WO2023183444A1 - Modulateurs de protéines kinases - Google Patents

Modulateurs de protéines kinases Download PDF

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Publication number
WO2023183444A1
WO2023183444A1 PCT/US2023/015993 US2023015993W WO2023183444A1 WO 2023183444 A1 WO2023183444 A1 WO 2023183444A1 US 2023015993 W US2023015993 W US 2023015993W WO 2023183444 A1 WO2023183444 A1 WO 2023183444A1
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mmol
alkyl
methyl
phenyl
stirred
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PCT/US2023/015993
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English (en)
Inventor
Paul Galatsis
Doug WERNER
Andrew HUNTSMAN
Khoi Huynh
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Vibliome Therapeutics, Llc
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Publication of WO2023183444A1 publication Critical patent/WO2023183444A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • the more than 523 typical and atypical kinases in the human kinome represent a constellation of enzymes that catalyze the transfer of a phosphate group from ATP to a variety of amino acid residues, such as tyrosine, serine, and threonine.
  • these enzymes and their interrelated networks are effectors of cellular signal transduction.
  • receptor tyrosine kinases (RTKs) coupled with their downstream intracellular kinases and phosphatases mediated cascades and feedback loops establish critical conduits for the transfer and regulation of signals from the cell exterior into the nucleus where transcriptional regulation takes place.
  • R 1 , R 2 , and R 3 are as defined herein.
  • These compounds act as modulators of protein kinase (e.g., kinase inhibitors) and are useful in treating conditions responsive to the inhibition of protein kinase (e.g., cancer). See e.g., Table 1 and 2.
  • compositions comprising the disclosed protein kinase inhibitors.
  • R 1 and R 2 are each independently selected from hydrogen, halo and (Ci-C4)alkyl
  • R 3 is phenyl or heteroaryl, each of which is optionally substituted with 1 to 2 groups selected from R a ;
  • R a is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci- C 4 )alkoxy, halo(Ci-C 4 )alkoxy, halo, -S(O)[(Ci-C 4 )alkyl], -S(O) 2 [(Ci-C 4 )alkyl], -S(Ci- C4)alkyl, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, phenyl, and 4- to 6-membered heteroaryl, wherein said phenyl and 4- to 6-membered heteroaryl are each optionally substituted with 1 to 2 groups selected from R b ; and wherein said (Ci-C4)alkyl, (Ci-C4)alkoxy, and -S(Ci- C4)alkyl are each optionally substituted with -NR c R
  • R c and R d are each independently selected from hydrogen and (Ci-C4)alkyl.
  • a hyphen designates the point of attachment of that group to the variable to which it is defined.
  • -NH(Ci-C4)alkyl means that the point of attachment for this group occurs on the nitrogen atom.
  • halo and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).
  • alkyl when used alone or as part of a larger moiety, such as “haloalkyl”, and the like, means saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e., (Ci-C4)alkyl.
  • Alkoxy means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl.
  • (Ci-C4)alkoxy includes methoxy, ethoxy, proproxy, and butoxy.
  • haloalkyl includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine (e.g., -CF3, - CHF 2 , etc.
  • Haloalkoxy is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to -OCHF2 or -OCF3.
  • heteroaryl used alone or as part of a larger moiety refers to a 5- to 12- membered (e.g., a 5- to 7-membered or 5- to 6-membered) aromatic radical containing 1-4 heteroatoms selected from N, O, and S.
  • a heteroaryl group may be mono- or bi-cyclic.
  • Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.
  • Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings.
  • Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.
  • subject and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, pigs, horses, sheep, goats and the like
  • laboratory animals e.g., rats, mice, guinea pigs and the like.
  • the subject is a human in need of treatment.
  • inhibitor includes a decrease in the baseline activity of a biological activity or process e.g., to inhibit the activity of one or more kinases.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.
  • compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
  • the salts of the compounds described herein refer to nontoxic “pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g. salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids).
  • Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s).
  • Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
  • Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.
  • Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.
  • an effective amount or “therapeutically effective amount” refers to an amount of a compound described herein that will elicit a desired or beneficial biological or medical response of a subject e.g., a dosage of between 0.01 - 100 mg/kg body weight/day.
  • the compound of Formula I is of the Formula II: or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.
  • the compound of Formula I is of the Formula III: or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.
  • the compound of Formula I is of the Formula IV : or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for
  • R 1 in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof is (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I.
  • R 1 in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof is methyl, wherein the remaining variables are as described above for Formula I.
  • R 3 in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof is selected from phenyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, imidazolyl, indolyl, and pyrrolyl, each of which are optionally substituted with 1 to 2 groups selected from R a , wherein the remaining variables are as described above for Formula I or the fifth embodiment.
  • R a in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, -S(O)[(Ci-C4)alkyl], -S(O)2[(Ci-C4)alkyl], -S(Ci-C4)alkyl, phenyl, and 4- to 6-membered heteroaryl, wherein said phenyl and 4- to 6-membered heteroaryl are each optionally substituted with 1 to 2 groups selected from R b and wherein said (Ci-C4)alkyl, (Ci- C4)alkoxy, and -S(Ci-C4)alkyl are each optionally substituted with -NR c R d , wherein the remaining variables are as described above for Formula I or the fifth or sixth embodiment.
  • R a in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof is selected from (Ci-C4)alkyl, halo(Ci- C 4 )alkyl, -S(O)[(Ci-C 4 )alkyl], -S(O) 2 [(Ci-C 4 )alkyl], -S[(Ci-C 4 )alkyl]N[(Ci-C 4 )alkyl] 2 , - O[(Ci-C4)alkyl]N[(Ci-C4)alkyl]2, phenyl, pyrazolyl, and imidazolyl wherein said phenyl, pyrazolyl, and imidazolyl are each optionally substituted with 1 to 2 groups selected from R b , wherein the remaining variables are as described above for Formula I or the fifth or sixth embodiment.
  • R b in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof is selected from halo and (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or the fifth, sixth, or seventh embodiment.
  • the compounds and compositions described herein are generally useful for modulating the activity of protein kinase. In some aspects, the compounds and pharmaceutical compositions described herein inhibit the activity of protein kinase. [0029] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a disorder associated with protein kinase function.
  • methods of treating a condition associated with protein kinase function comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a condition associated with protein kinase function.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a condition associated with protein kinase function for use in treating a condition associated with protein kinase function.
  • the compounds and pharmaceutical compositions described herein are useful in treating a condition selected from an inflammatory disease, a neurodegenerative disease, cardiovascular disease, metabolic disease, pain, and cancer.
  • inflammatory disease examples include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, osteo-arthritis, progression of atherosclerotic plaques, bone metastasis, asthma, interstitial cystitis, atopic dermatitis, psoriasis and systemic lupus erythematosus (SLE).
  • inflammatory disease include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, osteo-arthritis, progression of atherosclerotic plaques, bone metastasis, asthma, interstitial cystitis, atopic dermatitis, psoriasis and systemic lupus erythematosus (SLE).
  • neurodegenerative disease examples include, but are not limited to, Alzheimer’s, Parkinson's disease, and multiple sclerosis.
  • cardiovascular disease examples include, but are not limited to, hypertension, coronary and cerebral vasospasm, restenosis, atherosclerosis, stroke, and heart failure
  • cardiovascular disease examples include, but are not limited to, hypertension, coronary and cerebral vasospasm, restenosis, atherosclerosis, stroke, and heart failure
  • metabolic disease examples include, but are not limited to, type 1 diabetes, type 2 diabetes.
  • cancer examples include, but are not limited to, colon, lung, ovarian, kidney, pancreatic, thyroid, hepatocellular, renal, gastric, breast, and brain cancers.
  • a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition.
  • Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the pharmaceutical compositions are administered orally.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition.
  • NMR nuclear magnetic resonance pH: potential of hydrogen; a measure of the acidity or basicity of an aqueous solution
  • PE petroleum ether rt: room temperature s: singlet (spectral) t: triplet (spectral)
  • Shimadzu LCMS system consisting of Nexera XR HPLC stack (20 Series) with Nexera X2 SPD-M30A DAD and LCMS-2020 mass spectrometer using LabSolutions, v.5.89 software under the following parameters: Column temp: 45°C, Sample temp: 18°C. Gradient elution methods, mobile phase eluents, and columns are shown below.
  • LCMS Liquid Chromatography Mass Spectrometry
  • RP column 1 ACE EXCEL 3 C18; 3.0 urn, 100 x 3 mm (Mac-Mod Part # EXL- 111-1003U)
  • RP column 2 Zorbax Eclipse XDB C8; 1.8 um, 50 x 4.6 mm (Agilent Part # 922975-906)
  • ACE 5 C18-PFP 5.0 urn
  • 150 x 10 mm Advantor-ACE Part # ACE-1210-1510
  • GPC TSKgel a-2500; 7.0 urn, 300 x 7.8 mm; (TOSOH Part # 0018339)
  • H NMR Proton NMR was performed on the Varian Inova 500 spectrometer operating at 500 MHz in CDCI3, DMSO-tfo, or MeOD.
  • the mixture was stirred at rt for 3h.
  • the reaction mixture was quenched with aq sat NaHCOs (10 mL) and stirred for 1 h.
  • the solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCh (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL).
  • Aqueous layer was extracted with DCM (3 X 10 mL), dried, evaporated and combined with the filter cake.
  • reaction mixture was stirred at this temperature for Ih.
  • Cold water (10 mL) was added to the reaction mixture, solids were filtered, washed with saturated sodium bicarbonate solution (10 mL) followed by IM LiCl (2 x 10 mL), water (2 x 5 mL) and hexanes and dried under reduced pressure.
  • reaction mixture was quenched with aq. sat NaHCOs (10 mL) and stirred for 1 h.
  • the solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCL (2 x 5 mL), H2O (2 x 5 mL) and dried.
  • the solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCh (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL), dried overnight under high vacuum.
  • the solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCL (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL), dried overnight under high vacuum. Crude was dissolved in MeOH (2ml). The mixture was added 4N HC1 in Dioxane (0.5 ml) and stirred o/n. The mixture was filtered. The cake was washed with Et20, Sat.
  • Trifluoromethylindole 3-10 (92 mg, 0.497 mmol, 3.00 eq) in THF (1 mL, 0.0415 M) dropwise. The mixture was stirred for overnight. Solution change from trace suspension to cloudy. The mixture was evaporated to get THP protected product. The intermediate was dissolved in MeOH (2ml) and added 4M HC1 in dioxane (0.5 ml). The mixture was stirred for Ih and solvent was evaporated. The crude was purified by HPLC under acidic condition to give HC1 salt, which was dissolved in MeOH and passed through Amberlite IRA-67 resin.
  • the product was dry loaded onto a 40g silica column and purified over a 0-10% MeOH in DCM gradient to yield l-(4-fluorophenyl)-N-(4-methyl-3-((3-(9-(tetrahydro-2H- pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)amino)phenyl)-5-(methylsulfonyl)-lH-pyrazole-3- carboxamide.
  • the product was dry loaded onto a 40g silica column and purified over a 0-10% MeOH in DCM gradient to yield 5-(4-fluorophenyl)- 2-methylsulfinyl-N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]amino]phenyl]thiazole-4-carboxamide.
  • the reaction mixture was quenched with aq sat NaHCOs (5 mL) and stirred for 1 h.
  • the solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCOs (5 mL), IM LiCl (2 x 5 mL), H2O (2 x 5 mL).
  • the cake was dried o/n and triturated with ether (5 ml), filtered and dried overnight under high vacuum to afford 80mg of THP protected product, which was dissolved in DCM (1.5ml) and TFA (1.5 mL, 19.6 mmol, 112 eq) was added drop wise.
  • the mixture was stirred 3h until consumption of the starting material.
  • the mixture was stirred at rt for 3h.
  • the reaction mixture was quenched with aq sat NaHCOs (10 mL) and stirred for 1 h.
  • the solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCh (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL), dried overnight under high vacuum.
  • reaction mixture was stirred at this temperature for Ih.
  • Cold water (10 mL) was added to the reaction mixture, solids were filtered, washed with aq sat NaHCCh (10 mL) followed by IM LiCl (2 x 10 mL), water (2 x 5 mL) and hexanes and dried under reduced pressure.
  • reaction mixture was stirred at this temperature for Ih.
  • Cold water (10 mL) was added to the reaction mixture, solids were filtered, washed with aq sat NaHCCh (10 mL) followed by IM LiCl (2 x 10 mL), water (2 x 5 mL) and hexanes and dried under reduced pressure.
  • the precipitate obtained was filtered and washed with H2O (2 x 100 ml) to get some of the product (17 g) as a dark yellowish solid.
  • the filtrate was then extracted with EtOAc (2 x 500 ml) to extract more product from the water layer.
  • EtOAc 2 x 500 ml
  • the combined organic layers were washed (l x 200 ml) saturated brine solution.
  • the organics were then separated and dried over Na2SO4, filtered, and concentrated to dryness in vacuo.
  • the crude solid obtained was further purified using ISCO, Combiflash companion, Siliasep 330 g column (dry loaded in DCM) (eluting 0 to 50 % DCM/EtOAc gradient over 50 min to give another 22 g of N-(2-methyl-5-nitrophenyl)-3- (9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine 5-1 (39.00 g, 62.02% ) as a bright yellow solid.
  • a 2 L-hydrogenation bottle was charged with N-(2-methyl-5-nitrophenyl)-3-(9- (tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine 5-1 (25.00 g, 56.8 mmol). This was suspended in a mixture of 500 ml of THF and MeOH (60 mL, 0.0860 M), and a suspension of 10% Pd/C (3.02 g, 2.84 mmol) in 100 ml THF was slowly added to the hydrogenation bottle under a steady flow of nitrogen. The bottle was then purged with nitrogen gas for 10 mins, and then subjected to hydrogenation in a Parr shaker at 40 psig for 6 h.
  • the reaction mixture was then filtered through Celite.
  • the Celite was washed with THF (100 ml), MeOH (100 ml), and EtOAc (300 ml).
  • the filtrate was evaporated to get a greenish yellow residue.
  • the crude solid was further purified using ISCO, Combiflash Siliasep 330 g column (dry loaded in DCM, eluting 0 to 100 % DCM/EtOAc gradient over 60 min).
  • Reaction mixture was cooled to room temperature upon completion, as judged by TLC, before extracting with ethyl acetate twice. Solvent evaporated under reduced pressure. Crude reaction mixture was purified over gravity column using silica gel (100-200 mesh) with a gradient of 0 to 10% ethyl acetate in hexane as an eluent to afford ethyl 3-(4-fluorophenyl)furan-2-carboxylate 1- 15 (4.5 g (61%) as colorless liquid.
  • the disclosed compounds were tested for activity against a panel of at least 300 kinases.
  • Kinase panel screening was conducted by Nanosyn (Santa Clara, CA 95051) using an enzymatic inhibition assay accepted as valid by those skilled in the art (e.g., the Caliper LabChip® mobility shift assay, an ADP detection assay, or time-resolved fluorescence detection technology.
  • Compounds were screened at a concentration of 5 pM using an ATP concentration at the Km for each of the respective kinases and a 30-minute pre-incubation time-point.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des modulateurs de protéines kinases à petites molécules ayant la formule I, des compositions pharmaceutiques les comprenant et leurs utilisations dans le traitement d'une ou de plusieurs affections.
PCT/US2023/015993 2022-03-24 2023-03-23 Modulateurs de protéines kinases WO2023183444A1 (fr)

Applications Claiming Priority (2)

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US202263323094P 2022-03-24 2022-03-24
US63/323,094 2022-03-24

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110201602A1 (en) * 2004-05-07 2011-08-18 Amgen Inc. Protein kinase modulators and method of use
US20120316172A1 (en) * 2011-06-09 2012-12-13 Guido Galley Pyrazole derivatives
WO2016166250A1 (fr) * 2015-04-14 2016-10-20 Qurient Co., Ltd Dérivés de quinoléine utilisés comme inhibiteurs de rtk de tam
US20190300531A1 (en) * 2016-02-03 2019-10-03 Samjin Pharmaceutical Co., Ltd. Pyridine Derivative Inhibiting RAF Kinase and Vascular Endothelial Growth Factor Receptor, Method for Preparing Same, Pharmaceutical Composition Containing Same, and Use Thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110201602A1 (en) * 2004-05-07 2011-08-18 Amgen Inc. Protein kinase modulators and method of use
US20120316172A1 (en) * 2011-06-09 2012-12-13 Guido Galley Pyrazole derivatives
WO2016166250A1 (fr) * 2015-04-14 2016-10-20 Qurient Co., Ltd Dérivés de quinoléine utilisés comme inhibiteurs de rtk de tam
US20190300531A1 (en) * 2016-02-03 2019-10-03 Samjin Pharmaceutical Co., Ltd. Pyridine Derivative Inhibiting RAF Kinase and Vascular Endothelial Growth Factor Receptor, Method for Preparing Same, Pharmaceutical Composition Containing Same, and Use Thereof

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