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WO2023038481A1 - Composé de dérivé hétéroarylique en tant qu'inhibiteur de stat3 et utilisation associée - Google Patents

Composé de dérivé hétéroarylique en tant qu'inhibiteur de stat3 et utilisation associée Download PDF

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WO2023038481A1
WO2023038481A1 PCT/KR2022/013579 KR2022013579W WO2023038481A1 WO 2023038481 A1 WO2023038481 A1 WO 2023038481A1 KR 2022013579 W KR2022013579 W KR 2022013579W WO 2023038481 A1 WO2023038481 A1 WO 2023038481A1
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prop
thiophen
cancer
benzo
methoxybenzo
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PCT/KR2022/013579
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English (en)
Korean (ko)
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심태진
김지훈
이준호
이민범
임재성
노준기
최누리
이혜원
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주식회사 프롬바이오
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Publication of WO2023038481A1 publication Critical patent/WO2023038481A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • 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
    • 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
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • 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
    • C07D409/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel heteroaryl derivative compounds having STAT3 inhibitory activity and uses thereof.
  • STAT3 signal transducer and activator of transcription 3
  • STAT3 acts as a transcription factor that transmits external signals into the nucleus and regulates the expression of various subgenes.
  • IL-6 binds to the IL-6 receptor
  • the gp-130 receptor is attracted to form an IL-6/IL-6 ⁇ 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.
  • JAK kinases JAK kinases
  • 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.
  • 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 and fibrotic diseases is well known (Cell, Akira et al., 1994, 76(2): 253).
  • 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.
  • 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.
  • One object of the present invention is to provide a heteroaryl derivative compound exhibiting STAT3 inhibitory activity and a method for preparing the same.
  • Another object of the present invention is to provide a medicinal use of the heteroaryl derivative according to the present invention.
  • the present invention provides a compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • X 1 to X 5 are each independently CR X or N, and ⁇ wherein X 1 to X 5 , N cannot exceed 3 ⁇ ;
  • R X 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 R Xs are linked together to form a fused ring with a 6-membered aromatic ring;
  • Y is CR Y or N
  • R Y is -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 or -C 1-4 haloalkyl.
  • the compound represented by Formula 1 may be in the following range:
  • X 1 to X 5 are each independently CR X or N, and ⁇ wherein X 1 to X 5 , N cannot exceed two ⁇ ;
  • R X is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, -OR 3 , or -halo, or two adjacent R Xs are linked together to form a 9-10 membered ring together with a 6-membered aromatic ring. to form a fused ring;
  • Y is CR Y or N
  • R Y is -H, -OR 3 , or -halo
  • R 3 is -C 1-4 alkyl or -C 1-4 haloalkyl.
  • the compound represented by Formula 1 may be in the following range:
  • X 1 to X 5 are each independently —CR X or N, and ⁇ wherein X 1 to X 5 , N cannot exceed two ⁇ ;
  • R X is -H, -C 1-4 alkyl, -C 1-4 haloalkyl, -OR 3 , or -halo, or two adjacent R X 's are linked together to form a 6-membered aromatic ring together with naphthalene or benzo[ d] [1,3] forming a dioxole ring;
  • R 3 is -CH 3 or -CF 3 .
  • the compound represented by Formula 1 may be in the following range:
  • Y is CR Y or N
  • R Y is -H, -OR 3 , or -halo
  • R 3 is -CH 3 or -CF 3 .
  • 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, its optical isomer, or its pharmaceutically acceptable salt exhibits inhibitory activity against STAT3, it is used for the treatment of STAT3-related diseases, particularly cancer, fibrotic diseases, autoimmune diseases, or It can be useful for prevention.
  • STAT3 is known to be involved in cancer, fibrotic diseases, or autoimmune diseases by acting as a transcription factor and regulating the expression of various genes, cancer, fibrotic diseases, or autoimmune diseases can be prevented or treated by inhibiting STAT3 activity. there is.
  • 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 autoimmune disease refers to all diseases caused by direct or indirect causes of immune responses against self-antigens of pathological subjects, including psoriasis, rheumatoid arthritis, 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, juvenile diabetes, Goodpasture syndrome, pemphigoid common, pemphigoid, sympathetic ophthalmitis, phacosopic uveitis, May be autoimmune hemolytic anemia, idiopathic leukopenia, primary cholangiosclerosis, chronic active hepatitis, latent cirrhosis, ulcerative colitis, Sjogren's syndrome, scleroderma, Wegener's
  • 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.
  • the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • 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 heteroaryl 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.
  • Example 1 1-(benzo[ b ]thiophen-2-yl)-2-(4-chlorophenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(4-chlorophenyl)prop-2-en-1-one ⁇
  • Example 2 1-(benzo[ b ]thiophen-2-yl)-2-(benzo[ d ][1,3]dioxol-5-yl)prop-2-en-1-one ⁇ 1-(Benzo[ b ]thiophen-2-yl)-2-(benzo[ d ]Preparation of [1,3]dioxol-5-yl)prop-2-en-1-one ⁇
  • Example 3 1-(benzo[ b ]thiophen-2-yl)-2-(4-fluorophenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(4-fluorophenyl)prop-2-en-1-one ⁇
  • Example 4 1-(benzo[ b ]thiophen-2-yl)-2-(4-(trifluoromethyl)phenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one ⁇
  • Example 5 1-(benzo[ b ]thiophen-2-yl)-2-(4-methoxyphenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(4-methoxyphenyl)prop-2-en-1-one ⁇
  • Example 6 1-(benzo[ b ]thiophen-2-yl)-2-(4-(trifluoromethyl)phenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(4-(trifluoromethyl)phenyl)prop-2-en-1-one ⁇
  • Example 7 1-(benzo[ b ]thiophen-2-yl)-2-(p-tolyl)propen-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(p-tolyl)prop-2-en-1-one ⁇
  • Example 8 1-(benzo[ b ]thiophen-2-yl)-2-(3,4-dimethoxyphenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(3,4-dimethoxyphenyl)prop-2-en-1-one ⁇
  • Example 9 1-(benzo[ b ]thiophen-2-yl)-2-(3,4-difluorophenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(3,4-difluorophenyl)prop-2-en-1-one ⁇
  • Example 10 1-(benzo[ b ]thiophen-2-yl)-2-(4-(tert-butyl)phenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(4-(tert-butyl)phenyl)prop-2-en-1-one ⁇
  • Example 11 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(4-chlorophenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(4-chlorophenyl)prop-2-en-1-one ⁇
  • Example 12 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(4-fluorophenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(4-fluorophenyl)prop-2-en-1-one ⁇
  • Example 13 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(4-methoxyphenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(4-methoxyphenyl)prop-2-en-1-one ⁇
  • Example 14 2-(benzo[ d ][1,3]dioxol-5-yl)-1-(6-chlorobenzo[ b ]thiophen-2-yl)-1-(6-chlorobenzo[ b ]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(Benzo[ d ][1,3]dioxol-5-yl)-1-(6-chlorobenzo[ b Preparation of ]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 15 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(3,4-difluorophenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[b]thiophen-2-yl)-2- Preparation of (3,4-difluorophenyl)prop-2-en-1-one ⁇
  • Example 16 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one ⁇
  • Example 17 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(3,4-dichlorophenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(3,4-dichlorophenyl)prop-2-en-1-one ⁇
  • Example 18 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(4-(trifluoromethyl)phenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(4-(trifluoromethyl)phenyl)prop-2-en-1-one ⁇
  • Example 19 1-(benzo[ b ]thiophen-2-yl)-2-(3,4-dichlorophenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(3,4-dichlorophenyl)prop-2-en-1-one ⁇
  • Example 20 2-(4-(tert-butyl)phenyl)-1-(6-chlorobenzo[ b ]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(4-( tert -Butyl)phenyl)-1-(6-chlorobenzo[ b Preparation of ]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 21 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(p-tolyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(p-tolyl)prop-2-en-1-one ⁇
  • Example 22 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(3,4-dimethoxyphenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(3,4-dimethoxyphenyl)prop-2-en-1-one ⁇
  • Example 23 1-(benzo[ b ]thiophen-2-yl)-2-(2-fluorophenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(2-fluorophenyl)prop-2-en-1-one ⁇
  • Example 24 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(2-fluorophenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(2-fluorophenyl)prop-2-en-1-one ⁇
  • Example 25 1-(benzo[ b ]thiophen-2-yl)-2-(3-fluorophenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(3-fluorophenyl)prop-2-en-1-one ⁇
  • Example 26 1-(benzo[ b ]thiophen-2-yl)-2-(naphthalen-2-yl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(naphthalen-2-yl)prop-2-en-1-one ⁇
  • Example 27 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(naphthalen-2-yl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(naphthalen-2-yl)prop-2-en-1-one ⁇
  • Example 28 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(3-fluorophenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(3-fluorophenyl)prop-2-en-1-one ⁇
  • Example 29 1-(benzo[ b ]thiophen-2-yl)-2-(2-methoxyphenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(2-methoxyphenyl)prop-2-en-1-one ⁇
  • Example 30 1-(benzo[ b ]thiophen-2-yl)-2-(3-methoxyphenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(3-methoxyphenyl)prop-2-en-1-one ⁇
  • Example 31 1-(benzo[ b ]thiophen-2-yl)-2-(2,5-dimethoxyphenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(2,5-dimethoxyphenyl)prop-2-en-1-one ⁇
  • Example 32 1-(benzo[ b ]thiophen-2-yl)-2-(3,5-dimethoxyphenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(3,5-dimethoxyphenyl)prop-2-en-1-one ⁇
  • Example 33 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(3-methoxyphenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(3-methoxyphenyl)prop-2-en-1-one ⁇
  • Example 34 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(2-methoxyphenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(2-methoxyphenyl)prop-2-en-1-one ⁇
  • Example 35 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(2,5-dimethoxyphenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(2,5-dimethoxyphenyl)prop-2-en-1-one ⁇
  • Example 36 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(3,5-dimethoxyphenyl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(3,5-dimethoxyphenyl)prop-2-en-1-one ⁇
  • Example 37 1-(benzo[ b ]thiophen-2-yl)-2-(2,4-dimethoxyphenyl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(2,4-dimethoxyphenyl)prop-2-en-1-one ⁇
  • Example 38 2-(2,5-dimethoxyphenyl)-1-(thieno[2,3-c]pyridin-2-yl)prop-2-en-1-one ⁇ 2-( Preparation of 2,5-dimethoxyphenyl)-1-(thieno[2,3-c]pyridin-2-yl)prop-2-en-1-one ⁇
  • Example 39 1-(6-chlorobenzo[ b ]thiophen-2-yl)-2-(pyridin-3-yl)prop-2-en-1-one ⁇ 1-(6-Chlorobenzo[ b Preparation of ]thiophen-2-yl)-2-(pyridin-3-yl)prop-2-en-1-one ⁇
  • Example 40 1-(benzo[ b ]thiophen-2-yl)-2-(pyridin-2-yl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(pyridin-2-yl)prop-2-en-1-one ⁇
  • Example 41 1-(benzo[ b ]thiophen-2-yl)-2-(pyridin-3-yl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(pyridin-3-yl)prop-2-en-1-one ⁇
  • Example 42 1-(benzo[b]thiophen-2-yl)-2-(pyridin-4-yl)prop-2-en-1-one ⁇ 1-(Benzo[ b Preparation of ]thiophen-2-yl)-2-(pyridin-4-yl)prop-2-en-1-one ⁇
  • Example 43 2-(4-chlorophenyl)-1-(6-methoxybenzo[ b ]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(4-Chlorophenyl)-1-(6-methoxybenzo[ b Preparation of ]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 44 2-(4-fluorophenyl)-1-(6-methoxybenzo[ b ]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(4-Fluorophenyl)-1-(6-methoxybenzo[ b Preparation of ]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 45 1-(6-methoxybenzo[ b ]thiophen-2-yl)-2-(4-(trifluoromethyl)phenyl)prop-2-en-1-one ⁇ 1-(6-Methoxybenzo[b]thiophen-2-yl)-2 Preparation of -(4-(trifluoromethyl)phenyl)prop-2-en-1-one ⁇
  • Example 46 1-(6-methoxybenzo[ b ]thiophen-2-yl)-2-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one ⁇ 1-(6-Methoxybenzo[ b Preparation of ]thiophen-2-yl)-2-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one ⁇
  • Example 47 2-(3,4-dichlorophenyl)-1-(6-methoxybenzo[ b ]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(3,4-Dichlorophenyl)-1-(6-methoxybenzo[ b Preparation of ]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 48 2-(3,4-difluorophenyl)-1-(6-methoxybenzo[ b ]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(3,4-Difluorophenyl)-1-(6-methoxybenzo[ b Preparation of ]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 49 1-(6-methoxybenzo[b]thiophen-2-yl)-2-(p-tolyl)prop-2-en-1-one ⁇ 1-(6-methoxybenzo[b] Preparation of thiophen-2-yl)-2-(p-tolyl)prop-2-en-1-one ⁇
  • Example 50 2-(3,4-dimethoxyphenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(3 Preparation of ,4-dimethoxyphenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 51 1-(6-methoxybenzo[b]thiophen-2-yl)-2-(naphthalen-2-yl)prop-2-en-1-one ⁇ 1-(6-methoxybenzo[ Preparation of b] thiophen-2-yl) -2- (naphthalen-2-yl) prop-2-en-1-one ⁇
  • Example 52 1-(6-methoxybenzo[b]thiophen-2-yl)-2-(pyridin-2-yl)prop-2-en-1-one ⁇ 1-(6-methoxybenzo[ Preparation of b]thiophen-2-yl)-2-(pyridin-2-yl)prop-2-en-1-one ⁇
  • Example 53 1-(6-methoxybenzo[b]thiophen-2-yl)-2-(pyridin-3-yl)prop-2-en-1-one ⁇ 1-(6-methoxybenzo[ Preparation of b]thiophen-2-yl)-2-(pyridin-3-yl)prop-2-en-1-one ⁇
  • Example 54 1-(6-methoxybenzo[b]thiophen-2-yl)-2-(pyridin-4-yl)prop-2-en-1-one ⁇ 1-(6-methoxybenzo[ Preparation of b]thiophen-2-yl)-2-(pyridin-4-yl)prop-2-en-1-one ⁇
  • Example 55 2-(2,4-dimethoxyphenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(2 Preparation of ,4-dimethoxyphenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 56 1-(6-chlorobenzo[b]thiophen-2-yl)-2-(2,4-dimethoxyphenyl)prop-2-en-1-one ⁇ 1-(6- Preparation of chlorobenzo[b]thiophen-2-yl)-2-(2,4-dimethoxyphenyl)prop-2-en-1-one ⁇
  • Example 58 2-(3-fluorophenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(3-fluorophenyl) Preparation of -1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 59 1-(6-methoxybenzo[b]thiophen-2-yl)-2-(2-methoxyphenyl)prop-2-en-1-one ⁇ 1-(6-methoxybenzo[ Preparation of b]thiophen-2-yl)-2-(2-methoxyphenyl)prop-2-en-1-one ⁇
  • Example 60 2-(3,5-dimethoxyphenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(3 Preparation of ,5-dimethoxyphenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 61 1-(6-methoxybenzo[b]thiophen-2-yl)-2-(3-methoxyphenyl)prop-2-en-1-one ⁇ 1-(6-methoxybenzo[ Preparation of b]thiophen-2-yl)-2-(3-methoxyphenyl)prop-2-en-1-one ⁇
  • Example 62 2-(2,5-dimethoxyphenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(2 Preparation of ,5-dimethoxyphenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 63 2-(benzo[d][1,3]dioxol-5-yl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1 Preparation of -one ⁇ 2-(benzo[d][1,3]dioxol-5-yl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 64 2-(4-(tert-butyl)phenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇ 2-(4 Preparation of -(tert-butyl)phenyl)-1-(6-methoxybenzo[b]thiophen-2-yl)prop-2-en-1-one ⁇
  • Example 65 1-(6-methoxybenzo[b]thiophen-2-yl)-2-(4-methoxyphenyl)prop-2-en-1-one ⁇ 1-(6-methoxybenzo[ Preparation of b]thiophen-2-yl)-2-(4-methoxyphenyl)prop-2-en-1-one ⁇
  • Example 66 2-(3-methoxyphenyl)-1-(thieno[2,3-c]pyridin-2-yl)prop-2-en-1-one ⁇ 2-(3-methoxyphenyl Preparation of )-1-(thieno[2,3-c]pyridin-2-yl)prop-2-en-1-one ⁇
  • Example 68 2-(2-methoxyphenyl)-1-(thieno[2,3-c]pyridin-2-yl)prop-2-en-1-one ⁇ 2-(2-methoxyphenyl Preparation of )-1-(thieno[2,3-c]pyridin-2-yl)prop-2-en-1-one ⁇
  • Example 69 1-(thieno[2,3-c]pyridin-2-yl)-2-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one ⁇ 1- Preparation of (thieno[2,3-c]pyridin-2-yl)-2-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one ⁇
  • 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
  • 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 ⁇ M 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 ⁇ l 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 13,000 rpm and 4 °C for 2 minutes, the supernatant was transferred to a new tube.
  • 1x Luciferase Cell Culture Lysis Reagent Promega, Cat# E1500

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Abstract

La présente invention concerne un composé de dérivé hétéroarylique présentant une activité inhibitrice de STAT3, et une utilisation associée. Le composé de dérivé hétéroarylique selon la présente invention présente une excellente activité inhibitrice sélective de STAT3 par liaison au domaine SH2 de STAT3 et peut ainsi être efficacement utilisé pour prévenir ou traiter des maladies liées à STAT3.
PCT/KR2022/013579 2021-09-10 2022-09-08 Composé de dérivé hétéroarylique en tant qu'inhibiteur de stat3 et utilisation associée WO2023038481A1 (fr)

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WO2025046475A1 (fr) * 2023-08-29 2025-03-06 제이더블유중외제약 주식회사 Dérivé hétérocyclique destiné à être utilisé dans le traitement de la dermatite atopique

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Publication number Priority date Publication date Assignee Title
WO2001007431A2 (fr) * 1999-07-21 2001-02-01 Eli Lilly And Company Derives de benzothiophene
CN104844563A (zh) * 2015-03-31 2015-08-19 苏州大学 一类靶向stat3的抑制剂及其应用
CN110981868A (zh) * 2019-11-05 2020-04-10 中山大学 咪唑并吡啶类化合物、包含该化合物的药物组合物及其制备方法和用途

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WO2001007431A2 (fr) * 1999-07-21 2001-02-01 Eli Lilly And Company Derives de benzothiophene
CN104844563A (zh) * 2015-03-31 2015-08-19 苏州大学 一类靶向stat3的抑制剂及其应用
CN110981868A (zh) * 2019-11-05 2020-04-10 中山大学 咪唑并吡啶类化合物、包含该化合物的药物组合物及其制备方法和用途

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Title
LIU, M.-S. et al. Dual catalysis relay: coupling of aldehydes and alkenes enabled by visible-light and NHC-catalyzed cross-double C-H functionalizations. ACS Catalysis. 19 July 2021, vol. 11, pp. 9715-9721. *
ZHANG MINGMING, ZHU WEILIANG, LI YINGXIA: "Discovery of novel inhibitors of signal transducer and activator of transcription 3 (STAT3) signaling pathway by virtual screening", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 62, 1 April 2013 (2013-04-01), AMSTERDAM, NL , pages 301 - 310, XP093045557, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2013.01.009 *

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