WO2023075479A1 - Nouveau dérivé de thiéno [2,3-d] pyrimidine, son procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou d'une maladie auto-immune le comprenant en tant que principe actif - Google Patents

Nouveau dérivé de thiéno [2,3-d] pyrimidine, son procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou d'une maladie auto-immune le comprenant en tant que principe actif Download PDF

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WO2023075479A1
WO2023075479A1 PCT/KR2022/016628 KR2022016628W WO2023075479A1 WO 2023075479 A1 WO2023075479 A1 WO 2023075479A1 KR 2022016628 W KR2022016628 W KR 2022016628W WO 2023075479 A1 WO2023075479 A1 WO 2023075479A1
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Prior art keywords
amino
pyrimidin
methylthieno
phenyl
propan
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PCT/KR2022/016628
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English (en)
Korean (ko)
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김소영
문희겸
임춘영
배기훈
오유진
이승연
추민기
하유나
김남희
한예리
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재단법인 대구경북첨단의료산업진흥재단
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Priority claimed from KR1020220138748A external-priority patent/KR20230061269A/ko
Application filed by 재단법인 대구경북첨단의료산업진흥재단 filed Critical 재단법인 대구경북첨단의료산업진흥재단
Publication of WO2023075479A1 publication Critical patent/WO2023075479A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a thieno[2,3-d]pyrimidine derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer or autoimmune disease containing the same as an active ingredient.
  • Interleukin-1 (IL-1) receptor-associated kinase-4 is a serine/threonine kinase enzyme that plays an essential role in signal transduction by the Toll/IL-1 receptor (TIR).
  • TIR Toll/IL-1 receptor
  • Various IRAK enzymes are key components in signal transduction pathways mediated by the interleukin-1 receptor (IL-1R) and Toll-like receptors (TLRs).
  • IL-1R interleukin-1 receptor
  • TLRs Toll-like receptors
  • IRAK proteins as well as MyD88, have been demonstrated to play a role in the transduction of signals other than those derived from the IL-1R receptor, including signals triggered by activation of the IL-18 receptor and the LPS receptor.
  • IRAK-4 is considered the "master IRAK". Under overexpression conditions, all IRAKs can mediate activation of nuclear factor- ⁇ and stress-induced mitogen-activated protein kinase (MAPK)-signaling cascades. However, only IRAK-1 and IRAK-4 were found to have active kinase activity.
  • MAPK stress-induced mitogen-activated protein kinase
  • IRAK-1 kinase activity may be dispensable for its function in IL-1 induced NF- ⁇ activation, whereas IRAK-4 requires its kinase activity for signal transduction.
  • IRAK4 inhibitors are implicated as beneficial therapeutics for inflammatory diseases, sepsis and autoimmune disorders.
  • Non-Patent Document 1 Wietek C, et al, Mol. Interv. 2: 2002, 212-215.
  • a tumorigenically active MyD88 mutation in diffuse large B-cell lymphoma has been shown to be sensitive to IRAK4 inhibition.
  • IRAK4 inhibitors can block signals transmitted by the TLR pathway, as well as signals transmitted by IL-1 and the IL-1 family. Modulation of IL-1 is associated with gout, gouty arthritis, type 2 diabetes, autologous inflammatory disease, tumor necrosis factor receptor-associated periodic syndrome, familial Mediterranean fever, adult-type Still's disease, systemic juvenile idiopathic arthritis, stroke, and host It has already been found to be effective for various diseases such as graft disease, asymptomatic multiple myeloma, recurrent pericarditis, osteoarthritis and emphysema (Non-Patent Document 3, Dinarello, C.A., 2011, Eur. J. Immunol. 41: 1203-1217).
  • IL-1 can trigger the differentiation of the effector T cell subset Th17 as an important link in the adaptive immune system. Therefore, IRAK4 inhibitors are predicted to be effective in Th17 cell-related diseases including multiple sclerosis, psoriasis, inflammatory bowel disease, autoimmune uveitis and rheumatoid arthritis.
  • An object of the present invention is to provide novel thieno[2,3-d]pyrimidine derivatives that inhibit IRAK4.
  • Another object of the present invention is to provide a novel pharmaceutical composition for preventing or treating cancer or autoimmune diseases.
  • Another object of the present invention is to provide a novel health functional food composition for preventing or improving cancer or autoimmune diseases.
  • the present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen or C 1-10 alkyl
  • R 2 is unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, or
  • R 1 and R 2 together with the nitrogen atom to which they are bonded form an unsubstituted or substituted 5-10 membered heteroaryl;
  • R 2a and R 2b are independently hydrogen or C 1-10 alkyl
  • R 3 is substituted C 3-10 cycloalkyl, substituted C 6-10 aryl or substituted 5-10 membered heteroaryl ;
  • substituted 3-10 membered heterocycloalkyl is substituted with C 1-10 alkyl, C 3-10 cycloalkyl , 3-10 membered heterocycloalkyl or -NR 3a R 3b ;
  • R 3a and R 3b are each independently hydrogen, C 1-10 alkyl unsubstituted or substituted with -N(C 1-10 alkyl) 2 , or C 1-10 alkoxycarbonyl ;
  • R 4 is hydrogen or C 1-10 alkyl
  • Step 2 a method for preparing a compound represented by Chemical Formula 1 including the step (Step 2) of preparing a compound represented by Chemical Formula 1 by reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in Formula 1 above.
  • the present invention is for preventing or improving cancer or autoimmune diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition is provided.
  • the compound represented by Formula 1 described herein is expected to be useful in autoimmune diseases by suppressing cancer or cytokine expression due to excellent cytotoxicity against cancer cells while exhibiting excellent inhibitory activity against IRAK4.
  • alkylene or “alkyl” includes straight or branched chain saturated hydrocarbon moieties, unless otherwise specified.
  • C 1-6 alkyl means an alkyl having a backbone of 1 to 6 carbons. Specifically, C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n - butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl , hexyl, etc., and C 6 alkyl is a fully saturated hydrocarbon having 6 carbons, including regioisomers.
  • Alkyl means a monovalent substituent
  • alkylene means a divalent substituent.
  • cycloalkyl refers to a cyclic hydrocarbon moiety that forms a ring as a saturated hydrocarbon moiety
  • C 3-6 cycloalkyl refers to a cyclic hydrocarbon moiety containing 3 to 6 carbons as ring atoms. hydrocarbon residues.
  • heterocycloalkyl means, unless otherwise specified, one or more selected from N, O, or S (e.g., 1-5, 1-4, 1-3, 1-2, 1) means a monovalent saturated moiety consisting of 1 to 3 rings containing heteroatoms. The two or three rings may be bridged, fused or spiro heterocycloalkyl. When composed of a plurality of rings, heteroatoms may be present in all rings or only in some rings. “3-10 membered heterocycloalkyl” refers to a heterocycloalkyl having 3 to 10 ring atoms. On the other hand, when referring to a 3-10-membered heterocycloalkyl containing one or more N, it refers to one that always contains one or more nitrogen atoms (N) as a heteroatom constituting a ring.
  • N nitrogen atoms
  • aryl refers to an aromatic radical in which a single ring or two or three hydrocarbon aromatic rings are fused.
  • heteroaryl means one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) containing one or more aromatic rings (the remaining ring atoms are C), or a fused aromatic radical of 2 or 3 rings. When composed of a plurality of rings, heteroatoms may be present in all rings or only in some rings. “5-10 membered heteroaryl” refers to a heteroaryl having 5 to 10 atoms constituting a ring. On the other hand, when referring to a 5-10 membered heteroaryl containing one or more N, it refers to one containing one or more nitrogen atoms (N) as a heteroatom constituting a ring.
  • Alkoxy means a substituent in which an alkyl is linked to an oxygen atom
  • C 1-10 alkoxy refers to a substituent in which C 1-10 alkyl is linked to an oxygen atom and substituted through an oxygen atom.
  • Halogen means a halogen atom such as F, Cl, Br, I.
  • DiC 1-10 alkylamino means a substituent in which an amino group (—NH 2 ) is substituted with two C 1-10 alkyl groups through nitrogen .
  • isomers refers to compounds of the present invention that have the same chemical or molecular formula but differ structurally or sterically. Such isomers include constitutional isomers (or structural isomers) and stereoisomers.
  • structural isomer includes skeletal isomers and tautomers.
  • stereoisomer refers to R or S isomers (or DL isomers) that are produced by having asymmetric carbon or heteroatom (P, S, Si, N, etc.) centers, and those that can be produced by having two or more asymmetric atom centers. Includes enantiomers or diastereomers, geometric isomers (trans, cis), and the like.
  • hydrate refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or a salt thereof.
  • the hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water.
  • Such a hydrate may be prepared by crystallizing the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof of the present invention from water or a water-containing solvent.
  • solvate refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents in this regard are those that are volatile, non-toxic, and/or suitable for administration to humans.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt formed by ionic bonding with a compound containing a carboxylic acid or amine functional group.
  • the compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedios.
  • Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulphate, sulphite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i.
  • the acid addition salt according to the present invention can be prepared by a conventional method.
  • a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid thereto It may be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
  • a compound represented by Formula 1 below, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof are provided.
  • R 1 is hydrogen or C 1-10 alkyl
  • R 2 is unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, or
  • R 1 and R 2 together with the nitrogen atom to which they are bonded form an unsubstituted or substituted 5-10 membered heteroaryl;
  • R 2a and R 2b are independently hydrogen or C 1-10 alkyl ;
  • R 3 is substituted C 3-10 cycloalkyl, substituted C 6-10 aryl or substituted 5-10 membered heteroaryl ;
  • substituted 3-10 membered heterocycloalkyl is substituted with C 1-10 alkyl, C 3-10 cycloalkyl , 3-10 membered heterocycloalkyl or -NR 3a R 3b ;
  • R 3a and R 3b are each independently hydrogen, C 1-10 alkyl unsubstituted or substituted with N(C 1-10 alkyl ) 2 , or C 1-10 alkoxycarbonyl ;
  • R 4 is hydrogen or C 1-10 alkyl
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 is unsubstituted or substituted phenyl unsubstituted or substituted 5-10 membered heteroaryl containing at least one heteroatom selected from the group consisting of N and O, or
  • R 1 and R 2 together with the nitrogen atom to which they are bonded form a 5- to 10-membered heteroaryl containing one or more unsubstituted or substituted N atoms;
  • R 2a and R 2b are independently hydrogen or C 1-6 alkyl ;
  • R 3 is a 5-8 membered heteroaryl containing at least one heteroatom selected from the group consisting of substituted C 4-8 cycloalkyl, substituted phenyl or substituted N and O;
  • the 3-10 membered heterocycloalkyl is a 3-7 membered monocyclic heterocycloalkyl or a 7-10 membered spiro bicyclic heterocycloalkyl,
  • the substituted 3-10 membered heterocycloalkyl is C 1-6 alkyl , C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N and O, or -NR 3a R 3b is substituted;
  • R 3a and R 3b are each independently hydrogen, C 1-6 alkyl unsubstituted or substituted with N(C 1-6 alkyl) 2 , or C 1-6 alkoxycarbonyl ;
  • R 4 is hydrogen or C 1-6 alkyl
  • R 1 is hydrogen or C 1-4 alkyl
  • R 2 is an unsubstituted or substituted phenyl, an unsubstituted or substituted 5-6 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N and O, or one or more unsubstituted or substituted N atoms is a fused 9-10 membered heteroaryl comprising
  • R 1 and R 2 together with the nitrogen atom to which they are bonded form a 5-membered heteroaryl containing one or more unsubstituted or substituted N atoms;
  • R 2a and R 2b are independently hydrogen or C 1-4 alkyl ;
  • R 3 is substituted C 5-6 cycloalkyl, substituted phenyl or substituted 5-6 membered heteroaryl containing one or more N atoms;
  • substituted 4-10 membered heterocycloalkyl is substituted with C 1-4 alkyl , C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl or -NR 3a R 3b ;
  • R 3a and R 3b are each independently hydrogen, C 1-4 alkyl unsubstituted or substituted with N(C 1-4 alkyl) 2 , or C 1-4 alkoxycarbonyl ;
  • R 4 is hydrogen or C 1-4 alkyl
  • R 1 is hydrogen
  • R 2 is unsubstituted or substituted phenyl, unsubstituted or substituted heteroaryl, wherein heteroaryl is pyridyl, pyrazolyl, oxazolyl, indazolyl or quinolinyl; or
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a substituted imidazolyl
  • the substituted phenyl, substituted heteroaryl, and substituted imidazolyl are each independently selected from unsubstituted or substituted C 1-4 alkyl, halogen, C 1-4 alkoxy, hydroxy, C 1-4 alkylsulfonyl , di(C 1-4 alkyl)aminosulfonyl, C 1-4 alkoxycarbonyl, di(C 1-4 alkyl)phosphinyl , carboxyl, hydroxy substituted oxetanyl, hydroxy substituted cyclobutyl, and substituted with one or more selected from the group consisting of CONH 2 , wherein the substituted C 1-4 alkyl is substituted with hydroxy, C 1-4 alkoxy, halogen or CN;
  • R 3 is substituted cyclopentyl, cyclohexyl, phenyl or substituted pyrazolyl
  • the substituent of the substituted 3-10 membered heterocycloalkyl is C 1-2 alkyl , C 3-4 cycloalkyl, aziridinyl, azetidinyl, pyrrolidinyl, methylpiperazinyl, oxetanyl, NMe 2 , NEt 2 , NHMe, NHCO 2 t-Bu, methoxy, NH 2 or acetyl;
  • R 4 is hydrogen
  • R 3 is a compound selected from the following, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
  • substituted 3-10 membered heterocycloalkyl is substituted with C 1-10 alkyl, C 3-10 cycloalkyl , 3-10 membered heterocycloalkyl or -NR 3a R 3b ;
  • R 3a and R 3b are each independently hydrogen or C 1-10 alkyl unsubstituted or substituted with N(C 1-10 alkyl ) 2 ;
  • R 7a , R 8a and R 8b are each independently hydrogen, unsubstituted or hydroxy- or halogen-substituted C 1-10 alkyl, C 1-10 alkoxy , halogen , or C 1-10 alkoxycarbonyl;
  • R 9 is C 1-10 alkyl substituted with hydroxy or 3-10 membered heterocycloalkyl ;
  • R 9a and R 9b are hydrogen or hydroxy
  • n 1 or 2;
  • R 1 is hydrogen
  • R 2 is selected from;
  • R 1 and R 2 are bonded to each other form
  • R 3 is selected from
  • R 4 is hydrogen
  • R 5 is hydrogen or methyl
  • the compound represented by Formula 1 is selected from the following compound groups.
  • a method for preparing a compound represented by Chemical Formula 1 comprising the step of preparing a compound represented by Chemical Formula 1 by reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in Formula 1 above.
  • Step 1 is a step of subjecting a compound represented by Chemical Formula 2 to a compound represented by Chemical Formula 3 by a nucleophilic substitution reaction, wherein the compound represented by Chemical Formula 2 is reacted with a compound represented by Chemical Formula 3 to obtain Chemical Formula
  • This is a step for preparing a compound displayed in 1 package.
  • an organic solvent such as DMF or sec-butanol may be used as the solvent, and conditions commonly used for nucleophilic substitution reactions may be used.
  • the preparation method is not limited to one embodiment of the present invention presented as an example, and can be performed by modifying solvents, reactants, temperature conditions, etc. under conventional organic chemistry knowledge.
  • the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is intended for use in the prevention or treatment of cancer or autoimmune diseases.
  • a pharmaceutical composition for preventing or treating cancer or autoimmune disease containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound represented by Formula 1 is characterized in that it inhibits IRAK4.
  • the compound represented by Formula 1 is characterized by suppressing the expression of TNF- ⁇ and IL-6, which are inflammatory cytokines related to autoimmune diseases, as inflammatory factors.
  • the cancer is any one of leukemia, lymphoma, multiple myeloma, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, or skin cancer. may be
  • the autoimmune disease is psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplant rejection , Graft-versus-host disease (GVHD), lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis , primary biliary cirrhosis, allergic conjunctivitis, or atopic dermatitis.
  • GVHD Graft-versus-host disease
  • lupus erythematosus inflammatory disease
  • the term "contained as an active ingredient” means that it is contained in a dosage range that results in the prevention, improvement, or treatment of cancer or autoimmune disease, and the dosage range may vary depending on the severity and formulation. The number of times of application may also vary according to the age, weight and constitution of the target subject.
  • the compound represented by Formula 1 in the pharmaceutical composition of the present invention is, for example, 0.001 mg/kg or more, preferably 0.1 mg/kg or more, more preferably 10 mg/kg or more, more preferably 100 mg/kg or more, even more preferably 250 mg/kg or more, and most preferably 0.1 g/kg or more.
  • the upper limit of the amount of the compound represented by Formula 1 included in the pharmaceutical composition of the present invention can be selected and implemented within an appropriate range by those skilled in the art.
  • the pharmaceutical composition according to the present invention may include an effective amount of the compound represented by Formula 1 alone or may include one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • the pharmaceutically acceptable carrier, excipient or diluent refers to a material that is physiologically acceptable and does not cause an allergic reaction such as gastrointestinal disorder or dizziness or similar reaction when administered to humans.
  • the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto.
  • fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers and preservatives may be further included.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, and emulsions.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. depending on how
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, which is prepared in an ampoule or vial unit dosage form can be manufactured with
  • the composition may be sterilized and/or contain preservatives, stabilizers, hydration agents or emulsification accelerators, salts and/or buffers for osmotic pressure control, and other therapeutically useful substances, and may contain conventional methods such as mixing and granulation. It can be formulated according to the coating or coating method.
  • prevention means suppressing the symptoms of cancer or autoimmune disease by administering, ingesting, or applying the pharmaceutical composition or health functional food composition of the present invention to a subject not suffering from cancer or autoimmune disease.
  • blocking it means preventing symptoms of cancer or autoimmune disease from occurring in advance.
  • the term "treatment” refers to the cure of symptoms of cancer or autoimmune disease as well as the treatment of symptoms of cancer or autoimmune disease as a result of administering the pharmaceutical composition of the present invention to an individual suffering from cancer or autoimmune disease. It includes partial cure, improvement and remission.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • the term "pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment or improvement, and the effective dose level is the type and severity of the subject, age, It may be determined according to factors including sex, activity of drug, sensitivity to drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field. Examples include 0.001 mg/kg or more, 0.1 mg/kg or more, 10 mg/kg or more, 100 mg/kg or more, 250 mg/kg or more, and 0.1 g/kg or more. The upper limit of the amount of the pharmaceutical composition of the present invention can be selected and implemented by those skilled in the art within an appropriate range.
  • the compound represented by Formula 1 may be used in the form of not only pharmaceutically acceptable salts thereof, but also stereoisomers, solvates, and hydrates that may be prepared therefrom.
  • a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is administered as an individual therapeutic agent, It can be used in combination with other anticancer drugs currently in use.
  • a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is administered in combination with an anticancer agent. effect can be enhanced.
  • a health functional food composition for preventing or improving cancer or autoimmune diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the term "improvement" means that the pharmaceutical composition or food composition of the present invention is administered, ingested, or applied to a subject suffering from cancer or autoimmune disease to reduce or alleviate the symptoms of cancer or autoimmune disease. am.
  • cancer or autoimmunity comprising the step of administering to a subject in need of a compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof described herein.
  • a method for preventing or treating a disease is provided.
  • a compound represented by Formula 1 described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is used to prepare a medicament for preventing or treating cancer or autoimmune diseases.
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • Step 1 Preparation of 2-(6-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol
  • Step 2 2-(6-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)thieno[2,3-d]pyrimidin-4-yl)amino)pyridine -2-yl)propan-2-ol
  • Step 1 Methyl2-chloro-4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)thieno[2,3-d]pyrimidine-5-carboxylate manufacturing
  • a target compound was prepared by performing the same method as in step 1 of Example 1 above. MS m/z : 393 [M+H] +
  • Step 2 sec-butyl 2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-4-((6-(2-hydroxypropane- Preparation of 2-yl) pyridin-2-yl) amino) thieno [2,3-d] pyrimidine-5-carboxylate
  • a target compound was prepared by performing the same method as in step 2 of Example 1 above. MS m/z : 634 [M+H] +
  • the compound of Example 20 was prepared in the same manner as in the preparation method of Example 19, except for the reactants.
  • Step 1 2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-4-((6-(2-hydroxypropan-2-yl) Preparation of )pyridin-2-yl)amino)thieno[2,3-d]pyrimidine-5-carboxylic acid
  • Step 2 2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-4-((6-(2-hydroxypropan-2-yl) Preparation of )pyridin-2-yl)amino)thieno[2,3-d]pyrimidine-5-carboxamide
  • Example 22 The compound of Example 22 was prepared in the same manner as in Example 21, except for the reactants.
  • Step 1 Preparation of 2-(6-((2-chloro-5-methylthieno[2,3-d]pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol
  • a target compound was prepared in a manner similar to step 1 of Example 1 above.
  • Step 2 (1R,4R)-4-((4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5-methylthieno[2,3-d Preparation of ]pyrimidin-2-yl)amino)cyclohexan-1-ol
  • Step 1 Methyl 2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-4-((6-(2-hydroxypropan-2- Preparation of yl) pyridin-2-yl) amino) thieno [2,3-d] pyrimidine-5-carboxylate
  • Step 1 Preparation of 5-(tert-butyl)-N-(2-chloro-5-methylthieno[2,3-d]pyrimidin-4-yl)isoxazol-3-amine
  • Step 2 N4-(5-(tert-butyl)isoxazol-3-yl)-5-methyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)thieno[2,3- d] Preparation of pyrimidine-2,4-diamine
  • a target compound was prepared by performing similarly to step 2 of Example 1 above. MS m/z : 478 [M+H] +
  • Examples 54 to 63 Compounds of Examples 54-63 were prepared in a similar manner to Example 1.
  • Step 1 Preparation of 2-(3-((2-chloro-5-methylthieno[2,3-d]pyrimidin-4-yl)amino)phenyl)propan-2-ol
  • a target compound was prepared in the same manner as in Example 1, step 1. MS m/z : 334 [M+H] +
  • Step 2 2-(3-((2-((4-(4-(azetidin-1-yl)piperidin-1-yl)-3-methoxyphenyl)amino)-5-methylthieno Preparation of [2,3-d]pyrimidin-4-yl)amino)phenyl)propan-2-ol
  • Example 65 The compounds of Examples 65-68, 70-73, 75-76, and 78-80 were prepared in a similar manner to Example 1.
  • Example 69, 74, 77 and 81 were prepared in a similar manner to Example 64.
  • the compound of Example 81 was obtained in the form of a 2,2,2-trifluoroacetic acid salt as it was after purification by Prep HPLC.
  • Step 1 2-(6-((2-((3-methoxy-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)-5-methylthieno[2,3 -d] pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol, the preparation of 2,2,2-trifluoroacetic acid
  • Example 86 The compounds of Examples 86, 88-89, 101, 103, 108, 115, 117, 121, 124-125, and 128-130 were prepared in a similar manner to Example 64.
  • Step 1 Preparation of 5-(tert-butyl)-N-(2-chloro-5-methylthieno[2,3-d]pyrimidin-4-yl)isoxazol-3-amine
  • Example 135> The compound of Example 135 was prepared in a similar manner to Example 134.
  • Example 136-144, 147, 150-153, 155-161, 170, 172-178, 183-184, 186-191, 194-199, 201, 205, 207-209 in a similar manner to Example 1 compound was prepared.
  • Example 145-146 and 179-180 were prepared in a similar manner to Example 82.
  • Example 149 The compound of Example 149 was prepared in a similar manner to Example 134 above.
  • Tables 1-2 below show the structures of the compounds of Examples 1-209.
  • Tables 3 to 6 below show the names of compounds and analysis results.
  • a white 384-well plate 12 concentrations of compounds (including DMSO control) serially diluted in 5-fold were added, and MBP substrate at a concentration of 0.1 ⁇ g/ ⁇ l and ATP at a concentration of 10 ⁇ M were added per well, respectively, to obtain the final compound. After making the concentration 0.000005 ⁇ 50 ⁇ M, it was incubated for 1 hour in a 25°C incubator. After 1 hour, 5 ⁇ l of ADP-Glo (Promega) was treated and incubated in a 25°C incubator for 40 minutes, followed by 10 ⁇ l of Detection Reagent (Promega) and incubated in a 25°C incubator for 30 minutes. Then, the degree of kinase activity was measured through the luminescence value with a microplate reader. IC50 values were calculated using GraphPad Prism 7.0 (GraphPad Software Inc.).
  • the measured IC50 values of kinases were classified as A when less than 100 nM, B when 100 nM to 1 ⁇ M, and C when greater than 1 ⁇ M, and are summarized in Table 7 below.
  • the compounds of the present invention can effectively inhibit IRAK4 and thus be useful for the treatment of cancer or autoimmune diseases.
  • Example IRAK4 IC 50 Example IRAK4 IC 50 One B 106 A 2 A 107 A 3 A 108 A 4 B 109 B 5 B 110 A 6 B 111 B 7 B 112 B 8 C 113 A 9 B 114 A 10 A 115 A 11 C 116 B 12 B 117 A 13 C 118 C 14 A 119 C 15 B 120 A 16 B 121 A 17 A 122 A 18 A 123 B 19 C 124 A 20 C 125 B 21 B 126 B 22 B 127 B 23 C 128 A 24 B 129 A 25 C 130 A 26 B 131 C 27 B 132 C 28 B 133 B 29 C 134 B 30 A 135 B 31 A 136 A 32 B 137 B 33 A 138 B 34 B 139 B 35 B 140 B 36 B 141 A 37 C 142 C 38 B 143 C 39 B 144 C 40 A 145 B 41 A 146 B 42 A 147 C 43 A 148 A 44 A 149 B 45 A 150 C 46 A 151 C 47 B 152 C 48 C 153 A 49 C
  • hPBMC frozen human Peripheral Blood Mononuclear Cells
  • the measured percentage value is more than 50%, it is classified as A grade, 50% to 10% as B grade, and less than 10% as C grade, and summarized in Table 8 below.
  • the compounds of the present invention effectively inhibit the expression of TNF- ⁇ and IL-6, which are cytokines as inflammatory factors related to autoimmune diseases, and it was confirmed that they are effective in treating autoimmune diseases. .
  • Example TNF- ⁇ IL-6 Example TNF- ⁇ IL-6 2 C C 122 B A 3 B B 124 B B 30 B B 128 C B 31 B B 130 B B 33 B C 136 C C 41 C C 154 B B 42 C C 158 B B 43 C C 162 B B 44 C C 163 A B 45 B C 164 A A 46 B C 165 B B 60 B B 166 A A 64 B B 169 C B 69 B B 171 B B 87 B B 181 B B 88 B B 182 B B 89 A B 185 A B 100 B B 186 B B B 101 C B 192 B B 104 B B 193 A A 105 C C 201 C C C 107 B B 202 A A 108 B B 203 B B 110 C C C 204 B B B 113 C C 206 A A 114 B C 115 B B B 117 B C 120 A B 121 A B

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Abstract

La présente invention concerne un nouveau dérivé thiéno [2,3-D] pyrimidine, son procédé de préparation, et une composition pharmaceutique pour la prévention ou le traitement du cancer ou d'une maladie auto-immune, la composition pharmaceutique le comprenant en tant que principe actif. Un composé représenté par la formule chimique 1 décrit dans la présente invention présente une excellente activité inhibitrice contre IRAK4, et est considéré comme étant utile pour le cancer en raison d'une excellente cytotoxicité vis-à-vis des cellules cancéreuses ou d'une maladie auto-immune par l'inhibition de l'expression de cytokines.
PCT/KR2022/016628 2021-10-28 2022-10-28 Nouveau dérivé de thiéno [2,3-d] pyrimidine, son procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou d'une maladie auto-immune le comprenant en tant que principe actif WO2023075479A1 (fr)

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KR10-2021-0145624 2021-10-28
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KR10-2022-0138748 2022-10-25
KR1020220138748A KR20230061269A (ko) 2021-10-28 2022-10-25 신규한 티에노[2,3-d]피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140194417A1 (en) * 2013-01-10 2014-07-10 Nimbus Iris, Inc. Irak inhibitors and uses thereof
WO2017205762A1 (fr) * 2016-05-27 2017-11-30 Pharmacyclics Llc Inhibiteurs de la kinase associée au récepteur de l'interleukine 1

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140194417A1 (en) * 2013-01-10 2014-07-10 Nimbus Iris, Inc. Irak inhibitors and uses thereof
WO2017205762A1 (fr) * 2016-05-27 2017-11-30 Pharmacyclics Llc Inhibiteurs de la kinase associée au récepteur de l'interleukine 1

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry CAS; 6 December 2004 (2004-12-06), ANONYMOUS : "Thieno[2,3-d]pyrimidine2,4-diamine, N2-(2-m ethylphenyl)-N4-phe nyl- (", XP093062271, Database accession no. 793635-48-0 *
HOU NA, MAN JIANG‐HONG, WANG XIAN‐YU, HE SHENG‐JIE, LI QING, HU YANG‐GEN: "Efficient Synthesis and Biological Evaluation of 2,4‐Diaminothieno[2,3‐ d ]pyrimidine Derivative", CHEMISTRYSELECT, vol. 4, no. 17, 8 May 2019 (2019-05-08), DE , pages 4901 - 4904, XP093061928, ISSN: 2365-6549, DOI: 10.1002/slct.201900123 *
WANG RUIFENG; CHEN YIXUAN; ZHAO XIANGXIN; YU SIJIA; YANG BOWEN; WU TIANXIAO; GUO JING; HAO CHENZHOU; ZHAO DONGMEI; CHENG MAOSHENG: "Design, synthesis and biological evaluation of novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potential FAK inhibitors and anticancer agents", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 183, 18 September 2019 (2019-09-18), AMSTERDAM, NL , XP085892914, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2019.111716 *

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