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WO2025060940A1 - Formes solides d'un composé inhibiteur d'idh mutant et sel de celui-ci - Google Patents

Formes solides d'un composé inhibiteur d'idh mutant et sel de celui-ci Download PDF

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Publication number
WO2025060940A1
WO2025060940A1 PCT/CN2024/118413 CN2024118413W WO2025060940A1 WO 2025060940 A1 WO2025060940 A1 WO 2025060940A1 CN 2024118413 W CN2024118413 W CN 2024118413W WO 2025060940 A1 WO2025060940 A1 WO 2025060940A1
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Prior art keywords
compound
crystalline form
salt form
salt
formula
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English (en)
Chinese (zh)
Inventor
徐晓峰
陈亮
赵新涛
宋西镇
张俊
付勇
刘湘永
丁列明
王家炳
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Betta Pharmaceuticals Co Ltd
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Betta Pharmaceuticals Co Ltd
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Publication of WO2025060940A1 publication Critical patent/WO2025060940A1/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
    • 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
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a crystal form, a salt form and a crystal form of 6-(5-amino-6-chloro-4-fluoropyridin-2-yl)-N 2 ,N 4 -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine; and a pharmaceutical composition comprising the crystal form, the salt form and the crystal form of the salt form of the compound, and their use in inhibiting the activity of IDH1 and/or IDH2.
  • the present invention also relates to a preparation method of 6-(5-amino-6-chloro-4-fluoropyridin-2-yl)-N 2 ,N 4 -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine and its salt and its crystal form, as well as related intermediate compounds and their preparation methods.
  • the present invention also relates to a method for using the compound or its salt and the pharmaceutical composition for treating diseases or conditions associated with double mutations of IDH1 and/or IDH2.
  • IDH1 is located in the cytoplasm and peroxisomes, while IDH2 and IDH3 are located in mitochondria.
  • This type of protease can oxidize isocitrate to oxalosuccinate, and then convert it into ⁇ -ketoglutarate ( ⁇ -KG).
  • IDH1 gene mutation was accidentally discovered during gene sequencing of human glioblastoma, which opened the prelude to IDH in tumor research. Subsequently, a number of large-scale clinical glioma case-control studies found that IDH1 gene mutations are common in more than 75% of low-grade gliomas and 90% of secondary glioblastomas; IDH2 gene mutations are common in about 20% of acute myeloid leukemia. In addition, IDH gene mutations have also been reported in bile duct cancer (10% to 23%), melanoma (10%), and chondroid tumors (75%). It can be seen that IDH mutations exist in many tumors.
  • IDH1/R132H arginine residues located in the catalytic center
  • IDH2/R140Q arginine residues located in the catalytic center
  • IDH2/R172K 2-hydroxyglutarate
  • 2-HG 2-hydroxyglutarate
  • Agios Pharmaceuticals reported the IDH2 R140Q inhibitor AGI-6780 and IDH2 R132H inhibitor AGI-5198, as well as another IDH2 R140Q inhibitor AG-221 that the company later launched.
  • AGI-6780 and AGI-5198 can inhibit the production of 2-HG in cells carrying common IDH1 and IDH2 mutants, respectively.
  • IDH1 and IDH2 mutations such as glioma, acute myeloid leukemia, cholangiocarcinoma, melanoma, etc.
  • the IDH1 inhibitor AG120 and the IDH2 inhibitor AG221 are currently on the market, providing clinical drug options.
  • New research has found that IDH1 and IDH2 mutations may coexist in the same tumor, resulting in IDH1 or IDH2 Single inhibitors have limited efficacy and produce acquired drug resistance.
  • mutant IDH1 and IDH2 dual inhibitors with strong target inhibition ability and excellent selectivity for the treatment of related diseases mediated by mutant IDH1 and IDH2, to overcome the problem of acquired drug resistance after long-term use of single inhibitors, and to provide a new drug option for clinical use.
  • the present invention finds that 6-(5-amino-6-chloro-4-fluoropyridin-2-yl)-N 2 ,N 4 -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine has excellent cell inhibitory activity, good pharmacokinetic characteristics, and excellent anti-tumor activity, and is an excellent new mutant IDH1 and IDH2 dual inhibitor.
  • the present invention also studies and finds the dominant crystal form, salt form, and crystal form of the salt form of 6-(5-amino-6-chloro-4-fluoropyridin-2-yl)-N 2 ,N 4 -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine, which have drug properties that are beneficial to drug development.
  • One aspect of the present invention relates to a crystalline form of a compound (Compound 1) as shown in Formula I below:
  • the terms "compound of formula I”, “compound of formula I”, “Formula I” or “Compound 1” all refer to a compound having the above structure and its chemical name is 6-(5-amino-6-chloro-4-fluoropyridin-2-yl)-N 2 ,N 4 -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine.
  • Another aspect of the present invention relates to the salt form of the compound represented by formula I, and its crystal form.
  • Another aspect of the present invention relates to a pharmaceutical composition, which contains 0.5% to 85% by weight of the compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a mixture thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition containing 0.5% to 85% by weight of a compound of formula I, or its hydrochloride, phosphate, sulfate, methanesulfonate, L-malate, L-tartrate or L-lactate, or a mixture thereof.
  • Another aspect of the present invention provides a method for preparing the compound of formula I and its intermediate compounds.
  • Another aspect of the present invention also provides the use of a crystalline form of the compound represented by Formula I or a salt thereof, or the pharmaceutical composition in the preparation of a drug.
  • Another aspect of the present invention provides a method for treating a disease, comprising administering to a subject a therapeutically effective amount of a crystalline form of a compound of Formula I or a salt thereof, or a pharmaceutical composition comprising the same.
  • the solid form of compound 1 and its salt provided by the present invention is used as a dual inhibitor of IDH1 and IDH2.
  • the preferred solid form of compound 1 and its salt provided by the present invention has excellent stability, hygroscopicity, pharmacokinetics and other properties, which is conducive to the development of drugs.
  • the crystalline form of Compound 1 is Form B
  • the X-ray powder diffraction pattern of Form B comprises characteristic peaks with 2 ⁇ values of 5.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 17.6° ⁇ 0.2°.
  • the crystalline form of Compound 1 is Form B
  • the X-ray powder diffraction pattern of Form B comprises characteristic peaks with 2 ⁇ values of 5.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.6° ⁇ 0.2° and 23.5° ⁇ 0.2°.
  • the crystalline form of Compound 1 is Form B
  • the X-ray powder diffraction pattern of Form B comprises 5 or more (e.g., 6 or more, 7 or more, or 8) characteristic peaks with 2 ⁇ values selected from 5.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 14.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.6° ⁇ 0.2° and 23.5° ⁇ 0.2°.
  • the crystalline form of Compound 1 is Form D
  • the X-ray powder diffraction pattern of Form D comprises characteristic peaks with 2 ⁇ values of 8.6° ⁇ 0.2°, 10.5° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
  • the crystalline form of Compound 1 is Form D
  • the X-ray powder diffraction pattern of Form D comprises characteristic peaks with 2 ⁇ values of 8.6° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.8° ⁇ 0.2°, 14.0° ⁇ 0.2°, 17.3° ⁇ 0.2° and 21.1° ⁇ 0.2°.
  • the crystalline form of Compound 1 is Form D
  • the X-ray powder diffraction pattern of Form D comprises 5 or more (e.g., 6 or more, 7 or more, 8 or more, or 9) characteristic peaks with 2 ⁇ values selected from 8.6° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.8° ⁇ 0.2°, 14.0° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.8° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
  • the Form D has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
  • the Form D has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 6 , with a weight loss of about 10.9% before 200° C.
  • TGA thermogravimetric analysis
  • the Form D has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 7 .
  • DSC differential scanning calorimetry
  • the present invention also provides a crystalline form of the hydrochloride salt of compound 1 represented by formula II.
  • the crystalline form of the hydrochloride salt of Compound 1 is hydrochloride form A
  • the X-ray powder diffraction pattern of the hydrochloride form A comprises characteristic peaks with 2 ⁇ values of 11.6° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 19.2° ⁇ 0.2° and 21.1 ⁇ 0.2°.
  • the crystalline form of the hydrochloride salt of Compound 1 is hydrochloride form A
  • the X-ray powder diffraction pattern of the hydrochloride form A comprises characteristic peaks with 2 ⁇ values of 11.6° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.2° ⁇ 0.2° and 21.1 ⁇ 0.2°.
  • the crystalline form of the hydrochloride salt of Compound 1 is hydrochloride form A
  • the X-ray powder diffraction pattern of the hydrochloride form A comprises characteristic peaks with 2 ⁇ values of 11.6° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1 ⁇ 0.2°, 23.9 ⁇ 0.2° and 25.5 ⁇ 0.2°.
  • the crystalline form of the hydrochloride salt of Compound 1 is hydrochloride form A
  • the X-ray powder diffraction pattern of the hydrochloride form A contains 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more, or 14) 2 ⁇ values selected from 11.6° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.4° ⁇ 0.2°, 16.3° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1 ⁇ 0.2°, 22.6 ⁇ 0.2°, 23.9 ⁇ 0.2°, 25.5 ⁇ 0.2°, 28.0 ⁇ 0.2° and 31.8 ⁇ 0.2° characteristic peaks.
  • the hydrochloride salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 8.
  • the Raman spectrum of the hydrochloride salt Form A comprises peak shifts at 1572 cm -1 ⁇ 2 cm -1 , 1421 cm -1 ⁇ 2 cm -1 , 1289 cm -1 ⁇ 2 cm -1 , and 1248 cm -1 ⁇ 2 cm -1 .
  • the Raman spectrum of the hydrochloride salt form A comprises 5 or more peak shifts selected from 1572 cm -1 ⁇ 2 cm -1 , 1421 cm -1 ⁇ 2 cm -1 , 1312 cm -1 ⁇ 2 cm -1 , 1289 cm -1 ⁇ 2 cm -1 , 1269 cm -1 ⁇ 2 cm -1 and 1248 cm -1 ⁇ 2 cm -1 , 1206 cm -1 ⁇ 2 cm -1 , 999 cm -1 ⁇ 2 cm -1 , 841 cm -1 ⁇ 2 cm -1 , 426 cm -1 ⁇ 2 cm -1 , 136 cm -1 ⁇ 2 cm -1 .
  • the infrared spectrum of the hydrochloride salt form A comprises characteristic absorption peaks at 3421 cm -1 ⁇ 2 cm -1 , 3328 cm -1 ⁇ 2 cm -1 , 1655 cm -1 ⁇ 2 cm -1 , 1536 cm -1 ⁇ 2 cm -1 , 1268 cm -1 ⁇ 2 cm -1 , 1177 cm -1 ⁇ 2 cm -1 , and 797 cm -1 ⁇ 2 cm -1 .
  • the infrared spectrum of the hydrochloride salt form A comprises 5 or more characteristic absorption peaks selected from 3421 cm -1 ⁇ 2 cm -1 , 3328 cm -1 ⁇ 2 cm -1 , 3048 cm -1 ⁇ 2 cm -1 , 1655 cm -1 ⁇ 2 cm -1 , 1595 cm -1 ⁇ 2 cm -1 , 1536 cm -1 ⁇ 2 cm -1 , 1291 cm -1 ⁇ 2 cm -1 , 1268 cm -1 ⁇ 2 cm -1 , 1177 cm -1 ⁇ 2 cm -1 , 1154 cm -1 ⁇ 2 cm -1 , and 797 cm -1 ⁇ 2 cm -1 .
  • the hydrochloride salt Form A has an infrared spectrum substantially as shown in Figure 21.
  • the hydrochloride salt form A has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 9 , with almost no weight loss before 200° C.
  • TGA thermogravimetric analysis
  • the hydrochloride salt form A has a differential scanning calorimetry (DSC) substantially as shown in FIG. 10: Atlas.
  • the hydrochloride crystal form A has been characterized by single crystal analysis.
  • the unit cell stacking projection of the hydrochloride crystal form A single crystal is basically as shown in FIG14 , and the unit cell parameters are as follows:
  • the final chemical formula of the asymmetric unit was determined to be C 14 H 13 ClF 7 N 7 ⁇ HCl, the molecular weight of a single molecule was calculated to be 484.22, and the crystal density was calculated to be 1.607 g/cm 3 .
  • the present invention provides a mesylate salt of Compound 1, wherein the structure of the mesylate salt of Compound 1 is represented by the following formula III:
  • the present invention also provides a crystalline form of the mesylate salt of Compound 1 represented by Formula III.
  • the crystalline form of the mesylate salt of Compound 1 is mesylate Form A
  • the X-ray powder diffraction pattern of the mesylate Form A comprises characteristic peaks with 2 ⁇ values of 6.6° ⁇ 0.2°, 8.2° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
  • the crystalline form of the mesylate salt of Compound 1 is mesylate Form A
  • the X-ray powder diffraction pattern of the mesylate Form A comprises characteristic peaks with 2 ⁇ values of 6.6° ⁇ 0.2°, 8.2° ⁇ 0.2°, 17.3° ⁇ 0.2° and 19.3° ⁇ 0.2°.
  • the crystalline form of the mesylate salt of Compound 1 is mesylate Form A
  • the X-ray powder diffraction pattern of the mesylate Form A contains 3 or more (e.g., 4 or more, 5 or more, 6 or more, or 7) characteristic peaks with 2 ⁇ values selected from 6.6° ⁇ 0.2°, 8.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 17.3° ⁇ 0.2°, 19.3° ⁇ 0.2° and 20.2° ⁇ 0.2°.
  • the mesylate salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 11 .
  • the mesylate salt Form A has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 12 , with a weight loss of about 1.9% before 200° C.
  • TGA thermogravimetric analysis
  • the mesylate salt Form A has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 13 .
  • the X-ray powder diffraction patterns are all measured using the K ⁇ spectrum of a Cu target.
  • the experimental temperature of the present invention is room temperature.
  • substantially pure means that the content of the crystalline form is not less than 85% by weight, preferably not less than 95% by weight, and more preferably not less than 98% by weight.
  • salts in the classical sense formed by significant or complete proton exchange between API (e.g., compound shown in Formula I) and guest molecules (e.g., hydrochloric acid), and also includes multi-component systems, such as eutectics, formed by the coexistence of API (e.g., compound shown in Formula I) and guest molecules (e.g., L-malate) through hydrogen bonds and possible other non-covalent bonds.
  • the "salt (salt-type)” mentioned in the present invention includes salts in the classical sense, eutectics, or mixtures thereof, etc., which are well known to those skilled in the art.
  • the salt form of Compound 1 of the present invention may exist in various physical forms, for example, in the form of a solution, a suspension or a solid.
  • the compound When in a solid form, the compound may be in an amorphous form, a crystalline form or a mixture thereof.
  • crystalline form used in the present invention refers to a crystalline form having the same chemical composition but different spatial arrangements of molecules, atoms and/or ions forming the crystal, including anhydrous crystalline forms, hydrates and solvates.
  • polymorph used interchangeably, all of which refer to the solid form of the compound shown in formula I and its salt, which is different from the amorphous form of the compound shown in formula I and its salt.
  • amorphous form refers to a non-crystalline solid form.
  • Polymorphs of a compound may have different chemical and/or physical properties, including but not limited to, for example, stability, solubility, dissolution rate, optical properties, melting point, mechanical properties and/or density. These properties can affect the processing and/or manufacture of the raw material, the stability, dissolution and/or bioavailability of the drug, etc. Therefore, polymorphism can affect at least one property of the drug, including but not limited to quality, safety and/or efficacy.
  • the compound shown in formula I and its salt include any polymorph and amorphous state.
  • Polymorphs of a molecule can be obtained by many methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Polymorphs can be detected, identified, classified, and characterized using well-known techniques such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetry (TGA), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, solid-state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, and hot stage optical microscopy.
  • DSC differential scanning calorimetry
  • TGA thermogravimetry
  • XRPD X-ray powder diffractometry
  • NMR nuclear magnetic resonance
  • IR infrared
  • the terms "about” and “substantially” used in "having an X-ray powder diffraction pattern approximately as shown in FIG. 1", “having an X-ray powder diffraction pattern substantially as shown in FIG. 1" or “its X-ray powder diffraction pattern substantially as shown in FIG. 1" are intended to indicate the precise positions of the peaks in the accompanying drawings and should not be interpreted as absolute values.
  • the 2 ⁇ value of the X-ray powder diffraction pattern may produce errors due to different measurement conditions (such as the equipment and instruments used) and different samples (such as samples from different batches), the measurement error of the diffraction angle of the X-ray powder diffraction pattern is 5% or less, and generally, a difference of ⁇ 0.2° of a given value is considered appropriate.
  • the relative intensity of the peaks may fluctuate with experimental conditions and sample preparation, such as the preferred orientation of particles in the sample.
  • the use of automatic or fixed divergence slits will also affect the calculation of relative intensities.
  • the intensities shown in the XRD curves included here are only exemplary and cannot be used as absolute comparisons, and any crystalline form having a powder diffraction pattern substantially the same as those disclosed herein is within the scope of protection of the present invention.
  • the weight loss corresponds to the loss of trace residual solvent or water. Due to the changes in different sample batches, sample purity, sample residual solvent content, sample preparation and measurement conditions (such as heating rate), the data measured by TGA may vary to a certain extent. Therefore, the thermogravimetric curves cited in this application are not taken as absolute values, and such errors will be considered when interpreting TGA data.
  • IR and Raman spectra can be obtained, which can vary depending on the measurement conditions. Instruments, experimental conditions, sampling methods, and instrument calibration, etc. can all affect peak positions and intensities. Therefore, the spectra provided by the present invention should not be considered absolute, and any crystalline form whose spectra are substantially the same as those disclosed herein is within the scope of the present invention.
  • the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition contains 0.5 wt % to 85 wt % of Compound 1, or a pharmaceutically acceptable salt thereof, or a mixture thereof.
  • the pharmaceutical composition contains 0.5 wt%-85 wt% of Compound 1, or its hydrochloride, phosphate, sulfate, methanesulfonate, L-malate, L-tartrate or L-lactate, or a mixture thereof.
  • the pharmaceutical composition contains 0.5 wt%-85 wt% of Compound 1 Form B.
  • the pharmaceutical composition contains 0.5 wt % to 85 wt % of Compound 1 Form D.
  • the pharmaceutical composition contains 0.5 wt%-85 wt% of Compound 1 hydrochloride.
  • the pharmaceutical composition contains 0.5 wt%-85 wt% of Compound 1 hydrochloride Form A.
  • the pharmaceutical composition contains 0.5 wt% to 85 wt% of Compound 1 mesylate Form A.
  • the composition is for oral administration.
  • the oral dosage forms include tablets, capsules, cachets, pills, granules, oral liquids, suspensions, dispersions, emulsions, and powders.
  • the pharmaceutical composition contains 1 wt%-70 wt% of Compound 1, or a pharmaceutically acceptable salt thereof, or a mixture thereof.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carrier may include one or more of a diluent, a filler, a lubricant, a binder, and a disintegrant.
  • the compound 1 of the present invention is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques to form a pharmaceutical composition.
  • the pharmaceutical carrier can take a variety of forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention can be in the form of independent units suitable for oral administration, such as capsules, cachets or tablets containing a predetermined dose of the active ingredient.
  • the pharmaceutical composition of the present invention can be in the form of powder, granules, solution, aqueous suspension, non-aqueous liquid, water-in-oil emulsion, or oil-in-water emulsion.
  • the compound shown in formula I or its pharmaceutically acceptable salt can also be administered by controlled release and/or delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with a carrier constituting one or more necessary ingredients. Generally, the pharmaceutical composition is prepared by uniformly and uniformly mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. In addition, the product can be easily prepared into a desired appearance.
  • the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier.
  • Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, and water.
  • Gaseous carriers include carbon dioxide and nitrogen.
  • any pharmaceutically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants, etc.
  • oral liquid preparations such as suspensions, elixirs, and solutions
  • carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here.
  • tablet coating can use standard aqueous or non-aqueous preparation technology.
  • Tablets containing the compounds or pharmaceutical compositions of the present invention can be formed by compression or molding, and optionally, can be formed into tablets together with one or more auxiliary components or adjuvants.
  • the active ingredient is mixed in a free-flowing form such as powder or granules with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to obtain compressed tablets.
  • Molded tablets can be obtained by wetting the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding in a suitable machine.
  • each tablet contains about 0.05 mg to 5 g of the active ingredient
  • each cachet or capsule contains about 0.05 mg to 5 g of the active ingredient.
  • a formulation intended for oral administration to humans contains about 0.5 mg to about 5 g of the active ingredient, compounded with suitable and conveniently metered auxiliary materials, which account for about 5% to 95% of the total amount of the pharmaceutical composition.
  • Dosage unit forms generally contain from about 1 mg to about 2 g of active ingredient, typically 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared into an aqueous solution or suspension by adding the active ingredient into water.
  • Suitable surfactants such as hydroxypropylcellulose can be included.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Further, preservatives can also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
  • the present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions.
  • the above-mentioned pharmaceutical compositions can be prepared into sterile powder forms for immediate preparation of sterile injections or dispersions.
  • the final injection form must be sterile and, in order to be easy to inject, must be easy to flow.
  • the pharmaceutical composition must be stable during preparation and storage. Therefore, preferably, the pharmaceutical composition will be preserved under conditions of antimicrobial such as bacterial and fungal contamination.
  • the carrier can be a solvent or a dispersion medium, for example, water, ethanol, a polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), a vegetable oil and a suitable mixture thereof.
  • the pharmaceutical composition provided by the present invention can be in a form suitable for topical administration, for example, an aerosol, emulsion, ointment, lotion, dusting powder or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use with a transdermal drug delivery device.
  • These preparations can be prepared using the compound shown in formula I of the present invention, or a pharmaceutically acceptable salt thereof, by conventional processing methods.
  • an emulsion or ointment is prepared by adding about 5wt% to 10wt% of a hydrophilic material and water to obtain an emulsion or ointment with a desired consistency.
  • the pharmaceutical composition provided by the present invention can be in the form of solid as carrier, suitable for rectal administration.
  • the unit dose suppository is the most typical common dosage form.
  • Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be easily prepared by first mixing the pharmaceutical composition with softened or melted auxiliary materials, and then cooling and molding to make.
  • the above-mentioned formulation formula may also include, as appropriate, one or more additional auxiliary material components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants and preservatives (including antioxidants).
  • additional auxiliary material components such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants and preservatives (including antioxidants).
  • auxiliary drugs may also include penetration enhancers that adjust the osmotic pressure of the drug and the blood of the intended recipient.
  • the pharmaceutical composition containing the compound shown in Formula I, or a pharmaceutically acceptable salt thereof can be prepared in the form of a powder or a concentrated solution.
  • the present invention provides a method for preparing a compound of formula I:
  • the method comprises carrying out a deprotection reaction using a compound represented by formula IV,
  • the R1 is an amino protecting group
  • the R2 is H or an amino protecting group
  • the amino protecting group can be selected from one or two of -Boc, -Cbz, -Fmoc, -PMB and -Bn, more preferably a -Boc group.
  • the amino protecting group is a -Boc group
  • the compound of formula IV is reacted in a solvent containing TFA.
  • the preparation method further comprises using a compound represented by formula V With compound A07 A coupling reaction is carried out in the presence of a base and a palladium catalyst to obtain a compound represented by formula IV;
  • the R1 is an amino protecting group, and the R2 is H or an amino protecting group;
  • the R 3 is selected from H, C 1-4 alkyl, or two R 3 and the O atom to which they are connected together form a 5- or 6-membered heterocyclic ring containing two oxygen atoms and one boron atom, and the 5- or 6-membered heterocyclic ring may be optionally substituted by one or more C 1-4 alkyl groups.
  • the amino protecting group can be selected from one or two of -Boc, -Cbz, -Fmoc, -PMB and -Bn, more preferably -Boc group.
  • the base used in the reaction of the compound represented by Formula V with Compound A07 can be selected from one or more of K 2 CO 3 , AcOK, Na 2 CO 3 , AcONa, Cs 2 CO 3 , K 3 PO 4 , KF or TEA.
  • the palladium catalyst used in the reaction of the compound represented by Formula V with Compound A07 is selected from Pd(dppf)Cl 2 or Pd(OAc) 2 .
  • the solvent in the reaction process of the compound represented by Formula V and compound A07 can be selected from one or more of toluene, dioxane, DMF, ethanol, acetonitrile, tert-butanol, ethylene glycol dimethyl ether, diethoxymethane, tetrahydrofuran, or a mixture of one or more of the above solvents and water.
  • a ligand may be added during the reaction of the compound represented by Formula V with Compound A07.
  • the ligand may be selected from dppf, PPh 3 , XantPhos, Xphos, PCy 3 , SPhos, and P(t-Bu) 3 .
  • the compound represented by Formula V is reacted with Compound A07 at 70-100°C.
  • the preparation method further comprises using a compound represented by formula VI reacting with diboric acid pinacol ester in the presence of a base and a catalyst to obtain a compound represented by formula V;
  • R1 is an amino protecting group
  • R2 is H or an amino protecting group
  • the amino protecting group can be selected from one or two of -Boc, -Cbz, -Fmoc, -PMB and -Bn, more preferably -Boc group.
  • the base in the reaction of the compound represented by Formula VI and pinacol diboron is AcOK.
  • a ligand may be added during the reaction of the compound represented by Formula VI and pinacol diboronate, and the ligand may be selected from dppf or PPh 3 .
  • the present invention also provides a method for preparing compound A13:
  • the present invention also provides a method for preparing the compound represented by formula I.
  • the present invention also provides an intermediate for preparing the compound of formula I, which is selected from the compounds of the following formula:
  • the R1 is an amino protecting group, and the R2 is H or an amino protecting group;
  • the R 3 is selected from H, C 1-4 alkyl, or two R 3 and the O atom to which they are connected together form a 5- or 6-membered heterocyclic ring containing two oxygen atoms and one boron atom, and the 5- or 6-membered heterocyclic ring may be optionally substituted by one or more C 1-4 alkyl groups.
  • the amino protecting group can be selected from -Boc, -Cbz, -Fmoc, -PMB and -Bn. One or two.
  • the intermediate compound is selected from one or more of the following compounds:
  • the present invention further provides the crystal form, salt form and crystal form of the salt form of the compound 1, or the use of the pharmaceutical composition in the preparation of drugs.
  • Compound 1 hydrochloride crystal form A in the preparation of a drug.
  • the medicament is used to treat a disease mediated by mutant IDH1 and/or IDH2.
  • the disease is cancer.
  • the cancer is selected from glioma, melanoma, papillary thyroid tumor, bile duct cancer, lung cancer, breast cancer, sarcoma, glioma, glioblastoma multiforme, acute myeloid leukemia, non-Hodgkin's lymphoma, etc.
  • the cancer to be treated is glioma, glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, bile duct cancer or angioimmunoblastic lymphoma.
  • glioma glioblastoma
  • MDS myelodysplastic syndrome
  • MPN myeloproliferative neoplasm
  • AML acute myeloid leukemia
  • sarcoma melanoma
  • non-small cell lung cancer chondrosarcoma
  • bile duct cancer or angioimmunoblastic lymphoma.
  • the cancer to be treated is glioma, glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL).
  • glioma glioblastoma
  • MDS myelodysplastic syndrome
  • MPN myeloproliferative neoplasm
  • AML acute myeloid leukemia
  • melanoma chondrosarcoma
  • NDL angioimmunoblastic non-Hodgkin's lymphoma
  • the present invention also provides a method for treating and/or preventing diseases mediated by IDH1 and/or IDH2 by administering a therapeutically effective amount of at least any one of the crystalline forms, salt forms, and crystalline forms of the salt forms, or pharmaceutical compositions of Compound 1 to a subject.
  • the disease mediated by IDH1 and/or IDH2 is cancer.
  • a therapeutically effective amount of Form B of Compound 1 is administered to the subject.
  • a therapeutically effective amount of Compound 1 hydrochloride Form A is administered to the subject.
  • the present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least any one of the crystalline forms, salt forms and crystalline forms of the salt forms of Compound 1, or the pharmaceutical composition.
  • the present invention relates to a method for treating a cancer characterized by the presence of mutant IDH1 and/or IDH2, comprising administering to a patient in need thereof a therapeutically effective amount of the crystalline form, salt form and crystalline form of the salt form of Compound 1, or the pharmaceutical composition, wherein the cancer is selected from brain glioma, melanoma, papillary thyroid tumor, bile duct cancer, lung cancer, breast cancer, sarcoma, glioma, multiforme glioblastoma, Cell carcinoma, acute myeloid leukemia, non-Hodgkin's lymphoma, etc.
  • the subject to be treated is a human being.
  • disease or “disorder” or “condition” refers to any disease, illness, ailment, symptom or indication.
  • the term "therapeutically effective amount” refers to an amount of a compound that, when administered to a subject, is sufficient to affect the treatment of a disease, disorder, or symptom for the treatment of at least one clinical symptom of a disease or condition.
  • the “therapeutically effective amount” may vary with the compound, the disease, disorder, and/or symptoms of the disease or condition, the severity of the disease, disorder, and/or symptoms of the disease or condition, the age of the patient being treated, and/or the weight of the patient being treated. In any particular case, a suitable amount may be apparent to those skilled in the art or may be determined by routine experimentation.
  • a “therapeutically effective amount” refers to the total amount of the combined subject that is effective in treating the disease, disorder, or condition.
  • the compound or crystal form of the present invention is used alone or in combination as an active ingredient and mixed with a pharmaceutical carrier to form a pharmaceutical composition.
  • the pharmaceutical composition of the present invention includes pharmaceutical compositions suitable for oral, rectal, topical and parenteral (including subcutaneous administration, intramuscular injection, intravenous administration) administration, although in any given case, the most suitable mode of administration of the active ingredient depends on the specific subject receiving the administration, the subject's properties and the severity of the disease.
  • the pharmaceutical composition of the present invention can be conveniently present in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
  • the dosage level of the drug for treating the above-mentioned conditions or discomforts is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day.
  • the specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, overall health status, sex, diet, administration time, administration route, excretion rate, drug combination, and the severity of the specific disease being treated.
  • Figure 1 X-ray powder diffraction pattern of Compound 1 Form A.
  • Figure 2 X-ray powder diffraction pattern of Compound 1 Form B.
  • FIG. 4 Differential scanning calorimetry (DSC) spectrum of Compound 1 Form B.
  • Figure 5 X-ray powder diffraction pattern of Compound 1 Form D.
  • FIG. 7 Differential scanning calorimetry (DSC) spectrum of Compound 1 Form D.
  • Figure 8 X-ray powder diffraction pattern of Compound 1 hydrochloride form A.
  • FIG. 10 Differential scanning calorimetry (DSC) spectrum of Compound 1 hydrochloride form A.
  • Figure 11 X-ray powder diffraction pattern of Compound 1 mesylate salt Form A.
  • FIG. 12 Thermogravimetric analysis (TGA) spectrum of Compound 1 mesylate Form A.
  • FIG. 13 Differential scanning calorimetry (DSC) spectrum of Compound 1 mesylate salt Form A.
  • Figure 14 Unit cell stacking projection of a single crystal of Compound 1 hydrochloride form A along the a direction.
  • Figure 15 DVS curve of Compound 1 Form A.
  • Figure 16 DVS curve of Compound 1 Form B.
  • Figure 18 DVS curve of Compound 1 hydrochloride form A.
  • Figure 20 Raman spectrum of Compound 1 hydrochloride form A.
  • Figure 21 Infrared spectrum of Compound 1 hydrochloride form A.
  • Figure 22 shows the concentration change curve of the compound in the plasma of adult beagle dogs after intravenous administration and oral gavage administration, wherein the horizontal axis is the time after administration (h), and the vertical axis is the concentration of the compound in the dog's plasma (ng/ml), including the control group AG-881 (Control Example 1) and the compound 1 group.
  • Figure 23 is a curve showing the change of compound concentration in plasma of adult beagle dogs after oral administration or intragastric administration, wherein the abscissa is the time after administration (h), and the ordinate is the compound concentration in dog plasma (ng/ml).
  • the detection instrument information and detection method parameters used in the present invention are as follows:
  • Data were collected using a Thermo DXR3xi with 1.5 mW laser power, 0.00235 s exposure time, 5 scans, 10x objective, and 25 ⁇ m pinhole.
  • the data were collected using a Bruker Tensor 27 infrared spectrometer in the range of 400-4000 wavenumbers (cm -1 ) using potassium bromide pellets.
  • the present invention is further described below by giving examples, but the examples do not constitute any limitation to the scope of the present invention.
  • the techniques or methods are conventional techniques or methods in the art.
  • the raw materials and reagents are purchased from the market; the percentages, proportions, ratios or parts are calculated by weight.
  • API API/Active Pharmaceutical Ingredient
  • Boc tert-butyloxycarbonyl
  • DIEA N,N-diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • DPPA diphenylphosphoryl azide
  • NMP N-methylpyrrolidone
  • Fmoc fluorenylmethoxycarbonyl
  • K 2 CO 3 potassium carbonate
  • KF potassium fluoride
  • PMB p-methoxybenzyl
  • PCy 3 tricyclohexylphosphine
  • P(t-Bu) 3 tri-tert-butylphosphine
  • TEA triethylamine
  • DIEA diisopropylethylamine
  • LC-MS or LCMS Liquid chromatography-mass spectrometry
  • LiHMDS lithium bis(trimethylsilyl)amide
  • NBS N-bromosuccinimide
  • PE petroleum ether
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • RRT relative retention time
  • XRD/XRPD X-ray powder diffraction
  • SCXRD single crystal X-ray diffraction
  • DSC differential scanning calorimetry
  • DVS Dynamic moisture sorption
  • step 4 of Example 2 The same preparation method as in step 4 of Example 2 was used to obtain a crude product of compound 1, which was then purified by Prep-HPLC (Column: Luna-C18(3)-10-100; Size: 30*250nm, Conditions: acetonitrile/water (0.1% formic acid) 35%-65%, 20min, UV: 308nm) to obtain the target compound 1.
  • Prep-HPLC Column: Luna-C18(3)-10-100; Size: 30*250nm, Conditions: acetonitrile/water (0.1% formic acid) 35%-65%, 20min, UV: 308nm
  • the obtained target compound 1 was characterized by XRPD, and it had an XRPD spectrum substantially as shown in FIG. 1 , and the main data of its X-ray powder diffraction pattern were shown in Table 7, and it was named Compound 1 Form A.
  • Compound 1 Form A 10-20 mg was heated to 160° C. at a heating rate of 10° C./min using TGA and after equilibration at 160° C. for 15 min, Compound 1 solid was collected, and the Compound 1 solid was characterized by XRPD, TGA and DSC, which showed an XRPD spectrum substantially as shown in FIG. 2 , a TGA spectrum substantially as shown in FIG. 3 , and a DSC spectrum substantially as shown in FIG. 4 , and the DSC melting endothermic peak temperature was about 226° C. (Onset value), indicating that the obtained product was Compound 1 Form B.
  • the main data of the X-ray powder diffraction pattern of Compound 1 Form B are shown in Table 8.
  • Example 4 The sample (20 mg) obtained in Example 4 and the corresponding 2 molar equivalents of acid were added to a sample bottle, and the corresponding solvent (0.5 mL) was added and stirred at room temperature for 3 days. If the reaction system was a suspension, the sample was tested by XRPD after solid-liquid separation; if the reaction system was a clear solution, the clear sample was slowly evaporated at room temperature to obtain a solid and then tested by XRPD. The experimental results are shown in Table 10.
  • the solid was subjected to XRPD, TGA, DSC and Raman characterization, which showed an XRPD spectrum substantially as shown in Figure 8, a TGA spectrum substantially as shown in Figure 9, a DSC spectrum substantially as shown in Figure 10, a Raman spectrum substantially as shown in Figure 20, and an infrared spectrum substantially as shown in Figure 21, indicating that the target compound obtained is Compound 1 hydrochloride salt form A.
  • the filter cake was washed with 4.0L of methanol/water (1/1, v/v) mixed solvent.
  • the obtained filter cake was vacuum dried at 50°C.
  • the product was characterized by XRPD, TGA and DSC, which proved that hydrochloride crystal form A (1869.43g) was obtained.
  • the unit cell stacking projection diagram of the hydrochloride crystal form A single crystal is basically shown in Figure 14, and the unit cell parameters are as follows:
  • the final chemical formula of the asymmetric unit was determined to be C 14 H 13 ClF 7 N 7 ⁇ HCl, the molecular weight of a single molecule was calculated to be 484.22, and the crystal density was calculated to be 1.607 g/cm 3 .
  • Sample and experimental preparation Take an appropriate amount of Compound 1 hydrochloride crystal form A and place it in a watch glass, spread it into a thin layer of about 3-5 mm thickness, and place it under the following experimental conditions.
  • the experimental conditions are: high temperature (60°C, open), high humidity (RH92.5%, open), light (25°C, 4500lux ⁇ 500lux, open), long term (25°C/60%RH, aluminum-aluminum packaging) and accelerated (40°C/75%RH, aluminum-aluminum packaging).
  • Test items Samples were taken for testing on the 0th day, the 5th day, the 10th day or the 30th day, and XRPD and HPLC were tested and compared. The test results are shown in Table 13.
  • hydrochloride crystal form A has excellent physical and chemical stability, which is conducive to drug development.
  • the inhibitory ability of compound 1 on the enzyme activity of IDH1 R132H and IDH2 R140Q was expressed as the half inhibitory concentration (IC 50 ) value.
  • AG-881 was used as the positive control compound.
  • the compound was detected on the IDH1 R132H and IDH2 R140Q enzymes using a fluorescence method, with a starting concentration of 10000nM, 3-fold dilution, 10 concentrations, and single-well detection.
  • IDH2 R140Q enzyme detection add 25 ⁇ L IDH2 R140Q enzyme solution and incubate for 60 minutes; then add 25 ⁇ L substrate solution and incubate for 150 minutes; then add 25 ⁇ L detection buffer, shake for 1 minute, and incubate for 60 minutes. The final reading was performed using Synergy 2, Ex544/Em590 cutoff 590.
  • IDH1 R132H enzyme detection add 40 ⁇ L of 1.25 times final concentration of IDH1 R132H enzyme and NADPH mixture, incubate for 60 minutes; then add 10 ⁇ L of 5 times final concentration of substrate solution, incubate for 90 minutes; then add 25 ⁇ L of 3 times final concentration of detection buffer, shake for 1 minute. The final reading is performed using Synergy 2, Ex544/Em590 cutoff 590. .
  • %Inhibition (RFU_sample-RFU_min)/(RFU_max-RFU_min)*100%.
  • RFU-sample is the fluorescence intensity of the sample
  • RFU-min is the mean value of the negative control wells, representing the fluorescence intensity with enzyme
  • RFU-max is the mean value of the positive control wells, representing the fluorescence intensity without enzyme.
  • Graphpad Prism software was used for curve fitting to obtain the IC 50 value. The test results are shown in Table 15.
  • %Inhibition (1-Analyte Peak Area_sample/Analyte Peak Area_max) * 100%.
  • Analyte Peak Area_sample is the Analyte Peak Area of the sample with compound added
  • Analyte Peak Area_max is the average Analyte Peak Area of the positive control well (representing no compound).
  • Graphpad Prism software was used for curve fitting to obtain the IC 50 value. The test results are shown in Table 15.
  • the compounds of the present invention have excellent enzymatic and cellular activities.
  • LC-MS/MS Liquid chromatography-tandem mass spectrometry
  • Example D Pharmacokinetics of different solid forms in dogs
  • Compound 1 Form A and Hydrochloride Form A were placed in capsules and administered orally by gavage at a dose of 10 mg/kg (1 female and 1 male), and oral blood collection time: 15min, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h, 36h, 48h.
  • the collected blood samples were promptly placed in a test tube containing EDTA anticoagulant, then centrifuged at 4°C and 4000rpm for 10min, and the supernatant was transferred to a centrifuge tube and stored at -20°C.

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Abstract

La présente invention concerne une forme cristalline et une forme saline d'un composé 6-(5-amino-6-chloro-4-fluoropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine, et une forme cristalline du sel, une composition comprenant la forme cristalline et la forme saline du composé et la forme cristalline du sel, et l'utilisation de la forme cristalline et de la forme saline du composé et de la forme cristalline du sel dans le traitement de maladies. La présente invention concerne en outre un procédé de préparation de 6-(5-amino-6-chloro-4-fluoropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine.
PCT/CN2024/118413 2023-09-18 2024-09-12 Formes solides d'un composé inhibiteur d'idh mutant et sel de celui-ci Pending WO2025060940A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105473560A (zh) * 2013-07-11 2016-04-06 安吉奥斯医药品有限公司 治疗活性化合物及其使用方法
CN111527076A (zh) * 2017-11-02 2020-08-11 安吉奥斯医药品有限公司 共晶体、其药物组合物以及涉及其的治疗方法
WO2022095756A1 (fr) * 2020-11-09 2022-05-12 贝达药业股份有限公司 Inhibiteur d'idh1 et d'idh2 mutantes et son application
WO2023174235A1 (fr) * 2022-03-15 2023-09-21 贝达药业股份有限公司 Inhibiteur d'idh1 et d'idh2 mutantes et son application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105473560A (zh) * 2013-07-11 2016-04-06 安吉奥斯医药品有限公司 治疗活性化合物及其使用方法
CN111527076A (zh) * 2017-11-02 2020-08-11 安吉奥斯医药品有限公司 共晶体、其药物组合物以及涉及其的治疗方法
WO2022095756A1 (fr) * 2020-11-09 2022-05-12 贝达药业股份有限公司 Inhibiteur d'idh1 et d'idh2 mutantes et son application
WO2023174235A1 (fr) * 2022-03-15 2023-09-21 贝达药业股份有限公司 Inhibiteur d'idh1 et d'idh2 mutantes et son application

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