WO2017026718A1 - Nouveau composé 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine, qui est un inhibiteur de la kinase ret - Google Patents

Nouveau composé 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine, qui est un inhibiteur de la kinase ret Download PDF

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WO2017026718A1
WO2017026718A1 PCT/KR2016/008427 KR2016008427W WO2017026718A1 WO 2017026718 A1 WO2017026718 A1 WO 2017026718A1 KR 2016008427 W KR2016008427 W KR 2016008427W WO 2017026718 A1 WO2017026718 A1 WO 2017026718A1
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pyrazolo
pyrimidin
amine
isopropyl
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PCT/KR2016/008427
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Korean (ko)
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심태보
윤호종
곽연의
허우영
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한국과학기술연구원
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Publication of WO2017026718A1 publication Critical patent/WO2017026718A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel 3- (isoxazol-3-yl) -pyrazolo [3,4-d] pyrimidin-4-amine compounds, methods for preparing the compounds, and various cancer diseases caused by RET kinase activity of the compounds. It relates to a medicinal use for the prevention and treatment of medicament.
  • RET Rearranged during transfaction
  • RTK tyrosine kinase receptors
  • the RET gene causes various types of thyroid cancers (MEN2A, MEN2B, FMTC, PTC, etc.) when they have abnormal functions such as point mutations, chromosomal inversions and gene amplification.
  • MEN2A, MEN2B, and FMTC are caused by point mutations of the RET gene
  • PTC has been reported that the RET gene is caused by internal chromosomal translocation.
  • Non-Patent Document 2 Genome Res 2012, 22, 436-445
  • Non-small cell lung cancer is induced by the expression of the fusion type tyrosine kinase KIF5B-RET or CCDC6-RET with cancerous ability by fusion of the RET gene with the KIF5B gene or the CCDC6 gene. It has been reported.
  • fusion tyrosine kinases NCOA4-RET and TRIM33-RET in which the RET gene is fused with NCOA4 or TRIM33 (tripartite motif-containing 33) gene, have been reported.
  • RET tyrosine kinase inhibitors examples include Sorafenib, Sunitinib, XL184, Vandetanib, and Ponatinib, which are cell proliferations for cell lines expressing KIF5B-RET. Inhibitory activity has been reported. In addition, cabozantinib as a RET tyrosine kinase inhibitor has been reported to have a partial effect on non-small cell lung cancer due to RET fusion gene expression.
  • Patent Document 1 discloses a compound represented by the following formula (A).
  • Patent document 1 relates to a pyrazolo [3,4-d] pyrimidin-4-amine-based compound having an inhibitory effect on Btk (Bruton's Tyrosine Kinase) protein, and a pyrazolo [3,4-d] pyridine.
  • Btk Brunauer's Tyrosine Kinase
  • pyrazolo [3,4-d] pyridine Compounds in which various aryl or heteroaryl groups are substituted at the C3 position of the midin-4-amine nucleus are disclosed, and as the heteroaryl group, an isoxazol-5-yl group is substituted at the C3 position of the mother nucleus as represented by Formula A above.
  • the chemical structure of substituted compounds may also be described.
  • Patent Document 1 is effective for the treatment of lymphoma tumors by confirming the synthesis of the compound substituted with the phenoxyphenyl group at the C3 position of the pyrazolo [3,4-d] pyrimidin-4-amine parent nucleus and Btk inhibitory activity. To reveal That is, Patent Document 1 discloses only the chemical structure of the compound in which the isoxazol-5-yl group is substituted at the C3 position of the pyrazolo [3,4-d] pyrimidin-4-amine parent nucleus represented by the formula (A). Only a specific synthesis example of the compound represented by the formula (A) and Btk inhibitory activity are not disclosed at all.
  • the 3- (isoxazol-3-yl) -pyrazolo [3,4-d] pyrimidin-4-amine compound characterized by the present invention has an isoxazol-3-yl ring in the C3 position of the parent nucleus. It is substituted, and the structure is substituted with-(CH 2 ) n -A (wherein A is an alkyl, aryl or heteroaryl group, n is an integer of 0 to 4) at the C5 position of the isoxazol-3-yl ring It is a novel compound whose chemical structure has not been revealed to date.
  • novel compound characterized by the present invention has an effect of inhibiting the activity of the RET gene among protein kinases, it is useful for treating thyroid cancer, non-small cell lung cancer, and breast cancer caused by RET gene expression.
  • RET gene expression has excellent medicinal uses
  • Patent Document 1 WO 2013/010136 "Inhibitor of Bruton's Tyrosine Kinase (Btk)"
  • Non-Patent Document 1 “Preparation of 3-substituted-1-isopropyl-1H-pyrazolo [3,4-d] pyrimidin-4-amines as RET Kinase Inhibitors”, J. Med. Chem. 2012, 55, 4872-4876
  • Non-Patent Document 2 “A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing”, Genome Res 2012, 22, 436-445
  • Non-Patent Document 3 “Response to Cabozantinib in Patients with RET Fusion-Positive Lung Adenocarcinomas”, Cancer Discov 2013, 3 (6), 630-635
  • an object of the present invention is to provide a novel compound having excellent inhibitory activity and selectivity against RET kinase among protein kinases.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing and treating cancer diseases caused by abnormal expression of RET kinase containing the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a method for preparing the novel compound.
  • the present invention is a 3- (isoxazol-3-yl) -pyrazolo [3,4-d] pyrimidin-4-amine compound represented by the following general formula (1), pharmaceutically acceptable And a compound selected from the group consisting of salts thereof, hydrates thereof, solvates thereof and isomers thereof.
  • A is a hydrogen atom; C 1 -C 10 alkyl group; C 6 -C 15 aryl group; Or a 5 to 6 heteroaryl group containing 1 to 2 heteroatoms selected from S and N;
  • R is a hydrogen atom; C 1 -C 10 alkyl group; C 1 -C 10 hydroxyalkyl group; Benzyl groups; Or a 5- to 6-membered saturated or partially saturated heterocycloalkyl group containing 1 to 2 heteroatoms selected from O and N;
  • n an integer of 0 to 4.
  • the aryl group or heterocycloalkyl group is halo, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, R 1 -C (O)-(wherein R 1 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl), or R 2 -S (O) 2- , wherein R 2 is C 1 -C 10 alkyl.
  • 3- (isoxazol-3-yl) -pyrazolo [3,4-d] pyrimidin-4-amine compounds according to the present invention exhibit excellent inhibitory activity against RET protein kinases and are therefore induced by abnormal cell growth. It can be used for the purpose of preventing or treating a disease.
  • Diseases caused by abnormal cell growth in the present invention may include cancer diseases such as thyroid cancer, lung cancer, breast cancer and the like.
  • Pharmaceutically acceptable salts of the compounds represented by Formula 1 according to the present invention may be prepared by conventional methods in the art. Pharmaceutically acceptable salts are of low toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include pharmaceutically usable free acids and acid addition salts of base compounds of formula (1), alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), and organic salts and carboxyl compounds of formula (1). Organic base addition salts of acids and amino acid addition salts. Free acids that can be used for the preparation of pharmaceutically acceptable salts can be divided into inorganic acids and organic acids.
  • the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, or the like.
  • Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used.
  • Organic bases that can be used for the preparation of organic base addition salts are tris (hydroxymethyl) methylamine, dicyclohexylamine and the like.
  • Amino acids that can be used to prepare amino acid addition bases are natural amino acids such as alanine, glycine and the like.
  • the compound represented by Chemical Formula 1 according to the present invention includes all hydrates and solvates in addition to the pharmaceutically acceptable salts described above.
  • the pharmaceutically acceptable salts described above may be prepared by conventional methods, for example, in a solvent that may be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and the like. It may be prepared by melting and then crystallizing or recrystallizing after adding a free acid or free base.
  • the compound represented by Formula 1 according to the present invention may have one or more asymmetric centers, and in the case of such compounds, enantiomers or diastereomers may be present. Accordingly, the present invention includes each isomer or a mixture of these isomers. Different isomers can be separated or resolved by conventional methods, or any given isomer can be obtained by conventional synthesis or by stereospecific or asymmetric synthesis.
  • the present invention includes a radioactive derivative of the compound represented by Formula 1 according to the present invention, these radioactive compounds are useful in the field of biological research.
  • halo or "halogen atom” in the present invention is interchangeable with each other and means chloro, fluoro, bromo, and iodo.
  • 'Alkyl' in the present invention has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and refers to a linear, pulverized or cyclic aliphatic saturated hydrocarbon group. .
  • alkyl groups include methyl group, ethyl group, normal propyl group, isopropyl group, cyclopropyl group, cyclopropylmethyl group, normal butyl group, isobutyl group, tert-butyl group, cyclobutyl group, normal pentyl group and iso Pentyl group, neopentyl group, tert-pentyl group, cyclopentyl group, normal hexyl group, isohexyl group, cyclohexyl group, normal heptyl group, normal octyl group and the like can be included.
  • 'hydroxyalkyl' refers to an aliphatic saturated hydrocarbon group in which at least one hydroxy group (—OH) is bonded to a linear or pulverized carbon chain as defined above.
  • hydroxyalkyl groups include hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 1-hydroxy-isopropyl group, 2-hydroxybutyl group, 4-hydroxybutyl group, 2-methyl-2-hydroxypropyl group and the like can be included.
  • Heterocycloalkyl' in the present invention refers to an aliphatic ring group containing 5 to 6, saturated or partially saturated hetero atoms selected from O and N.
  • Specific examples of such heterocycloalkyl groups include tetrahydrofuranyl group, 2,3-dihydrofuranyl group, 2,5-dihydrofuranyl group, pyrrolidinyl group, 2,3-dihydropyrrolidinyl group, 2 , 5-dihydropyrrolidinyl group, tetrahydro-2H-pyranyl group, 3,4-dihydro-2H-pyranyl group, 4H-pyranyl group, piperidinyl group, 1,2,3,4-tetrahydropyripy Denyl groups, 1,4-dihydropyridinyl groups, piperazinyl, N-protected piperazinyl, morpholino groups, and the like.
  • the N-protecting group of piperazinyl may typically contain an
  • Aryl in the present invention means a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 15 carbon atoms. Specific examples of such an aryl group may include a phenyl group, naphthyl group, anthracenyl group, phenanthrenyl group, and the like.
  • Heteroaryl in the present invention means an aromatic ring group containing 1 to 2 heteroatoms selected from S and N, and having 4 to 13 carbon atoms.
  • Such heteroaryl includes pyrrolyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, pyridinyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, indolyl group, isoindoleyl group, Indazolyl group, benzimidazolyl group, benzothiazolyl group, benzisothiazolyl group, quinolinyl group, isoquinolinyl group, phthalazinyl group, quinazolinyl group and the like can be included.
  • A is a hydrogen atom; C 1 -C 10 alkyl group; C 6 -C 15 aryl group; Or a 5 to 6 heteroaryl group containing 1 to 2 heteroatoms selected from S and N;
  • R is a hydrogen atom; C 1 -C 10 alkyl group; C 1 -C 10 hydroxyalkyl group; Benzyl groups; Or a 5- to 6-membered saturated or partially saturated heterocycloalkyl group containing 1 to 2 heteroatoms selected from O and N;
  • n an integer of 0 to 4.
  • the aryl group or heterocycloalkyl group is halo, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, R 1 -C (O)-(wherein R 1 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl), or R 2 -S (O) 2- , wherein R 2 is C 1 -C 10 alkyl.
  • A is a hydrogen atom; Methyl group, ethyl group, normal propyl group, isopropyl group, cyclopropyl group, cyclopropyl methyl group, normal butyl group, isobutyl group, tert-butyl group, cyclobutyl group, normal pentyl group, isopentyl group, neopentyl group, tert
  • An alkyl group selected from a pentyl group, a cyclopentyl group, a normal hexyl group, an isohexyl group, a cyclohexyl group and a normal heptyl group; Phenyl group unsubstituted or substituted with a substituent selected from halo, methyl, ethyl, normal propyl, isopropyl, cyclopropyl, methoxy and ethoxy; Thiopennyl group; Or a
  • R is a hydrogen atom
  • An alkyl group selected from a pentyl group, a cyclopentyl group, a normal hexyl group, an isohexyl group, a cyclohexyl group and a normal heptyl group
  • Hydroxyalkyl groups selected from 2-methyl-2-hydroxypropyl group, 2-hydroxybutyl group and 4-hydroxybutyl group
  • Benzyl groups Tetrahydro-2H-pyranyl group
  • A represents a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a thiophen-2-yl group or a thiophen-2-yl group;
  • R is methyl group, ethyl group, normal propyl group, isopropyl group, cyclopropyl group, cyclopropyl methyl group, normal butyl group, isobutyl group, tert- butyl group, cyclobutyl group, normal pentyl group, isopentyl group, neophene
  • An alkyl group selected from a methyl group, tert-pentyl group, cyclopentyl group, normal hexyl group, isohexyl group, cyclohexyl group and normal heptyl group; Hydroxyalkyl groups selected from 2-methyl-2
  • the present invention is characterized by a method for producing a compound represented by the formula (1).
  • the manufacturing method according to the present invention will be described in detail.
  • the reaction is a reaction of 3-bromo-1H-pyrazolo [3,4-d] pyrimidin-4-amine represented by Chemical Formula 2 with a compound represented by RX (wherein X represents a halogen atom). By doing so, it is a process for preparing a compound represented by the formula (3) wherein various R is introduced.
  • the i) reaction may proceed under conditions of heating to 70 °C to 80 °C in the presence of an inorganic base.
  • the inorganic base may be selected from hydroxides, oxides, carbonates, sulfates, and the like of alkali metals or earth metals, and preferably carbonates of alkali metals such as potassium carbonate.
  • the reaction solvent a conventional organic solvent may be used, and the examples of the present invention mainly dimethylformamide (DMF) are specifically illustrated, but the solvent of the present invention is not limited thereto.
  • the reaction is a process of preparing the compound represented by Chemical Formula 4, wherein a vinyl group is introduced into the compound represented by Chemical Formula 3 by a Stille reaction.
  • the stille reaction is carried out under reflux conditions using a metal catalyst such as palladium (Pd) or nickel (Ni) and an organic tin compound as a coupling reagent.
  • a metal catalyst such as palladium (Pd) or nickel (Ni) and an organic tin compound as a coupling reagent.
  • the metal catalyst tetrakis (triphenylphosphine) palladium [Pd (PPh 3 ) 4 ] may be typically used, and tributylvinyl tin may be typically used as the organic tin compound.
  • aromatic hydrocarbons such as toluene may be used, and the reaction solvent may be in the range of about 120 ° C. to 150 ° C. as a reflux temperature of the solvent used.
  • the reaction is a process of preparing the compound represented by Chemical Formula 5 by converting the vinyl group of the compound represented by Chemical Formula 4 to an aldehyde group by oxidative cleavage and then to an oxime group.
  • Oxidative cleavage for converting vinyl groups to aldehyde groups can be carried out using ozone (O 3 ).
  • the oxidative cleavage reaction was carried out after a hydroxide reaction using osmium tetroxide (OsO 4 ) as a catalyst and N-methylmorpholine-N-oxide (NMO) as an oxidant, followed by sodium periodate (NaIO). 4 ) can be carried out under the conditions of the reaction with.
  • the aldehyde compound is then reacted with hydroxylamine (NH 2 OH) under an ethanol solvent to introduce an oxime group.
  • the reaction is a process for preparing the compound represented by Chemical Formula 1 by nitrile oxide cycloaddition of nitrile oxide.
  • the cycloaddition reaction is carried out using a hypervalent iodine compound such as (diacetoxyiodo) benzene or phenyliodine bis (trifluoroacetate) as a reaction reagent, under a mixed solvent of alcohol and water. It is carried out at room temperature (20 °C to 30 °C) conditions.
  • R is a hydrogen atom; C 1 -C 10 alkyl group; C 1 -C 10 hydroxyalkyl group; benzyl group; or 5 to 6 each of 1 to 2 hetero atoms selected from O and N containing Saturated or partially saturated heterocycloalkyl groups.
  • R is a hydrogen atom; C 1 -C 10 alkyl group; C 1 -C 10 hydroxyalkyl group; benzyl group; or 5 to 6 each of 1 to 2 hetero atoms containing 1 to 2 hetero atoms selected from N and Saturated or partially saturated heterocycloalkyl groups.
  • the intermediate compound represented by Formula 4 may typically include 1-isopropyl-3-vinyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine.
  • the intermediate compound represented by Chemical Formula 5 may typically include (E) -4-amino-1-isopropyl-1H-pyrazolo [3,4-d] pyrimidine-3-carbaaldehyde oxime.
  • a compound represented by the following Chemical Formula 1 may be prepared by performing a three-step preparation process using the malononitrile compound represented by the following Chemical Formula 6 as a starting material.
  • a) Reaction is a process for producing a 1H-pyrazole-4-carbonitrile compound represented by the formula (7) by cyclization reaction with the malononitrile compound represented by the formula (6) and hydrazine (NH 2 NH 2 ) hydrate .
  • the a) reaction may be carried out under conditions of room temperature (20 ° C. to 30 ° C.) in alcohol solvents such as methanol and ethanol.
  • the reaction is carried out by the cyclization reaction of the 1H-pyrazole-4-carbonitrile compound represented by the formula (7) and the formamide compound (HC (O) NH 2 ), and the 1H-pyrazolo [3] represented by the formula (8). , 4-d] pyrimidin-4-amine compound.
  • the b) reaction may be carried out under the conditions of heating to a temperature of 130 °C to 180 °C.
  • the reaction is a reaction of the 1H-pyrazolo [3,4-d] pyrimidin-4-amine compound represented by Formula 8 with the alcohol compound represented by ROH, where various R are introduced
  • the process of preparing the compound proceeds through a Mitsunobu reaction using triphenylphosphine (PPh 3 ) and an azodicarboxylate compound.
  • the azodicarboxylate compound may include, for example, diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).
  • the Mitsunobu reaction may be performed under conditions of room temperature (20 ° C. to 30 ° C.) using a polar solvent such as tetrahydrofuran.
  • the present invention includes a compound represented by the formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof is a pharmaceutical composition containing the active ingredient.
  • the compound represented by Formula 1 exhibits excellent inhibitory activity against RET kinase, it may be used as a prophylactic or therapeutic agent for diseases caused by abnormal cell growth.
  • Cancer diseases caused by abnormal cell growth in the present invention may specifically include thyroid cancer, lung cancer, breast cancer.
  • the effect of inhibiting the activity of RET kinase is excellent, it is useful as a prophylactic and therapeutic agent for medullary thyroid cancer, non-small cell lung cancer, breast cancer.
  • the pharmaceutical composition of the present invention contains a compound represented by the formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof as an active ingredient, and a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient And the like can be formulated into conventional formulations in the pharmaceutical field, for example, oral or parenteral formulations such as tablets, capsules, troches, solutions, suspensions and the like.
  • Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like.
  • lactose dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.
  • the dosage of the compound according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally 0.01 based on an adult patient having a weight of 70 kg. It is-1,000 mg / day, and may be dividedly administered once to several times a day at regular time intervals depending on the judgment of the doctor or pharmacist.
  • Step 2 1-isopropyl-3-vinyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine
  • Step 3 (E) -4-amino-1-isopropyl-1H-pyrazolo [3,4-d] pyrimidine-3-carbaaldehyde oxime
  • Step 4 1-isopropyl-3- (5-phenylisoxazol-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine
  • Step 1 2- (methoxy (5-phenylisoxazol-3-yl) methylene) malononitrile
  • Step 4 3- (5-phenylisoxazol-3-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine
  • novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • Injectables were prepared by containing 100 mg as active ingredient, as well as 180 mg of mannitol, 26 mg of Na 2 HPO 4 12H 2 O and 2974 mg of distilled water.
  • the inhibitory activity (% inhibition) of RET (Rearranged during transfaction) kinase of the compound represented by Chemical Formula 1 according to the present invention was shown in Table 1 below.
  • the compound of the present invention was generally excellent in RET kinase inhibitory activity, and the compound of the compounds Nos. 2, 3, 7, 8, 22 to 29 can be confirmed that the inhibitory effect is excellent.
  • the inhibitory activity of RET variant kinase was evaluated for the compound of Compound No. 2.
  • the inhibitory activity of the phosphorylation reaction of biotinylated peptide (EGPWLEEEEEAYGWMDF) using RET variant kinase with GST tag at the N-terminus of RET kinase domain (Carna Biosciences, Millipore) was used as an index. It was. Phosphorylated biotinylated peptide was detected by TR-FRET method using antiphosphorylated antibody bound with Europium label. The inhibitory activity for each variant of RET kinase was calculated as an IC 50 value and is shown in Table 2 below.
  • RET IC 50 Cabozantinib (control) Compound number 2 RET (wt) 9 ⁇ 10 RET (G691S) 14 ⁇ 10 RET (Y791F) 7 ⁇ 10 RET (V804L) 230 ⁇ 30 RET (V804M) 358 ⁇ 10 RET (S891A) 5 ⁇ 10 RET (M918T) 18 ⁇ 10
  • the thyroid medulla cancer cell line TT American Type Culture Collection
  • a normal thyroid epithelial cell line Nthy-ori 3-1
  • a RET kinase activation mutation C634W
  • the cell proliferation inhibitory activity was compared, and cell proliferation inhibitory activity of parental Ba / F3 cell line without modification and RET-Ba / F3 cell line with RET was measured.
  • F-12K Nutrient Mixture containing 10% FBS in a 96 well plate containing 5,000 cells per well of Nthy-ori 3-1 cells, TT cells, Parental Ba / F3 cells, and RET-Ba / F3 cells (Life Technologies Corporation) ) was incubated overnight at 37 ° C., 5% CO 2 . Then, the test compound was added to dimethyl sulfoxide, diluted to a final concentration of 1 nM to 10 ⁇ M, and added to a 96 well plate. After culturing for 5 days at 37 ° C.
  • Compound number 23 > 10 ⁇ 1 > 10 ⁇ 1
  • Compound number 24 > 2 ⁇ 1 > 10 ⁇ 1
  • Compound number 26 > 10 ⁇ 5 > 10 ⁇ 3
  • Compound number 28 ⁇ 10 ⁇ 5 > 10 ⁇ 3
  • Compound number 29 > 10 ⁇ 5 > 10 ⁇ 3
  • Compound number 30 > 10 ⁇ 10 > 10 ⁇ 5
  • the compound of the present invention does not show inhibitory activity against normal cell lines (Nthy-ori 3-1 cells, Parental Ba / F3 cells), abnormally expressed cell line (TT cells or RET- Ba / F3 cells) can be confirmed that the selective inhibitory activity was excellent.

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Abstract

La présente invention concerne un nouveau composé 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine, un procédé de préparation pour le composé, et une utilisation pharmaceutique du composé pour la prévention et le traitement de diverses maladies cancéreuses provoquées par l'activité de kinases RET.
PCT/KR2016/008427 2015-08-07 2016-08-01 Nouveau composé 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine, qui est un inhibiteur de la kinase ret WO2017026718A1 (fr)

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018071454A1 (fr) 2016-10-10 2018-04-19 Andrews Steven W Composés de pyrazolo[1,5-a]pyridine substitués en tant qu'inhibiteurs de la kinase ret
US10023570B2 (en) 2015-07-16 2018-07-17 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2018136663A1 (fr) 2017-01-18 2018-07-26 Array Biopharma, Inc. Inhibiteurs de ret
WO2018136661A1 (fr) 2017-01-18 2018-07-26 Andrews Steven W Composés de pyrazolo[1,5-a]pyrazine substitués utilisés en tant qu'inhibiteurs de la kinase ret
US10112942B2 (en) 2016-10-10 2018-10-30 Array Biopharma Inc. Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
WO2019075114A1 (fr) 2017-10-10 2019-04-18 Mark Reynolds Formulations comprenant du 6-(2-hydroxy-2-méthylpropoxy)-4-(6-(6-((6-méthoxypyridin-3-yl)méthyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075108A1 (fr) 2017-10-10 2019-04-18 Metcalf Andrew T Formes cristallines
WO2019143991A1 (fr) * 2018-01-18 2019-07-25 Array Biopharma Inc. Composés de pyrazolo[3,4-d]pyrimidine substitués utilisés en tant qu'inhibiteurs de la kinase ret
WO2019143977A1 (fr) 2018-01-18 2019-07-25 Array Biopharma Inc. Composés de pyrrolo[2,3-d]pyrimidines substitués utilisés en tant qu'inhibiteurs de la kinase ret
WO2019143994A1 (fr) 2018-01-18 2019-07-25 Array Biopharma Inc. Composés de pyrazolyl[4,3-c]pyridine substitués utilisés en tant qu'inhibiteurs de la kinase ret
CN110506043A (zh) * 2017-04-13 2019-11-26 癌症研究科技有限公司 适用作ret抑制剂的化合物
WO2020055672A1 (fr) 2018-09-10 2020-03-19 Array Biopharma Inc. Composés hétérocycliques condensés comme inhibiteurs de kinases ret
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
WO2020132269A1 (fr) * 2018-12-20 2020-06-25 KSQ Therapeutics, Inc. Pyrazolopyrimidines substituées et purines substituées et leur utilisation en tant qu'inhibiteurs de protéase 1 de traitement spécifique de l'ubiquitine
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
US11718624B2 (en) 2020-10-30 2023-08-08 KSQ Therapeutics, Inc. Solid state forms of substituted pyrazolopyrimidines and uses thereof
WO2023239422A2 (fr) 2021-10-22 2023-12-14 University Of Houston System Méthodes et compositions pour traiter une lésion inflammatoire chronique, une métaplasie, une dysplasie et des cancers des tissus épithéliaux

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100004235A1 (en) * 2006-04-27 2010-01-07 Bayer Healthcare Ag Heterocyclic Substituted, Anellated Pyrazole Derivative and its uses
WO2013010136A2 (fr) * 2011-07-13 2013-01-17 Pharmacyclics, Inc. Inhibiteurs de tyrosine kinase de bruton
WO2014047662A2 (fr) * 2012-09-24 2014-03-27 Whitehead Institute For Biomedical Research Dérivés d'indazole et leurs utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100004235A1 (en) * 2006-04-27 2010-01-07 Bayer Healthcare Ag Heterocyclic Substituted, Anellated Pyrazole Derivative and its uses
WO2013010136A2 (fr) * 2011-07-13 2013-01-17 Pharmacyclics, Inc. Inhibiteurs de tyrosine kinase de bruton
WO2014047662A2 (fr) * 2012-09-24 2014-03-27 Whitehead Institute For Biomedical Research Dérivés d'indazole et leurs utilisations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DINER, P. ET AL.: "Preparation of 3-substituted-1-isopropyl-1 H-pyrazolo [3,4-d] Pyrimidin-4-amines as RET Kinase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 10, 2012, pages 4872 - 4876, XP055363610 *
YOON, H. ET AL.: "A Pyrazolo [3, 4-d] Pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 1, 10 December 2015 (2015-12-10), pages 358 - 373, XP055363611 *

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