WO2023006057A1 - Cristal de composé aminopyrazolopyrimidine - Google Patents

Cristal de composé aminopyrazolopyrimidine Download PDF

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WO2023006057A1
WO2023006057A1 PCT/CN2022/108846 CN2022108846W WO2023006057A1 WO 2023006057 A1 WO2023006057 A1 WO 2023006057A1 CN 2022108846 W CN2022108846 W CN 2022108846W WO 2023006057 A1 WO2023006057 A1 WO 2023006057A1
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Prior art keywords
crystal
compound
formula
xrpd pattern
peaks
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PCT/CN2022/108846
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English (en)
Chinese (zh)
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张艳阳
项立伟
朱益忠
刘飞
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正大天晴药业集团股份有限公司
首药控股(北京)股份有限公司
连云港润众制药有限公司
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Priority to CN202280046317.1A priority Critical patent/CN117751121A/zh
Publication of WO2023006057A1 publication Critical patent/WO2023006057A1/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
    • A61K31/495—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
    • 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 application relates to crystals of aminopyrazolopyrimidine compounds, preparation methods and uses thereof in the prevention and treatment of diseases mediated by TRK kinases.
  • NTRK/TRK Tropomyosin receptor kinase
  • the TRK family mainly includes three members, NTRK1/TRKA, NTRK2/TRKB and NTRK3/TRKC.
  • the complete TRK kinase includes three parts: extracellular region, transmembrane region and intracellular region. After the extracellular region of TRK kinase binds to the corresponding ligand, it can cause a change in the kinase configuration and form a dimer.
  • TRK kinase undergoes autophosphorylation to activate its own kinase activity, and further activates downstream signal transduction pathways (such as MAPK, AKT, PKC, etc.) to produce corresponding biological functions; among them, NGF (nerve growth factor) Binds TRKA, BDNF (derived neurotrophic factor) binds TRKB, and NT3 (neurotrophic factor 3) binds TRKC.
  • NGF nerve growth factor
  • TRKA nerve growth factor
  • BDNF derived neurotrophic factor
  • NT3 neurotrophic factor 3
  • TRK signal transduction pathways are also strongly correlated with the occurrence and development of tumors.
  • Activated TRK signaling proteins have been found in neurocytoma, prostate cancer, and breast cancer.
  • TRK fusion proteins have shown its biological function of promoting tumorigenesis. The earliest TPM3-TRKA fusion protein was found in colon cancer cells, with an incidence of about 1.5% in clinical patients tested.
  • TRK fusion proteins were found in different types of clinical tumor patient samples such as lung cancer, head and neck cancer, breast cancer, thyroid cancer, glioma, etc., such as CD74-NTRK1, MPRIP-NTRK1, QKI-NTRK2, ETV6 -NTRK3, BTB1-NTRK3, etc.
  • These different NTRK fusion proteins are in a state of highly activated kinase activity without the need for ligand binding, so they can continuously phosphorylate downstream signaling pathways, induce cell proliferation, and promote the occurrence and development of tumors.
  • Target mutations that appear after continuous administration are an important reason for tumor drug resistance. Recently, there have been clinical cases of NTRK mutations.
  • WO2018077246 discloses compounds of formula (I) as NTRK/TRK inhibitors: 2-amino-5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine-1 -yl) pyrazolo[1,5-a]pyrimidine-3-carboxamide for preventing or treating diseases mediated by TRK tyrosine kinase receptors.
  • the application provides crystals of the compound of formula (I), or pharmaceutically acceptable salts or crystals thereof
  • the pharmaceutically acceptable salt of the compound of formula (I) above is selected from methanesulfonate, sulfate, hydrochloride, hydrobromide or p-toluenesulfonic acid.
  • the present application provides crystals of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present application provides crystals of a compound of Formula (I).
  • the crystals of the compound of formula (I) of the present application are type A crystals, and in its X-ray powder diffraction (XRPD) pattern, 2 ⁇ has peaks at 9.92, 11.38 or 18.72 ⁇ 0.2°; in some embodiments, 2 ⁇ has peaks at 9.92, 11.38, 18.72, 19.98 or 27.55 ⁇ 0.2° in its XRPD pattern; in some embodiments, 2 ⁇ has a peak at 9.92, 11.38, 17.55, 18.72, 19.98, 22.56, 25.75 or 27.55 ⁇ 0.2° in its XRPD pattern; in some embodiments, 2 ⁇ is at 9.92, 11.38 in its XRPD pattern , 17.55, 18.72, 19.98, 21.18, 22.56, 23.09, 24.00, 24.70, 25.75 or 27.55 ⁇ 0.2 ° place peak; , 21.18, 22.56, 25.75, 27.23, 27.55 or 28.95 ⁇ 0.2 ° have
  • its XRPD pattern has a 2 ⁇ peak at 9.92, 11.38, 14.98, 17.55, 18.72, 19.98, 21.18, 22.56, 23.09, 24.00, 24.70, 25.75, 27.23, or 27.55 ⁇ 0.2°. In some embodiments, its XRPD pattern has a 2 ⁇ peak at 9.92, 11.38, 14.98, 17.55, 18.72, 19.98, 21.18, 22.56, 23.09, 24.00, 24.70, 25.75, 27.23, 27.55, or 28.95 ⁇ 0.2°.
  • the crystals of the compound of formula (I) in the present application are type A crystals, characterized in that the X-ray powder diffraction pattern is selected from 9.92, 11.38, 14.98, 17.55, 18.72, 19.98, 21.18, 22.56, At least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 specific diffraction peaks at a 2 ⁇ value of 23.09, 24.00, 24.70, 25.75, 27.23, or 27.55 ⁇ 0.2° .
  • the crystals of the compound of formula (I) of the present application are type A crystals, which are characterized by peaks at 9.92, 11.38, 18.72, 19.98 ⁇ 0.2° at 2 ⁇ in the X-ray powder diffraction pattern, further, Having at least 7, at least 8, at least 9, or at least 10 specific diffractions at a 2 ⁇ value selected from 14.98, 17.55, 21.18, 22.56, 23.09, 24.00, 24.70, 25.75, 27.23, 27.55, or 28.95 ⁇ 0.2° peak.
  • the peak positions and relative intensities of the diffraction peaks are represented by the following table 1:
  • the crystals of the compound of formula (I) in the present application are type A crystals, and its X-ray powder diffraction pattern is shown in FIG. 1 .
  • the crystals of the compound of formula (I) in the present application are type A crystals, and its DSC spectrum has the onset of endothermic peak at 245.55°C. In some embodiments, the crystals of the compound of formula (I) in the present application are type A crystals, and its DSC spectrum has the onset of endothermic peak at 245.55°C ⁇ 5°C, preferably 245.55°C ⁇ 3°C.
  • the crystals of the compound of formula (I) in the present application are type A crystals, and its DSC spectrum is shown in FIG. 2 .
  • the crystals of the compound of formula (I) of the present application are type A crystals, and its TG spectrum is shown in FIG. 3 .
  • the present application provides a preparation method of compound A of formula (I), comprising mixing the compound of formula (I) with a solvent to dissolve, and isolating the solid.
  • the volume mass ratio of the solvent to the compound of formula (I) is 5-50mL/g; or 5-40mL/g; or 5-30mL/g; or 5-20mL/g; or 10-20mL /g; or 12.5mL/g.
  • the above solvent is selected from one or more of isopropanol, acetone, acetonitrile and water.
  • the aforementioned solvent is selected from a mixture of isopropanol and water.
  • the volume ratio of the above-mentioned isopropanol to water is selected from 50:1 to 1:50; or 10:1 to 1:10; or 5:1 to 1:5; or 2:1 to 1:2 ; or 1:1 ⁇ 1:1.5.
  • the above preparation method is carried out under the condition of heating to 70-90°C; or under the condition of heating to 80-85°C.
  • the above method further includes the step of drying the isolated solid; optionally, drying at 40-50°C (preferably 45°C) under vacuum conditions.
  • the crystals of the compound of formula (I) of the present application are type B crystals, and in its X-ray powder diffraction (XRPD) pattern, 2 ⁇ has a peak at 7.58, 18.78 or 23.57 ⁇ 0.2°; in some embodiments In the scheme, 2 ⁇ has a peak at 7.58, 17.03, 18.78, 21.22 or 23.57 ⁇ 0.2° in its XRPD pattern; There is a peak at °; in some embodiments, 2 ⁇ has a peak at 7.58, 8.80, 14.91, 17.03, 18.78, 21.22, 21.90, 22.40 or 23.57 ⁇ 0.2° in its XRPD pattern; in some embodiments, its XRPD pattern 2 ⁇ peaks at 7.58, 8.80, 12.06, 14.91, 17.03, 18.78, 21.22, 21.90, 22.40, 23.57, 25.91 or 29.25 ⁇ 0.2°; in some embodiments, 2 ⁇ is at 7.58, 8.80, 12.06 , 14.91, 15.
  • the 2 ⁇ in its XRPD pattern is 7.58, 8.80, 9.60, 12.06, 14.91, 15.10, 16.31, 17.03, 18.24, 18.78, 21.22, 21.90, 22.40, 22.76, 23.57, 24.37, 24.66, 25.91, 27.28, There are peaks at 28.30, 28.68, 29.25 or 34.78 ⁇ 0.2°.
  • the crystals of the compound of formula (I) of the present application are type B crystals, characterized in that the X-ray powder diffraction pattern is selected from 7.58, 8.80, 12.06, 14.91, 17.03, 18.78, 21.22, 21.90, There are at least 7, at least 8, at least 9, at least 10 or at least 11 specific diffraction peaks at a 2 ⁇ value of 22.40, 23.57, 25.91 or 29.25 ⁇ 0.2°.
  • the crystals of the compound of formula (I) of the present application are type B crystals, which are characterized by peaks at 7.58, 17.03, 18.78, 21.22, 23.57 ⁇ 0.2° in the X-ray powder diffraction pattern, further Preferably, there are at least 5, at least 6, at least 7 specific diffraction peaks at 2 ⁇ values selected from 8.80, 12.06, 14.91, 21.90, 22.40, 23.57, 25.91 or 29.25 ⁇ 0.2°.
  • the crystals of the compound of formula (I) of the present application are type B crystals, which are characterized by peaks at 7.58, 17.03, 18.78, 21.22, 23.57 ⁇ 0.2° in the X-ray powder diffraction pattern, further Preferably, there are at least 5, at least 6, at least 7 specific diffraction peaks at 2 ⁇ values selected from 8.80, 12.06, 14.91, 21.90, 22.40, 25.91 or 29.25 ⁇ 0.2°.
  • the peak positions and relative intensities of the diffraction peaks are represented by the following table 1:
  • the crystals of the compound of formula (I) in the present application are type B crystals, and its X-ray powder diffraction pattern is shown in FIG. 4 .
  • the crystals of the compound of formula (I) in the present application are type B crystals, and its DSC spectrum has the onset of endothermic peak at 246.30°C. In some embodiments, the crystals of the compound of formula (I) in the present application are type B crystals, and its DSC spectrum has an endothermic peak starting point at 246.30°C ⁇ 5°C, preferably 246.30°C ⁇ 3°C.
  • the crystals of the compound of formula (I) of the present application are type B crystals, and its DSC spectrum is shown in FIG. 5 .
  • the present application provides a preparation method of compound B crystal of formula (I), comprising mixing the compound of formula (I) with a solvent, and isolating the solid.
  • the aforementioned solvent is selected from tetrahydrofuran.
  • the volume mass ratio of tetrahydrofuran to the compound of formula (I) is selected from 5-50mL/g; or 5-40mL/g; or 5-30mL/g; or 5-20mL/g; or 10-20mL /g; or 10mL/g.
  • the above preparation method is carried out under the condition of heating to 50-80°C; or under the condition of heating to 60-65°C.
  • the above method further includes the step of drying the isolated solid; optionally, drying at 40-50°C (preferably 45°C) under vacuum conditions.
  • the present application provides a crystalline composition, wherein the above-mentioned crystals of the present application account for more than 50%, preferably more than 80%, more preferably more than 90%, most preferably more than 95% of the weight of the crystalline composition.
  • said crystals are selected from the group consisting of: type A crystals or type B crystals of the compound of formula (I).
  • the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned crystals of the present application, or a crystalline composition thereof.
  • the pharmaceutical composition of the present application further comprises pharmaceutically acceptable excipients.
  • the present application describes a method for treating or preventing TRK kinase-mediated diseases in mammals, comprising administering a therapeutically effective amount of the above-mentioned crystals of the present application, or a crystalline composition thereof, to a mammal (preferably a human being) in need of the treatment Or its pharmaceutical composition.
  • the present application describes the use of the above-mentioned crystals of the present application, its crystal composition or its pharmaceutical composition in the preparation of medicines for preventing or treating diseases mediated by TRK kinase.
  • the present application describes the use of the above-mentioned crystals of the present application, its crystal composition or its pharmaceutical composition in the prevention or treatment of TRK kinase-mediated diseases.
  • the present application describes the above-mentioned crystals of the present application, its crystal form composition or its pharmaceutical composition for preventing or treating TRK kinase-mediated diseases.
  • the TRK kinase-mediated disease is selected from cancer.
  • crystals in the present application include type A crystals or type B crystals of the compound of formula (I).
  • X-ray powder diffraction Bruker D2 X-ray diffractometer; target tube - Cu.
  • TGA Thermogravimetric analysis
  • DSC Differential scanning calorimetry
  • the crystals obtained in the present application have high stability, including low total impurities, low maximum single impurity content, few types of impurities, stable content of the compound of formula (I) under different conditions, low increase in impurity content, basically no or no crystal transformation, Low hygroscopicity, good solubility, good fluidity for preparation, and good removal of impurities.
  • the crystals obtained in this application have good bioavailability in vivo, and there will be no obvious accumulation; the distribution in the body is the most distributed in the liver and adrenal gland, followed by the distribution in tissues such as the kidney, small intestine, pancreas, and stomach wall; Good acceptance, low toxicity and side effects (such as low impact on cardiovascular system, respiratory system, nervous system, etc.); can achieve ideal drug effect.
  • the position of the peak or the relative intensity of the peak may vary due to factors such as measuring instruments, measuring methods/conditions, and the like.
  • the error in the determination of the 2 ⁇ value can be about ⁇ 0.2°. Therefore, when determining each crystal form, this error should be taken into consideration, and within the error also belongs to the scope of the present application.
  • the position of the endothermic peak in DSC may vary due to factors such as measuring instruments, measuring methods/conditions, and the like.
  • the error may be about ⁇ 5°C, and may be about ⁇ 3°C. Therefore, when determining each crystal form, this error should be taken into consideration, and within the error also belongs to the scope of the present application.
  • “Pharmaceutically acceptable excipients” refer to the inert substances that are administered together with the active ingredients and are beneficial to the administration of the active ingredients, including but not limited to the acceptable substances approved by the State Food and Drug Administration for human or animal (such as livestock) any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, Isotonic agent, solvent or emulsifier.
  • Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of crystals described herein, crystalline compositions, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular , subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Therapeutic dosages of the compounds of the present application may depend, for example, on the particular use for the treatment, the mode of administration of the compound, the health and state of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compounds of the present application in the pharmaceutical composition may vary, depending on various factors, including dosage, chemical properties (eg, hydrophobicity) and route of administration.
  • treating means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound, composition or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing a disease or disease state from occurring in a mammal, Especially when such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • the term "therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • parameter values should be understood as being modified by the term "about”.
  • the term “about” indicates an error value exists, for example, it means a variation within ⁇ 5%, such as ⁇ 1% or ⁇ 0.1%, of a certain value.
  • Figure 5 is the type B crystallization DSC spectrum of the compound of formula I.
  • the compound of formula (I) can be prepared by referring to the method disclosed in Example 36 of WO2018077246.
  • Embodiment 1 Preparation of formula (I) compound A type crystal
  • Embodiment 2 the preparation of formula (I) compound B type crystal
  • test product Places the test product in an open, suitable clean flat weighing bottle, and place it at 40°C and 60°C for 10 days to sample; (2) Place the test sample in an open, suitable In clean flat weighing bottles, samples were taken at 75%RH/25°C and 92.5%RH/25°C for 10 days respectively; Samples were placed in a light irradiation test chamber (temperature 25°C, illuminance 5000 Lux, near-ultraviolet energy 85.0 ⁇ W/cm 2 ) for 10 days.
  • the chromatographic column is Agilent Eclipse Plus C18 (150 ⁇ 4.6mm, 3.5 ⁇ m); the detection wavelength is 260nm; the column temperature is 30°C; the injection volume is 10 ⁇ L.
  • Mobile phase A is 5mmol/L diammonium hydrogen phosphate solution (adjust pH value to 6.0 with phosphoric acid)-acetonitrile (90:10)
  • mobile phase B is 5mmol/L diammonium hydrogen phosphate solution (adjust pH value to 6.0 with phosphoric acid) - Acetonitrile (30:70) at a flow rate of 1.0 ml per minute with a linear gradient elution condition as follows:
  • the test results show that the properties, related substances and purity of the crystal form of the compound of formula (I) obtained in the present application do not change significantly under the conditions of high temperature, high humidity and light.
  • the crystal form of the compound of formula (I) has almost no hygroscopicity and good stability; the crystal form has not changed.
  • Acid degradation Weigh 25 mg of the crystals of the compound of formula (I) of the present application, add 1 ml of 0.1M HCl aqueous solution, and after standing at room temperature for 24 hours, neutralize with 1 ml of 0.1M NaOH aqueous solution.
  • Test example 6 crystal habit (scanning electron microscope)
  • mice were randomly divided into several groups, and administered by intragastric administration at a dose of 10 mg/kg.
  • the tested animals were fasted for 12 hours before administration, given food 4 hours after administration, and had free access to water before, after and during the experiment. Blood was collected at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10 and 24 hours after administration, and blood was collected from the orbit to prepare plasma samples to be tested. Aspirate 20 ⁇ L of the plasma sample to be tested and the standard song sample, add an acetonitrile solution containing an internal standard to obtain a supernatant through protein precipitation, dilute it for LC/MS/MS determination, and record the chromatogram.
  • Rat test Male SD rats were divided into groups and administered by intragastric administration at a dose of 5 mg/kg.
  • the tested animals were fasted for 12 hours before administration, given food 4 hours after administration, and had free access to water before, after and during the experiment. Blood was collected at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10 and 24 hours after administration. 0.3mL whole blood was collected through the fundus venous plexus and placed in EDTA-K2 anticoagulant tubes. The samples were centrifuged at 4000 rpm for 5 min at 4°C, and the plasma was transferred to a centrifuge tube and stored at -80°C until analysis. The samples in plasma were extracted by protein precipitation, the extract was analyzed by LC/MS/MS, and the chromatograms were recorded.
  • Beagle dog test Male Beagle dogs, after a period of adaptation, were randomly divided into groups and administered at a dose of 2.5 mg/kg orally.
  • test animals male Beagle dogs
  • Male Beagle dogs were fasted for 12 hours before administration, given food 4 hours after administration, and had free access to water before and after the experiment and during the experiment.
  • After administration at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, 24, 30, 48, and 72 hours, about 0.5 mL of blood was taken from the forelimb vein and placed in EDTA-K2 anticoagulant vacuum
  • the plasma was transferred to 4°C, 4000rpm, and centrifuged for 10min within 30min to separate the plasma. All plasma was collected and immediately stored at -80°C for testing.

Abstract

L'invention concerne un cristal d'un composé aminopyrazolopyrimidine tel que représenté par la formule (I), son procédé de préparation, et son utilisation dans la prévention et le traitement de maladies médiées par TRK.
PCT/CN2022/108846 2021-07-30 2022-07-29 Cristal de composé aminopyrazolopyrimidine WO2023006057A1 (fr)

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CN202280046317.1A CN117751121A (zh) 2021-07-30 2022-07-29 氨基吡唑并嘧啶化合物的晶体

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CN202110874030 2021-07-30

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013028263A1 (fr) * 2011-08-24 2013-02-28 Glaxosmithkline Llc Dérivés pyrazolopyrimidines en tant qu'inhibiteurs de pi3 kinase
WO2014143242A1 (fr) * 2013-03-15 2014-09-18 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de la kinase atr
CN104650092A (zh) * 2013-11-16 2015-05-27 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
CN104995172A (zh) * 2013-02-19 2015-10-21 小野药品工业株式会社 Trk抑制化合物
WO2018077246A1 (fr) * 2016-10-28 2018-05-03 正大天晴药业集团股份有限公司 Composé amino-pyrazolopyrimidine utilisé en tant qu'inhibiteur du récepteur de la tyrosine kinase du facteur neurotrophique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013028263A1 (fr) * 2011-08-24 2013-02-28 Glaxosmithkline Llc Dérivés pyrazolopyrimidines en tant qu'inhibiteurs de pi3 kinase
CN104995172A (zh) * 2013-02-19 2015-10-21 小野药品工业株式会社 Trk抑制化合物
WO2014143242A1 (fr) * 2013-03-15 2014-09-18 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de la kinase atr
CN104650092A (zh) * 2013-11-16 2015-05-27 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
WO2018077246A1 (fr) * 2016-10-28 2018-05-03 正大天晴药业集团股份有限公司 Composé amino-pyrazolopyrimidine utilisé en tant qu'inhibiteur du récepteur de la tyrosine kinase du facteur neurotrophique

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