 질환, 염증성 질환, 또는 자가면역질환인 조성물.Wherein the STAT3-related disease is cancer, fibrotic disease, inflammatory disease, or autoimmune disease.
  8. 제 7 항에 있어서, According to claim 7,
    상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 두경부암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인 조성물.The cancer is pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, head and neck cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater, bladder cancer , peritoneal cancer, parathyroid cancer, adrenal cancer, rhinosinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, Heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoma, gastrointestinal epilepsy Cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, chorionic villus disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinum cancer, rectal cancer, rectal carcinoid carcinoma, vaginal cancer, spinal cord cancer , acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, larynx cancer, pleural cancer, hematological cancer , And at least one composition selected from the group consisting of thymic cancer.
  9. 제 7 항에 있어서, According to claim 7,
    상기 섬유화 질환은 간 섬유증, 폐 섬유증, 당뇨성 섬유증, 심장 섬유증, 신장 섬유증, 경피증, 골격근 섬유증, 장 섬유증, 췌장 섬유증, 관절 섬유증, 골수 섬유증, 심근 섬유증, 진피 섬유증, 탄력 섬유증, 후복막 섬유증, 낭성 섬유증, 자궁 섬유증, 및 세포성 섬유증으로 이루어진 군으로부터 선택되는 1종 이상인 조성물.The fibrotic disease is liver fibrosis, pulmonary fibrosis, diabetic fibrosis, cardiac fibrosis, kidney fibrosis, scleroderma, skeletal muscle fibrosis, intestinal fibrosis, pancreatic fibrosis, articular fibrosis, bone marrow fibrosis, myocardial fibrosis, dermal fibrosis, elastic fibrosis, retroperitoneal fibrosis, At least one composition selected from the group consisting of cystic fibrosis, uterine fibrosis, and cellular fibrosis.
  10. 제 9 항에 있어서,According to claim 9,
    상기 간 섬유증은 비알코올성 지방간질환(NAFLD) 또는 비알코올성 지방간염(NASH)인 조성물.The composition of claim 1, wherein the liver fibrosis is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).
  11. 제 7 항에 있어서, According to claim 7,
    상기 염증성 질환 또는 자가면역질환은 건선, 아토피 피부염, 페렴, 임파선염, 류마티스 관절염, 면역 혈소판감소증, 천식, 크론병, 다발성 경화증, 중증 근무력증, 갑상선염, 포도막염, 하시모토 갑상선염, 원발성 점액수종, 갑상샘 중독증, 악성 빈혈, 자가 면역 위축 위염, 애디슨 질환, 조기 폐경, 남성 불임증, 제1형 당뇨병, 굿파스처 증후군, 보통 천포창, 유천포창, 교감성 안염, 수정체성 포도막염, 자가면역 용혈성 빈혈, 특발성 백혈구 감소, 원발성 담관 경화증, 만성 활동성 간염, 만성 폐쇄성 폐질환, 잠재성 간경변증, 궤양성 대장염, 쇼그렌 증후군, 경피증, 베게너 육아종증, 다발근육염, 피부근육염, 원판상루푸스, 및 전신홍반루푸스로 이루어진 군으로부터 선택되는 1종 이상인 조성물.The inflammatory disease or autoimmune disease is psoriasis, atopic dermatitis, pneumonia, lymphadenitis, rheumatoid arthritis, immune thrombocytopenia, asthma, Crohn's disease, multiple sclerosis, myasthenia gravis, thyroiditis, uveitis, Hashimoto's thyroiditis, primary myxedema, thyrotoxicosis, Pernicious anemia, autoimmune atrophic gastritis, Addison's disease, premature menopause, male infertility, type 1 diabetes, Goodpasture syndrome, pemphigus common, pemphigoid, sympathetic ophthalmitis, phacosomal uveitis, autoimmune hemolytic anemia, idiopathic leukopenia, selected from the group consisting of primary biliary sclerosis, chronic active hepatitis, chronic obstructive pulmonary disease, latent cirrhosis, ulcerative colitis, Sjogren's syndrome, scleroderma, Wegener's granulomatosis, polymyositis, dermatomyositis, discoid lupus, and systemic lupus erythematosus One or more compositions.
  12. 제 1 항 내지 제 5 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는, STAT3 관련 질환을 치료 또는 예방하는 방법.STAT3, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Methods for treating or preventing related diseases.
  13. 제 1 항 내지 제 5 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용 가능한 염의 용도.Use of a compound according to any one of claims 1 to 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  14. STAT3 관련 질환의 치료 또는 예방에 사용하기 위한 약제의 제조에 사용하기 위한, 제 1 항 내지 제 5 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도.Use of a compound according to any one of claims 1 to 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment or prevention of a STAT3-associated disease.
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