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WO2025167975A1 - Inhibiteur cristallin de kinase dépendante de la cycline (cdk) 12 et/ou cdk13 et ses utilisations - Google Patents

Inhibiteur cristallin de kinase dépendante de la cycline (cdk) 12 et/ou cdk13 et ses utilisations

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Publication number
WO2025167975A1
WO2025167975A1 PCT/CN2025/075983 CN2025075983W WO2025167975A1 WO 2025167975 A1 WO2025167975 A1 WO 2025167975A1 CN 2025075983 W CN2025075983 W CN 2025075983W WO 2025167975 A1 WO2025167975 A1 WO 2025167975A1
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Prior art keywords
solid state
xrpd
compound
radiation
measured
Prior art date
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English (en)
Inventor
Lijun Zhang
Qingshuo MENG
Xing LIANG
Hongfu LU
Feng Ren
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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Publication of WO2025167975A1 publication Critical patent/WO2025167975A1/fr
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • CDKs Cyclin-dependent kinases
  • the solid state form is an amorphous form.
  • the solid state form is a crystalline form.
  • the solid state form is crystalline Compound 1 as a freebase.
  • the solid state form is crystalline Compound 1 freebase Type A.
  • the solid state form is crystalline Compound 1 as a pharmaceutically acceptable adduct.
  • the adduct is a salt of Compound 1.
  • the adduct is a cocrystal of Compound 1.
  • the solid state form is a salt or a cocrystal.
  • the solid state form is crystalline Compound 1 fumaric acid adduct Type A, Compound 1 succinic acid adduct Type A, or Compound 1 p-toluenesulfonate adduct Type A.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 disclosed herein and a pharmaceutically acceptable excipient. Also disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form disclosed herein and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of treating a disease or disorder in a subject, the method comprising administering to the subject a crystalline form disclosed herein or a pharmaceutical composition disclosed herein, wherein the disease or disorder is cancer or neoplastic disease.
  • FIG. 1A shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 Freebase Type A.
  • FIG. 1B shows the Differential Scanning Calorimetry (DSC) thermogram of Compound 1 Freebase Type A.
  • FIG. 1C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 Freebase Type A.
  • FIG. 1D shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 Freebase Type A.
  • FIG. 1E shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 Freebase Type A with different water content.
  • FIG. 2A shows the X-Ray Powder Diffraction (XRPD) pattern ofCompound 1 Freebase amorphous solid state form.
  • FIG. 2B shows the Modulated Differential Scanning Calorimetry (mDSC) thermogram of Compound 1 Freebase amorphous solid state form.
  • FIG. 2C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 Freebase amorphous solid state form.
  • FIG. 3A shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 fumaric acid adduct Type A.
  • FIG. 3B shows the Differential Scanning Calorimetry (DSC) thermogram of Compound 1 fumaric acid adduct Type A.
  • FIG. 3C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 fumaric acid adduct Type A.
  • FIG. 3D shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 fumaric acid adduct Type A.
  • FIG. 4A shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 succinic acid adduct Type A.
  • FIG. 4B shows the Differential Scanning Calorimetry (DSC) thermogram of Compound 1 succinic acid adduct Type A.
  • FIG. 4C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 succinic acid adduct Type A.
  • FIG. 4D shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 succinic acid adduct Type A.
  • FIG. 5A shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 p-toluenesulfonate adduct Type A.
  • FIG. 5B shows the Differential Scanning Calorimetry (DSC) thermogram of Compound 1 p-toluenesulfonate adduct Type A.
  • FIG. 5C shows the Thermogravimetric Analysis (TGA) thermogram of Compound 1 p-toluenesulfonate adduct Type A.
  • FIG. 5D shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 p-toluenesulfonate adduct Type A.
  • polymorphism While small molecule inhibitors are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers. Compound 1
  • Compound 1 is (R) -1- (4- (3- ( (4- (1-methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) pyrrolidin-1-yl) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) prop-2-en-1-one: (Compound 1) .
  • Compound 1 is in the form of a freebase.
  • Compound 1 is in the form of a pharmaceutically acceptable adduct.
  • Compound 1 is in the form of a pharmaceutically acceptable salt.
  • Compound 1 is in the form of a fumaric acid adduct.
  • Compound 1 is in the form of a fumaric acid salt. In some embodiments, Compound 1 is in the form of a fumaric acid cocrystal. In some embodiments, Compound 1 is in the form of a succinic acid adduct. In some embodiments, Compound 1 is in the form of a succinic acid salt. In some embodiments, Compound 1 is in the form of a succinic acid cocrystal. In some embodiments, Compound 1 is in the form of a succinic acid cocrystal. In some embodiments, Compound 1 is in the form of a p-toluenesulfonate adduct.
  • Compound 1 is in the form of a p-toluenesulfonate salt. In some embodiments, Compound 1 is in the form of a p-toluenesulfonate cocrystal. Solid State Form of Compound 1
  • the solid state form is an amorphous form.
  • the solid state form is a crystalline form.
  • the solid state form is crystalline Compound 1 freebase. In some embodiments, the solid state form is crystalline Compound 1 freebase Type A. In some embodiments, the Compound 1 freebase Type A is hydrated.
  • the solid state form is an adduct. In some embodiments, the adduct is a salt. In some embodiments, the adduct is a cocrystal. In some embodiments, the solid state form is a salt. In some embodiments, the solid state form is a cocrystal. In some embodiments, the solid state form is Compound 1 fumaric acid adduct. In some embodiments, the solid state form is Compound 1 fumaric acid adduct Type A. In some embodiments, the solid state form is Compound 1 fumaric acid salt. In some embodiments, the solid state form is Compound 1 fumaric acid cocrystal. In some embodiments, the solid state form is Compound 1 succinic acid adduct.
  • the solid state form is Compound 1 succinic acid adduct Type A. In some embodiments, the solid state form is Compound 1 succinic acid salt. In some embodiments, the solid state form is Compound 1 succinic acid cocrystal. In some embodiments, the solid state form is Compound 1 p-toluenesulfonate adduct. In some embodiments, the solid state form is Compound 1 p-toluenesulfonate adduct Type A. In some embodiments, the solid state form is Compound 1 p-toluenesulfonate salt. In some embodiments, the solid state form is Compound 1 p-toluenesulfonate cocrystal. Compound 1 Freebase Type A
  • the crystalline form is Compound 1 freebase characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1A as measured using Cu K ⁇ . radiation; (b) an X-Ray powder diffraction (XRPD) pattern with at least one peak selected from 7.8 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , and 23.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ .
  • XRPD X-Ray powder diffraction
  • XRPD X-Ray powder diffraction
  • the crystalline form is Compound 1 freebase characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.8 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , and 23.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation; (b) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 62°C; (c) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 104°C; or (d) combinations thereof.
  • XRPD X-Ray powder diffraction
  • the crystalline form is Compound 1 freebase characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1A as measured using Cu K ⁇ . radiation; (b) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.8 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , and 23.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation; (c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 1B; (d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 1C; or (e) combinations thereof.
  • XRPD X-Ray powder diffraction
  • XRPD X-Ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1A as measured using Cu K ⁇ .radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 1.1 or Table 1.2 as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 1.1 or Table 1.2 , ⁇ 0.2° 2 ⁇ , as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the peaks found in Table 1.2, ⁇ 0.2° 2 ⁇ , as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , and 23.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 18.9 ⁇ 0.2° 2 ⁇ , 19.4 ⁇ 0.2° 2 ⁇ , and 22.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 13.4 ⁇ 0.2° 2 ⁇ , 16.0 ⁇ 0.2° 2 ⁇ , and 27.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 18.9 ⁇ 0.2° 2 ⁇ , 19.4 ⁇ 0.2° 2 ⁇ , 22.3 ⁇ 0.2° 2 ⁇ and 23.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ⁇ 0.2° 2 ⁇ , 13.4 ⁇ 0.2° 2 ⁇ , 16.0 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 18.9 ⁇ 0.2° 2 ⁇ , 19.4 ⁇ 0.2° 2 ⁇ , 22.3 ⁇ 0.2° 2 ⁇ , 23.2 ⁇ 0.2° 2 ⁇ and 27.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or all of the peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 13.4 ⁇ 0.2° 2 ⁇ , 16.0 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 18.9 ⁇ 0.2° 2 ⁇ , 19.4 ⁇ 0.2° 2 ⁇ , 22.3 ⁇ 0.2° 2 ⁇ , 23.2 ⁇ 0.2° 2 ⁇ and 27.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 62°C.
  • thermogram is substantially the same as shown in FIG. 1C.
  • the crystalline form is a hydrate.
  • the crystalline is a hydrate with about 4%to about 18 %by weight of water.
  • the crystalline is a hydrate with about 5%to about 9 %by weight of water.
  • the crystalline form is stable.
  • the crystalline form is thermodynamically stable.
  • the crystalline form is substantially pure. In another embodiment, the crystalline form has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • Table 1.2 XRPD peaks table of Compound 1 freebase Type A Compound 1 freebase amorphous solid state form
  • the amorphous solid state form is freebase characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 2A as measured using Cu K ⁇ . radiation; (b) a Modulated Differential Scanning Calorimetry (mDSC) thermogram substantially the same as shown in FIG. 2B; (c) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 2C; or (d) combinations thereof.
  • XRPD X-Ray powder diffraction
  • mDSC Modulated Differential Scanning Calorimetry
  • TGA Thermogravimetric Thermal Analysis
  • Compound 1 fumaric acid adduct such as salt or cocrystal
  • Compound 1 fumaric acid adduct such as salt or cocrystal
  • Type A the crystalline form is Compound 1 fumaric acid adduct characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3A as measured using Cu K ⁇ .
  • XRPD X-Ray powder diffraction
  • XRPD X-Ray powder diffraction
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Thermal Analysis
  • the crystalline form is Compound 1 fumaric acid adduct characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern with peaks at 12.0 ⁇ 0.2° 2 ⁇ , 19.3 ⁇ 0.2° 2 ⁇ , and 25.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation; (b) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 149 °C; (c) a TGA thermogram exhibiting a mass loss of less than about 0.8 %from the onset of heating up to about 150 °C; or (d) combinations thereof.
  • XRPD X-Ray powder diffraction
  • DSC Differential Scanning Calorimetry
  • the crystalline form is Compound 1 fumaric acid adduct characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3A as measured using Cu K ⁇ . radiation; (b) an X-Ray powder diffraction (XRPD) pattern with peaks at 12.0 ⁇ 0.2° 2 ⁇ , 19.3 ⁇ 0.2° 2 ⁇ , and 25.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation; (c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 3B; (d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 3C; or (e) combinations thereof.
  • XRPD X-Ray powder diffraction
  • XRPD X-Ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3A as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 2.1 or Table 2.2 as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 2.1 or Table 2.2, ⁇ 0.2° 2 ⁇ , as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the peaks found in Table 2.2, ⁇ 0.2° 2 ⁇ , as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.0 ⁇ 0.2° 2 ⁇ , 19.3 ⁇ 0.2° 2 ⁇ , and 25.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 23.3 ⁇ 0.2° 2 ⁇ , 25.7 ⁇ 0.2° 2 ⁇ , and 29.4 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.8 ⁇ 0.2° 2 ⁇ , 21.1 ⁇ 0.2° 2 ⁇ , and 21.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.0 ⁇ 0.2° 2 ⁇ , 19.3 ⁇ 0.2° 2 ⁇ , 23.3 ⁇ 0.2° 2 ⁇ , 25.1 ⁇ 0.2° 2 ⁇ , 25.7 ⁇ 0.2° 2 ⁇ , and 29.4 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 10.8 ⁇ 0.2° 2 ⁇ , 12.0 ⁇ 0.2° 2 ⁇ , 19.3 ⁇ 0.2° 2 ⁇ , 21.1 ⁇ 0.2° 2 ⁇ , 21.9 ⁇ 0.2° 2 ⁇ , 23.3 ⁇ 0.2° 2 ⁇ , 25.1 ⁇ 0.2° 2 ⁇ , 25.7 ⁇ 0.2° 2 ⁇ , and 29.4 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or all of the peaks selected from 10.8 ⁇ 0.2° 2 ⁇ , 12.0 ⁇ 0.2° 2 ⁇ , 19.3 ⁇ 0.2° 2 ⁇ , 21.1 ⁇ 0.2° 2 ⁇ , 21.9 ⁇ 0.2° 2 ⁇ , 23.3 ⁇ 0.2° 2 ⁇ , 25.1 ⁇ 0.2° 2 ⁇ , 25.7 ⁇ 0.2° 2 ⁇ , and 29.4 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 3B.
  • DSC Differential Scanning Calorimetry
  • thermogram is substantially the same as shown in FIG. 3C.
  • a TGA thermogram exhibiting a mass loss of less than about 0.8 %from the onset of heating up to about 150 °C.
  • the mole ratio of Compound 1 to fumaric acid is about 1: (0.9-1.1) . In some embodiments, the mole ratio of Compound 1 to fumaric acid is about 1: 1.
  • the crystalline form is stable.
  • the crystalline form is chemically stable.
  • the crystalline form is thermodynamically stable.
  • Compound 1 succinic adduct such as salt or cocrystal
  • Compound 1 succinic acid adduct such as salt or cocrystal
  • Type A the crystalline form is Compound 1 succinic acid adduct characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 4A as measured using Cu K ⁇ .
  • XRPD X-Ray powder diffraction
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Thermal Analysis
  • the crystalline form is Compound 1 succinic acid adduct characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 4A as measured using Cu K ⁇ . radiation; (b) an X-Ray powder diffraction (XRPD) pattern with peaks at 12.2 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 25.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ .
  • XRPD X-Ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 3.1 or Table 3.2 as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 3.1 or Table 3.2, ⁇ 0.2° 2 ⁇ , as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the peaks found in Table 3.2, ⁇ 0.2° 2 ⁇ , as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.2 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 25.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 16.1 ⁇ 0.2° 2 ⁇ , 19.5 ⁇ 0.2° 2 ⁇ , and 22.0 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 17.5 ⁇ 0.2° 2 ⁇ , 18.9 ⁇ 0.2° 2 ⁇ , and 21.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 12.2 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 19.5 ⁇ 0.2° 2 ⁇ , 22.0 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 25.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks selected from 12.2 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.5 ⁇ 0.2°2 ⁇ , 18.9 ⁇ 0.2° 2 ⁇ , 19.5 ⁇ 0.2° 2 ⁇ , 21.3 ⁇ 0.2° 2 ⁇ , 22.0 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 25.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or all of the peaks selected from 12.2 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.5 ⁇ 0.2° 2 ⁇ , 18.9 ⁇ 0.2° 2 ⁇ , 19.5 ⁇ 0.2° 2 ⁇ , 21.3 ⁇ 0.2° 2 ⁇ , 22.0 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 25.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 4B.
  • DSC Differential Scanning Calorimetry
  • thermogram is substantially the same as shown in FIG. 4C.
  • the mole ratio of Compound 1 to succinic acid is about 1: (0.9-1.1) . In some embodiments, the mole ratio of Compound 1 to succinic acid is about 1: 1.
  • the crystalline form is stable.
  • the crystalline form is chemically stable.
  • the crystalline form is thermodynamically stable.
  • the crystalline form is substantially pure. In another embodiment, the crystalline form has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • Compound 1 p-toluenesulfonate adduct such as salt or cocrystal
  • Compound 1 p-toluenesulfonate adduct such as salt or cocrystal
  • the crystalline form is Compound 1 p-toluenesulfonate adduct characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5A as measured using Cu K ⁇ .
  • XRPD X-Ray powder diffraction
  • XRPD X-Ray powder diffraction
  • the crystalline form is Compound 1 p-toluenesulfonate adduct characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5A as measured using Cu K ⁇ . radiation; (b) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.5 ⁇ 0.2° 2 ⁇ , 18.7 ⁇ 0.2° 2 ⁇ , and 23.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ .
  • XRPD X-Ray powder diffraction
  • the crystalline form is Compound 1 p-toluenesulfonate adduct characterized as having at least one of the following properties: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5A as measured using Cu K ⁇ . radiation; (b) an X-Ray powder diffraction (XRPD) pattern with peaks at 7.5 ⁇ 0.2° 2 ⁇ , 18.7 ⁇ 0.2° 2 ⁇ , and 23.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation; (c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 5B; (d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 5C; or (e) combinations thereof.
  • XRPD X-Ray powder diffraction
  • XRPD X-Ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5A as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 4.1 or Table 4.2 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with one or more peaks (e.g., one, two, three, four, five, six, seven, eight, nine, or all peaks) found in Table 4.1 or Table 4.2, ⁇ 0.2° 2 ⁇ , as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the peaks found in Table 4.2, ⁇ 0.2° 2 ⁇ , as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 14.2 ⁇ 0.2° 2 ⁇ , 20.2 ⁇ 0.2° 2 ⁇ , and 21.5 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 11.2 ⁇ 0.2° 2 ⁇ , 23.8 ⁇ 0.2° 2 ⁇ and 26.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.5 ⁇ 0.2° 2 ⁇ , 14.2 ⁇ 0.2° 2 ⁇ , 18.7 ⁇ 0.2° 2 ⁇ , 20.2 ⁇ 0.2° 2 ⁇ , 21.5 ⁇ 0.2° 2 ⁇ , and 23.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.5 ⁇ 0.2° 2 ⁇ , 11.2 ⁇ 0.2° 2 ⁇ , 14.2 ⁇ 0.2° 2 ⁇ , 18.7 ⁇ 0.2° 2 ⁇ , 20.2 ⁇ 0.2° 2 ⁇ , 21.5 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 23.8 ⁇ 0.2° 2 ⁇ and 26.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 5B.
  • thermogram is substantially the same as shown in FIG. 5C.
  • the mole ratio of Compound 1 to p-toluenesulfonate is about 1: (0.9-1.1) . In some embodiments, the mole ratio of Compound 1 to p-toluenesulfonate is about 1: 1.
  • the crystalline form is a hydrate. In some embodiments of Compound 1 p-toluenesulfonate adduct, the crystalline form is a monohydrate. In some embodiments, the crystalline is a hydrate with about 2%to about 3 %by weight of water. In some embodiments, the crystalline is a hydrate with about 2.3%to about 2.7 %by weight of water. In some embodiments, the crystalline is a hydrate with about 2.5%.
  • the crystalline form is stable.
  • the crystalline form is chemically stable.
  • the crystalline form is thermodynamically stable.
  • the crystalline form is substantially pure.
  • the crystalline form has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • compositions containing the compound (s) described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial. Routes of Administration
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds of this invention may be administered to animals.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A.
  • apharmaceutically acceptable adduct covers both pharmaceutically acceptable salts and pharmaceutically acceptable cocrystals of a compound.
  • the term “apharmaceutically acceptable salt” is to be understood to include acid addition salts and basic addition salts.
  • the acid includes inorganic or organic acid, including but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethaned
  • the base includes inorganic or organic base, including but not limited to an amine (primary, secondary or tertiary) , hydroxide, carbonate, bicarbonate, sulfate of an alkali metal or alkaline earth metal, or the like.
  • Representative bases include, for example, amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like.
  • cocrystal is to be understood to refer to solids that are crystalline single-phase materials composed of a compound and at least one other molecular and/or ionic compound, herein referred to as a co-former, generally in a stoichiometric ratio.
  • a compound and its co-former have a ⁇ pKa (pKa (base) -pKa (acid) ) > 3, there will be substantial proton transfer resulting in ionization and potential formation of a salt as opposed to a co-crystal.
  • a compound and its co-former have a ⁇ pKa (pKa (base) -pKa (acid) ) ⁇ 3, there will be less than substantial proton transfer and the compound-co-former entity should be classified as a cocrystal.
  • the compound and co-former molecules interact by hydrogen bonding and possibly other non-covalent interactions. It may be noted that a cocrystal may itself form solvates, including hydrates.
  • crystal form As used herein, the terms “crystal form” , “crystalline form” and “Form” interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD) , single crystal X-ray diffraction, differential scanning calorimetry (DSC) , thermogravimetric analysis (TGA) , and/or dynamic vapor sorption (DVS) .
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVD dynamic vapor sorption
  • crystalline Form [X] of Compound (I) refers to unique crystalline forms that can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD) , single crystal X-ray diffraction, differential scanning calorimetry (DSC) , thermogravimetric analysis (TGA) , and/or dynamic vapor sorption (DVS) .
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVD dynamic vapor sorption
  • the novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (° 2 ⁇ ) .
  • solvate refers to a crystal form comprising one or more molecules of the compound of the present disclosure and, incorporated into the crystal lattice, one or more molecules of a solvent or solvents in stoichiometric or nonstoichiometric amounts.
  • solvent water
  • solvate is referred to as a “hydrate. ”
  • XRPD refers to the analytical characterization method of X-ray powder diffraction.
  • X-ray powder diffractogram X-ray powder diffraction pattern
  • XRPD pattern XRPD pattern
  • an X-ray powder diffractogram may include one or more broad signals; and for a crystalline material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 2 ⁇ (° 2 ⁇ ) , depicted on the abscissa of an X-ray powder diffractogram.
  • a “peak” as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum.
  • One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.
  • the repeatability of the measured angular values is in the range of ⁇ 0.2° 2 ⁇ , i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value -0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta) .
  • the repeatability of the measured angular values is in the range of ⁇ 0.1° 2 ⁇ .
  • amorphous refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.
  • substantially pure when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight %of Compound I, based on the weight of the compound.
  • the remaining material comprises other form (s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation.
  • a crystalline form of Compound (I) may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight %of material comprises other form (s) of Compound (I) and/or reaction impurities and/or processing impurities.
  • composition refers to a formulation containing the compound or solid forms thereof provided herein in a form suitable for administration to a subject.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion) , topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • enhancement means to increase, or prolong either in potency or duration a desired effect.
  • enhancing refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount, ” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • subject or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the term “about” means within a statistically meaningful range of a value, such as a stated concentration range, time frame, molecular weight, particle size, temperature, or pH, etc. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, and even more typically within 3%of the indicated value or range. Sometimes, such a range can be within the experimental error typical of standard methods used for the measurement and/or determination of a given value or range. The allowable variation encompassed by the term “about” will depend upon the particular system under study, and can be readily appreciated by one of ordinary skill in the art. Whenever a range is recited within this application, every whole number integer within the range is also contemplated as an embodiment of the disclosure.
  • Characteristic peaks are a subset of representative peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being crystalline forms having the same chemical composition) . Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ⁇ 0.2 °2 ⁇ . Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.
  • preferred orientation refers to an extreme case of non-random distribution of the crystallites of a solid state form.
  • XRPD XRPD
  • the ideal sample is homogenous and the crystallites are randomly distributed in the bulk solid.
  • each possible reflection from a given set of planes will have and equal number of crystallites contributing to it.
  • comparing the intensity between a randomly oriented diffraction pattern and a preferred oriented diffraction pattern can look entirely different. Quantitative analysis depending on intensity ratios are greatly distorted by preferred orientation. Careful sample preparation is important for decreasing the incidence of a preferred orientation.
  • Example A Preparation of Compound 1 amorphous free base
  • Example B The objective of this experiment was to assess the potential inhibitory effect of compounds on CDK12/CyclinK kinase.
  • Testing compounds were dissolved to 10 mM by adding fresh DMSO.
  • Echo655 was used to transfer the compound dilution (50 nl for CDK12/CyclinK) to each well of the assay plate (784075, Greiner) .
  • the final concentration of DMSO was 1%.
  • the assay plate was sealed, and the compound plates were centrifuged at 1000g for 1 min.
  • 1 ⁇ kinase buffer was prepared by mixing 1 volume of 5x kinase buffer with 4 volumes of distilled water; 1.5 mM DTT.
  • 2 ⁇ kinase solution (5 ng/ ⁇ L for CDK12/CyclinK) was prepared in 1 ⁇ kinase buffer.
  • kinase detection reagents 8 ⁇ L kinase detection reagents were added. The plate was centrifuged at 1000 g for 1 min and incubated at room temperature for 40 min. The plate was centrifuged at 1000 g for 1 min. The luminescence signal was read on Envision 2104 plate reader.
  • Table 7 The results for exemplary compounds of the present application are illustrated in Table 7. Table 7. IC 50 values of exemplary compounds CDK12 IC 50 (nM) : 25 nM ⁇ B ⁇ 100 nM;
  • mice CD-1 mice of SPF.
  • Source Sino-British SIPPR/BK Lab Animal Ltd, Shanghai.
  • Three mice were intravenously administrated with given compound 1 (Formulation: 5%DMSO + 10%Solutol + 85%Saline) or orally gavage administrated with given compound 1 (Formulation: 5%DMSO + 10%Solutol + 85%Saline) .
  • the blood samples were taken via cephalic vein at timepoints 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous (iv) administration or at timepoints 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6h, 8 h, and 24 h after oral gavage administration, 30 ⁇ L/time point.
  • Blood samples were placed in tubes containing K2-EDTA and stored on ice until centrifuged. The blood samples were centrifuged at 6800 g for 6 minutes at 2-8 °C within 1 h after collected and stored frozen at approximately -80 °C.
  • Example C The data for Example C is shown in Table 8 and Table 9 Table 8.
  • Table 9 Mouse PK profile after oral administration at 5 mg/kg
  • FIG. 1A The XRPD pattern of Free base Type A of Compound 1 is shown in FIG. 1A.
  • DSC result is shown in FIG. 1B.
  • TGA result is shown in FIG. 1C.
  • DVS result is shown in FIG. 1D.
  • Compound 1 Freebase Type A is a hydrate with 4.1%-17.6%water by weight (measured by Karl Fischer method) , as shown in FIG. 1E.
  • the XRPD pattern of fumaric acid adduct of Compound 1 is shown in FIG. 3A.
  • DSC result is shown in FIG. 3B.
  • TGA result is shown in FIG. 3C.
  • DVS result is shown in FIG. 3D.
  • the XRPD pattern of succinic acid adduct Type A of Compound 1 is shown in FIG. 4A.
  • DSC result is shown in FIG. 4B.
  • TGA result is shown in FIG. 4C.
  • DVS result is shown in FIG. 4D.
  • the XRPD pattern of p-toluenesulfonate adduct Type A of Compound 1 is shown in FIG. 5A.
  • DSC result is shown in FIG. 5B.
  • TGA result is shown in FIG. 5C.
  • DVS result is shown in FIG. 5D.

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Abstract

L'invention concerne des formes cristallines d'un inhibiteur de kinase dépendante de la cycline (cdk) 12 et/ou cdk13 à petites molécules, ainsi que des compositions pharmaceutiques de celles-ci, et leurs procédés d'utilisation dans le traitement du cancer ou d'une maladie néoplasique.
PCT/CN2025/075983 2024-02-07 2025-02-06 Inhibiteur cristallin de kinase dépendante de la cycline (cdk) 12 et/ou cdk13 et ses utilisations Pending WO2025167975A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112638373A (zh) * 2018-06-29 2021-04-09 金耐特生物制药公司 细胞周期蛋白依赖性激酶抑制剂
CN114401955A (zh) * 2019-07-17 2022-04-26 金耐特生物制药公司 细胞周期蛋白依赖性激酶的抑制剂
WO2023091726A1 (fr) * 2021-11-18 2023-05-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase 12 dépendante de la cycline (cdk12)
WO2024032561A1 (fr) * 2022-08-08 2024-02-15 Insilico Medicine Ip Limited Inhibiteurs de kinase 12 dépendante de la cycline (cdk) et/ou cdk13 et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112638373A (zh) * 2018-06-29 2021-04-09 金耐特生物制药公司 细胞周期蛋白依赖性激酶抑制剂
CN114401955A (zh) * 2019-07-17 2022-04-26 金耐特生物制药公司 细胞周期蛋白依赖性激酶的抑制剂
WO2023091726A1 (fr) * 2021-11-18 2023-05-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase 12 dépendante de la cycline (cdk12)
WO2024032561A1 (fr) * 2022-08-08 2024-02-15 Insilico Medicine Ip Limited Inhibiteurs de kinase 12 dépendante de la cycline (cdk) et/ou cdk13 et leurs utilisations

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