WO2022257965A1 - Inhibiteur de kinase 9 dépendante de la cycline sous forme solide et son utilisation - Google Patents

Inhibiteur de kinase 9 dépendante de la cycline sous forme solide et son utilisation Download PDF

Info

Publication number
WO2022257965A1
WO2022257965A1 PCT/CN2022/097623 CN2022097623W WO2022257965A1 WO 2022257965 A1 WO2022257965 A1 WO 2022257965A1 CN 2022097623 W CN2022097623 W CN 2022097623W WO 2022257965 A1 WO2022257965 A1 WO 2022257965A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
ray powder
crystal form
compound
powder diffraction
Prior art date
Application number
PCT/CN2022/097623
Other languages
English (en)
Chinese (zh)
Inventor
李志怀
赵亮亮
赵杰
郝红茹
道硕
曹泽峰
何影
Original Assignee
石药集团中奇制药技术（石家庄）有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 石药集团中奇制药技术（石家庄）有限公司 filed Critical 石药集团中奇制药技术（石家庄）有限公司
Publication of WO2022257965A1 publication Critical patent/WO2022257965A1/fr

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the application relates to a compound in solid form as a cyclin-dependent kinase 9 (CDK9) inhibitor, and its application in the preparation of drugs for treating CDK9-related diseases.
  • CDK9 cyclin-dependent kinase 9
  • CDKs Cyclin-dependent kinases
  • CDKs are a class of serine/threonine protein kinases that play key roles in regulating the cell cycle and transcription.
  • CDKs can be activated by cell cycle proteins and play different biological functions. CDKs can be divided into two types according to their functions. One controls the cell cycle and the other regulates cell transcription.
  • CDK1, 2, 3, 4, and 6 directly intervene in the cell cycle; CDK5 does not regulate the cell cycle, but plays a key role in the complex migration of neurons after mitosis; CDK7 acts indirectly as an activator of these CDKs; CDK9 acts only in the cell transcription play a role in the regulation of the cell cycle.
  • CDK9 is an important member of the transcriptional CDKs subfamily, a group of kinases whose function is to control the main steps in the synthesis and processing of mRNA by eukaryotic RNA polymerase II (Pol II). CDK9 is present in all mammalian cells. The activation of CDK9 in vivo depends on its binding to the corresponding cyclin (Cyclin T/K) to form a heterodimer, that is, positive transcription elongation factor b (P-TEFb).
  • NELFs negative transcriptional elongation factors
  • CTD RNA polymerase II
  • CDK9 cyclin-dependent kinase inhibitors
  • CDK9 inhibitors Although some small molecules of CDK9 inhibitors have been disclosed (for example, WO2009047359, WO2014076091, etc.), no drugs have been approved for marketing, and it is still necessary to develop new compounds with good efficacy, good safety, and good drug-making potential. Benefit more patients clinically.
  • the present application provides a compound represented by formula (A) in crystalline form.
  • the above-mentioned crystalline form is characterized in that the crystalline form is a solvent-free and anhydrous crystalline form or a hydrate crystalline form, preferably a solvent-free and anhydrous crystalline form.
  • the application provides the crystal form I of the compound represented by formula (A), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 23.0 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.5 ⁇ 0.2°, 23.0 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.1 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.5 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.1 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.5 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.1 ⁇ 0.2°, 26.6 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.3 ⁇ 0.2°, 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.5 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.1 ⁇ 0.2°, 26.6 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.3 ⁇ 0.2°, 12.4 ⁇ 0.2°, 13.3 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.5 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.1 ⁇ 0.2°, 26.6 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.3 ⁇ 0.2°, 12.4 ⁇ 0.2°, 13.3 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.4 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.0 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.1 ⁇ 0.2°, 26.6 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.3 ⁇ 0.2°, 12.4 ⁇ 0.2°, 13.1 ⁇ 0.2°, 13.3 ⁇ 0.2°, 15.4 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.4 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.4 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.0 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.1 ⁇ 0.2°, 26.6 ⁇ 0.2°.
  • the above crystal form I uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks ( ⁇ 0.2°) at the following 2 ⁇ angles:
  • the above-mentioned crystal form I using Cu-K ⁇ radiation, has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the differential scanning calorimetry curve of the above crystal form I has an endothermic peak at 204.33 ⁇ 5°C.
  • the above-mentioned crystal form I has a DSC spectrum substantially as shown in FIG. 2 .
  • thermogravimetric analysis curve of the above crystal form I has a weight loss of 0.565% ⁇ 0.2% between room temperature and 180°C ⁇ 5°C.
  • the above-mentioned crystal form I has a TGA spectrum substantially as shown in FIG. 2 .
  • the application provides the crystal form V of the compound represented by formula (A), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 11.3 ⁇ 0.2°, 18.3 ⁇ 0.2°, 22.8 ⁇ 0.2°.
  • the above crystal form V uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 11.3 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.3 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.8 ⁇ 0.2°.
  • the above crystal form V uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 11.3 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.3 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.5 ⁇ 0.2°.
  • the above crystal form V uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.4 ⁇ 0.2°, 11.3 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.7 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.5 ⁇ 0.2°.
  • the above crystal form V uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.5 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.3 ⁇ 0.2°, 16.2 ⁇ 0.2°, 16.7 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.7 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.5 ⁇ 0.2°.
  • the above crystal form V uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.5 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.3 ⁇ 0.2°, 16.2 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.0 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.7 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.5 ⁇ 0.2°.
  • the above crystal form V uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.5 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.3 ⁇ 0.2°, 13.1 ⁇ 0.2°, 16.2 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.0 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.7 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.4 ⁇ 0.2°.
  • the above crystal form V uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks ( ⁇ 0.2°) at the following 2 ⁇ angles:
  • the above-mentioned crystal form V using Cu-K ⁇ radiation, has an X-ray powder diffraction pattern substantially as shown in FIG. 3 .
  • the differential scanning calorimetry curve of the above crystal form V has an endothermic peak at 185.87 ⁇ 5°C.
  • the above-mentioned crystal form V has a DSC spectrum substantially as shown in FIG. 4 .
  • thermogravimetric analysis curve of the above crystal form V has a weight loss of 0.926% ⁇ 0.2% between room temperature and 170 ⁇ 5°C.
  • the above-mentioned crystal form V has a TGA spectrum substantially as shown in FIG. 4 .
  • the application provides the crystal form XIII of the compound represented by formula (A), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 15.8 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.8 ⁇ 0.2°.
  • the above crystal form XIII uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 14.3 ⁇ 0.2°, 15.8 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.8 ⁇ 0.2°.
  • the above crystal form XIII uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.5 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.8 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.8 ⁇ 0.2°, 24.4 ⁇ 0.2°.
  • the above crystal form XIII uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.5 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.8 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.2 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.8 ⁇ 0.2°, 24.4 ⁇ 0.2°, 26.3 ⁇ 0.2°.
  • the above crystal form XIII uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.5 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.2 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.8 ⁇ 0.2°, 24.4 ⁇ 0.2°, 26.3 ⁇ 0.2°, 26.9 ⁇ 0.2°.
  • the above crystal form XIII uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks ( ⁇ 0.2°) at the following 2 ⁇ angles:
  • the above crystal form XIII, using Cu-K ⁇ radiation has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
  • the differential scanning calorimetry curve of the above crystal form XIII has two endothermic peaks at 194.07 ⁇ 5°C and 200.51 ⁇ 5°C respectively.
  • the above crystal form XIII has a DSC spectrum substantially as shown in FIG. 6 .
  • thermogravimetric analysis curve of the above crystal form XIII has a weight loss of 0.216% ⁇ 0.2% between room temperature and 180 ⁇ 5°C.
  • the above crystal form XIII has a TGA spectrum substantially as shown in FIG. 6 .
  • Another object of the present application is to provide a crystalline composition comprising Form I, Form V, Form XIII or two or more of the compound of formula (A).
  • the crystal form I accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% or more than 95% of the weight of the crystalline composition.
  • the crystal form V accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% or more than 95% of the weight of the crystalline composition.
  • the crystal form XIII accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% or more than 95% of the weight of the crystalline composition.
  • Another object of the present application is to provide a pharmaceutical composition, which comprises the compound represented by formula (A) in solid form, the compound represented by formula (A) in crystal form or its crystal composition.
  • the above-mentioned pharmaceutical composition comprises the crystal form I, crystal form V, or crystal form XIII of the compound represented by formula (A).
  • Another object of the present application is to provide a pharmaceutical composition, which comprises a compound represented by formula (A) in solid form, a compound represented by formula (A) in crystal form or a crystal composition thereof, and a pharmaceutically acceptable carrier .
  • the above-mentioned pharmaceutical composition comprises crystalline form I, crystalline form V, or crystalline form XIII of the compound of formula (A), and a pharmaceutically acceptable carrier.
  • the present application also provides the above-mentioned compound represented by formula (A) in solid form, the compound represented by formula (A) in crystalline form, crystal form I, crystal form V, and crystal form of the compound represented by formula (A) XIII.
  • the above-mentioned use wherein the CDK9-mediated disease includes a cell proliferative disease or an inflammatory disease.
  • the present application also provides the above-mentioned compound represented by formula (A) in solid form, the compound represented by formula (A) in crystalline form, crystal form I, crystal form V, and crystal form of the compound represented by formula (A) XIII.
  • the drug is used to treat diseases mediated by CDK9.
  • the CDK9-mediated diseases include cell proliferative diseases or inflammatory diseases.
  • the aforementioned CDK9-mediated disease refers to a disease involving changes in CDK9 gene, protein, activity or expression thereof.
  • the aforementioned cell proliferative disease or inflammatory disease involves changes in CDK9 gene, protein, activity or expression thereof.
  • the aforementioned cell proliferative disease is a tumor; preferably, the tumor is a hematological tumor or a solid tumor; preferably a relapsed or refractory hematological tumor or a solid tumor; preferably a malignant hematological tumor or an advanced solid tumor Tumor; more preferably advanced hematological malignancy or advanced malignant solid tumor; more preferably relapsed or refractory advanced hematological malignancy or advanced malignant solid tumor.
  • the blood tumor is leukemia, lymphoma or myeloma; preferably, the leukemia is acute myeloid leukemia; preferably, the lymphoma is non-Hodgkin's lymphoma; cell lymphoma or diffuse large B-cell lymphoma; preferably, the myeloma is multiple myeloma.
  • the solid tumor is selected from liver cancer, breast cancer and prostate cancer; preferably, the breast cancer is triple-negative breast cancer.
  • the present application also provides the use of the compound represented by the formula (A) in solid form or the compound represented by formula (A) in crystalline form in the preparation of crystal form I, crystal form V, or crystal form XIII.
  • the present application also provides the above-mentioned compound represented by formula (A) in solid form, the compound represented by formula (A) in crystalline form, crystal form I, crystal form V, and crystal form of the compound represented by formula (A) XIII.
  • the above crystalline composition or the above pharmaceutical composition which is used for preventing and/or treating CDK9-mediated diseases.
  • the present application also provides the above-mentioned compound represented by formula (A) in solid form, the compound represented by formula (A) in crystalline form, crystal form I, crystal form V, and crystal form of the compound represented by formula (A) XIII.
  • the CDK9 inhibitor is used to treat CDK9-mediated diseases.
  • the aforementioned CDK9-mediated diseases include cell proliferative diseases or inflammatory diseases.
  • the aforementioned CDK9-mediated disease refers to a disease involving changes in CDK9 gene, protein, activity or expression thereof.
  • the aforementioned cell proliferative disease or inflammatory disease involves changes in CDK9 gene, protein, activity or expression thereof.
  • the aforementioned cell proliferative disease is a tumor; preferably, the tumor is a hematological tumor or a solid tumor; preferably a relapsed or refractory hematological tumor or a solid tumor; preferably a malignant hematological tumor or an advanced solid tumor Tumor; more preferably advanced hematological malignancy or advanced malignant solid tumor; more preferably relapsed or refractory advanced hematological malignancy or advanced malignant solid tumor.
  • the blood tumor is leukemia, lymphoma or myeloma; preferably, the leukemia is acute myeloid leukemia; preferably, the lymphoma is non-Hodgkin's lymphoma; cell lymphoma or diffuse large B-cell lymphoma; preferably, the myeloma is multiple myeloma.
  • the solid tumor is selected from liver cancer, breast cancer and prostate cancer; preferably, the breast cancer is triple-negative breast cancer.
  • the present application also provides a method for treating a disease mediated by CDK9, the method comprising administering a therapeutically effective amount of the compound represented by the above formula (A) in solid form, the formula (A) in crystal form to an individual in need
  • the CDK9-mediated diseases include cell proliferative diseases or inflammatory diseases.
  • the CDK9-mediated disease refers to a disease involving changes in CDK9 gene, protein, activity or expression thereof.
  • the cell proliferative disease or inflammatory disease involves changes in CDK9 gene, protein, activity or expression thereof.
  • the cell proliferative disease is a tumor; preferably, the tumor is a hematological tumor or a solid tumor; preferably a relapsed or refractory hematological tumor or a solid tumor; preferably a malignant hematological tumor or an advanced Solid tumor; more preferably advanced hematological malignancy or advanced malignant solid tumor; more preferably relapsed or refractory advanced hematological malignancy or advanced malignant solid tumor.
  • the blood tumor is leukemia, lymphoma or myeloma; preferably, the leukemia is acute myeloid leukemia; preferably, the lymphoma is non-Hodgkin's lymphoma; cell lymphoma or diffuse large B-cell lymphoma; preferably, the myeloma is multiple myeloma.
  • the solid tumor is selected from liver cancer, breast cancer and prostate cancer; preferably, the breast cancer is triple-negative breast cancer.
  • the "compound represented by formula (A) in solid form” mentioned in the present application refers to the compound represented by formula (A) in solid state, including its crystalline form and amorphous form.
  • the "compound represented by formula (A) in crystalline form” mentioned in this application refers to the compound represented by formula (A) in crystalline form, including the anhydrous and solvent-free form and hydrate form of the compound represented by formula (A) , solvate form and co-crystal form; preferably include anhydrous and solvent-free form, hydrate form and solvate form of the compound shown in formula (A); preferably include anhydrous and anhydrous of the compound shown in formula (A) Solvent form and hydrate form.
  • solvate refers to a complex with variable stoichiometry formed by a solute (in this application, a compound represented by formula (A)) and a solvent.
  • the solvents used for the purposes of this application must not interfere with the biological activity of the solute.
  • Suitable solvates include pharmaceutically acceptable solvates, and also include both stoichiometric solvates and non-stoichiometric solvates.
  • solvates with non-pharmaceutically acceptable solvents are within the scope of the present application, for example, they can be used as intermediates for the preparation of compounds represented by formula (A) or other crystal forms.
  • the solvent used is water, and the solvate obtained at this time may also be called a hydrate.
  • the term “hydrate” refers to a compound provided herein that further includes stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.
  • solvent-free and anhydrous crystalline form means that the sample does not contain solvent molecules or water molecules that are combined with the compound represented by formula (A) by intermolecular forces.
  • a sample contains not more than 3.0%, such as not more than 1.5%, such as not more than 1%, by weight of water or solvent when measured by thermogravimetric analysis (TGA).
  • crystalline composition refers to a solid form comprising the crystalline form I, crystalline form V, crystalline form XIII or two or more thereof mentioned in this application. Moreover, in addition to the crystal forms mentioned in this application, the crystalline composition may optionally contain other crystal forms or other amorphous forms of the compound represented by formula (A) or its salt, or impurities other than these substances. Those skilled in the art should understand that the sum of the contents of each component in the crystalline composition should be 100%.
  • room temperature is the room temperature in the conventional sense in the field, generally 10-30°C, preferably 25°C ⁇ 5°C.
  • the terms “substantially” or “substantially as shown” refer to a substantially pure crystalline form having at least 50% of the powder X-ray diffraction pattern, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks present in the given spectrum .
  • the content of a certain crystalline form in the product gradually decreases, some diffraction peaks in the X-ray powder diffraction pattern attributed to the crystalline form may decrease due to the detection sensitivity of the instrument.
  • the term "substantially” or “substantially as shown in the figure” means that for the same crystal form of the same compound, in continuous analysis, the thermal transition onset temperature, endothermic
  • the error of peak-to-peak temperature, exothermic peak-to-peak temperature, melting point, weight loss onset temperature or weight loss end temperature etc. is typically within about 5°C, usually within about 3°C.
  • cell proliferative disorder refers to a disorder in which a population of cells grows at a rate that is either slower or higher than expected for a given physiological state and conditions.
  • tumor includes benign tumors, malignant tumors and borderline tumors, where malignant tumors are collectively referred to as cancer.
  • prevention means, when used for a disease or disorder (eg, cancer), that the A compound or drug is capable of reducing the frequency or delaying the onset of symptoms of a medical condition in an individual or subject.
  • treating means alleviating, alleviating or ameliorating the symptoms of a disease or disorder, ameliorating an underlying metabolically caused symptom, inhibiting a disease or symptom, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, causing a disease Regression of a disease or disorder, alleviation of a condition caused by a disease or disorder, or arrest of symptoms of a disease or disorder.
  • the term "individual” or “subject” refers to a cell or a mammal, such as a human, but can also be other mammals, such as livestock or experimental animals (for example, including but not limited to mice, rats, rabbits, dogs, monkeys, sheep, etc.) etc.
  • composition of the present application can be prepared by conventional methods in the art.
  • the term "pharmaceutically acceptable carrier” or “excipient” or “pharmaceutically acceptable adjuvant” or “pharmaceutically acceptable adjuvant” means no significant irritation to the organism, and Those excipients that do not impair the biological activity and performance of the active compound.
  • pharmaceutically acceptable excipients includes: solvents, propellants, solubilizers, co-solvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, Stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adherents, antioxidants, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers Agents, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc.
  • the solid form of the compound represented by the formula (A), the crystalline form and the specific crystal form of the compound represented by the formula (A) provided by the application have one or more of the following beneficial effects:
  • the crystal form and specific crystal form of the compound represented by formula (A) mentioned in this application have good crystallinity and are easy to purify, filter and separate;
  • results of in vitro kinase activity test and cell test show that the compound (A) of the present application has good in vitro kinase inhibitory activity against CDK9, good selectivity for other CDK subtypes, and strong inhibitory effect on various tumor cells;
  • the hERG inhibitory activity test in vitro shows that the compound represented by formula (A) has a lower risk of cardiotoxicity
  • Figure 1 X-ray powder diffraction pattern of Form I of Example 1.
  • Figure 3 X-ray powder diffraction pattern of Form V of Example 2.
  • Figure 5 X-ray powder diffraction pattern of Form XIII of Example 3.
  • Test method About 2 ⁇ 10mg sample is used for XRPD detection
  • Phototube voltage 40kV
  • phototube current 40mA
  • Test method Take the sample and place it in the DSC sample tray, cover the sample tray and punch holes, equilibrate the sample at 25°C and heat it to the final temperature at a heating rate of 10°C/min.
  • Termination temperature 250°C.
  • Test method Place the sample in a balanced open aluminum sample pan. After the sample quality is automatically weighed in the TGA heating furnace, the sample is heated to the final temperature at a rate of 10°C/min.
  • Heating start temperature room temperature
  • Termination temperature 300°C.
  • Test method add enough sample (15mg) into the instrument to simulate dynamic water vapor adsorption, and record the different humidity in the range of 0%-90% at 25°C (the humidity change of each gradient is 10%, the humidity change : 50%-95%-0%-50%) weight change during balance.
  • the end point of the gradient is judged by the dm/dt method, and the end point of the gradient is defined as the dm/dt is less than 0.002% and maintained for 10 minutes.
  • Hygroscopicity moisture absorption weight gain is less than 15% but not less than 2%
  • moisture absorption weight gain is less than 2% but not less than 0.2%
  • Injection volume 5 ⁇ L.
  • the preparation process of the pH buffer is shown in the table below. Add the sample of the crystal form to be tested to 2.0mL of different pH 2-7 buffer media to prepare a suspension, shake at a constant temperature of 25°C for 24 hours, and centrifuge the suspension; take the remaining supernatant to test its pH value , carry out XRPD test on remaining solid.
  • the preparation process of the biological medium is shown in the table below. Samples of different crystal forms were added to 4.0mL of water and biological medium (FaSSIF, FeSSIF, FaSSGF, FaSSIF/FeSSIF/FaSSGF powder manufacturer Biorelevant, powder product number FFF01, batch number FFF-1219-A) to prepare a suspension, in Shake at a constant temperature of 37°C for 24 hours, test the pH value of the supernatant at the time point of 24 hours, and carry out XRPD test on the remaining solid.
  • biological medium FeSSIF, FeSSIF, FaSSGF, FaSSIF/FeSSIF/FaSSGF powder manufacturer Biorelevant, powder product number FFF01, batch number FFF-1219-A
  • FaSSIF Simulates the intestinal juice in the small intestine under the state of hunger before a meal
  • FeSSIF simulates the intestinal juice in the small intestine under the state of satiety after a meal
  • FaSSGF simulates the gastric juice in the empty stomach under the state of human starvation.
  • the intermediate compounds and/or compounds of the present application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods in the art
  • the equivalent replacements known to the skilled person, and preferred implementations include but not limited to the examples of the present application.
  • a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
  • Embodiment 1 Preparation of formula (A) compound crystal form I
  • Embodiment 2 Preparation of formula (A) compound crystal form V
  • Embodiment 3 Preparation of formula (A) compound crystal form XIII
  • Test Example 1 Research on Hygroscopicity of Different Crystal Forms of Compound of Formula (A)
  • the crystalline form I (Example 1) and the crystalline form V (Example 2) of the compound of formula (A) were placed in the DVS sample chamber for testing.
  • the samples after DVS were taken for X-ray powder diffraction.
  • Test Example 3 Stability experiment of different crystal forms of the compound of formula (A) in different pH solutions
  • Test Example 4 Stability experiment of different crystal forms of the compound of formula (A) in biosolvent media
  • Example 1 The data show that the crystalline form I of Example 1 and the crystalline form V of Example 2 can maintain stable crystal forms in water and different biosolvent media.
  • Test Example 1 The inhibitory effect test of the compound of the present application on CDK9, CDK1, CDK2, CDK4, CDK5, CDK6 and CDK7
  • the compound of formula (A) was diluted with DMSO to 11 concentrations, 3-fold dilution, wherein the highest concentration of the reference compound staurosporine was 1 ⁇ M, and the highest concentration of the test compound was 10 ⁇ M.
  • Test Example 2 In vitro inhibitory effect of the compound represented by formula (A) on the proliferation of different tumor cell lines
  • MTT is thiazolium blue, which is a tetrazolium salt of a dye that can accept hydrogen atoms.
  • Amber dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to insoluble blue-purple crystals and deposit them in cells, while dead cells have no such function.
  • Dimethyl sulfoxide can dissolve the blue-purple complex in the cells, and its light absorption value is measured at a wavelength of 490-550nm with an enzyme-linked immunosorbent detector, which can indirectly reflect the number of cells. Within a certain cell number range, the amount of MTT crystal formation is proportional to the cell number.
  • the drug to be tested was diluted to different concentrations in sequence, and added to a 96-well plate. After a certain period of drug action, the OD value was measured. The OD value can reflect the number of living cells, and the IC 50 value was calculated with SPSS19.0.
  • MTT working solution Weigh 0.5g of MTT and dissolve in 100mL PBS, filter and sterilize with a 0.22 ⁇ m microporous membrane, and store in a 4°C refrigerator (use within two weeks) or -20°C for long-term storage.
  • Suspension cells Count after resuspension by centrifugation. After making a certain density of cell suspension with complete medium, pipette and blow evenly to inoculate in a 96-well plate, 100 ⁇ L per well, and then culture in a CO 2 incubator, and use it for detection after 24 hours of attachment.
  • MTT method Add 20 ⁇ L of MTT to each well, incubate in the incubator for about 4 hours, discard the liquid in the well, add 150 ⁇ L DMSO to each well, place in a shaker for 5-10 minutes, and detect with a microplate reader at a wavelength of 550 nm.
  • Inhibition rate (%) (OD value of normal well - OD value of administration well) / (OD value of normal well - OD value of blank well) ⁇ 100%
  • Test Example 3 Investigation of hERG Inhibitory Activity in Vitro
  • This test includes the following aspects:
  • hERG currents were recorded using the whole-cell patch clamp technique. Take the cell suspension and add it to the cell tank, and place it on the stage of the upright microscope. After the cells adhered to the wall, they were perfused with extracellular fluid at a flow rate of 1–2 mL/min. The glass microelectrode is drawn in two steps by a microelectrode pulling instrument, and its water resistance value is 2-5M ⁇ . After establishing whole-cell recordings, the clamping potential was maintained at -80mV. Depolarization to +60mV and repolarization to -50mV elicited hERG tail currents when voltage stimulation was given. All recordings were performed after the current was stabilized.
  • the administration of extracellular perfusion starts at a low concentration, and each concentration lasts for 5-10 minutes until the current is stable, and then the next concentration is given.
  • the half maximal inhibitory concentration (IC50 ) of the test compound was obtained by the best fit of the Logistic equation.
  • Amitriptyline is one of the most widely used drugs for blocking hERG current, so it was used as a positive control drug in this study.
  • Table 12 IC 50 values of compounds represented by formula (A) on hERG current recorded on CHO-K1 stable cell line
  • the IC 50 result of the active control drug amitriptyline on hERG current inhibition is consistent with the historical results of the test party and also with the results reported in the literature, indicating that the results of this test are credible.
  • the above test results show that the compound shown in the measured formula (A) can not reach the half -inhibition of hERG current at the highest test concentration, so the IC cannot be measured, indicating that within the detection concentration range of this test, the compound shown in the formula (A) The compound has no obvious inhibitory effect on the hERG channel, which can reflect to a certain extent that the compound represented by the formula (A) has low or no cardiotoxicity, and has positive significance for drug safety evaluation.
  • Test Example 4 In vivo investigation of anti-tumor activity of drugs - in vivo pharmacodynamics of the compound represented by formula (A) in human acute myeloid leukemia MV 4-11 cell subcutaneous xenograft tumor model
  • IMDM medium containing 10% fetal bovine serum (FBS), 37°C, 5% CO 2 .
  • NODSCID mice female, 6-8 weeks old, weighing about 18-22 grams, were subcutaneously inoculated with 0.1 mL (1 ⁇ 10 8 ) of MV 4-11 cells on the right back of each mouse.
  • the tumor volume was measured twice a week, and the volume was measured in cubic millimeters.
  • the administration was terminated, and the difference in average tumor volume between the test compound group and the solvent group was compared.
  • the antitumor efficacy of compounds was evaluated by TGI (%).
  • TGI (%) reflects tumor growth inhibition rate.
  • Solvent DMSO:HP- ⁇ -CD (0.5g/mL):water ratio is 2%:20%:78% (v/v/v).
  • TGI (%) [1-(average tumor volume at the end of certain treatment group administration-average tumor volume at the beginning of this treatment group)/(average tumor volume at the end of solvent control group administration-solvent The average tumor volume at the beginning of the control group)] ⁇ 100%. The results are shown in Table 13.
  • the compound represented by the formula (A) exhibits good drug efficacy in vivo in the human acute myeloid leukemia MV 4-11 cell subcutaneous xenograft tumor model, and has a significant tumor inhibitory effect.
  • Test Example 5 In vivo investigation of the antitumor activity of the drug - the in vivo drug effect of the compound represented by formula (A) in the subcutaneous xenograft tumor model of human promyelocytic acute leukemia HL-60 cells.
  • IMDM medium containing 20% fetal bovine serum (FBS), 37°C, 5% CO 2 ;
  • NU/NU mice female, 6-8 weeks old, weighing about 18-22 grams, each mouse was subcutaneously inoculated with 0.1 mL of HL-60 cell suspension (containing about 1 ⁇ 10 7 cells) in the armpit of the right forelimb.
  • HL-60 cell suspension containing about 1 ⁇ 10 7 cells
  • the tumor volume was measured 2-3 times a week, and the volume was measured in cubic millimeters.
  • the administration was terminated, and the difference in average tumor volume between the test compound group and the solvent group was compared.
  • the antitumor efficacy of compounds was evaluated by TGI (%). TGI (%) reflects tumor growth inhibition rate.
  • Solvent DMSO:HP- ⁇ -CD (0.5g/mL):water ratio is 2%:20%:78% (v/v/v).
  • TGI (%) [1-(average tumor volume at the end of certain treatment group administration-average tumor volume at the beginning of this treatment group)/(average tumor volume at the end of solvent control group administration-solvent The average tumor volume at the beginning of the control group)] ⁇ 100%. The results are shown in Table 14.
  • the compound represented by formula (A) exhibits good drug efficacy in vivo in the subcutaneous xenograft tumor model of human promyelocytic acute leukemia HL-60 cells. Nine days after the start of administration, the compound represented by formula (A) has a significant tumor-inhibiting effect.
  • mice ICR mice (5 weeks), male and female
  • Solvent Solvent: DMSO:HP- ⁇ -CD (0.5g/mL):water ratio is 2%:20%:78% (v/v/v).
  • Test method ICR mice were divided into 7 groups according to weight balance, with 5 males and 5 mice in each group.
  • the method of administration is intragastric administration, once a day, for 7 consecutive days, and the dosage and results are shown in the table below.

Abstract

L'invention concerne un composé de formule (A) sous une forme solide, en particulier sous une forme cristalline, une forme cristalline spécifique, et son utilisation. Le composé représenté par la formule (A) a une excellente activité inhibitrice de la kinase 9 dépendante de la cycline, une excellente activité inhibitrice in vitro des cellules tumorales, une excellente activité antitumorale in vivo, et une meilleure innocuité, et la forme cristalline obtenue du composé représenté par la formule (A) présente les caractéristiques d'une bonne cristallinité, d'une faible hygroscopicité, et d'une bonne stabilité, et a un bon potentiel médicamenteux.
PCT/CN2022/097623 2021-06-09 2022-06-08 Inhibiteur de kinase 9 dépendante de la cycline sous forme solide et son utilisation WO2022257965A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110644313 2021-06-09
CN202110644313.0 2021-06-09

Publications (1)

Publication Number Publication Date
WO2022257965A1 true WO2022257965A1 (fr) 2022-12-15

Family

ID=84297287

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/097623 WO2022257965A1 (fr) 2021-06-09 2022-06-08 Inhibiteur de kinase 9 dépendante de la cycline sous forme solide et son utilisation

Country Status (2)

Country Link
CN (1) CN115448874A (fr)
WO (1) WO2022257965A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116120322A (zh) * 2021-11-15 2023-05-16 石药集团中奇制药技术（石家庄）有限公司 氮杂稠环酰胺类化合物的盐、其结晶形式及其用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102471310A (zh) * 2009-09-04 2012-05-23 诺瓦提斯公司 用于治疗增生性疾病的联吡啶化合物
CN102482265A (zh) * 2009-09-04 2012-05-30 诺瓦提斯公司 用于治疗增殖性疾病的吡嗪基吡啶化合物
CN102498107A (zh) * 2009-09-04 2012-06-13 诺瓦提斯公司 作为激酶抑制剂的杂芳基化合物
CN102834380A (zh) * 2010-03-10 2012-12-19 Ingenium制药有限责任公司 蛋白激酶的抑制剂
WO2021115335A1 (fr) * 2019-12-09 2021-06-17 石药集团中奇制药技术（石家庄）有限公司 Composé utile en tant qu'inhibiteur de la kinase 9 dépendante de la cycline et son utilisation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2212297B1 (fr) * 2007-10-12 2011-05-25 Ingenium Pharmaceuticals GmbH Inhibiteurs de protéine kinases
WO2012101064A1 (fr) * 2011-01-28 2012-08-02 Novartis Ag Composés à base de n-acyl-pyrimidine-biaryl convenant comme inhibiteurs de protéine kinase
CN103565653B (zh) * 2012-07-16 2017-01-25 广东东阳光药业有限公司 取代的吡唑酮化合物及其使用方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102471310A (zh) * 2009-09-04 2012-05-23 诺瓦提斯公司 用于治疗增生性疾病的联吡啶化合物
CN102482265A (zh) * 2009-09-04 2012-05-30 诺瓦提斯公司 用于治疗增殖性疾病的吡嗪基吡啶化合物
CN102498107A (zh) * 2009-09-04 2012-06-13 诺瓦提斯公司 作为激酶抑制剂的杂芳基化合物
CN102834380A (zh) * 2010-03-10 2012-12-19 Ingenium制药有限责任公司 蛋白激酶的抑制剂
WO2021115335A1 (fr) * 2019-12-09 2021-06-17 石药集团中奇制药技术（石家庄）有限公司 Composé utile en tant qu'inhibiteur de la kinase 9 dépendante de la cycline et son utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CIDADO JUSTIN, BOIKO SCOTT, PROIA THERESA, FERGUSON DOUGLAS, CRISCIONE STEVEN W., SAN MARTIN MARYANN, POP-DAMKOV PETAR, SU NANCY, : "AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells", CLINICAL CANCER RESEARCH, ASSOCIATION FOR CANCER RESEARCH, US, vol. 26, no. 4, 15 February 2020 (2020-02-15), US, pages 922 - 934, XP093013476, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-19-1853 *

Also Published As

Publication number Publication date
CN115448874A (zh) 2022-12-09

Similar Documents

Publication Publication Date Title
CN107873032B (zh) 苯并氧氮杂*噁唑烷酮化合物及其使用方法
JP6530792B2 (ja) Ｓｙｋ阻害剤
CN107995911B (zh) 苯并氧氮杂*噁唑烷酮化合物及其使用方法
CN104936953B (zh) 化合物
CN109970745B (zh) 取代的吡咯并三嗪类化合物及其药物组合物及其用途
KR102090453B1 (ko) 상피 성장 인자 수용체 키나제 억제제의 염
US20200361908A1 (en) Crystals of aniline pyrimidine compound serving as egfr inhibitor
JP2022526926A (ja) イミダゾロニルキノリン化合物およびそれらの治療への使用
WO2022257965A1 (fr) Inhibiteur de kinase 9 dépendante de la cycline sous forme solide et son utilisation
JP2021523120A (ja) セルデュラチニブ（ｃｅｒｄｕｌａｔｉｎｉｂ）の固体形態
KR20160087902A (ko) N-(4-((3-(2-아미노-4-피리미디닐)-2-피리디닐)옥시)페닐)-4-(4-메틸-2-티에닐)-1-프탈라진아민 염의 약제학적으로 허용가능한 결정형 및 이의 용도
TW202023562A (zh) 喹唑啉化合物及其鹽酸鹽之結晶形態
EP3971175A1 (fr) Forme cristalline de composé quinazolinone et son procédé de préparation
WO2020192637A1 (fr) Composé inhibiteur de brd4 sous forme solide, son procédé de préparation et son application
US11465986B2 (en) Crystal form of c-MET inhibitor and salt form thereof and preparation method therefor
US11584750B2 (en) Crystalline forms of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazine-7-yl)ethyl)amino)pyrimidine-5-carbonitrile as inhibitors of phosphatidylinositol-3-kinase
EP3896063A1 (fr) Sel d'inhibiteur de syk et forme cristalline correspondante
WO2018099451A1 (fr) Forme cristalline d'un composé
WO2021164789A1 (fr) Forme cristalline d'un composé de pyrazolopyrimidine et son utilisation
WO2022016420A1 (fr) Forme cristalline d'un composé quinazolinone, son procédé de préparation et son utilisation
WO2023202706A1 (fr) Forme saline et forme cristalline de composé hétérocyclique de sélénium et leur application
CN113227073B (zh) Egfr酪氨酸激酶的选择性抑制剂的盐及其晶型
WO2023093861A1 (fr) Mono-p-toluènesulfonate d'inhibiteur de kinase axl et forme cristalline de celui-ci
WO2020224585A1 (fr) Sel et forme cristalline d'un inhibiteur d'activité de double kinase mtorc1/2 et son procédé de préparation
WO2022242688A1 (fr) Forme cristalline d'un composé macrocyclique cyano-substitué et son procédé de préparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22819562

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE