WO2023093861A1 - Axl激酶抑制剂的单对甲苯磺酸盐及其晶型 - Google Patents

Axl激酶抑制剂的单对甲苯磺酸盐及其晶型 Download PDF

Info

Publication number
WO2023093861A1
WO2023093861A1 PCT/CN2022/134410 CN2022134410W WO2023093861A1 WO 2023093861 A1 WO2023093861 A1 WO 2023093861A1 CN 2022134410 W CN2022134410 W CN 2022134410W WO 2023093861 A1 WO2023093861 A1 WO 2023093861A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
toluenesulfonate
mono
ray powder
hydrate
Prior art date
Application number
PCT/CN2022/134410
Other languages
English (en)
French (fr)
Inventor
马昌友
张林林
冯海威
赵廷丽
吴舰
徐丹
朱春霞
田舟山
Original Assignee
南京正大天晴制药有限公司
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 南京正大天晴制药有限公司 filed Critical 南京正大天晴制药有限公司
Priority to EP22897943.1A priority Critical patent/EP4438613A1/en
Priority to US18/713,611 priority patent/US20250026773A1/en
Priority to CN202280078369.7A priority patent/CN118302430A/zh
Priority to JP2024531383A priority patent/JP2024543921A/ja
Priority to CA3239187A priority patent/CA3239187A1/en
Priority to AU2022395869A priority patent/AU2022395869A1/en
Publication of WO2023093861A1 publication Critical patent/WO2023093861A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • 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 invention belongs to the technical field of medicine, and the compound is an AXL kinase inhibitor, in particular to p-toluenesulfonate of the AXL inhibitor and its crystal form.
  • RTKs Receptor tyrosine kinases
  • Ligand-receptor binding induces receptor dimerization and activation of its intracellular kinase domain, which in turn leads to the recruitment, phosphorylation and activation of multiple downstream signaling cascades (Robinson, D.R. et al., Oncogene, 19:5548-5557, 2000).
  • RTKs have been identified in the human genome that regulate a variety of cellular processes, including cell survival, growth, differentiation, proliferation, adhesion, and motility (Segaliny, A.I. et al., J. Bone Oncol, 4:1 -12, 2015).
  • AXL (also known as UFO, ARK, and Tyro7) belongs to the TAM family of receptor tyrosine kinases, which also includes Mer and Tyro3. Among them, AXL and Tyro3 have the most similar gene structure, while AXL and Mer have the most similar amino acid sequence of tyrosine kinase domain. Like other receptor tyrosine kinases (RTKs), the structure of the TAM family consists of an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain of AXL has a unique structure juxtaposing immunoglobulin and type III fibronectin repeat units and is reminiscent of a neutrophil adhesion molecule.
  • TAM family members have a common ligand—growth arrest specific protein 6 (Gas6), which can bind to all TAM receptor tyrosine kinases. After AXL binds to Gas6, it will lead to receptor dimerization and AXL autophosphorylation, thereby activating multiple downstream signal transduction pathways and participating in multiple processes of tumorigenesis (Linger, R.M et al., Ther.Targets, 14(10 ), 1073-1090, 2010; Rescigno, J. et al., Oncogene, 6(10), 1909-1913, 1991).
  • Gas6 growth arrest specific protein 6
  • AXL is widely expressed in normal tissues of the human body, such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver, and kidney, among which the expression is highest in cardiac muscle and skeletal muscle, and bone marrow CD34+ cells and stromal cells also have a higher expression High expression, very low expression in normal lymphoid tissue (Wu YM, Robinson DR, Kung HJ, Cancer Res, 64(20), 7311-7320, 2004; hung BI et al., DNA Cell Biol, 22(8), 533-540 , 2003).
  • AXL gene was overexpressed or ectopically expressed in hematopoietic cells, mesenchymal cells and endothelial cells.
  • the overexpression of AXL kinase is particularly prominent.
  • Inhibition of AXL receptor tyrosine kinase can reduce the pro-survival signals of tumor cells, block the invasion ability of tumors, and increase the sensitivity of targeted drug therapy and chemotherapy. Therefore, finding effective AXL inhibitors is an important direction for the development of tumor-targeted drugs.
  • the present invention provides a (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzene [7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide mono-p-toluenesulfonate or hydrate .
  • X is 0, 0.25, 0.5, 0.7, 1, 1.25, 1.5 or 1.75.
  • X is 0.
  • X is 0.7.
  • X is 1.
  • X is 1.5.
  • the present invention provides a (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzene [7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide mono-p-toluenesulfonate hydrate.
  • the invention provides a (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetra Mono-p-toluenesulfonic acid of hydrogen-5H-benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide
  • the monohydrate of the salt, the concrete structure is as formula II,
  • the invention provides a (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetra Mono-p-toluenesulfonic acid of hydrogen-5H-benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide
  • the sesquihydrate of the salt, the concrete structure is as shown in formula III,
  • the present invention provides (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro- 5H-Benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide mono-p-toluenesulfonate or its hydrate.
  • the present invention provides (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro- 5H-Benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide mono-p-toluenesulfonate or
  • its X-ray powder diffraction pattern has diffraction peaks at 2 ⁇ of 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.2° ⁇ 0.2° and 21.8° ⁇ 0.2°.
  • the crystal has an X-ray powder diffraction pattern at 2 ⁇ of 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.2° ⁇ 0.2° , 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 21.8° ⁇ 0.2° and 22.6° ⁇ 0.2° have diffraction peaks.
  • the crystal has an X-ray powder diffraction pattern at 2 ⁇ of 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.2° ⁇ 0.2° , 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6° ⁇ 0.2° and 29.4 There is a diffraction peak at ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal is 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 12.3° ⁇ 0.2° at 2 ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 14.1° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.1° ⁇ 0.2° , 18.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.0° ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6 ° ⁇ 0.2°, 23.3° ⁇ 0.2°, 23.7° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.4° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.1° ⁇ 0.2°, 26.2° ⁇ 0.2°, 26.6° ⁇ 0.2°, 27.0° ⁇ 0.2°, 27.7° ⁇ 0.2°
  • the crystallization has an endothermic peak at an initial temperature of 195 ⁇ 5°C to 205 ⁇ 5°C in a thermogram measured by differential scanning calorimetry.
  • the crystallization has an endothermic peak at an initial temperature of 198 ⁇ 5°C to 203 ⁇ 5°C in a thermogram measured by differential scanning calorimetry.
  • the crystallization has an endothermic peak at an initial temperature of 200 ⁇ 5° C. in a thermogram measured by differential scanning calorimetry.
  • the crystal has an X-ray powder diffraction pattern at 2 ⁇ of 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.2° ⁇ 0.2° , 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 21.8° ⁇ 0.2° and 22.6° ⁇ 0.2° have diffraction peaks.
  • the crystal has an X-ray powder diffraction pattern at 2 ⁇ of 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.2° ⁇ 0.2° , 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6° ⁇ 0.2° and 29.4 There is a diffraction peak at ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal is 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 12.3° ⁇ 0.2° at 2 ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 14.1° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.1° ⁇ 0.2° , 18.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.0° ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6 ° ⁇ 0.2°, 23.3° ⁇ 0.2°, 23.7° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.4° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.1° ⁇ 0.2°, 26.2° ⁇ 0.2°, 26.6° ⁇ 0.2°, 27.0° ⁇ 0.2°, 27.7° ⁇ 0.2°
  • the crystallization has an endothermic peak at an initial temperature of 195 ⁇ 5°C to 205 ⁇ 5°C in a thermogram measured by differential scanning calorimetry.
  • the crystallization has an endothermic peak at an initial temperature of 198 ⁇ 5°C to 203 ⁇ 5°C in a thermogram measured by differential scanning calorimetry.
  • the crystal has an endothermic peak at an initial temperature of 200°C ⁇ 5°C in a thermogram measured by differential scanning calorimetry.
  • the present invention provides a (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzene and[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide mono-p-toluenesulfonate monohydrate
  • Form B its X-ray powder diffraction pattern has diffraction peaks at 2 ⁇ of 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.2° ⁇ 0.2° and 21.8° ⁇ 0.2°.
  • the crystal form B has an X-ray powder diffraction pattern at 2 ⁇ of 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.2° ⁇ 0.2° , 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 21.8° ⁇ 0.2° and 22.6° ⁇ 0.2° have diffraction peaks.
  • the crystal form B has an X-ray powder diffraction pattern at 2 ⁇ of 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 13.2° ⁇ 0.2° , 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6° ⁇ 0.2° and 29.4 There is a diffraction peak at ⁇ 0.2°.
  • the crystal form B has an X-ray powder diffraction pattern at 2 ⁇ of 6.0° ⁇ 0.2°, 6.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 12.3° ⁇ 0.2° , 12.4° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 14.1° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.0 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.0° ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.3° ⁇ 0.2°, 23.7° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.4° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.1° ⁇ 0.2°, 26.2° ⁇ 0.2°, 26.6° ⁇ 0.2° , 27.0° ⁇ 0.2°, 27.7° ⁇ 0.2°, 2
  • the X-ray powder diffraction of the crystal form B expressed in 2 ⁇ angle has the data as described in the following table:
  • the X-ray powder diffraction of the crystal form B expressed in 2 ⁇ angle has a pattern as shown in FIG. 1 .
  • the crystal form B has an endothermic peak at an initial temperature of 85 ⁇ 5°C to 95 ⁇ 5°C in the thermal analysis chart measured by differential scanning calorimetry and at the initial temperature There is an endothermic peak at 195 ⁇ 5°C ⁇ 205 ⁇ 5°C.
  • the crystal form B has an endothermic peak at an initial temperature of 88 ⁇ 5°C to 93 ⁇ 5°C in the thermal analysis chart measured by differential scanning calorimetry and an endothermic peak at the initial temperature There is an endothermic peak at 198 ⁇ 5°C ⁇ 203 ⁇ 5°C.
  • the crystal form B has an endothermic peak at an initial temperature of 90 ⁇ 5°C and an endothermic peak at an initial temperature of 200 ⁇ 5°C in a thermogram measured by differential scanning calorimetry. There are endothermic peaks.
  • the crystal form B has a spectrum as shown in FIG. 2 in a thermogram measured by differential scanning calorimetry.
  • the crystal form B has the following absorption bands in the spectrum measured by Fourier transform attenuated total reflection infrared spectroscopy, expressed as the reciprocal of wavelength (cm ⁇ 1 ): 432 ⁇ 2, 471 ⁇ 2, 552 ⁇ 2, 570 ⁇ 2, 711 ⁇ 2, 747 ⁇ 2, 779 ⁇ 2, 818 ⁇ 2, 836 ⁇ 2, 863 ⁇ 2, 932 ⁇ 2, 966 ⁇ 2, 1295 ⁇ 2, 1318 ⁇ 2, 2635 ⁇ 2, 2721 ⁇ 2, 2927 ⁇ 2, 3005 ⁇ 2, 3110 ⁇ 2, 3185 ⁇ 2, 3256 ⁇ 2, and 3556 ⁇ 2.
  • the crystal form B has the following absorption bands in the spectrum measured by Fourier transform attenuated total reflection infrared spectroscopy, expressed as the reciprocal of wavelength (cm ⁇ 1 ): 432 ⁇ 2, 471 ⁇ 2, 497 ⁇ 2, 552 ⁇ 2, 570 ⁇ 2, 681 ⁇ 2, 711 ⁇ 2, 747 ⁇ 2, 779 ⁇ 2, 818 ⁇ 2, 836 ⁇ 2, 863 ⁇ 2, 932 ⁇ 2, 966 ⁇ 2, 1008 ⁇ 2, 1030 ⁇ 2, 1096 ⁇ 2, 1121 ⁇ 2, 1159 ⁇ 2, 1229 ⁇ 2, 1295 ⁇ 2, 1318 ⁇ 2, 1374 ⁇ 2, 1413 ⁇ 2, 1456 ⁇ 2, 1512 ⁇ 2, 1527 ⁇ 2, 1571 ⁇ 2, 1609 ⁇ 2, 2635 ⁇ 2, 2721 ⁇ 2, 2927 ⁇ 2, 3005 ⁇ 2, 3110 ⁇ 2, 3185 ⁇ 2, 3256 ⁇ 2 and 3556 ⁇ 2.
  • the crystal form B has the following absorption bands in the spectrum measured by Fourier transform Raman spectroscopy, expressed as the reciprocal of wavelength (cm -1 ): 1609 ⁇ 2, 1572 ⁇ 2, 1553 ⁇ 2, 1535 ⁇ 2, 1508 ⁇ 2, 1494 ⁇ 2, 1476 ⁇ 2, 1457 ⁇ 2, 1420 ⁇ 2, 1374 ⁇ 2, 1344 ⁇ 2, 1331 ⁇ 2, 1285 ⁇ 2, 1262 ⁇ 2, 1228 ⁇ 2, 1213 ⁇ 2, 1173 ⁇ 2, 1147 ⁇ 2, 1135 ⁇ 2, 1099 ⁇ 2, 1059 ⁇ 2, 1029 ⁇ 2, 1115 ⁇ 2, 1006 ⁇ 2, 970 ⁇ 2, 965 ⁇ 2, 819 ⁇ 2, 799 ⁇ 2, 744 ⁇ 2, 733 ⁇ 2, 678 ⁇ 2, 658 ⁇ 2, 634 ⁇ 2, 613 ⁇ 2, 570 ⁇ 2, 534 ⁇ 2, 497 ⁇ 2, 471 ⁇ 2, 448 ⁇ 2, 425 ⁇ 2, 393 ⁇ 2, 369 ⁇ 2, 313 ⁇ 2, 287 ⁇ 2, 262 ⁇ 2, 241 ⁇ 2, 217 ⁇ 2, 177 ⁇ 2, 156 ⁇ 2, 104 ⁇ 2 and 82 ⁇ 2.
  • the Form B has a weight loss of 2.4% in the temperature range of 25°C-150°C.
  • the crystalline form B has a TGA spectrum as shown in FIG. 3 .
  • the crystal form B has single crystal crystal parameters and structural data as described in the following table:
  • the present invention provides a (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzene Sesquihydration of mono-p-toluenesulfonate of a[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide
  • the crystal form C of the compound, the concrete structure is as shown in formula III:
  • the X-ray powder diffraction pattern of Form C is 12.1° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.0° ⁇ 0.2°, 16.9° ⁇ 0.2°, 18.4° ⁇ 0.2° at 2 ⁇ , 19.3° ⁇ 0.2°, 19.8° ⁇ 0.2°, 21.8° ⁇ 0.2°, 23.6° ⁇ 0.2° and 24.3° ⁇ 0.2° have diffraction peaks.
  • the X-ray powder diffraction pattern of Form C is 6° ⁇ 0.2°, 10.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.0° ⁇ 0.2° at 2 ⁇ , 16.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.0° ⁇ 0.2°, 19.3° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, 23.6 There are diffraction peaks at ° ⁇ 0.2°, 24.3° ⁇ 0.2°, 25.5° ⁇ 0.2° and 26.6° ⁇ 0.2°.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the crystal form C is detailed in the table below:
  • the X-ray powder diffraction of the crystal form C in 2 ⁇ angle has a spectrum as shown in FIG. 7 .
  • the crystal form C has single crystal crystal parameters and structural data as described in the following table:
  • the present invention provides a crystal form A of the compound of formula IV, whose X-ray powder diffraction pattern is 7.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 17.6° ⁇ 0.2°, 20.3° ⁇ 0.2° at 2 ⁇ There are diffraction peaks at 20.9° ⁇ 0.2°.
  • the crystal form A has an X-ray powder diffraction pattern at 2 ⁇ of 4.1° ⁇ 0.2°, 7.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.0° ⁇ 0.2 °, 17.6° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2° and 22.2° ⁇ 0.2° have diffraction peaks.
  • the crystal form A has an X-ray powder diffraction pattern at 2 ⁇ of 4.1° ⁇ 0.2°, 5.6° ⁇ 0.2°, 7.6° ⁇ 0.2°, 10.2° ⁇ 0.2°, 10.9° ⁇ 0.2° , 12.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.2° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.2° ⁇ 0.2°, 23.2 There are diffraction peaks at ° ⁇ 0.2°, 24.6° ⁇ 0.2°, 27.0° ⁇ 0.2°, 28.8° ⁇ 0.2°, 37.0° ⁇ 0.2° and 37.7° ⁇ 0.2°.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the crystal form A is detailed in the following table:
  • the X-ray powder diffraction of the crystal form A represented by 2 ⁇ angle has a spectrum as shown in FIG. 9 .
  • the present invention provides (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzene And[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide monop-toluenesulfonate or its pharmaceutically acceptable
  • the preparation method of the accepted hydrate comprises the step of salting the compound of formula IV and p-toluenesulfonic acid.
  • the present invention provides a preparation method of the compound of formula I or its crystal form, comprising the step of salting the compound of formula IV with p-toluenesulfonic acid.
  • the crystalline form of the compound of formula I can be prepared by suspension stirring, gas-solid diffusion, solvent volatilization or cooling crystallization.
  • the present invention provides a preparation method of crystal form B, which comprises reacting the compound of formula IV with p-toluenesulfonic acid monohydrate in an alcohol solvent, and crystallizing in an anti-solvent.
  • the alcoholic solvent may be an alcoholic solvent or a mixed solvent of alcohol and water, and the alcoholic solvent is selected from one of methanol, ethanol, and isopropanol, preferably ethanol or isopropanol.
  • the anti-solvent is selected from ester solvents, ketone solvents or ether solvents, and the ketone solvents are acetone, 2-butanone or methyl isobutyl ketone, preferably acetone; the ethers
  • the solvent is methyl tert-butyl ether or 1,4-dioxane, preferably methyl tert-butyl ether;
  • the ester solvent is selected from ethyl acetate, butyl acetate or isopropyl acetate, preferably isopropyl acetate ester.
  • the present invention provides a method comprising (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide mono-p-toluenesulfonate or Hydrate pharmaceutical composition.
  • the present invention provides a pharmaceutical composition comprising a compound of formula I.
  • the present invention provides a pharmaceutical composition comprising a compound of formula II.
  • the present invention provides a pharmaceutical composition comprising a compound of formula III.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is a solid pharmaceutical preparation suitable for oral administration, preferably a tablet or a capsule.
  • the present invention provides a crystal form composition
  • a crystal form composition comprising crystal form A, wherein the weight of the crystal form A accounts for more than 50%; preferably more than 80%; more preferably more than 90% of the weight of the crystal form composition; Still more preferably 95% or more; most preferably 98% or more.
  • the present invention also provides a pharmaceutical composition comprising the crystalline form A or a crystalline form composition thereof.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is a solid pharmaceutical preparation suitable for oral administration, preferably a tablet or a capsule.
  • the present invention provides a crystal composition comprising crystal form B, wherein the weight of the crystal form B accounts for more than 50%; preferably more than 80%; more preferably more than 90% of the weight of the crystal composition; Still more preferably 95% or more; most preferably 98% or more.
  • the present invention also provides a pharmaceutical composition comprising the crystal form B or the crystal form composition.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is a solid pharmaceutical preparation suitable for oral administration, preferably a tablet or a capsule.
  • the present invention provides a crystal composition comprising Form C, wherein the weight of Form C accounts for more than 50%; preferably more than 80%; more preferably more than 90% of the weight of the crystal composition; Still more preferably 95% or more; most preferably 98% or more.
  • the present invention also provides a pharmaceutical composition comprising the crystal form C or a crystal form composition thereof.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is a solid pharmaceutical preparation suitable for oral administration, preferably a tablet or a capsule.
  • the present invention also provides a compound of formula I or a pharmaceutical composition thereof for use as a medicine.
  • the present invention also provides a compound of formula II or a pharmaceutical composition thereof for use as a medicine.
  • the present invention also provides the compound of formula III or its pharmaceutical composition for use as medicine.
  • the present invention also provides the crystal form A used as medicine, its crystal form composition or its pharmaceutical composition.
  • the present invention also provides the crystal form B used as medicine, its crystal form composition or its pharmaceutical composition.
  • the present invention also provides the crystal form C used as medicine, its crystal form composition or its pharmaceutical composition.
  • the present invention also provides (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- Mono-p-toluenesulfonate of benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide, its hydrate
  • the present invention also provides the use of the compound of formula I or its pharmaceutical composition in the preparation of a medicament for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the use of the compound of formula II or its pharmaceutical composition in the preparation of a medicament for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the use of the compound of formula III or its pharmaceutical composition in the preparation of a medicament for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the use of the crystal form A or its pharmaceutical composition in the preparation of medicines for preventing and/or treating diseases or disease states mediated by AXL kinase.
  • the present invention also provides the use of the crystal form B or the pharmaceutical composition thereof in the preparation of medicines for preventing and/or treating diseases or disease states mediated by AXL kinase.
  • the present invention also provides the use of the crystal form C or its pharmaceutical composition in the preparation of medicines for preventing and/or treating diseases or disease states mediated by AXL kinase.
  • the present invention also provides (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- Mono-p-toluenesulfonate salt of benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide or its hydrate
  • the present invention also provides the use of the compound of formula I in the preparation of a medicament for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the use of the compound of formula II in the preparation of a medicament for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the use of the compound of formula III in the preparation of a medicament for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the use of the crystalline composition in the preparation of medicines for preventing and/or treating diseases or disease states mediated by AXL kinase.
  • the present invention also provides the use of the crystalline form A, its crystalline form composition or its pharmaceutical composition for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the use of the crystal form B, its crystal form composition or its pharmaceutical composition for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the use of the crystalline form C, its crystalline form composition or its pharmaceutical composition for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering (S)-(2-((5- Chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)amino)pyrimidin-4-yl) Amino)-5-(methoxymethyl)phenyl)mono-p-toluenesulfonate of dimethylphosphine oxide, its hydrate or its pharmaceutical composition.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the compound of formula I of the present invention or a pharmaceutical composition thereof to an individual in need.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the compound of formula II of the present invention or a pharmaceutical composition thereof to an individual in need.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the compound of formula III of the present invention or a pharmaceutical composition thereof to an individual in need.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the crystalline form composition of the present invention to individuals in need.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the crystalline form A of the present invention or its pharmaceutical composition to individuals in need.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the crystal form B of the present invention or a pharmaceutical composition thereof to individuals in need.
  • the present invention also provides a method for preventing and/or treating AXL kinase-mediated diseases or disease states, which comprises administering the crystalline form C of the present invention or a pharmaceutical composition thereof to individuals in need.
  • the present invention also provides (S)-(2-((5-chloro-2-((7-(pyrrole) Alkyl-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl yl) phenyl) dimethylphosphine oxide mono-p-toluenesulfonate or its hydrate.
  • the present invention also provides the compound of formula I of the present invention for use in the prevention and/or treatment of AXL kinase-mediated diseases or disease states.
  • the present invention also provides the compound of formula II of the present invention for use in the prevention and/or treatment of AXL kinase-mediated diseases or disease states.
  • the present invention also provides the compound of formula III of the present invention for use in the prevention and/or treatment of AXL kinase-mediated diseases or disease states.
  • the present invention also provides the crystalline composition of the present invention for preventing and/or treating diseases or disease states mediated by AXL kinase.
  • the present invention also provides the crystalline form A of the present invention or its pharmaceutical composition for preventing and/or treating AXL kinase-mediated diseases or disease states.
  • the present invention also provides the crystalline form B of the present invention or a pharmaceutical composition thereof for preventing and/or treating diseases or disease states mediated by AXL kinase.
  • the present invention also provides the crystalline form C of the present invention or a pharmaceutical composition thereof for preventing and/or treating diseases or disease states mediated by AXL kinase.
  • the AXL kinase-mediated disease or condition is cancer.
  • the cancer is associated with hematological tumors.
  • the monop-toluenesulfonate of the compound of formula IV prepared by the present invention, its hydrate and the crystal form of the hydrate have good stability, which solves the problem of instability of the free base (compound of formula IV) under high temperature, high humidity and light conditions problems, and the prepared crystal form has the advantages of stability, easy processing, and high solubility.
  • pharmaceutically acceptable carrier refers to those carriers that have no obvious stimulating effect on the body and will not impair the biological activity and performance of the active compound. Including but not limited to any diluents, disintegrants, binders, glidants, and wetting agents approved by the State Food and Drug Administration for human or animal use.
  • the "X-ray powder diffraction pattern" in the present invention is obtained by using Cu-K ⁇ radiation measurement.
  • 2 ⁇ or “2 ⁇ angle” in the present invention refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20°.
  • the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal, where the relative intensity of the bands (especially at low angles) may vary due to The effect of dominant orientation due to differences in crystallization conditions, particle size and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic of the targeted crystals.
  • XRPD X-ray powder diffraction
  • the position of the peak can move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of their XRPD spectra are similar on the whole, and the relative intensity error may be large.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric analysis refers to a thermal analysis technique that measures the relationship between the mass of the sample to be tested and the temperature change at a programmed temperature.
  • TGA Thermogravimetric analysis
  • hydrate refers to a specific solvate wherein the solvent is water, examples of hydrates include hemihydrate, monohydrate, sesquihydrate, dihydrate and the like.
  • Different crystalline forms of a particular substance may include both anhydrous forms of the substance and hydrated forms of the substance, wherein each of the anhydrous and hydrate forms is passed through a different XRPD pattern and determined by This indicates that different lattices are distinguished from each other.
  • a single crystalline form (identified, for example, by individual XRPD images) may have variable water or solvent content, wherein the crystal lattice substantially remains unchanged (as represented by the XRPD image).
  • IMDM Iscove'sModifiedDulbecco'sMedium: Iscove (person's name) modified Dulbecco (person's name) medium.
  • Fig. 1 is the X-ray powder diffraction (XRPD) spectrogram of crystal form B in embodiment 3;
  • Fig. 2 is the differential scanning calorimetry (DSC) spectrogram of crystal form B in embodiment 3;
  • Fig. 3 is the thermogravimetric (TGA) spectrogram of crystal form B in embodiment 3;
  • Fig. 4 is the FT-infrared (FT-IR) spectrogram of crystal form B in embodiment 3;
  • Fig. 5 is the FT-Raman (FT-Raman) spectrogram of crystal form B in embodiment 3;
  • Fig. 6 is the dynamic water adsorption (DVS) spectrogram of crystal form B in embodiment 3;
  • Fig. 7 is the X-ray powder diffraction (XRPD) spectrogram of crystal form C in embodiment 6;
  • Fig. 8 is the X-ray powder diffraction (XRPD) spectrogram of crystal form A in embodiment 8;
  • Fig. 9 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound mesylate in embodiment 10;
  • Fig. 10 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound monohydrochloride in embodiment 10;
  • Fig. 11 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound dihydrochloride in embodiment 10;
  • Fig. 12 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound phosphate in embodiment 10;
  • Fig. 13 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound hippurate in embodiment 10;
  • Fig. 14 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound sulfate in embodiment 10;
  • Fig. 15 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound hydrobromide in embodiment 10;
  • Fig. 16 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound besylate in embodiment 10;
  • Fig. 17 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound oxalate in embodiment 10;
  • Fig. 18 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound fumarate in embodiment 10;
  • Fig. 19 is the X-ray powder diffraction (XRPD) spectrogram of formula IV compound citrate in embodiment 10;
  • test conditions of each instrument are as follows:
  • Temperature rise range room temperature - 300°C
  • Method Put the sample in an aluminum pan, then place the aluminum pan in a platinum pan, expose it in a nitrogen atmosphere, and raise the temperature from room temperature to the set temperature at a rate of 10°C/min.
  • Heating range 20-300°C
  • the sample was placed in an aluminum pan, and after capping, the temperature was raised from 20°C to the set temperature at a rate of 10°C/min in a nitrogen atmosphere.
  • X-ray light tube setting tube voltage 50KV, tube current 1.2mA
  • Embodiment 1 (5)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7] wheel Preparation of En-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide
  • the crude product is purified by reverse-phase high-performance liquid chromatography (column is YMCActusTriartC18, 30*150mm, particle diameter 5 ⁇ m, mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60mL/min, gradient : 20%B to 50%B, 8min, wavelength: 220nm, retention time: 6.83min, column temperature: 25°C), the title product (20.2mg) was obtained.
  • Example 1 Related compounds prepared in Example 1 carry out related enzyme activities, cells, and related activities in vivo
  • the specific structure of the positive drug 1 (BGB324) used in the activity test is as follows:
  • 1 ⁇ enzyme buffer 200 ⁇ L of Enzymatic buffer kinase 5X, 10 ⁇ L of 500 mM MgCl 2 , 10 ⁇ L of 100 mM DTT, 6.
  • DMSO dilute the compound and positive drug prepared in Example 1 from 10 mM to 100 ⁇ M, and titrate with a compound titrator (Tecan, D300e). 1 concentration is 1 ⁇ M, 1/2 log gradient dilution, a total of 8 concentrations. Centrifuge at 2500rpm for 30s and incubate at room temperature for 15min.
  • ATP (Sigma, A7699) was diluted with 1 ⁇ enzyme buffer, from 10 mM to 75 ⁇ M (5 ⁇ ), the final concentration was 15 ⁇ M; substrate TKSubstrate 3-biotin (Cisbio, 61TK0BLC ) with 1 ⁇ enzyme buffer, dilute from 500 ⁇ M to 5 ⁇ M (5 ⁇ ), the final concentration is 1 ⁇ M; mix equal volumes of ATP and substrate, add 4 ⁇ L to each well using a BioTek automatic dispenser; centrifuge at 2500 rpm for 30 seconds, and react at 25 °C for 45 minutes .
  • Streptavidin-XL665 (Cisbio, 610SAXLG) was diluted with HTRFK in EASE detection buffer (cisbio) from 16.67 ⁇ M to 250nM (4 ⁇ ), the final concentration was 62.5nM; TK Antibody-Cryptate (Cisbio) was used HTRF KinEASE detection buffer (cisbio) was diluted from 100 ⁇ to 5 ⁇ , and the final concentration was 1 ⁇ ; XL665 was mixed with Antibody in equal volume, and 10 ⁇ L was added to each well using a BioTek automatic dispenser, centrifuged at 2500 rpm for 30 seconds, and reacted at 25°C for 1 hour. After the reaction, the multifunctional plate reader HTRF was used for detection.
  • MV-4-11 human myelomonocytic leukemia cell line, medium: IMDM+10% fetal bovine serum
  • IMDM+10% fetal bovine serum was purchased from Nanjing Kebai Biotechnology Co., Ltd., and placed in an incubator at 37°C and 5% CO 2 nourish.
  • Cells in the logarithmic growth phase were plated in 96-well plates at cell densities of 8000/well, 6000/well, 5000/well, 4000/well and 3000/well, and a blank control group was set at the same time.
  • Signal value of the test substance the mean value of the fluorescent signal of the cell + medium + compound group
  • Signal value of the blank group the average value of the fluorescence signal of the culture medium group (containing 0.5% DMSO);
  • Signal value of negative control group mean value of fluorescence signal of cell+medium group (containing 0.5% DMSO).
  • the IC 50 (MV4-11, nM) of the antiproliferative activity of the compound of Example 1 on MV4-11 cells was 6.97.
  • test compound The inhibitory effect of the test compound and the positive drug on the growth of human acute monocytic leukemia cell MV-4-11 xenografted tumor model in nude mice in vivo.
  • MV-4-11 cells in the logarithmic growth phase, count the cells and resuspend, adjust the cell concentration to 7.0 ⁇ 10 7 cells/mL; inject 200 ⁇ L (14 ⁇ 10 6 cells/only) to establish the MV-4-11 xenograft tumor model.
  • the tumor volume reaches 100-300 mm 3 , tumor-bearing mice with good health and similar tumor volume are selected.
  • Solvent control group PEG400&citric acid buffer (20:80, v:v).
  • tumor volume (mm 3 ) l ⁇ w 2 /2
  • RTV relative tumor volume
  • TV initial is the tumor volume measured during group administration
  • TV t is the tumor volume at each measurement during administration.
  • TV t (T) represents the tumor volume measured each time in the treatment group
  • TV initial (T) represents the tumor volume of the treatment group when administered in groups
  • TV t (C) represents the tumor volume measured each time in the solvent control group
  • TV initial (C) represents the tumor volume of the solvent control group at the time of group administration.
  • RTV T represents the RTV of the treatment group
  • RTV C represents the RTV of the solvent control group.
  • the experimental data in the table is the relevant data obtained when the experiment ends (the end of the experiment is defined as: after 21 days or when the tumor volume of the solvent control group reaches 2000 mm 3 and the experiment ends (whichever is reached earlier)).
  • Each compound was prepared as a 10 mg/mL stock solution in DMSO.
  • mice Male ICR mice aged 6-10 weeks (source of mice: Weitong Lihua Experimental Animal Technology Co., Ltd.), 6 in each group, were fasted overnight and fed 4 hours after administration. On the day of the experiment, the mice were given 10 mg ⁇ kg -1 compound test solution by intragastric administration. At 0, 5min, 15min, 30min, 1h, 2h, 4h, 8h, and 24h after administration, about 100 ⁇ L of blood was collected from the orbit of the mice and placed in an EDTA-K 2 anticoagulant tube. Whole blood samples were centrifuged at 1500-1600 g for 10 min, and the separated plasma was stored in a -40-20°C refrigerator for biological sample analysis. LC-MS/MS method was used to determine the plasma concentration.
  • the system was cooled down to 60°C, and methyl tert-butyl ether (200 mL) was added to the reaction kettle. After the addition is complete, stir and ripen at 60°C for 1 hour. After the aging is completed, the temperature of the system is lowered to 20° C., and the stirring and aging are continued for 1 hour.
  • Single crystal culture method Dissolve the monohydrate form B sample in 95% ethanol-water, prepare a 9.1mg/mL suspension, heat up to 50-60°C to dissolve, filter and cool down at room temperature to crystallize. The elongated needle-like single crystal was obtained, and its crystal parameters and structure data are listed below.
  • the crystal form B is a monohydrate.
  • Embodiment 6 (S)-(2-((5-chloro-2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7] wheel En-2-yl)amino)pyrimidin-4-yl)amino)-5-(methoxymethyl)phenyl)dimethylphosphine oxide mono-p-toluenesulfonate sesquihydrate (compound of formula III) crystal Preparation of Form C
  • Dissolve monohydrate crystal form B in water prepare a suspension of about 3mg/mL, heat up to 50-60°C to dissolve, filter and crystallize at room temperature to obtain a slender needle-shaped single crystal, namely crystal Form C sesquihydrate. See Figure 7 for its XRPD spectrum, and see Table 11 for details;
  • the crystal form C is a sesquihydrate.
  • Embodiment 7 Solubility related determination
  • Solubility testing method of mono-p-toluenesulfonate monohydrate crystal form B of compound of formula IV at various pH values Accurately weigh about 0.2g of crystal form B, add solvent to it dropwise, record the amount of solvent added and the dissolution state of crystal form B , when the crystal form B is completely dissolved, record the amount of solvent added, and calculate the critical saturation solubility; if more than 50ml of solvent is added and still cannot be dissolved, take a sample and centrifuge to test the saturation solubility.
  • the solubility of the mono-p-toluenesulfonate monohydrate crystal form B of the compound of formula IV is detailed in the table below:
  • X-ray powder of formula IV compound hydrochloride, dihydrochloride, phosphate, hippurate, sulfate, hydrobromide, benzenesulfonate, oxalate, fumarate, citrate Diffraction (XRPD) spectra are shown in Figures 10-19, respectively.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供一种(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐、其水合物和晶型，该对甲苯磺酸盐晶型具有良好的稳定性，且易加工，溶解度高。

Description

AXL激酶抑制剂的单对甲苯磺酸盐及其晶型 技术领域
本发明属于医药技术领域，所述化合物是AXL激酶抑制剂，具体涉及AXL抑制剂的对甲苯磺酸盐及其晶型。
背景技术
受体酪氨酸激酶(RTK)是多域跨膜蛋白，可作为细胞外配体的传感器。配体受体结合诱导受体二聚化并激活其胞内激酶结构域，继而导致多个下游信号级联反应的募集、磷酸化和激活(Robinson,D.R.等,Oncogene,19:5548-5557,2000)。迄今为止，已在人类基因组中鉴定出58个RTK，它们可调节多种细胞过程，包括细胞存活、生长、分化、增殖、粘附和运动(Segaliny,A.I.等,J.Bone Oncol,4:1-12,2015)。
AXL(又称为UFO、ARK和Tyro7)属于受体酪氨酸激酶TAM家族，该家族成员还包括Mer和Tyro3。其中，AXL和Tyro3具有最为相似的基因结构，而AXL和Mer具有最为相似的酪氨酸激酶域氨基酸序列。与其他受体酪氨酸激酶(RTKs)一样，TAM家族的结构包含胞外域、跨膜域和保守的胞内激酶域。AXL的细胞外结构域具有独特的使免疫球蛋白和III型纤维连接蛋白重复单元并置的结构并且使人联想到中性细胞粘附分子的结构。TAM家族成员有1个共同配体—生长抑制特异性蛋白6(Gas6)，该配体能够与所有TAM受体酪氨酸激酶结合。AXL与Gas6结合后，会导致受体二聚化和AXL自磷酸化，从而激活下游多条信号转导通路，并参与肿瘤发生的多个过程(Linger,R.M等，Ther.Targets，14(10),1073-1090，2010；Rescigno,J.等，Oncogene,6(10),1909-1913，1991)。
AXL广泛表达于人体正常组织，如单核细胞、巨噬细胞、血小板、内皮细胞、小脑、心脏、骨骼肌、肝脏和肾脏等，其中心肌和骨骼肌表达最高，骨髓CD34+细胞和基质细胞也有较高的表达，正常淋巴组织表达很低(Wu YM,Robinson DR,Kung HJ,Cancer Res,64(20),7311-7320,2004；hung BI等，DNA Cell Biol,22(8)，533-540，2003)。在对许多癌细胞的研究中发现，在造血细胞、间质细胞和内皮细胞中，AXL基因都存在着超表达或异位表达。在各类白血病和多数的实体瘤中，AXL激酶的超表达现象尤为突出。通过抑制AXL受体酪氨酸激酶可以降低肿瘤细胞的促存活信号、阻滞肿瘤的侵袭能力，增加靶向药物治疗和化疗敏感度。因此寻找有效的AXL抑制剂是当前肿瘤靶向药物研发的重要方向。
发明内容
一方面，本发明提供一种(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物。
进一步地，本发明所述的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物，具体结构如式I所示：
Figure PCTCN2022134410-appb-000001
其中，X＝0～2。
进一步地，X＝0～1或1.5。
进一步地，X为0、0.25、0.5、0.7、1、1.25、1.5或1.75。
在一些典型的实施方案中，X为0。
在一些典型的实施方案中，X为0.7。
在一些典型的实施方案中，X为1。
在一些典型的实施方案中，X为1.5。
进一步的，本发明提供一种(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐的水合物。
在一些典型的实施方案中，本发明提供一种(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7] 轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐的一水合物，具体结构如式II，
Figure PCTCN2022134410-appb-000002
在一些典型的实施方案中，本发明提供一种(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐的倍半水合物，具体结构如式III所示，
Figure PCTCN2022134410-appb-000003
进一步地，本发明提供一种结晶形式的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物。
进一步地，本发明提供一种结晶形式的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、13.2°±0.2°和21.8°±0.2°处具有衍射峰。
在一些典型的实施方案中，所述结晶，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、21.8°±0.2°和22.6°±0.2°处具有衍射峰。
在一些典型的实施方案中，所述结晶，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.4°±0.2°、19.7°±0.2°、21.8°±0.2°、22.6°±0.2°和29.4°±0.2°处具有衍射峰。
在一些更为典型的实施方案中，所述结晶，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、12.3°±0.2°、12.4°±0.2°、12.6°±0.2°、13.2°±0.2°、14.1°±0.2°、15.2°±0.2°、15.9°±0.2°、16.7°±0.2°、17.1°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.0°±0.2°、19.4°±0.2°、19.7°±0.2°、21.1°±0.2°、21.8°±0.2°、22.6°±0.2°、23.3°±0.2°、23.7°±0.2°、24.1°±0.2°、24.4°±0.2°、24.7°±0.2°、25.1°±0.2°、26.2°±0.2°、26.6°±0.2°、27.0°±0.2°、27.7°±0.2°、28.0°±0.2°、28.3°±0.2°、28.7°±0.2°、28.8°±0.2°、29.4°±0.2°、30.2°±0.2°和33.9°±0.2°处具有衍射峰。
在一些实施方案中，所述结晶在差示扫描量热法测得的热分析图中，在起始温度195±5℃～205±5℃处有吸热峰。
在一些实施方案中，所述结晶在差示扫描量热法测得的热分析图中，在起始温度198±5℃～203±5℃处有吸热峰。
在一些实施方案中，所述结晶在差示扫描量热法测得的热分析图中，在起始温度200±5℃处有吸热峰。
进一步地，本发明提供一种式I化合物的结晶形式，其中X＝0～1，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、13.2°±0.2°和21.8°±0.2°处具有衍射峰。
在一些典型的实施方案中，所述结晶，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、21.8°±0.2°和22.6°±0.2°处具有衍射峰。
在一些典型的实施方案中，所述结晶，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.4°±0.2°、19.7°±0.2°、21.8°±0.2°、22.6°±0.2°和29.4°±0.2°处具有衍射峰。
在一些更为典型的实施方案中，所述结晶，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、12.3°±0.2°、12.4°±0.2°、12.6°±0.2°、13.2°±0.2°、14.1°±0.2°、15.2°±0.2°、15.9°±0.2°、16.7°±0.2°、17.1°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.0°±0.2°、19.4°±0.2°、19.7°±0.2°、21.1°±0.2°、21.8°±0.2°、22.6°±0.2°、23.3°±0.2°、23.7°±0.2°、24.1°±0.2°、24.4°±0.2°、24.7°±0.2°、25.1°±0.2°、26.2°±0.2°、26.6°±0.2°、27.0°±0.2°、27.7°±0.2°、28.0°±0.2°、 28.3°±0.2°、28.7°±0.2°、28.8°±0.2°、29.4°±0.2°、30.2°±0.2°和33.9°±0.2°处具有衍射峰。
在一些实施方案中，所述结晶在差示扫描量热法测得的热分析图中，在起始温度195±5℃～205±5℃处有吸热峰。
在一些实施方案中，所述结晶在差示扫描量热法测得的热分析图中，在起始温度198±5℃～203±5℃处有吸热峰。
在一些更为典型的实施方案中，所述结晶在差示扫描量热法测得的热分析图中，在起始温度200℃±5℃处有吸热峰。
进一步地，本发明提供一种(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐一水合物的晶型B，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、13.2°±0.2°和21.8°±0.2°处具有衍射峰。
在一些实施方案中，所述晶型B，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、21.8°±0.2°和22.6°±0.2°处具有衍射峰。
在一些实施方案中，所述晶型B，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.4°±0.2°、19.7°±0.2°、21.8°±0.2°、22.6°±0.2°和29.4°±0.2°处具有衍射峰。
在一些实施方案中，所述晶型B，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、12.3°±0.2°、12.4°±0.2°、12.6°±0.2°、13.2°±0.2°、14.1°±0.2°、15.2°±0.2°、15.9°±0.2°、16.7°±0.2°、17.1°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.0°±0.2°、19.4°±0.2°、19.7°±0.2°、21.1°±0.2°、21.8°±0.2°、22.6°±0.2°、23.3°±0.2°、23.7°±0.2°、24.1°±0.2°、24.4°±0.2°、24.7°±0.2°、25.1°±0.2°、26.2°±0.2°、26.6°±0.2°、27.0°±0.2°、27.7°±0.2°、28.0°±0.2°、28.3°±0.2°、28.7°±0.2°、28.8°±0.2°、29.4°±0.2°、30.2°±0.2°和33.9°±0.2°处具有衍射峰。
在一些更为典型的实施方案中，所述晶型B以2θ角度表示的X射线粉末衍射具有如下表所述的数据：
表1晶型B的X射线粉末衍射图数据
2θ(°) 计数(counts) I/I 0(％)
6.0 1772 100.0
6.3 1424 80.3
7.7 36 2.0
8.1 26 1.4
9.2 12 0.7
9.7 16 0.9
10.5 1448 81.7
11.5 970 54.8
12.3 215 12.1
12.4 133 7.5
12.6 169 9.5
13.2 1033 58.3
13.6 53 3.0
14.1 190 10.7
15.2 804 45.4
15.9 281 15.9
16.7 323 18.2
17.1 292 16.5
18.0 974 54.9
18.6 947 53.4
18.7 449 25.3
19.0 354 20.0
19.4 764 43.1
19.7 487 27.5
20.6 50 2.8
21.1 239 13.5
21.8 1152 65.0
22.6 844 47.6
23.4 106 6.0
23.7 232 13.1
24.1 184 10.4
24.4 181 10.2
24.7 274 15.5
25.1 227 12.8
25.6 71 4.0
26.3 177 10.0
26.6 223 12.6
27.0 371 20.9
27.7 249 14.1
28.0 143 8.1
28.3 226 12.8
28.7 109 6.2
28.8 303 17.1
29.4 459 25.9
30.2 281 15.8
32.0 81 4.5
33.1 68 3.9
33.9 152 8.6
35.1 58 3.3
35.7 44 2.5
。
在一些实施方案中，所述晶型B以2θ角度表示的X射线粉末衍射具有如图1所示的图谱。
在一些实施方案中，所述晶型B在差示扫描量热法测得的热分析图中，在起始温度为85±5℃～95±5℃处有吸热峰和在起始温度195±5℃～205±5℃处有吸热峰。
在一些实施方案中，所述晶型B在差示扫描量热法测得的热分析图中，在起始温度为88±5℃～93±5℃处有吸热峰和在起始温度198±5℃～203±5℃处有吸热峰。
在一些实施方案中，所述晶型B在差示扫描量热法测得的热分析图中，在起始温度为90±5℃处有吸热峰和在起始温度200±5℃处有吸热峰。
在一些实施方案中，所述晶型B在差示扫描量热法测得的热分析图中，具有如图2所示的图谱。
在一些实施方案中，所述晶型B在傅里叶变换衰减全反射红外光谱法测得的光谱中具有下列吸收光带，以波长的倒数表示(cm -1)：432±2、471±2、552±2、570±2、711±2、747±2、779±2、818±2、836±2、863±2、932±2、966±2、1295±2、1318±2、2635±2、2721±2、2927±2、3005±2、3110±2、3185±2、3256±2和3556±2。
在一些实施方案中，所述晶型B在傅里叶变换衰减全反射红外光谱法测得的光谱中具有下列吸收光带，以波长的倒数表示(cm -1)：432±2、471±2、497±2、552±2、570±2、681±2、711±2、747±2、779±2、818±2、836±2、863±2、932±2、966±2、1008±2、1030±2、1096±2、1121±2、1159±2、1229±2、1295±2、1318±2、1374±2、1413±2、1456±2、1512±2、1527±2、1571±2、1609±2、2635±2、2721±2、2927±2、3005±2、3110±2、3185±2、3256±2和3556±2。
在一些实施方案中，所述晶型B在傅里叶变换拉曼光谱法测得的光谱中具有下列吸收光带，以波长的倒数表示(cm -1)：1609±2，1572±2，1553±2，1535±2，1508±2，1494±2，1476±2，1457±2，1420±2，1374±2，1344±2，1331±2，1285±2，1262±2，1228±2，1213±2，1173±2，1147±2，1135±2，1099±2，1059±2，1029±2，1115±2，1006±2，970±2，965±2，819±2，799±2，744±2，733±2，678±2，658±2，634±2，613±2，570±2，534±2，497±2，471±2，448±2，425±2，393±2，369±2，313±2，287±2，262±2，241±2，217±2，177±2，156±2，104±2和82±2。
在一些实施方案中，所述晶型B在25℃-150℃的温度范围内失重2.4％。
在一些实施方案中，所述晶型B具有如图3所示的TGA图谱。
在一些更为典型的实施方案中，所述晶型B具有如下表所述的单晶晶体参数及结构数据：
表2晶型B晶体参数及结构数据表
Figure PCTCN2022134410-appb-000004
Figure PCTCN2022134410-appb-000005
进一步地，本发明提供一种(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐的倍半水合物的晶型C，具体结构如式III所示：
Figure PCTCN2022134410-appb-000006
其X射线粉末衍射图在2θ为13.4°±0.2°、18.4°±0.2°、19.3°±0.2°、19.8°±0.2°和21.8°±0.2°处具有衍射峰。
在一些实施方案中，所述晶型C，其X射线粉末衍射图在2θ为12.1°±0.2°、13.4°±0.2°、15.0°±0.2°、16.9°±0.2°、18.4°±0.2°、19.3°±0.2°、19.8°±0.2°、21.8°±0.2°、23.6°±0.2°和24.3°±0.2°处具有衍射峰。
在一些实施方案中，所述晶型C，其X射线粉末衍射图在2θ为6°±0.2°、10.8°±0.2°、12.1°±0.2°、13.4°±0.2°、15.0°±0.2°、16.9°±0.2°、18.4°±0.2°、19.0°±0.2°、19.3°±0.2°、19.8°±0.2°、20.9°±0.2°、21.8°±0.2°、23.2°±0.2°、23.6°±0.2°、24.3°±0.2°、25.5°±0.2°和26.6°±0.2°处具有衍射峰。
在一些更为典型的实施方案中，所述晶型C，其X射线粉末衍射图的2θ详见下表：
表3晶型C的X射线粉末衍射图数据
2θ(°) 计数(counts) I/I 0(％)
6.0 105 22.2
10.8 60 12.8
12.1 227 48.2
13.4 322 68.5
15.0 220 46.7
16.9 221 46.9
18.4 471 100.0
19.0 176 37.5
19.3 238 50.5
19.8 306 65.0
20.9 154 32.8
21.8 310 65.9
23.2 172 36.6
23.6 231 49.1
24.3 213 45.2
25.5 62 13.1
26.6 103 21.8
27.7 38 8.0
29.7 93 19.7
。
在一些实施方案中，所述晶型C以2θ角度表示的X射线粉末衍射具有如图7所示的图谱。
在一些更为典型的实施方案中，所述晶型C具有如下表所述的单晶晶体参数及结构数据：
表错误！文档中没有指定样式的文字。晶型C晶体参数及结构数据表
Figure PCTCN2022134410-appb-000007
另一方面，本发明提供了一种式IV化合物的晶型A，其X射线粉末衍射图在2θ为7.6°±0.2°、10.2°±0.2°、17.6°±0.2°、20.3°±0.2°和20.9°±0.2°处具有衍射峰。
Figure PCTCN2022134410-appb-000008
在一些实施方案中的，所述晶型A，其X射线粉末衍射图在2θ为4.1°±0.2°、7.6°±0.2°、10.2°±0.2°、12.6°±0.2°、13.0°±0.2°、17.6°±0.2°、19.7°±0.2°、20.3°±0.2°、20.9°±0.2°和22.2°±0.2°处具有衍射峰。
在一些实施方案中，所述晶型A，其X射线粉末衍射图在2θ为4.1°±0.2°、5.6°±0.2°、7.6°±0.2°、10.2°±0.2°、 10.9°±0.2°、12.6°±0.2°、13.0°±0.2°、15.2°±0.2°、17.6°±0.2°、19.7°±0.2°、20.3°±0.2°、20.9°±0.2°、22.2°±0.2°、23.2°±0.2°、24.6°±0.2°、27.0°±0.2°、28.8°±0.2°、37.0°±0.2°和37.7°±0.2°处具有衍射峰。
在一些更为典型的实施方案中，所述晶型A，其X射线粉末衍射图的2θ详见下表：
表5晶型A的X射线粉末衍射图数据
2θ(°) 计数(counts) I/I 0(％)
4.1 45 15.4
5.6 42 14.3
7.6 109 36.9
10.2 107 36.4
10.9 13 4.4
12.6 59 20.1
13.0 44 14.8
15.2 18 6.2
17.6 246 83.4
19.7 85 28.9
20.3 184 62.5
20.9 294 100.0
22.2 60 20.5
23.2 22 7.5
24.6 19 6.6
27.0 40 13.6
28.8 14 4.6
37.0 6 2.1
37.7 12 4.1
。
在一些更为典型的实施方案中，所述晶型A以2θ角度表示的X射线粉末衍射具有如图9所示的图谱。
另一方面，本发明提供了(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦单对甲苯磺酸盐或其药学上可接受水合物的制备方法，其包括将式IV的化合物与对甲苯磺酸成盐的步骤。
另一方面，本发明提供了式I化合物或其晶型的制备方法，包括将式IV的化合物与对甲苯磺酸成盐的步骤。
在一些实施方案中，式I化合物的晶型可以通过混悬搅拌、气固扩散、溶剂挥发或降温析晶的方法制备得到。
另一方面，本发明提供了晶型B的制备方法，将式IV化合物与一水合对甲苯磺酸在醇类溶剂中反应，在反溶剂中析晶。
在一些实施方案中，所述醇类溶剂可以为醇溶剂或醇与水的混合溶剂，所述醇溶剂选自甲醇、乙醇、异丙醇中的一种，优选乙醇或异丙醇。
在一些实施方案中，所述反溶剂选自酯类溶剂、酮类溶剂或醚类溶剂，所述酮类溶剂为丙酮、2-丁酮或甲基异丁酮，优选丙酮；所述醚类溶剂为甲基叔丁基醚或1,4-二氧六环，优选甲基叔丁基醚；所述酯类溶剂选自乙酸乙酯、乙酸丁酯或乙酸异丙酯，优选乙酸异丙酯。
另一方面，本发明提供了一种包含(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦单对甲苯磺酸盐或其水合物的药物组合物。
另一方面，本发明提供了一种包含式I化合物的药物组合物。
另一方面，本发明提供了一种包含式II化合物的药物组合物。
另一方面，本发明提供了一种包含式III化合物的药物组合物。
在一些实施方案中，所述药物组合物进一步包含一种或多种药学上可接受的载体。
在一些实施方案中，所述药物组合物为适于口服的固体药物制剂，优选片剂或胶囊。
另一方面，本发明提供了一种包含晶型A的晶型组合物，其中所述晶型A的重量占晶型组合物重量的50％以上；优选80％以上；进一步优选90％以上；更进一步优选95％以上；最优选98％以上。
另一方面，本发明还提供了包含所述晶型A或其晶型组合物的药物组合物。
在一些实施方案中，所述药物组合物进一步包含一种或多种药学上可接受的载体。
在一些实施方案中，所述药物组合物为适于口服的固体药物制剂，优选片剂或胶囊。
另一方面，本发明提供了一种包含晶型B的晶型组合物，其中所述晶型B的重量占晶型组合物重量的50％以上；优选80％以上；进一步优选90％以上；更进一步优选95％以上；最优选98％以上。
另一方面，本发明还提供了包含所述晶型B或晶型组合物的药物组合物。
在一些实施方案中，所述药物组合物进一步包含一种或多种药学上可接受的载体。
在一些实施方案中，所述药物组合物为适于口服的固体药物制剂，优选片剂或胶囊。
另一方面，本发明提供了一种包含晶型C的晶型组合物，其中所述晶型C的重量占晶型组合物重量的50％以上；优选80％以上；进一步优选90％以上；更进一步优选95％以上；最优选98％以上。
另一方面，本发明还提供了包含所述晶型C或其晶型组合物的药物组合物。
在一些实施方案中，所述药物组合物进一步包含一种或多种药学上可接受的载体。
在一些实施方案中，所述药物组合物为适于口服的固体药物制剂，优选片剂或胶囊。
另一方面，本发明还提供了用作药物的式I化合物或其药物组合物。
另一方面，本发明还提供了用作药物的式II化合物或其药物组合物。
另一方面，本发明还提供了用作药物的式III化合物或其药物组合物。
另一方面，本发明还提供了用作药物的晶型A、其晶型组合物或其药物组合物。
另一方面，本发明还提供了用作药物的晶型B、其晶型组合物或其药物组合物。
另一方面，本发明还提供了用作药物的晶型C、其晶型组合物或其药物组合物。
另一方面，本发明还提供了(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐、其水合物及其药物组合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述式I化合物或其药物组合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述式II化合物或其药物组合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述式III化合物或其药物组合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述晶型A或其药物组合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述晶型B或其药物组合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述晶型C或其药物组合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述式I化合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述式II化合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述式III化合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述晶型组合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
另一方面，本发明还提供了所述晶型A、其晶型组合物或其药物组合物用于预防和/或治疗AXL激酶介导的疾病或疾病状态的用途。
另一方面，本发明还提供了所述晶型B、其晶型组合物或其药物组合物用于预防和/或治疗AXL激酶介导的疾 病或疾病状态的用途。
另一方面，本发明还提供了所述晶型C、其晶型组合物或其药物组合物用于预防和/或治疗AXL激酶介导的疾病或疾病状态的用途。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐、其水合物或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的所述式I化合物或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的所述式II化合物或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的所述式III化合物或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明所述的晶型组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的所述晶型A或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的所述晶型B或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的所述晶型C或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的所述式I化合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的所述式II化合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的所述式III化合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的所述晶型组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的所述晶型A或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的所述晶型B或其药物组合物。
另一方面，本发明还提供了用于预防和/或治疗AXL激酶介导的疾病或疾病状态的本发明的所述晶型C或其药物组合物。
在一些实施方案中，所述AXL激酶介导的疾病或疾病状态为癌症。
在一些典型的实施方案中，所述癌症与血液肿瘤相关。
本发明制备的式IV的化合物单对甲苯磺酸盐、其水合物以及水合物的晶型具有良好的稳定性，解决了游离碱(式IV化合物)高温高湿、光照条件下不稳定性的问题，且制备得到的晶型具有稳定、易加工、溶解度高等优点。
相关定义
除非有特定说明，下列用在说明书和权利要求书中的术语具有下述含义：
术语“药学上可接受的载体”是指对机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。包括但不限于国家食品药品监督管理局许可的可用于人或动物的任何稀释剂、崩解剂、粘合剂、助流剂、润湿剂。
本发明中的“X射线粉末衍射图谱”为使用Cu-Kα辐射测量得到。
本发明中的“2θ”或“2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20°。
需要说明的是，在X射线粉末衍射光谱(XRPD)中，由结晶化合物得到的衍射谱图对于特定的结晶往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径和其它测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的结晶并非是特征性的。判断是否与已知的结晶相同时，更应该注意的是峰的相对位置而不是它们的相对强度。此外，对任何给定的结晶而言，峰的位置可能存在轻微误差，这 在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品移动、或仪器的标定等，峰的位置可以移动，2θ值的测定误差有时约为±0.2°。因此，在确定每种结晶结构时，应该将此误差考虑在内。在XRPD图谱中通常用2θ角或晶面距d表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面距，λ代表入射X射线的波长，θ为衍射角。对于同种化合物的同种结晶，其XRPD谱的峰位置在整体上具有相似性，相对强度误差可能较大。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的结晶是特征性的。
差示扫描量热法(DSC)测定当晶体由于其晶体结构发生变化或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内，通常在约3℃之内。当描述某个化合物具有某一给定的DSC峰或熔点时，指的是该DSC峰或熔点±5℃。DSC提供了一种辨别不同晶型的辅助方法。不同的晶体形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰或熔点可能会在更大的范围内波动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。
热重分析(TGA)指的是在程序控制温度下测量待测样品的质量与温度变化之间关系的一种热分析技术。当被测物质在加热过程中有升华或汽化现象时，其分解出了气体或失去了结晶水时，引起被测物质量发生变化。这时，热重曲线就不是直线而是有所下降。通过分析热重曲线，即可知道被测物质在什么温度下产生变化，并且根据所失重量，可计算失去了多少物质量。
在提到例如XRPD图谱、DSC图谱或TGA图谱时，术语“如……所示”包括与本文描绘的那些不一定相同，但在被本领域技术人员考虑时落入实验误差的限度内的图谱。
如本文使用的术语“水合物”是特定的溶剂合物，其中溶剂是水，水合物实例包括半水合物、一水合物、倍半水合物、二水合物等。
特定物质如本发明的盐的不同晶态形式可包括该物质的无水形式和该物质的水合物形式两者，其中无水形式和水合物形式中的每一种通过不同的XRPD图像且由此表示不同的晶格来互相区分。在一些实例中，单一的晶态形式(例如，通过单独的XRPD图像鉴定)可具有可变的水含量或溶剂含量，其中，除相对于水和/或溶剂的组成变化之外，晶格基本上保持不变(如XRPD图像所表示的)。
如无特殊说明，本发明的简称具有如下含义：
M：mol/L
mM：mmol/L
nM：nmol/L
Boc:叔丁氧羰基
1HNMR：核磁共振氢谱
MS(ESI+)：质谱
DMSO-d 6：氘代二甲基亚砜
CDCl 3：氘代氯仿
DTT：二硫苏糖醇
SEB：SupplementedEnzymaticBuffer(补充酶缓冲液)
IMDM(Iscove'sModifiedDulbecco'sMedium):Iscove(人名)改良的Dulbecco(人名)培养基。
室温：25℃。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，还可以根据这些附图获得其他的附图。
图1为实施例3中晶型B的X-射线粉末衍射(XRPD)谱图；
图2为实施例3中晶型B的差示扫描量热(DSC)谱图；
图3为实施例3中晶型B的热重(TGA)谱图；
图4为实施例3中晶型B的FT-红外(FT-IR)谱图；
图5为实施例3中晶型B的FT-拉曼(FT-Raman)谱图；
图6为实施例3中晶型B的动态水分吸附(DVS)谱图；
图7为实施例6中晶型C的X-射线粉末衍射(XRPD)谱图；
图8为实施例8中晶型A的X-射线粉末衍射(XRPD)谱图；
图9为实施例10中式IV化合物甲磺酸盐的X-射线粉末衍射(XRPD)谱图；
图10为实施例10中式IV化合物单盐酸盐的X-射线粉末衍射(XRPD)谱图；
图11为实施例10中式IV化合物二盐酸盐的X-射线粉末衍射(XRPD)谱图；
图12为实施例10中式IV化合物磷酸盐的X-射线粉末衍射(XRPD)谱图；
图13为实施例10中式IV化合物马尿酸盐的X-射线粉末衍射(XRPD)谱图；
图14为实施例10中式IV化合物硫酸盐的X-射线粉末衍射(XRPD)谱图；
图15为实施例10中式IV化合物氢溴酸盐的X-射线粉末衍射(XRPD)谱图；
图16为实施例10中式IV化合物苯磺酸盐的X-射线粉末衍射(XRPD)谱图；
图17为实施例10中式IV化合物草酸盐的X-射线粉末衍射(XRPD)谱图；
图18为实施例10中式IV化合物富马酸盐的X-射线粉末衍射(XRPD)谱图；
图19为实施例10中式IV化合物柠檬酸盐的X-射线粉末衍射(XRPD)谱图；
图20为实施例11制备的式I化合物的X-射线粉末衍射(XRPD)谱图。
具体实施方式
下面通过实施例更详细地描述本发明。但这些具体描述仅用于说明本发明的技术方案，不对本发明构成任何限制。
各仪器测试条件如下：
(1)X-射线粉末衍射仪(X-ray Powder Diffraction，XRPD)
仪器型号：Bruker D2 Phaser2 nd
Figure PCTCN2022134410-appb-000009
(2)热重分析仪(Thermogravimetric，TGA)
仪器型号：TA Instruments TGA 25
吹扫气：氮气
升温速率：10℃/min
升温范围：室温-300℃
方法：将样品置于铝盘中，再将铝盘置于铂盘中，敞口在氮气氛围中以10℃/min的速度从室温升温至设定的温度。
(3)差示扫描量热仪(Differential Scanning Calorimeter，DSC)
仪器型号：TA Instruments DSC 25
吹扫气：氮气
升温速率：10℃/min
升温范围：20-300℃
方法：样品置于铝盘中，压盖后在氮气氛围中以10℃/min的速度从20℃升温至设定的温度。
(4)傅里叶变换红外光谱法(FT-IR)
仪器型号：Thermo傅里叶红外光谱仪ID1-summit
仪器校正：聚苯乙烯薄膜
测试条件：KBr压片法
(5)傅里叶变换拉曼光谱法(FT-Raman)
仪器型号：尼高力傅里叶变换拉曼光谱仪DXR780
曝光时间：20s
曝光次数：10次
光源：780nm
狭缝：400lines/mm
激光强度：14mW
扫描范围：50cm-1—3000cm-1
(6)动态水分吸附(DVS)
仪器型号：Surface Measurement System(SMS)-DVS Intrinsic
Figure PCTCN2022134410-appb-000010
具体仪器设定参数如下：
(7)单晶衍射仪及其参数信息：
单晶X-射线衍射仪(Single Crystal X-ray Diffraction,SCXRD)
仪器型号：Bruker D8 Venture
光源：Cu-Kα,
Figure PCTCN2022134410-appb-000011
探测器：CMOS面探测器
分辨率：
Figure PCTCN2022134410-appb-000012
X射线光管设定：管电压50KV，管电流1.2mA
曝光时间：50s
测试温度：170(2)K
(8)HPLC的分析条件
Figure PCTCN2022134410-appb-000013
Figure PCTCN2022134410-appb-000014
实施例1(5)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的制备
Figure PCTCN2022134410-appb-000015
a)2-碘-4-(甲氧基甲基)苯胺
在二氯甲烷(261mL)/水(135mL)的溶液中加入4-(甲氧基甲基)苯胺(9g)、碘(16.65g)和碳酸氢钠(16.53g)，22℃下搅拌16h。反应液用饱和硫代硫酸钠(10ml)在室温下下猝灭。所得混合物用二氯甲烷(3x100mL)萃取，接着用饱和氯化钠水溶液(1x100mL)洗涤合并的有机层，有机层再用无水硫酸钠干燥。过滤后，滤液减压浓缩。残渣经硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1v/v)，得到标题产物(16g)。MS(ESI+):264.0(M+H).
b)(2-氨基-5-(甲氧基甲基)苯基)二甲基氧化膦
在氮气气氛下，向N,N-二甲基甲酰胺(224mL)中加入2-碘-4-(甲氧基甲基)苯胺(16g，60.82mmol，1.00当量)、磷酸钾(14.20g)、醋酸钯(0.68g)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(1.76g)的搅拌溶液中添加二甲基氧化膦(5.22g)，于120℃下搅拌反应2小时。将混合物冷却至室温。过滤所得混合物，用N,N-二甲基甲酰胺(3x5mL)洗涤滤饼。滤液减压浓缩。用硅胶柱层析(二氯甲烷/甲醇＝20/1v/v)纯化残余物得到标题产物(12.9g)。MS(ESI+):214.1(M+H).
c)(2-((2,5-二氯嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦
在室温下向N,N-二甲基甲酰胺(22mL)中加入(2-氨基-5-(甲氧基甲基)苯基)二甲基氧化膦(1.10g)、2,4,5-三氯嘧啶(1.23g)和N,N-二异丙基乙胺(2.00g)搅拌3h。所得混合物用二氯甲烷(30mL)稀释。在0℃下加水(10ml)使反应猝灭。所得混合物用二氯甲烷(3x50mL)萃取。合并的有机层用饱和氯化钠(1x50mL)洗涤并用无水硫酸钠干燥。过滤后，滤液减压浓缩。用硅胶柱层析(二氯甲烷/甲醇＝20/1v/v)纯化残余物得到标题产物(1.28g)。
MS(ESI+):360.0(M+H).
d)(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦
向异丙醇(2mL)中加入(2-((2,5-二氯嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(50.00mg)和(S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺(31.98mg)，然后加入氯化氢的1，4-二氧六环溶液(10滴，4M),130℃下用微波辐射3.5小时。然后混合物冷却到室温，减压浓缩。粗品经反相高效液相色谱法纯化(柱为YMCActusTriartC18，30*150mm，粒径5μm，流动相A：水(10mmol/L碳酸氢铵)，流动相B:乙腈，流速：60mL/min，梯度：20％B至50％B，8min，波长：220nm，保留时间：6.83min，柱温：25℃)，得标题产物(20.2mg)。
1HNMR(400MHz,DMSO-d 6,ppm)δ11.07(s,1H),9.26(s,1H),8.52(d,J＝4.6Hz,1H),8.17(s,1H),7.53(dd,J＝14.0,2.0Hz,1H),7.44(q,J＝3.1Hz,2H),7.26(dd,J＝8.1,2.3Hz,1H),6.97(d,J＝8.1Hz,1H),4.42(s,2H),3.31(s,3H),3.01–2.75(m,2H),2.55(s,5H),2.50(s,2H),1.84(s,2H),1.81(s,3H),1.77(s,3H),1.70(q,J＝3.6,3.2Hz,4H),1.54(s,2H).MS(ESI+):554.2(M+H).
实施例2活性测定
实施例1制备的相关化合物进行相关的酶活、细胞、体内相关的活性
活性测试中所使用的阳性药1(BGB324)具体结构如下：
Figure PCTCN2022134410-appb-000016
阳性药2(TP0903)具体结构如下：
Figure PCTCN2022134410-appb-000017
以上化合物均从上海升泓生物科技有限公司购买。
(1)AXL激酶抑制活性
1.实验流程
a)AXL酶(Carna，08-107)配置及加入：用1×酶缓冲液(用200μL的Enzymatic buffer kinase 5X、10μL的500mM的MgCl 2，10μL的100mM的DTT、6.26μL的2500nM的SEB，加入773.75μL的H 2O，配置成1ml的1×酶缓冲液)将33.33ng/μL的AXL酶稀释到0.027ng/μL(1.67×，final conc.＝0.016ng/uL)，使用BioTek(MultiFloFX)自动分液仪，化合物孔和阳性对照孔分别加6μL的1.67倍终浓度的酶溶液；在阴性对照孔中加6μL的1×Enzymatic buffer。
b)化合物配制及加入：使用DMSO将实施例1中制备的化合物及阳性药从10mM稀释到100μM，用化合物滴定仪(Tecan，D300e)进行滴定，滴定仪自动喷入每孔所需浓度，第1个浓度为1μM，1/2log梯度稀释，共8个浓度。2500rpm离心30s，室温孵育15min。
c)ATP、底物配制及加入：ATP(Sigma，A7699)用1×酶缓冲液进行稀释，从10mM稀释到75μM(5×)，终浓度为15μM；底物TKSubstrate 3-biotin(Cisbio，61TK0BLC)用1×酶缓冲液，从500μM稀释到5μM(5×)，终浓度为1μM；ATP同底物等体积混合，使用BioTek自动分液仪4μL加入每孔；2500rpm离心30s，25℃反应45min。
d)检测试剂配制及加入：Streptavidin-XL665(Cisbio，610SAXLG)用HTRFK in EASE detection buffer(cisbio)从16.67μM稀释到250nM(4×)，终浓度为62.5nM；TK Antibody-Cryptate(Cisbio)用HTRF KinEASE detection buffer(cisbio)从100×稀释到5×，终浓度为1×；XL665同Antibody等体积混合，使用BioTek自动分液仪10μL加入每孔，2500rpm离心30s，25℃反应1小时。反应结束后，用多功能读板仪HTRF进行检测。
2.数据分析
使用GraphPad Prism 5软件log(inhibitor)vs.response-Variable slope拟合量效曲线，得到化合物对AXL激酶抑制的IC 50值。
抑制率计算公式如下：
Figure PCTCN2022134410-appb-000018
3.实验结果详见下表
表6实施例1化合物的AXL抑制活性IC 50数据
Figure PCTCN2022134410-appb-000019
Figure PCTCN2022134410-appb-000020
(2)化合物对细胞增殖抑制检测
1.实验流程
MV-4-11(人髓性单核细胞白血病细胞株，培养基：IMDM+10％胎牛血清)购自南京科佰生物科技有限公司，置于37℃,5％CO 2的培养箱中培养。取对数生长期的细胞分别以8000个/孔、6000个/孔、5000个/孔、4000个/孔和3000个/孔的细胞密度铺在96孔板中，并同时设置空白对照组。
将待测化合物以及阳性药溶解在二甲基亚砜中以制备10mM的储液，并置于-80℃冰箱中长期保存。细胞铺板24h后，用二甲基亚砜稀释10mM的化合物储液得到200倍浓度的工作液(最高浓度200或2000μM，3倍梯度，共10个浓度)，每个浓度各取3μL加入到197μL的完全培养基中，稀释得到3倍浓度的工作液，然后取50μL加入到100μL的细胞培养液中(二甲基亚砜终浓度为0.5％,v/v)，每个浓度设置两个复孔。加药处理72h后，每孔加入50μl的Cell
Figure PCTCN2022134410-appb-000021
(购自Promega)，按照说明书的操作流程在Envision(PerkinElmer)上测定荧光信号，使用GraphPadPrism5软件log(inhibitor)vs.response-Variable slope拟合量效曲线，得到化合物对细胞增殖抑制的IC 50值。抑制率计算公式：
Figure PCTCN2022134410-appb-000022
其中：
受试物信号值：细胞+培养基+化合物组荧光信号均值；
空白组信号值：培养基组(含0.5％DMSO)荧光信号均值；
阴性对照组信号值：细胞+培养基组(含0.5％DMSO)荧光信号均值。
2.实验结果
实施例1的化合物MV4-11细胞的抗增殖活性的IC 50(MV4-11,nM)为6.97。
(3)化合物的MV4-11体内药效
测试化合物以及阳性药对人急性单核细胞白血病细胞MV-4-11裸鼠移植瘤模型肿瘤体内生长的抑制作用。
1.小鼠模型的构建
收取对数生长期MV-4-11细胞，细胞计数后重悬后，调整细胞浓度至7.0×10 7细胞/mL；注射到裸鼠前右侧腋窝皮下，每只动物接种200μL(14×10 6细胞/只)，建立MV-4-11移植瘤模型。待瘤体积达到100～300mm 3，挑选健康状况良好、肿瘤体积相近的荷瘤鼠。
2.化合物的配置
将化合物以及阳性药，用适当的溶剂涡旋振荡后超声使化合物完全溶解后缓慢加入适量体积柠檬酸缓冲液，涡旋振荡，使液体混合均匀，得到浓度为0.1、0.5、1mg·mL -1的给药制剂。
溶剂对照组：PEG400&柠檬酸缓冲液(20:80，v:v)。
3.动物分组及给药
将建模的小鼠随机分组(n＝6)，于分组当天开始给予相关化合物和阳性药，21天后或溶剂对照组肿瘤体积达到2000mm 3结束实验(以先达到指标为准)，给药体积均为10mL·kg -1。化合物以及阳性药均采取灌胃方式给予，每天给予一次。实验开始后每周测量2次瘤径和动物体重，计算肿瘤体积。
4.数据分析
肿瘤体积(TV)计算公式为：肿瘤体积(mm 3)＝l×w 2/2，
其中，l表示肿瘤长径(mm)；w表示肿瘤短径(mm)。
相对肿瘤体积(RTV)的计算公式为：RTV＝TV t/TV initial
其中，TV initial为分组给药时测量到的肿瘤体积；TV t为给药期间每一次测量时的肿瘤体积。
肿瘤生长抑制率TGI(％)的计算公式为：TGI＝100％×[1－(TV t(T)－TV initial(T))/(TV t(C)－TV initial(C))]
其中，TV t(T)表示治疗组每次测量的肿瘤体积；TV initial(T)表示分组给药时治疗组的肿瘤体积；TV t(C)表示溶剂对照组每次测量的肿瘤体积；TV initial(C)表示分组给药时溶剂对照组的肿瘤体积。
相对肿瘤增殖率(％T/C)的计算公式为：％T/C＝100％×(RTV T/RTV C)
其中，RTV T表示治疗组RTV；RTV C表示溶剂对照组RTV。
试验数据用Microsoft Office Excel 2007软件进行计算和相关统计学处理。
5.实验结果如下
表7:实施例1化合物的体内药效
Figure PCTCN2022134410-appb-000023
备注：表中的实验数据为实验结束(实验结束定义为：21天后或溶剂对照组肿瘤体积达到2000mm 3结束实验(以先达到指标为准))时，获得的相关数据。
(4)化合物的ICR小鼠药代动力学研究
1.化合物的灌胃处方配置
将各化合物用DMSO配制成10mg/mL的储备液。
混合溶媒配制：Tween 80:PEG 400:Water＝1:9:90(v/v/v)
分别准确吸取浓度为10mg/mL的化合物DMSO储备液450μl至玻璃瓶，加入适当体积的DMSO和混合溶媒，最终制剂中溶媒的比例为DMSO:混合溶媒(v/v)＝10:90，涡旋(或超声)，分散均匀，分别得浓度为1mg/mL的4.5mL给药试液。
2.试验方案
取雄性6～10周龄ICR小鼠(小鼠来源：维通利华实验动物技术有限公司)，每组6只，小鼠禁食过夜，给药后4小时喂食。实验当天，小鼠分别灌胃给予10mg·kg -1化合物试液。给药后小鼠在0、5min、15min、30min、1h、2h、4h、8h、24h，由眼眶采血约100μL，置于EDTA-K 2抗凝管中。将全血样品于1500～1600g离心10min，将分离得到的血浆保存于-40～-20℃冰箱中，用于生物样品分析。LC-MS/MS方法测定血药浓度。
3.数据分析及结果
采用Pharsight Phoenix 7.0中的非房室模型计算药代动力学参数，具体结果详见下表。
表8：实施例1化合物的小鼠药代动力学结果
化合物 Cmax(ng/mL) Tmax(h) AUC 0-24(ng.h/mL) T 1/2(h)
实施例1 324 2.17 1300 1.35
阳性药2(TP-0903) 26.8 0.25 52.2 1.20
实施例3(5)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦单对甲苯磺酸盐一水合物(式II化合物)晶型B的制备
Figure PCTCN2022134410-appb-000024
向500-mL双层玻璃夹套反应釜中添加一水合对甲苯磺酸(6.87g)和99％异丙醇-水(体积百分比，140mL)，升温至70℃机械搅拌溶清。将(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基))嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(式IV化合物，按照实施例1方法制备)(20g)溶于99％异丙醇-水(体积百分比，60mL)并将其滴入反应釜中，约15分钟加毕。搅拌数分钟后反应釜内析出大量固体，继续搅拌约15分钟。将体系降温至60℃，向反应釜中加入甲基叔丁基醚(200mL)。加毕，在60℃下搅拌熟化1小时。熟化完毕，将体系降温至20℃，继续搅拌熟化1小时。熟化完毕，抽滤，湿滤饼在真空下于40℃下干燥15小时，得到淡黄色固体粉末状的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基))嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦单对甲苯磺酸盐一水合物晶型B：23.67g(收率：88.3％)。
1HNMR(400MHz,DMSO-d6):11.11(s,1H)；9.40(br,1H)；9.37(s,1H)；8.56-8.54(m,1H)；8.19(s,1H)；7.56(dd,J＝14,2Hz,1H)； 7.50-7.45(m,4H)；7.37(dd,J＝8.2,2.2Hz,1H)；7.11(d,J＝7.9,2H)；7.04(d,J＝8.2,1H)；4.44(s,2H)；3.48(s,3H)；3.33(s,3H)；3.15(s,2H)；2.82-2.62(m,4H)；2.32(s,2H)；2.29(s,3H)；1.98(s,2H)；1.85-1.83(m,2H)；1.81(d,J＝2.4Hz,3H)；1.77(d,J＝2.4Hz,3H)；1.39(q,J＝11.9Hz,2H).
其X射线粉末衍射图数据详见表9图详见图1；DSC图谱显示在90℃，200℃有吸热峰，具体详见图2；TGA图谱在25-150℃有2.4％的失重，具体数据详见图3；FT-IR图谱详见图4；FT-Raman图谱详见图5，DVS图谱详见图6。
表9晶型B的X射线粉末衍射图数据
2θ(°) 计数(counts) I/I 0(％)
6.0 1772 100.0
6.3 1424 80.3
7.7 36 2.0
8.1 26 1.4
9.2 12 0.7
9.7 16 0.9
10.5 1448 81.7
11.5 970 54.8
12.3 215 12.1
12.4 133 7.5
12.6 169 9.5
13.2 1033 58.3
13.6 53 3.0
14.1 190 10.7
15.2 804 45.4
15.9 281 15.9
16.7 323 18.2
17.1 292 16.5
18.0 974 54.9
18.6 947 53.4
18.7 449 25.3
19.0 354 20.0
19.4 764 43.1
19.7 487 27.5
20.6 50 2.8
21.1 239 13.5
21.8 1152 65.0
22.6 844 47.6
23.4 106 6.0
23.7 232 13.1
24.1 184 10.4
24.4 181 10.2
24.7 274 15.5
25.1 227 12.8
25.6 71 4.0
26.3 177 10.0
26.6 223 12.6
27.0 371 20.9
27.7 249 14.1
28.0 143 8.1
28.3 226 12.8
28.7 109 6.2
28.8 303 17.1
29.4 459 25.9
30.2 281 15.8
32.0 81 4.5
33.1 68 3.9
33.9 152 8.6
35.1 58 3.3
35.7 44 2.5
实施例4(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦单对甲苯磺酸盐一水合物(式II化合物)晶型B的制备
向50-mL玻璃瓶中添加(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(式IV化合物，2.34g)、一水合对甲苯磺酸(0.80g)和乙醇(11.7mL)，常温磁力搅拌溶清。约10分钟后析出大量固体。继续搅拌约30分钟。向玻璃瓶中加入乙酸异丙酯(11.7mL)。加毕，常温下搅拌熟化约30分钟。熟化完毕，向玻璃瓶中加入乙酸异丙酯(11.7mL)，继续熟化约1.5小时。熟化完毕，抽滤，湿滤饼在真空下于40℃下干燥24小时，得到淡黄色固体粉末状的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基))嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦单对甲苯磺酸盐一水合物晶型B：2.35g(收率：74.8％)。
实施例5(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦单对甲苯磺酸盐一水合物(式II化合物)晶型B单晶的制备
单晶培养方法：将一水合物晶型B样品溶解于95％乙醇-水中，配制成9.1mg/mL的混悬液，升温至50-60℃溶清，过滤后在室温下降温析晶即得到细长针状单晶，其晶体参数及结构数据表如下。
表10晶型B晶体参数及结构数据表
Figure PCTCN2022134410-appb-000025
经X射线单晶衍射数据分析，晶型B为一水合物。
实施例6(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦单对甲苯磺酸盐倍半水合物(式III化合物)晶型C的制备
将一水合物晶型B溶解于水中，配制成约3mg/mL的混悬液，升温至50-60℃溶清，过滤后在室温下降温析晶即得到细长针状单晶，即晶型C倍半水合物。其XRPD图谱参见图7，数据详见表11；
表11晶型C的X射线粉末衍射图数据
2θ(°) 计数(counts) I/I 0(％)
6.0 105 22.2
10.8 60 12.8
12.1 227 48.2
13.4 322 68.5
15.0 220 46.7
16.9 221 46.9
18.4 471 100.0
19.0 176 37.5
19.3 238 50.5
19.8 306 65.0
20.9 154 32.8
21.8 310 65.9
23.2 172 36.6
23.6 231 49.1
24.3 213 45.2
25.5 62 13.1
26.6 103 21.8
27.7 38 8.0
29.7 93 19.7
晶型C单晶XRD晶体参数及结构数据详见表12所述：
表12晶型C倍半水合物晶体参数及结构数据表
Figure PCTCN2022134410-appb-000026
通过上述单晶解析数据可以确定该晶型C为倍半水合物。
实施例7溶解度相关测定
式IV化合物单对甲苯磺酸盐一水合物晶型B在水中溶解度测试方法：精密称取约0.5g晶型B，向其中滴加水，记录溶剂加入量与晶型B溶解状态，当晶型B完全溶清时，记录溶剂的加入量，计算临界饱和溶解度；若加入50ml以上溶剂仍无法溶清，则取样离心检测饱和溶解度。
式IV化合物单对甲苯磺酸盐一水合物晶型B在各个pH值中溶解度测试方法：精密称取约0.2g晶型B，向其中滴加溶剂，记录溶剂加入量与晶型B溶解状态，当晶型B完全溶清时，记录溶剂的加入量，计算临界饱和溶解 度；若加入50ml以上溶剂仍无法溶清，则取样离心检测饱和溶解度。式IV化合物单对甲苯磺酸盐一水合物晶型B的溶解度详见下表：
表13晶型B在各个介质中的溶解度
Figure PCTCN2022134410-appb-000027
实施例8(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(式IV化合物)晶型A的制备
于3mL玻璃瓶中先后加入200mg按照实施例1方法制备的S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦和2mL纯化水，常温磁力搅拌6小时后，将样品离心，取湿样置于40℃减压干燥21小时后得176mg的晶型A，收率88.0％，其XRPD图谱详见图8，X射线粉末衍射图数据详见表14。
表14晶型A的X射线粉末衍射图数据
2θ(°) 计数(counts) I/I 0(％)
4.1 45 15.4
5.6 42 14.3
7.6 109 36.9
10.2 107 36.4
10.9 13 4.4
12.6 59 20.1
13.0 44 14.8
15.2 18 6.2
17.6 246 83.4
19.7 85 28.9
20.3 184 62.5
20.9 294 100.0
22.2 60 20.5
23.2 22 7.5
24.6 19 6.6
27.0 40 13.6
28.8 14 4.6
37.0 6 2.1
37.7 12 4.1
实施例9(5)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦晶型的物理化学稳定性研究
将式IV化合物游离碱晶型A、式IV化合物单对甲苯磺酸盐晶型B分别放置在40℃/75％RH，60℃，75％RH，92.5％RH和光照条件下，检测其稳定性，具体试验方法参照《中国药典》2020年版四部通则9001原料药物与制剂 稳定性试验指导原则要求。利用XRPD和HPLC检测样品的物理和化学稳定性情况。具体结果详见下表：
表15晶型B稳定性试验结果汇总
Figure PCTCN2022134410-appb-000028
表16游离碱晶型A稳定性数据
Figure PCTCN2022134410-appb-000029
Figure PCTCN2022134410-appb-000030
实施例10(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦(式IV化合物)其它酸的盐型以及晶型的制备
分别取约50mg式IV化合物(按照实施例1方法制备)和1.05当量的酸(盐酸同时设置酸与式IV化合物摩尔比为2.10的情况)，加入1mL溶剂并在室温下搅拌2天。所得澄清液通过5℃搅拌和缓慢挥发的方法尝试结晶，固体通过离心分离，在40℃下，鼓风干燥或减压干燥2-5小时后用于XRPD表征。
表16式IV化合物成盐结果
Figure PCTCN2022134410-appb-000031
Figure PCTCN2022134410-appb-000032
具体地，式IV化合物的甲磺酸盐的制备方法如下：
分别取约50mg式IV化合物和1.05当量的甲磺酸，加入1mL甲苯，并在室温下搅拌2天。然后所得液体在5℃搅拌下缓慢挥发结晶。固体经离心分离后，在40℃下减压干燥2-5小时后得到(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基))嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的甲磺酸盐晶型，其XRPD如图9所示。
式IV化合物盐酸盐、二盐酸盐、磷酸盐、马尿酸盐、硫酸盐、氢溴酸盐、苯磺酸盐、草酸盐、富马酸盐、柠檬酸盐的X-射线粉末衍射(XRPD)谱图分别如图10-19所示。
实施例11(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6，7，8，9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物(式I化合物)的制备
将实施例4制备的晶型B，在40℃下减压干燥16小时，制备得到式I化合物单对甲苯磺酸盐的水合物(X＝0～1)， 取样品进行XRPD检测，其X射线粉末衍射图详见图20。
Figure PCTCN2022134410-appb-000033

Claims (11)

  1. 一种(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物。
  2. 根据权利要求1所述的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物，其具体结构如式I所示：
    Figure PCTCN2022134410-appb-100001
    其中，X＝0～2，进一步地，X＝0～1或1.5；进一步地，X为0、0.25、0.5、0.7、1、1.25、1.5或1.75。
  3. 一种结晶形式的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、13.2°±0.2°和21.8°±0.2°处具有衍射峰；
    进一步地，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、21.8°±0.2°和22.6°±0.2°处具有衍射峰；
    进一步地，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.4°±0.2°、19.7°±0.2°、21.8°±0.2°、22.6°±0.2°和29.4°±0.2°处具有衍射峰；
    进一步地，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、12.3°±0.2°、12.4°±0.2°、12.6°±0.2°、13.2°±0.2°、14.1°±0.2°、15.2°±0.2°、15.9°±0.2°、16.7°±0.2°、17.1°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.0°±0.2°、19.4°±0.2°、19.7°±0.2°、21.1°±0.2°、21.8°±0.2°、22.6°±0.2°、23.3°±0.2°、23.7°±0.2°、24.1°±0.2°、24.4°±0.2°、24.7°±0.2°、25.1°±0.2°、26.2°±0.2°、26.6°±0.2°、27.0°±0.2°、27.7°±0.2°、28.0°±0.2°、28.3°±0.2°、28.7°±0.2°、28.8°±0.2°、29.4°±0.2°、30.2°±0.2°和33.9°±0.2°处具有衍射峰。
  4. 根据权利要求1所述的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物，其为一水合物，所述一水合物的具体结构如式II所示：
    Figure PCTCN2022134410-appb-100002
  5. 根据权利要求4所述的单对甲苯磺酸盐或其水合物，所述一水合物晶型的X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、13.2°±0.2°和21.8°±0.2°处具有衍射峰；
    进一步地，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、21.8°±0.2°和22.6°±0.2°处具有衍射峰；
    进一步地，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、13.2°±0.2°、15.2°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.4°±0.2°、19.7°±0.2°、21.8°±0.2°、22.6°±0.2°和29.4°±0.2°处具有衍射峰；
    进一步地，其X射线粉末衍射图在2θ为6.0°±0.2°、6.3°±0.2°、10.5°±0.2°、11.5°±0.2°、12.3°±0.2°、12.4°±0.2°、12.6°±0.2°、13.2°±0.2°、14.1°±0.2°、15.2°±0.2°、15.9°±0.2°、16.7°±0.2°、17.1°±0.2°、18.0°±0.2°、18.6°±0.2°、18.7°±0.2°、19.0°±0.2°、19.4°±0.2°、19.7°±0.2°、21.1°±0.2°、21.8°±0.2°、22.6°±0.2°、23.3°±0.2°、23.7°±0.2°、24.1°±0.2°、24.4°±0.2°、24.7°±0.2°、25.1°±0.2°、26.2°±0.2°、26.6°±0.2°、27.0°±0.2°、27.7°±0.2°、28.0°±0.2°、28.3°±0.2°、28.7°±0.2°、28.8°±0.2°、29.4°±0.2°、30.2°±0.2°和33.9°±0.2°处具有衍射峰；
    进一步的以2θ角度表示的X射线粉末衍射具有如图1所示的图谱。
  6. 根据权利要求1所述的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物，其为倍半水合物，所述倍半水合物的具体结构如式III所示：
    Figure PCTCN2022134410-appb-100003
  7. 根据权利要求6所述的单对甲苯磺酸盐或其水合物，所述倍半水合物的晶型的X射线粉末衍射图在2θ为13.4°±0.2°、18.4°±0.2°、19.3°±0.2°、19.8°±0.2°和21.8°±0.2°处具有衍射峰；
    进一步地，其X射线粉末衍射图在2θ为12.1°±0.2°、13.4°±0.2°、15.0°±0.2°、16.9°±0.2°、18.4°±0.2°、19.3°±0.2°、19.8°±0.2°、21.8°±0.2°、23.6°±0.2°和24.3°±0.2°处具有衍射峰；
    进一步地，其X射线粉末衍射图在2θ为6°±0.2°、10.8°±0.2°、12.1°±0.2°、13.4°±0.2°、15.0°±0.2°、16.9°±0.2°、18.4°±0.2°、19.0°±0.2°、19.3°±0.2°、19.8°±0.2°、20.9°±0.2°、21.8°±0.2°、23.2°±0.2°、23.6°±0.2°、24.3°±0.2°、25.5°±0.2°和26.6°±0.2°处具有衍射峰；
    进一步以2θ角度表示的X射线粉末衍射具有如图7所示的图谱。
  8. 根据权利要求1所述的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物的制备方法，包括将式IV化合物与对甲苯磺酸成盐的步骤，所述式IV化合物结构如下：
    Figure PCTCN2022134410-appb-100004
  9. 晶型组合物，其中权利要求1-7中任一项所述的单对甲苯磺酸盐或其水合物、或权利要求8制备得到的单对甲苯磺酸盐或其水合物占所述晶型组合物重量的50％以上；
    进一步占所述晶型组合物重量的80％以上；
    进一步占所述晶型组合物重量的90％以上；
    进一步占所述晶型组合物重量的95％以上。
  10. 一种(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基) -5-(甲氧基甲基)苯基)二甲基氧化膦单对甲苯磺酸盐的药物组合物，其包括权利要求1-7中任一项所述的单对甲苯磺酸盐或其水合物、权利要求8制备得到的单对甲苯磺酸盐或其水合物、或权利要求9所述的晶型组合物。
  11. 一种权利要求1-7中任一项所述的(S)-(2-((5-氯-2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-(甲氧基甲基)苯基)二甲基氧化膦的单对甲苯磺酸盐或其水合物、权利要求8制备得到的单对甲苯磺酸盐或其水合物、权利要求9所述的晶型组合物、或权利要求10所述的药物组合物在制备用于预防和/或治疗AXL激酶介导的疾病或疾病状态的药物中的用途。
PCT/CN2022/134410 2021-11-26 2022-11-25 Axl激酶抑制剂的单对甲苯磺酸盐及其晶型 WO2023093861A1 (zh)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP22897943.1A EP4438613A1 (en) 2021-11-26 2022-11-25 Mono-p-toluenesulfonate of axl kinase inhibitor and crystal form thereof
US18/713,611 US20250026773A1 (en) 2021-11-26 2022-11-25 Mono-p-toluenesulfonate of axl kinase inhibitor and crystal form thereof
CN202280078369.7A CN118302430A (zh) 2021-11-26 2022-11-25 Axl激酶抑制剂的单对甲苯磺酸盐及其晶型
JP2024531383A JP2024543921A (ja) 2021-11-26 2022-11-25 ＡＸＬキナーゼ阻害剤のモノ－ｐ－トルエンスルホン酸塩およびその結晶形
CA3239187A CA3239187A1 (en) 2021-11-26 2022-11-25 Mono-p-toluenesulfonate of axl kinase inhibitor and crystal form thereof
AU2022395869A AU2022395869A1 (en) 2021-11-26 2022-11-25 Mono-p-toluenesulfonate of axl kinase inhibitor and crystal form thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111425629.7A CN116178434A (zh) 2021-11-26 2021-11-26 Axl激酶抑制剂的单对甲苯磺酸盐及其晶型
CN202111425629.7 2021-11-26

Publications (1)

Publication Number Publication Date
WO2023093861A1 true WO2023093861A1 (zh) 2023-06-01

Family

ID=86435054

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/134410 WO2023093861A1 (zh) 2021-11-26 2022-11-25 Axl激酶抑制剂的单对甲苯磺酸盐及其晶型

Country Status (7)

Country Link
US (1) US20250026773A1 (zh)
EP (1) EP4438613A1 (zh)
JP (1) JP2024543921A (zh)
CN (2) CN116178434A (zh)
AU (1) AU2022395869A1 (zh)
CA (1) CA3239187A1 (zh)
WO (1) WO2023093861A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024141040A1 (zh) * 2022-12-30 2024-07-04 南京正大天晴制药有限公司 作为axl抑制剂的药物组合物

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024199102A1 (zh) * 2023-03-24 2024-10-03 南京正大天晴制药有限公司 一种axl抑制剂的制备方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101796046A (zh) * 2007-07-16 2010-08-04 阿斯利康(瑞典)有限公司 嘧啶衍生物934
CN102356075A (zh) * 2009-01-23 2012-02-15 里格尔药品股份有限公司 抑制jak途径的组合物和方法
WO2015038868A1 (en) * 2013-09-13 2015-03-19 Cephalon, Inc. Fused bicyclic 2,4-diaminopyrimidine derivatives
CN106458914A (zh) * 2014-03-28 2017-02-22 常州捷凯医药科技有限公司 作为axl抑制剂的杂环化合物
WO2018102366A1 (en) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors
WO2020253860A1 (zh) * 2019-06-21 2020-12-24 江苏豪森药业集团有限公司 芳基磷氧化物类衍生物抑制剂、其制备方法和应用
WO2021125803A1 (ko) * 2019-12-16 2021-06-24 한국화학연구원 신규한 피리미딘 유도체 및 이의 용도
WO2021239133A1 (zh) * 2020-05-29 2021-12-02 南京正大天晴制药有限公司 作为axl抑制剂的嘧啶类化合物

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101796046A (zh) * 2007-07-16 2010-08-04 阿斯利康(瑞典)有限公司 嘧啶衍生物934
CN102356075A (zh) * 2009-01-23 2012-02-15 里格尔药品股份有限公司 抑制jak途径的组合物和方法
WO2015038868A1 (en) * 2013-09-13 2015-03-19 Cephalon, Inc. Fused bicyclic 2,4-diaminopyrimidine derivatives
CN106458914A (zh) * 2014-03-28 2017-02-22 常州捷凯医药科技有限公司 作为axl抑制剂的杂环化合物
WO2018102366A1 (en) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors
WO2020253860A1 (zh) * 2019-06-21 2020-12-24 江苏豪森药业集团有限公司 芳基磷氧化物类衍生物抑制剂、其制备方法和应用
WO2021125803A1 (ko) * 2019-12-16 2021-06-24 한국화학연구원 신규한 피리미딘 유도체 및 이의 용도
WO2021239133A1 (zh) * 2020-05-29 2021-12-02 南京正大天晴制药有限公司 作为axl抑制剂的嘧啶类化合物

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
HUNG BL ET AL., DNA CELL BIOL, vol. 22, no. 8, 2003, pages 533 - 540
LINGER, R. M ET AL., THER. TARGETS, vol. 14, no. 10, 2010, pages 1073 - 1090
RESCIGNO, J. ET AL., ONCOGENE, vol. 6, no. 10, 1991, pages 1909 - 1913
ROBINSON, DR ET AL., ONCOGENE, vol. 19, 2000, pages 5548 - 5557
SEGALINY, AL ET AL., J. BONE ONCOL, vol. 4, 2015, pages 1 - 12
WU YMROBINSON DRKUNG HJ, CANCER RES, vol. 64, no. 20, 2004, pages 7311 - 7320

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024141040A1 (zh) * 2022-12-30 2024-07-04 南京正大天晴制药有限公司 作为axl抑制剂的药物组合物

Also Published As

Publication number Publication date
US20250026773A1 (en) 2025-01-23
EP4438613A1 (en) 2024-10-02
CN118302430A (zh) 2024-07-05
JP2024543921A (ja) 2024-11-26
CN116178434A (zh) 2023-05-30
CA3239187A1 (en) 2023-06-01
AU2022395869A1 (en) 2024-06-13

Similar Documents

Publication Publication Date Title
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
RU2686722C1 (ru) Новые кристаллы урацильного соединения
EP1559715B1 (en) N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-n'-(5-methyl-3-isoxazolyl)urea salt in crystalline form
WO2023093861A1 (zh) Axl激酶抑制剂的单对甲苯磺酸盐及其晶型
WO2020147838A1 (zh) 一种egfr抑制剂的盐、晶型及其制备方法
CN117769560A (zh) Egfr抑制剂的盐、晶型及其组合物和应用
CN117247382A (zh) 吡啶并嘧啶酮化合物的晶型
CN111205290B (zh) 一种jak激酶抑制剂的结晶形式及其制备方法
JP7430656B2 (ja) Ｃｄｋ４／６活性阻害化合物の結晶形およびその使用
CN113966332A (zh) Cdk9抑制剂的多晶型物及其制法和用途
ES2784325T3 (es) Formas cristalinas de sales farmacéuticamente aceptables de N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(4-metil-2-tienil)-1-ftalazinamina y usos de las mismas
WO2023093859A1 (zh) Axl激酶抑制剂的盐、其制备方法和用途
CN115448874B (zh) 固体形式的周期蛋白依赖性激酶9抑制剂及其用途
CN114853762A (zh) 一种咪唑并三嗪类化合物的固体形式及其制备方法和用途
CN114685455A (zh) Azd9291结晶固体
WO2018099451A1 (zh) 化合物的晶型
WO2024141040A1 (zh) 作为axl抑制剂的药物组合物
TWI826013B (zh) 咪唑啉酮衍生物的晶型
CN113929663B (zh) Azd9291-2-吲哚甲酸盐及其制备方法
CN112654623B (zh) 新型氮杂三环类化合物的盐型、晶型及其用途
WO2024027825A1 (zh) 一种cdk抑制剂及其磷酸盐的多晶型
WO2023109761A1 (zh) 吡唑并嘧啶酮类化合物及其盐的结晶
WO2024260348A1 (zh) 二氢蝶啶酮类化合物的结晶及其制备方法
CN119630674A (zh) 一种5,6-二氢噻吩并[3,4-h]喹唑啉类化合物的盐型、晶型及其制备方法
TW202416984A (zh) 化合物i或其鹽的固體形式

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: 22897943

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2024531383

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3239187

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 18713611

Country of ref document: US

Ref document number: 202280078369.7

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2022395869

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2022395869

Country of ref document: AU

Date of ref document: 20221125

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2022897943

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022897943

Country of ref document: EP

Effective date: 20240626