WO2023040876A1 - Composé aza-aromatique, polymorphe de sel pharmaceutiquement acceptable de celui-ci, composition pharmaceutique et application - Google Patents

Composé aza-aromatique, polymorphe de sel pharmaceutiquement acceptable de celui-ci, composition pharmaceutique et application Download PDF

Info

Publication number
WO2023040876A1
WO2023040876A1 PCT/CN2022/118654 CN2022118654W WO2023040876A1 WO 2023040876 A1 WO2023040876 A1 WO 2023040876A1 CN 2022118654 W CN2022118654 W CN 2022118654W WO 2023040876 A1 WO2023040876 A1 WO 2023040876A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
ray powder
compound
powder diffraction
free base
Prior art date
Application number
PCT/CN2022/118654
Other languages
English (en)
Chinese (zh)
Inventor
赵双妮
王吉标
陶涛
Original Assignee
上海海雁医药科技有限公司
扬子江药业集团有限公司
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 上海海雁医药科技有限公司, 扬子江药业集团有限公司 filed Critical 上海海雁医药科技有限公司
Priority to CN202280060100.6A priority Critical patent/CN117915919A/zh
Publication of WO2023040876A1 publication Critical patent/WO2023040876A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • This application relates to the field of medical technology, in particular to an azaaromatic compound 3-(4-amino-6-(1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H -1,2,3-triazol-4-yl)-5-fluoropyrimidin-2-yl)-2-methylbenzonitrile polymorphs or pharmaceutically acceptable salts thereof, and polymorphs comprising the polymorph
  • the pharmaceutical composition of the crystal form, the preparation method and application of the polymorph and the pharmaceutical composition are examples of the crystal form, the preparation method and application of the polymorph and the pharmaceutical composition.
  • Adenosine is an endogenous nucleoside throughout human cells, composed of adenine and ribose, which is widely distributed inside and outside cells. Adenosine participates in a variety of physiological and biochemical functions in the body. For example, adenosine can directly enter the myocardium and be phosphorylated to generate adenosine triphosphate (ATP), which participates in the energy metabolism of the myocardium. In the central nervous system (Central Nervous System, CNS), adenosine controls the release of neurotransmitters and the response of postsynaptic neurons, and plays an important role in regulating movement, protecting neurons, affecting sleep and wakefulness, etc. . In pathological conditions, the extracellular adenosine concentration increases significantly under tumor or hypoxic conditions. Adenosine can play an important role in tumor immunosuppression by promoting tumor angiogenesis, proliferation, development and tumor migration.
  • ATP adenosine triphosphate
  • Adenosine receptor belongs to G protein-coupled receptor (Guanosine-binding Protein Coupled Receptor, GPCR) family, and its endogenous ligand is adenosine.
  • the currently known adenosine receptors are composed of four subtype receptors, A 1 , A 2A , A 2B and A 3 .
  • the combination of adenosine with A1 or A3 receptors can inhibit the production of cyclic adenosine monophosphate (cAMP); while the combination with A2A or A2B receptors can activate adenosine activating enzyme, and then up-regulate the level of cAMP, and play a further role.
  • cAMP cyclic adenosine monophosphate
  • a 1 and A 3 receptors are mainly expressed in the central nervous system, while A 2A and A 2B adenosine receptors are expressed in both the central nervous system and the peripheral system.
  • A2A and A2B are widely expressed in immune cells and have strong immunosuppressive functions.
  • the increase of extracellular adenosine concentration is one of the important mechanisms of immune escape of tumor cells, and its concentration level is jointly determined by the level of ATP and the expression levels of CD39 and CD73.
  • the increase in extracellular adenosine concentration is related to the release of large amounts of ATP by cell death or hypoxia in the tumor microenvironment, and its concentration can reach 10-20 times that of normal tissues.
  • Adenosine binds to adenosine receptors in the tumor microenvironment, which can inhibit anti-tumor responses, such as inhibiting the function of CD8+ T cells, enhancing the function of immunosuppressive regulatory T cells, and inhibiting the function of antigen-presenting cells through dendritic cells wait. Recent studies have shown that binding to A2A receptors can also inhibit the tumor-killing effect of natural killer cells.
  • A2A adenosine receptor antagonists can improve the activity and killing ability of dendritic antigen-presenting cells, T cells and natural killer cells, and inhibit regulatory T cells (T-regs), bone marrow-derived suppressive Cells (MDSCs) and tumor-associated macrophages (TAMs) eliminate tumor immune tolerance and promote the occurrence of tumor immune responses, which in turn lead to suppressed tumor growth and prolong the survival of mice.
  • T-regs regulatory T cells
  • MDSCs bone marrow-derived suppressive Cells
  • TAMs tumor-associated macrophages
  • A2B receptors have also been reported to promote tumor migration in mouse melanoma and triple-negative breast cancer models, so A2B receptor antagonists are also effective targets for cancer therapy.
  • blocking the activation of adenosine signaling pathway to reduce or relieve immunosuppression and enhance the anti-tumor function of immune cells—especially T cells is considered to be one of the effective methods for cancer treatment.
  • the A2A / A2B dual receptor antagonist is used to simultaneously block the activation of these two receptors. Mechanistically speaking, it is regulating different immune cell populations and comprehensively blocking the immune response brought about by adenosine in the microenvironment. Inhibitory effect has far-reaching clinical application value for tumor therapy.
  • the present application provides a polymorph of an azaaromatic compound represented by formula (X) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing it, a preparation method or application thereof,
  • the pharmaceutically acceptable salt is selected from: hydrochloride, sulfate, citrate, fumarate or succinate.
  • the polymorphs of the compound of Formula X or the polymorphs of the pharmaceutically acceptable salt of the compound of Formula X are each independently in an anhydrous form, a hydrate form, or a solvate form.
  • Each of the X-ray powder diffraction patterns involved in the present application can be obtained independently using Cu-K ⁇ radiation.
  • the type I crystal form of the compound represented by formula (X) is provided, that is, the free base crystal form I, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ (°) angle: 7.57 ⁇ 0.2 , 13.41 ⁇ 0.2, 14.64 ⁇ 0.2, 19.81 ⁇ 0.2, and 24.43 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form I further includes one or two characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 24.87 ⁇ 0.2 and 27.46 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form I further includes 2 or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 8.56 ⁇ 0.2, 15.40 ⁇ 0.2, 18.55 ⁇ 0.2, 21.25 ⁇ 0.2, 23.05 ⁇ 0.2, 23.59 ⁇ 0.2, and 25.60 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 7.57 ⁇ 0.2, 8.56 ⁇ 0.2, 10.60 ⁇ 0.2, 11.80 ⁇ 0.2, 13.41 ⁇ 0.2 0.2, 14.16 ⁇ 0.2, 14.64 ⁇ 0.2, 15.40 ⁇ 0.2, 16.63 ⁇ 0.2, 17.23 ⁇ 0.2, 18.55 ⁇ 0.2, 19.81 ⁇ 0.2, 21.25 ⁇ 0.2, 22.18 ⁇ 0.2, 22.46 ⁇ 0.2, 23.05 ⁇ 0.2, 23.59 ⁇ 0.2, 24.43 ⁇ 0.2, 24.87 ⁇ 0.2, 25.60 ⁇ 0.2, 26.03 ⁇ 0.2, and 27.46 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form I has diffraction peaks at the 2 ⁇ (°) values shown in Table 1, and the relative intensities of each diffraction peak are shown in Table 1. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the free base crystalline form I is substantially as shown in FIG. 1 .
  • the X-ray powder diffraction pattern of the free base crystalline form I is shown in FIG. 1 .
  • the differential scanning calorimetry curve of the free base crystalline form I has an endothermic peak at 179.10 ⁇ 3°C.
  • the differential scanning calorimetry curve of the free base crystalline form I has an endothermic peak at 179.10 ⁇ 2°C.
  • the differential scanning calorimetry curve of the free base crystalline form I has an endothermic peak at 179.10 ⁇ 0.5°C.
  • the differential scanning calorimetry curve of the free base Form I is substantially as shown in FIG. 2 .
  • the differential scanning calorimetry curve of the free base crystalline form I is shown in FIG. 2 .
  • the compound of formula (X) is mixed with the I-3 solvent, heated to dissolve at a temperature of 45°C to 85°C, cooled to 0°C to room temperature, separated to obtain the I-3 solid, and
  • said 1-3 solvent is methanol or ethanol.
  • the preparation method of free base crystal form I comprises the following steps:
  • the compound of formula (X) is mixed with the I-3 solvent, heated to dissolve at a temperature of 45°C to 55°C, cooled to 0°C to 4°C, separated to obtain the I-3 solid, and
  • said 1-3 solvent is methanol or ethanol.
  • the preparation method of free base crystal form I comprises the following steps:
  • said I-3A solvent is ethanol.
  • the preparation method of free base crystal form I comprises the following steps:
  • the compound of formula (X) is mixed with the I-3B solvent, heated to dissolve at a temperature of 60° C. to 70° C., cooled to room temperature, and separated to obtain the I-3 solid, and
  • said I-3B solvent is methanol.
  • the third aspect of the present application provides the type IV crystal form of the compound of formula (X), that is, the free base crystal form IV, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 11.88 ⁇ 0.2, 14.17 ⁇ 0.2, 16.96 ⁇ 0.2, 22.63 ⁇ 0.2, 23.56 ⁇ 0.2, and 25.66 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form IV further includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 15.76 ⁇ 0.2 and 26.08 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form IV further includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 15.76 ⁇ 0.2, 26.08 ⁇ 0.2 and 37.48 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form IV further includes 2 or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 14.89 ⁇ 0.2, 21.73 ⁇ 0.2, 24.43 ⁇ 0.2, 26.65 ⁇ 0.2, 27.39 ⁇ 0.2, 28.42 ⁇ 0.2, and 30.24 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form IV further includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 8.71 ⁇ 0.2, 19.93 ⁇ 0.2 and 31.78 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form IV has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 8.71 ⁇ 0.2, 9.57 ⁇ 0.2, 11.88 ⁇ 0.2, 14.17 ⁇ 0.2, 14.89 ⁇ 0.2 0.2, 15.76 ⁇ 0.2, 16.96 ⁇ 0.2, 19.93 ⁇ 0.2, 21.73 ⁇ 0.2, 22.63 ⁇ 0.2, 23.56 ⁇ 0.2, 24.43 ⁇ 0.2, 25.66 ⁇ 0.2, 26.08 ⁇ 0.2, 26.65 ⁇ 0.2, 27.39 ⁇ 0.2, 28.42 ⁇ 0.2, 30.24 ⁇ 0.2, 31.78 ⁇ 0.2, and 33.15 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form IV has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 8.71 ⁇ 0.2, 9.57 ⁇ 0.2, 11.88 ⁇ 0.2, 14.17 ⁇ 0.2, 14.89 ⁇ 0.2 0.2, 15.76 ⁇ 0.2, 16.96 ⁇ 0.2, 19.93 ⁇ 0.2, 21.73 ⁇ 0.2, 22.63 ⁇ 0.2, 23.56 ⁇ 0.2, 24.43 ⁇ 0.2, 25.66 ⁇ 0.2, 26.08 ⁇ 0.2, 26.65 ⁇ 0.2, 27.39 ⁇ 0.2, 28.42 ⁇ 0.2, 30.24 ⁇ 0.2, 31.78 ⁇ 0.2, 33.15 ⁇ 0.2, and 37.48 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form IV has diffraction peaks at the 2 ⁇ (°) values shown in Table 2, and the relative intensity of each diffraction peak is shown in Table 2. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the free base crystalline Form IV is substantially as shown in FIG. 4 .
  • the X-ray powder diffraction pattern of the free base crystalline form IV is shown in FIG. 4 .
  • the differential scanning calorimetry curve of the free base crystalline form IV has an endothermic peak at 170.43 ⁇ 3°C.
  • the differential scanning calorimetry curve of the free base crystalline form IV has an endothermic peak at 170.43 ⁇ 2°C.
  • the differential scanning calorimetry curve of the free base crystalline form IV has an endothermic peak at 170.43 ⁇ 0.5°C.
  • the differential scanning calorimetry curve of the free base crystalline Form IV is substantially as shown in FIG. 5 .
  • the differential scanning calorimetry curve of the free base crystalline Form IV is shown in FIG. 5 .
  • a method for preparing free base crystal form IV comprising the following steps:
  • the V-type crystal form of the compound of formula (X) is provided, that is, the free base crystal form V, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 11.88 ⁇ 0.2, 16.36 ⁇ 0.2, 16.99 ⁇ 0.2, 22.99 ⁇ 0.2, 23.47 ⁇ 0.2, and 26.41 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form V has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 11.88 ⁇ 0.2, 16.36 ⁇ 0.2, 16.99 ⁇ 0.2, 22.99 ⁇ 0.2, 23.47 ⁇ 0.2, 26.41 ⁇ 0.2 and 37.48 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form V further includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 7.90 ⁇ 0.2, 13.71 ⁇ 0.2, 14.14 ⁇ 0.2, 15.31 ⁇ 0.2, 17.80 ⁇ 0.2, 18.76 ⁇ 0.2, 21.34 ⁇ 0.2, 24.82 ⁇ 0.2, 25.51 ⁇ 0.2, 27.88 ⁇ 0.2, and 30.46 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form V further includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 7.90 ⁇ 0.2, 13.71 ⁇ 0.2, 14.14 ⁇ 0.2, 15.31 ⁇ 0.2, 17.80 ⁇ 0.2, 18.76 ⁇ 0.2, 21.34 ⁇ 0.2, 24.82 ⁇ 0.2, 25.51 ⁇ 0.2, 27.88 ⁇ 0.2, 30.46 ⁇ 0.2, and 43.60 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form V further includes 2 or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 15.77 ⁇ 0.2, 20.03 ⁇ 0.2, 28.40 ⁇ 0.2, 30.85 ⁇ 0.2, 32.71 ⁇ 0.2, 33.15 ⁇ 0.2, and 34.62 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form V has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 7.90 ⁇ 0.2, 8.62 ⁇ 0.2, 9.73 ⁇ 0.2, 11.88 ⁇ 0.2, 13.71 ⁇ 0.2 0.2, 14.14 ⁇ 0.2, 15.31 ⁇ 0.2, 15.77 ⁇ 0.2, 16.36 ⁇ 0.2, 16.99 ⁇ 0.2, 17.80 ⁇ 0.2, 18.76 ⁇ 0.2, 20.03 ⁇ 0.2, 21.34 ⁇ 0.2, 22.99 ⁇ 0.2, 23.47 ⁇ 0.2, 24.82 ⁇ 0.2, 25.51 ⁇ 0.2, 26.41 ⁇ 0.2, 27.88 ⁇ 0.2, 28.40 ⁇ 0.2, 30.46 ⁇ 0.2, 30.85 ⁇ 0.2, 32.71 ⁇ 0.2, 33.15 ⁇ 0.2, and 34.62 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form V has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 7.90 ⁇ 0.2, 8.62 ⁇ 0.2, 9.73 ⁇ 0.2, 11.88 ⁇ 0.2, 13.71 ⁇ 0.2 0.2, 14.14 ⁇ 0.2, 15.31 ⁇ 0.2, 15.77 ⁇ 0.2, 16.36 ⁇ 0.2, 16.99 ⁇ 0.2, 17.80 ⁇ 0.2, 18.76 ⁇ 0.2, 20.03 ⁇ 0.2, 21.34 ⁇ 0.2, 22.99 ⁇ 0.2, 23.47 ⁇ 0.2, 24.82 ⁇ 0.2, 25.51 ⁇ 0.2, 26.41 ⁇ 0.2, 27.88 ⁇ 0.2, 28.40 ⁇ 0.2, 30.46 ⁇ 0.2, 30.85 ⁇ 0.2, 32.71 ⁇ 0.2, 33.15 ⁇ 0.2, 34.62 ⁇ 0.2, 37.48 ⁇ 0.2, and 43.60 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form V has diffraction peaks at the 2 ⁇ (°) values shown in Table 3, and the relative intensity of each diffraction peak is shown in Table 3. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the free base Form V is substantially as shown in FIG. 6 .
  • the X-ray powder diffraction pattern of the free base form V is shown in FIG. 6 .
  • the differential scanning calorimetry curve of the free base crystal form V has an endothermic peak at 179.02 ⁇ 3°C.
  • the differential scanning calorimetry curve of the free base crystalline form V has an endothermic peak at 179.02 ⁇ 2°C.
  • the differential scanning calorimetry curve of the free base form V has an endothermic peak at 179.02 ⁇ 0.5°C.
  • the differential scanning calorimetry curve of the free base Form V is substantially as shown in FIG. 7 .
  • the differential scanning calorimetry curve of the free base Form V is shown in FIG. 7 .
  • a method for preparing free base crystal form V comprising the following steps:
  • the seventh aspect of the present application provides the VIII crystal form of the compound of formula (X), that is, the free base crystal form VIII, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 6.40 ⁇ 0.2, 13.12 ⁇ 0.2 and 15.91 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form VIII further includes one or two characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 22.69 ⁇ 0.2 and 26.95 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form VIII further includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 11.62 ⁇ 0.2, 12.36 ⁇ 0.2, 16.62 ⁇ 0.2, 18.34 ⁇ 0.2, 18.88 ⁇ 0.2, 24.94 ⁇ 0.2, and 29.65 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form VIII further includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 11.62 ⁇ 0.2, 12.36 ⁇ 0.2, 16.62 ⁇ 0.2, 18.34 ⁇ 0.2, 18.88 ⁇ 0.2, 24.94 ⁇ 0.2, 29.65 ⁇ 0.2, and 37.48 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form VIII has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 6.40 ⁇ 0.2, 11.62 ⁇ 0.2, 12.36 ⁇ 0.2, 13.12 ⁇ 0.2, 15.91 ⁇ 0.2 0.2, 16.62 ⁇ 0.2, 18.34 ⁇ 0.2, 18.88 ⁇ 0.2, 22.69 ⁇ 0.2, 24.94 ⁇ 0.2, 26.95 ⁇ 0.2, and 29.65 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form VIII has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 6.40 ⁇ 0.2, 11.62 ⁇ 0.2, 12.36 ⁇ 0.2, 13.12 ⁇ 0.2, 15.91 ⁇ 0.2 0.2, 16.62 ⁇ 0.2, 18.34 ⁇ 0.2, 18.88 ⁇ 0.2, 22.69 ⁇ 0.2, 24.94 ⁇ 0.2, 26.95 ⁇ 0.2, 29.65 ⁇ 0.2, and 37.48 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the free base crystal form VIII has diffraction peaks at the 2 ⁇ (°) values shown in Table 4, and the relative intensities of each diffraction peak are shown in Table 4. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the free base Form VIII is substantially as shown in FIG. 8 .
  • the X-ray powder diffraction pattern of the free base form VIII is shown in FIG. 8 .
  • the differential scanning calorimetry curve of the free base crystalline form VIII has an endothermic peak at 162.93 ⁇ 3°C.
  • the differential scanning calorimetry curve of the free base crystalline form VIII has an endothermic peak at 162.93 ⁇ 2°C.
  • the differential scanning calorimetry curve of the free base crystalline form VIII has an endothermic peak at 162.93 ⁇ 0.5°C.
  • the differential scanning calorimetry curve of the free base Form VIII is substantially as shown in FIG. 9 .
  • the differential scanning calorimetry curve of the free base crystalline Form VIII is shown in FIG. 9 .
  • the eighth aspect of the present application provides a method for preparing free base crystal form VIII, comprising the following steps:
  • the free base crystal form I, free base crystal form IV or free base crystal form V described in the above aspects with the Z 3 -1 solvent, suspend and shake at room temperature for 70 to 80 hours, and separate to obtain the second Z 3 -1 solid, drying the Z 3 -1 solid to obtain the free base crystal form VIII; wherein the Z 3 -1 solvent is acetone or ethanol aqueous solution with a volume fraction of 50%.
  • the hydrochloride salt crystal form I of the compound of formula (X) is provided, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 11.95 ⁇ 0.2, 24.37 ⁇ 0.2, 25.21 ⁇ 0.2 and 26.35 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the hydrochloride salt form I also includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 8.83 ⁇ 0.2, 14.13 ⁇ 0.2, 15.33 ⁇ 0.2, 15.68 ⁇ 0.2, 18.86 ⁇ 0.2, 23.64 ⁇ 0.2, 27.67 ⁇ 0.2, and 28.57 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the hydrochloride salt form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 8.83 ⁇ 0.2, 11.95 ⁇ 0.2, 14.13 ⁇ 0.2, 15.33 ⁇ 0.2, 15.68 ⁇ 0.2, 17.25 ⁇ 0.2, 18.86 ⁇ 0.2, 23.64 ⁇ 0.2, 24.37 ⁇ 0.2, 25.21 ⁇ 0.2, 26.35 ⁇ 0.2, 27.67 ⁇ 0.2, and 28.57 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the hydrochloride salt form I has diffraction peaks at the 2 ⁇ (°) values shown in Table 5, and the relative intensity of each diffraction peak is shown in Table 5. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the hydrochloride salt form I is substantially as shown in FIG. 10 .
  • the X-ray powder diffraction pattern of the hydrochloride salt form I is shown in FIG. 10 .
  • Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 8.22 ⁇ 0.2, 11.29 ⁇ 0.2, 14.14 ⁇ 0.2, 16.96 ⁇ 0.2, 18.13 ⁇ 0.2, 22.27 ⁇ 0.2, 23.86 ⁇ 0.2 and 27.79 ⁇ 0.2 .
  • the X-ray powder diffraction pattern of the sulfate crystal form I further includes 2 or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 6.54 ⁇ 0.2 and 11.64 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the sulfate crystal form I further includes 2 or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 6.54 ⁇ 0.2, 11.64 ⁇ 0.2 and 37.48 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the sulfate crystal form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 6.54 ⁇ 0.2, 8.22 ⁇ 0.2, 11.29 ⁇ 0.2, 11.64 ⁇ 0.2, 14.14 ⁇ 0.2 0.2, 16.96 ⁇ 0.2, 18.13 ⁇ 0.2, 22.27 ⁇ 0.2, 23.86 ⁇ 0.2, and 27.79 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the sulfate crystal form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 6.54 ⁇ 0.2, 8.22 ⁇ 0.2, 11.29 ⁇ 0.2, 11.64 ⁇ 0.2, 14.14 ⁇ 0.2 0.2, 16.96 ⁇ 0.2, 18.13 ⁇ 0.2, 22.27 ⁇ 0.2, 23.86 ⁇ 0.2, 27.79 ⁇ 0.2, and 37.48 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the sulfate salt form I has diffraction peaks at the 2 ⁇ (°) values shown in Table 6, and the relative intensity of each diffraction peak is shown in Table 6. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the sulfate salt form I is substantially as shown in FIG. 11 .
  • the X-ray powder diffraction pattern of the sulfate crystalline form I is shown in FIG. 11 .
  • the citrate crystal form I of the compound of formula (X) is provided, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 12.55 ⁇ 0.2, 14.50 ⁇ 0.2, 21.55 ⁇ 0.2 and 22.75 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the citrate crystal form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 12.55 ⁇ 0.2, 14.50 ⁇ 0.2, 21.55 ⁇ 0.2, 22.75 ⁇ 0.2, 37.51 ⁇ 0.2 and 43.63 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the citrate crystal form I further includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 5.38 ⁇ 0.2, 9.78 ⁇ 0.2 and 13.63 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the citrate crystal form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 5.38 ⁇ 0.2, 9.78 ⁇ 0.2, 12.55 ⁇ 0.2, 13.63 ⁇ 0.2, 14.50 ⁇ 0.2, 21.55 ⁇ 0.2, and 22.75 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the citrate crystal form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 5.38 ⁇ 0.2, 9.78 ⁇ 0.2, 12.55 ⁇ 0.2, 13.63 ⁇ 0.2, 14.50 ⁇ 0.2, 21.55 ⁇ 0.2, 22.75 ⁇ 0.2, 37.51 ⁇ 0.2, and 43.63 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the citrate crystal form I has diffraction peaks at the 2 ⁇ (°) values shown in Table 7, and the relative intensity of each diffraction peak is shown in Table 7. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the citrate salt form I is substantially as shown in FIG. 12 .
  • the X-ray powder diffraction pattern of the citrate salt form I is shown in FIG. 12 .
  • the fumarate salt crystal form I of the compound of formula (X) is provided, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 7.12 ⁇ 0.2, 11.71 ⁇ 0.2 and 16.90 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the fumarate salt form I also includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 23.26 ⁇ 0.2, 23.65 ⁇ 0.2, 24.64 ⁇ 0.2 and 25.54 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the fumarate salt form I also includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 8.02 ⁇ 0.2, 15.69 ⁇ 0.2, 18.22 ⁇ 0.2 and 26.44 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the fumarate salt form I also includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 8.02 ⁇ 0.2, 15.69 ⁇ 0.2, 18.22 ⁇ 0.2 , 26.44 ⁇ 0.2 and 37.87 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the fumarate salt form I also includes 2 or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 10.48 ⁇ 0.2, 13.80 ⁇ 0.2 , 22.00 ⁇ 0.2 and 22.42 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the fumarate salt form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 7.12 ⁇ 0.2, 8.02 ⁇ 0.2, 10.48 ⁇ 0.2, 11.71 ⁇ 0.2 .
  • the X-ray powder diffraction pattern of the fumarate salt form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 7.12 ⁇ 0.2, 8.02 ⁇ 0.2, 10.48 ⁇ 0.2, 11.71 ⁇ 0.2 , 13.80 ⁇ 0.2, 15.69 ⁇ 0.2, 16.90 ⁇ 0.2, 18.22 ⁇ 0.2, 22.00 ⁇ 0.2, 22.42 ⁇ 0.2, 23.26 ⁇ 0.2, 23.65 ⁇ 0.2, 24.64 ⁇ 0.2, 25.54 ⁇ 0.2, 26.44 ⁇ 0.2, and 37.87 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the fumarate salt form I has diffraction peaks at the 2 ⁇ (°) values shown in Table 8, and the relative intensity of each diffraction peak is shown in Table 8. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the fumarate salt form I is substantially as shown in FIG. 13 .
  • the X-ray powder diffraction pattern of the fumarate salt form I is shown in FIG. 13 .
  • the succinate salt crystal form I of the compound of formula (X) is provided, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 13.78 ⁇ 0.2, 14.14 ⁇ 0.2 and 22.12 ⁇ 0.2.
  • the X-ray powder diffraction pattern of succinate salt form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 13.78 ⁇ 0.2, 14.14 ⁇ 0.2, 22.12 ⁇ 0.2 and 37.84 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the succinate salt form I further includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 4.87 ⁇ 0.2, 9.31 ⁇ 0.2, 18.16 ⁇ 0.2, 20.71 ⁇ 0.2 and 26.83 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the succinate salt form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 4.87 ⁇ 0.2, 9.31 ⁇ 0.2, 13.78 ⁇ 0.2, 14.14 ⁇ 0.2, 15.69 ⁇ 0.2, 18.16 ⁇ 0.2, 20.71 ⁇ 0.2, 22.12 ⁇ 0.2, and 26.83 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the succinate salt form I has characteristic diffraction peaks at the following 2 ⁇ (°) angles:
  • the X-ray powder diffraction pattern of the succinate salt form I has diffraction peaks at the 2 ⁇ (°) values shown in Table 9, and the relative intensity of each diffraction peak is shown in Table 9. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the succinic salt form I is substantially as shown in FIG. 14 .
  • the X-ray powder diffraction pattern of the succinic salt crystal form I is shown in FIG. 14 .
  • the fourteenth aspect of the present application provides the succinate crystal form II of the compound of formula (X), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 12.49 ⁇ 0.2 and 14.50 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the succinate crystal form II also includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 11.86 ⁇ 0.2, 15.22 ⁇ 0.2, 16.90 ⁇ 0.2, 21.64 ⁇ 0.2, 22.87 ⁇ 0.2, and 25.75 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the succinate crystal form II also includes at least one characteristic diffraction peak selected from the following 2 ⁇ (°) angles: 11.86 ⁇ 0.2, 15.22 ⁇ 0.2, 16.90 ⁇ 0.2, 21.64 ⁇ 0.2, 22.87 ⁇ 0.2, 25.75 ⁇ 0.2, and 37.84 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the succinate crystal form II has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 5.35 ⁇ 0.2, 11.86 ⁇ 0.2, 12.49 ⁇ 0.2, 14.50 ⁇ 0.2, 15.22 ⁇ 0.2, 16.90 ⁇ 0.2, 21.64 ⁇ 0.2, 22.87 ⁇ 0.2, and 25.75 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the succinate crystal form II has characteristic diffraction peaks at the following 2 ⁇ (°) angles: 5.35 ⁇ 0.2, 11.86 ⁇ 0.2, 12.49 ⁇ 0.2, 14.50 ⁇ 0.2, 15.22 ⁇ 0.2, 16.90 ⁇ 0.2, 21.64 ⁇ 0.2, 22.87 ⁇ 0.2, 25.75 ⁇ 0.2, and 37.84 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the succinate salt form II has diffraction peaks at the 2 ⁇ (°) values shown in Table 10, and the relative intensity of each diffraction peak is shown in Table 10. Among them, the definition of each relative intensity symbol is shown in Table 12.
  • the X-ray powder diffraction pattern of the succinic salt form II is substantially as shown in FIG. 15 .
  • the X-ray powder diffraction pattern of the succinate salt form II is shown in FIG. 15 .
  • the acid is hydrochloric acid, sulfuric acid, citric acid, fumaric acid, or succinic acid.
  • the solvent is ethanol, ethyl acetate, or acetone.
  • the anti-solvent is n-heptane.
  • composition comprising:
  • the seventeenth aspect of the present application provides free base crystal form I, free base crystal form IV, free base crystal form V, free base crystal form VIII, or hydrochloride crystal form of the compound of formula (X) as described above I, sulfate salt crystal form I, citrate crystal form I, fumarate salt crystal form I, succinate salt crystal form I, succinate crystal form II in the preparation of A2A receptor or A2B receptor inhibitors Applications.
  • polymorphs of the above-mentioned compound of formula (X) or a pharmaceutically acceptable salt thereof are provided, such as free base crystal form I, free base crystal form IV, free base crystal form V, Free base form VIII, or its hydrochloride form I, sulfate form I, citrate form I, fumarate form I, succinate form I, succinate form II, Or the use of the pharmaceutical composition described in the sixteenth aspect of the present application in the preparation of drugs for preventing or treating diseases mediated by adenosine A 2A receptors and/or adenosine A 2B receptors.
  • the present application provides a method for preventing or treating diseases mediated by adenosine A 2A receptors and/or adenosine A 2B receptors, comprising administering to patients in need thereof a therapeutically effective amount of A polymorphic form of the compound of formula (X) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the above embodiments.
  • the application provides the polymorphic form of the compound of formula (X) or its pharmaceutically acceptable salt as described in the above embodiment, or the pharmaceutical composition as described in the above embodiment for the prevention or treatment of adenosine A 2A receptor and/or adenosine A 2B receptor-mediated diseases.
  • the disease is cancer or an immune-related disease.
  • the cancer is selected from the group consisting of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, stomach cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer , neck cancer, melanoma, basal cancer, mesothelial lining cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer, non-small cell lung cancer, adrenal gland cancer, thyroid cancer, kidney cancer cancer and bone cancer; or malignant glioma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, basal cell carcinoma of the skin, and testicular seminoma.
  • the immune-related disease is selected from rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, anemic fibromyalgia, Alzheimer's Haimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis, and others Eczema, systemic sclerosis, and multiple sclerosis.
  • the compound of formula (X) of the present application the polymorphic form of the compound of formula X, the polymorphic form of the pharmaceutically acceptable salt of the compound of formula X, or the polymorphic form comprising the compound of formula (X) and the compound of formula (X)
  • the pharmaceutical composition of the polymorphic form of the pharmaceutically acceptable salt of the compound of formula X has good pharmacological activity of inhibiting A2A receptor and/or A2B receptor.
  • the polymorphic form of the compound of formula (X) and the polymorphic form of the pharmaceutically acceptable salt of the compound of formula X have good stability, so they have the potential to be developed into medicines.
  • Fig. 1 is the XPRD spectrum of the free base crystal form I of the compound of formula X prepared in Example 2 (using Cu-K ⁇ radiation, the abscissa is angle 2 ⁇ (°), and the ordinate is SQR (counts)), wherein SQR represents intensity square root of
  • Fig. 2 is the DSC spectrum of the free base crystal form I of the compound of formula X prepared in Example 2 (abscissa is temperature (°C), ordinate is heat flow rate (W/g));
  • Fig. 3 is the TGA spectrum of the free base crystal form I of the compound of formula X prepared in Example 2 (the abscissa is temperature (°C), and the ordinate is weight change (%));
  • Figure 4 is the XPRD spectrum of the free base crystal form IV of the compound of formula X prepared in Example 3 (using Cu-K ⁇ radiation, the abscissa is the angle 2 ⁇ (°), and the ordinate is SQR (counts)), wherein SQR represents the intensity square root of
  • Fig. 5 is the DSC spectrum of the free base crystal form IV of the compound of formula X prepared in Example 3 (the abscissa is temperature (°C), and the ordinate is heat flow rate (W/g));
  • Fig. 6 is the XPRD spectrum of the free base crystal form V of the compound of formula X prepared in Example 4 (using Cu-K ⁇ radiation, the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity (counts));
  • Figure 7 is the DSC spectrum of the free base crystal form V of the compound of formula X prepared in Example 4 (the abscissa is temperature (°C), and the ordinate is heat flow rate (W/g));
  • Fig. 8 is the XPRD spectrum of the free base crystal form VIII of the compound of formula X prepared in Example 5 (using Cu-K ⁇ radiation, the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity (counts));
  • Figure 9 is the DSC spectrum of the free base crystal form VIII of the compound of formula X prepared in Example 5 (the abscissa is temperature (°C), and the ordinate is heat flow rate (W/g));
  • Figure 10 is the XPRD spectrum of the hydrochloride salt form I of the compound of formula X prepared in Example 6 (using Cu-K ⁇ radiation, the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity (counts));
  • Figure 11 is the XPRD spectrum of the sulfate crystal form I of the compound of formula X prepared in Example 7 (using Cu-K ⁇ radiation, the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity (counts));
  • Figure 12 is the XPRD spectrum of the citrate crystal form I of the compound of formula X prepared in Example 8 (using Cu-K ⁇ radiation, the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity (counts));
  • Figure 13 is the XPRD spectrum of the fumarate salt form I of the compound of formula X prepared in Example 9 (using Cu-K ⁇ radiation, the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity (counts));
  • Figure 14 is the XPRD spectrum of the succinate salt form I of the compound of formula X prepared in Example 10 (using Cu-K ⁇ radiation, the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity (counts));
  • Fig. 15 is the XPRD spectrum of the succinate crystal form II of the compound of formula X prepared in Example 11 (using Cu-K ⁇ radiation, the abscissa is the angle 2 ⁇ (°), and the ordinate is the intensity (counts)).
  • first aspect”, “second aspect”, “third aspect”, “fourth aspect”, “fifth aspect” and so on are used for descriptive purposes only, and cannot be understood as indicating or implying relative importance or Quantity, nor should it be understood as implying the importance or quantity of the indicated technical features.
  • first”, “second”, “third”, “fourth”, “fifth” and so on are only for the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on the quantity.
  • the above numerical interval is considered continuous, and includes the minimum and maximum values of the range, and every value between such minimum and maximum values.
  • a range refers to an integer, every integer between the minimum and maximum of the range is included.
  • the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.
  • the percentage content involved in this application refers to mass percentage for solid-liquid mixing and solid-solid phase mixing, and refers to volume percentage for liquid-liquid phase mixing.
  • the percentage concentration involved in this application refers to the final concentration.
  • the final concentration refers to the proportion of the added component in the system after the component is added.
  • the temperature parameters in this application are allowed to be treated at a constant temperature, and also allowed to be treated within a certain temperature range.
  • the isothermal treatment allows the temperature to fluctuate within the precision of the instrument control.
  • the compound of formula (X) is 3-(4-amino-6-(1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3 -triazol-4-yl)-5-fluoropyrimidin-2-yl)-2-methylbenzonitrile, which has high inhibitory activity on adenosine A 2A receptors and/or adenosine A 2B receptors.
  • the polymorphic form of the compound of formula (X) includes the polymorphic form of the free base of the compound of formula (X) and the polymorphic form of the pharmaceutically acceptable salt of the compound of formula (X).
  • the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, citrate, fumarate or succinate.
  • Polymorphs of the compound of formula (X) and its pharmaceutically acceptable salts include but are not limited to free base crystal form I, free base crystal form IV, free base crystal form V, free base crystal form of the compound of formula (X) VIII, Hydrochloride Form I, Sulfate Form I, Citrate Form I, Fumarate Form I, Succinate Form I, and Succinate Form II.
  • therapeutically effective amount refers to the amount of the compound of the present application that will cause the individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, relieving symptoms, slowing down or delaying disease progression or preventing diseases, etc. quantity.
  • pharmaceutically acceptable carrier should be non-toxic and inert in principle.
  • the form of the “pharmaceutically acceptable carrier” is not particularly limited, including but not limited to solid, semi-solid, liquid and the like.
  • the pharmaceutically acceptable carrier should be compatible with the patient, preferably a mammal, more particularly a human.
  • One of the roles of the pharmaceutically acceptable carrier is to be suitable for delivering the active agent to the target site of interest without terminating the activity of the agent.
  • pharmaceutically acceptable carrier includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorbing agents compatible with pharmaceutical administration Retardants and the like.
  • Each carrier is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • patient refers to an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • treating refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing its development, or alleviating to some extent one or more symptoms of a disease or disorder.
  • Solids exist either in amorphous or crystalline form. In the case of crystalline forms, the molecules are positioned within three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize in a different spatial lattice arrangement (a property known as "polymorphism"), forming crystals with different crystalline forms, which are referred to as Known as "polymorphs". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystalline form, packing mode, flowability and/or solid state stability.
  • Production-scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound is exceeded. This can be accomplished by various methods, for example, dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit; or reducing the volume of the liquid by boiling, evaporation at atmospheric pressure, vacuum drying, or by some other method; The solubility of a compound can be reduced by adding an anti-solvent or a solvent in which the compound has low solubility, or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallization see Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
  • XRPD can detect information such as crystal form changes, crystallinity, and crystal structure state, and is a common method for identifying crystal forms.
  • the peak position of the XRPD pattern mainly depends on the structure of the crystal form, and the measurement of 2 ⁇ of the XRPD pattern may be slightly different between different instruments, so the value of 2 ⁇ cannot be regarded as absolute. According to the conditions of the instrument used in the test of this application, the diffraction peaks allow a certain error (such as ⁇ 0.2°). It can be understood that for different test instruments and test conditions, the error range is not absolute.
  • the crystal form of the compound of formula X in the present application has a specific crystal form, and has specific characteristic peaks in the XRPD pattern.
  • the X-ray powder diffraction pattern has a characteristic diffraction peak at a specific 2 ⁇ (°) angle", which means that the peak value of the peak is within the indicated numerical range, the indicated numerical point, and the vicinity of the indicated numerical range or near the indicated numerical point.
  • the X-ray powder diffraction pattern has a peak at a diffraction angle of 7.57 ⁇ 0.2
  • the peak of the peak can be located within the range of 7.57 ⁇ 0.2 or near this range, as long as it does not affect the identification of the crystal form as a whole.
  • ⁇ 0.2 here only means the error of the peak in the diffraction angle position, and has nothing to do with the peak shape and peak width of the peak.
  • the "substantially" in "the X-ray powder diffraction pattern is basically characterized by a specific figure" should also be understood similarly, as long as it can be recognized as a whole that a certain X-ray powder diffraction pattern is consistent with the X-ray powder diffraction pattern described in this application. Figures constitute substantially the same, it should be considered to fall within the scope of protection of the present application.
  • differential scanning calorimetry curve in the present application and the position of the endothermic peak shown therein should also be understood similarly, allowing slight discrepancies with the specific numerical values or specific numerical ranges or specific spectrograms disclosed in the present application. Inconsistent, but as long as part or all of the endothermic peak positions in the differential scanning calorimetry curve, or the entire curve is substantially consistent with the present application, it should be deemed to fall within the protection scope of the present application.
  • DSC scanning analysis Also known as “differential calorimetry scanning analysis", it is a technique to measure the relationship between the energy difference and temperature between the measured substance and the reference substance during the heating process.
  • the peak position, shape and number of peaks on the DSC spectrum are related to the properties of the substance, so it can be used to identify the substance qualitatively. This method is commonly used in the field to detect various parameters such as phase transition temperature, glass transition temperature, and heat of reaction of substances.
  • the peak position of the DSC spectrum may vary slightly between different instruments, so the value of the peak position of the DSC endothermic peak cannot be regarded as absolute.
  • the value of the experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C.
  • TGA is a technique for measuring the quality of substances with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sublimation and decomposition of samples. It can be speculated that crystals contain crystal water or crystallization solvents.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments. According to the condition of the instrument used in the test of this application, the error of mass change is not absolute, and a certain error (such as ⁇ 0.1%) is allowed.
  • optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. Additionally, many crystallization methods use combinations of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperature, followed by the addition of an appropriate volume of antisolvent in a controlled manner to bring the system just below saturation levels. At this point, seeds of the desired form can be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.
  • room temperature generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • the polymorphic form of the compound of formula (X) in the present application has a specific crystal form, and has specific characteristic peaks in the X-ray powder diffraction pattern (XPRD).
  • XPRD X-ray powder diffraction pattern
  • the position of each peak is determined by 2 ⁇ (°). It is understood that different instruments and/or conditions may result in slightly different data, with variations in the position and relative intensity of peaks. Those skilled in the art should understand that when determining the crystal form based on the XRPD pattern, the peaks at low diffraction angles and their intensity, peak shape integrity and other factors are relatively more meaningful. In this application, after further research, the applicant found that when using the above-mentioned instrument for testing, strong background peaks of a blank metal disk appeared near the two 2 ⁇ (°) values of 37 and 44 at high diffraction angles.
  • the peak near 37° in Figure 4 is presumed to be the peak produced by a blank metal disk (such as the peak at 37.48° in Table 2), and the peak near 37° and 43° in Figure 6 is speculated to be a blank metal disk
  • the peaks produced (as the peaks at 37.48° and 43.60° in Table 3)
  • the peaks near 37° in Figure 8 are speculated to be the peaks produced by blank metal disks (as the peaks at 37.48° in Table 4)
  • Figure 11 The peak near 37 ° in the middle is presumed to be the peak produced by the blank metal disc (as the peak at 37.48 ° in Table 6)
  • the peak near 37 ° and 43 ° in Figure 12 is speculated to be the peak produced by the blank metal disc (
  • the peak near 37° in Figure 13 is speculated to be the peak produced by the blank metal disk (as the peak at 37.87° in Table 8), near 37° in Figure 14
  • each crystal form takes the diffraction peak with the highest peak height as the base peak, defines its relative intensity as 100%, and regards it as I 0 , and uses the ratio of the peak height of the other peaks to the base peak peak height as its relative intensity.
  • Intensity I/I 0 the division definition of the relative intensity of each peak is shown in Table 12 below.
  • the DSC spectrum was collected on a DISCOVERY DSC25 differential scanning calorimeter, and the test parameters are shown in Table 13 below.
  • the structure and purity of the compounds are determined by nuclear magnetic resonance ( 1 HNMR) and/or liquid chromatography-mass spectrometry (LC-MS).
  • 1 HNMR Bruker AVANCE-400 nuclear magnetic analyzer, the internal standard is tetramethylsilane (TMS).
  • LC-MS Agilent 1200 HPLC System/6140 MS liquid mass spectrometry (manufacturer: Agilent), column WatersX-Bridge, 150 ⁇ 4.6 mm, 3.5 ⁇ m.
  • the starting materials known in the application can be adopted or synthesized according to methods known in the art, or can be obtained from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Darui Chemicals Wait for the company to buy.
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • EA ethyl acetate
  • PE petroleum ether
  • Pd(dppf)Cl2 [ 1 ,1'-bis(diphenylphosphine)ferrocene]palladium dichloride
  • Pd(PPh 3 ) 2 Cl 2 bis(triphenylphosphine)palladium(II) chloride
  • DPPA diphenylphosphoryl azide Esters
  • DBU 1,8-diazabicycloundec-7-ene.
  • the compound 1-ethylpyrazole-3-carboxylic acid ethyl ester (11.5g, 68.37mmol) was dissolved in THF (150mL), the temperature was lowered to -10°C under the protection of argon, and LiAlH 4 (3.89g, 102.56mmol) was added in batches ), and then stirred at about 0°C for 1 hour.
  • 5.0 g of sodium sulfate decahydrate was added in batches to the reaction solution at 0° C., stirred at 0° C. for 1 hour, then slowly raised to room temperature and stirred for 1 hour.
  • the obtained solid compound of formula X was sent to XRPD for detection, and its powder X-ray diffraction pattern had no characteristic peaks, and it was in an amorphous form.
  • Test Example 1 Inhibitory Activity of Formula X Compounds on A2A Receptors and A2B Receptors
  • CHO-K1/ADORA 2A /G ⁇ 15 (GenScript, M00246) and CHO-K1/ADORA 2B /G ⁇ 15 (GenScript, M00329) cells were cultured in Ham's F-12 (Gibco, 31765092) medium.
  • the culture medium conditions are 10% FBS, 200 ⁇ g/mL Zeocin and 100 ⁇ g/mL Hygromycin B or 10% FBS, 400 ⁇ g/mL G418 and 100 ⁇ g/mL Hygromycin B.
  • the screening steps are as follows:
  • mice healthy adult male ICR mice (weight 25g-40g, 12 mice, the mice in the intravenous injection group were free to drink water and food, and the intragastric administration group was fasted overnight, and free to drink water and food after 4 hours of administration), provided by Beijing Weiwei Provided by Tonglihua Laboratory Animal Technology Co., Ltd.;
  • ICR mice select animals that meet the experimental requirements before administration, and weigh the marks. ICR mice were administered via tail vein (2mg/kg, 5% DMSO, pH4.5 20% Captisol) and intragastrically (10mg/kg, 5% DMSO, pH4.5 20% Captisol).
  • Blood sample collection about 100 ⁇ L of blood was collected through the jugular vein at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 7.5 hours and 24 hours after administration for both intravenous and intragastric administration.
  • the blood was transferred to a 1.5mLEP tube pre-added with EDTA2K, centrifuged for 4min (8000rpm, 4°C), and the plasma was separated. The whole process was completed within 15min after blood collection. All plasma samples need to be stored in a -20°C freezer until sample analysis.
  • Table 15 shows the pharmacokinetic properties parameters of the compound of formula X in the present application in mice in the form of intravenous administration.
  • Table 16 shows the parameters of pharmacokinetic properties of compound X of the present application in mice in the form of intragastric administration.
  • Test Example 3 In vivo drug efficacy experiment of the compound of formula X of the present application
  • This test example investigates the mouse melanoma cell line B16F10-OVA-hPD-L1 subcutaneously transplanted tumor mice, after administering the compound of formula X of this application through the oral administration route, test its effect on melanoma B16F10-OVA-hPD-L1 In vivo drug efficacy in L1 tumor-bearing mice.
  • mice female
  • mouse melanoma B16F10-OVA-hPD-L1 cells (Shanghai Jiaotong University cell bank), cultured in vitro as a monolayer, and the culture conditions are DMEM medium containing 10% fetal bovine serum , cultured at 37 °C in a 5% CO 2 incubator. Routine digestion with trypsin-EDTA was performed for passage. When the cells were in the exponential growth phase and the saturation was 80%-90%, the cells were harvested and counted.
  • Compound preparation Measure the compound of formula X and add it into the solvent (40% sulfobutyl- ⁇ -cyclodextrin (captisol) in acetic acid buffer, pH 4.0) to prepare a sample with the target concentration.
  • Experimental operation resuspend the cells in phosphate buffered saline at a density of 5 ⁇ 10 6 cells/mL.
  • the mice were randomly divided into groups according to their body weight, with 10 mice in each group.
  • the drug was administered twice a day for 19 days. Animals were weighed and their health monitored daily throughout the experimental period. Tumor diameters were measured twice a week with vernier calipers.
  • V 0.5 ⁇ a ⁇ b 2 , where a and b represent the long diameter and short diameter of the tumor, respectively.
  • the antitumor efficacy of compounds was evaluated by relative tumor proliferation rate T/C (%).
  • Relative tumor proliferation rate T/C (%) Vt/Vc ⁇ 100% (Vt: average tumor volume of treatment group; Vc: average tumor volume of negative control group). Vt and Vc take the data of the same day. The results at the end of the administration are shown in Table 17.
  • the DSC spectrum of the free base crystal form I is shown in Figure 2, in which the endothermic peak is 179.10°C, and there is an endothermic peak at 104.32°C, and the TGA spectrum is shown in Figure 3, and the weight loss before 150°C is about 8.8%.
  • Form I contains the solvent ethanol.

Abstract

Un composé aza-aromatique, un polymorphe d'un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le comprenant, un procédé de préparation de celui-ci, et une application du polymorphe ou de la composition pharmaceutique le comprenant dans la préparation d'un médicament pour la prévention ou le traitement du cancer ou de maladies liées au système immunitaire médiées par un récepteur de l'adénosine A2A et/ou un récepteur de l'adénosine A2B.
PCT/CN2022/118654 2021-09-15 2022-09-14 Composé aza-aromatique, polymorphe de sel pharmaceutiquement acceptable de celui-ci, composition pharmaceutique et application WO2023040876A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280060100.6A CN117915919A (zh) 2021-09-15 2022-09-14 氮杂芳环类化合物及其药学上可接受的盐的多晶型物、药物组合物和应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111080394 2021-09-15
CN202111080394.2 2021-09-15

Publications (1)

Publication Number Publication Date
WO2023040876A1 true WO2023040876A1 (fr) 2023-03-23

Family

ID=85602437

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/118654 WO2023040876A1 (fr) 2021-09-15 2022-09-14 Composé aza-aromatique, polymorphe de sel pharmaceutiquement acceptable de celui-ci, composition pharmaceutique et application

Country Status (2)

Country Link
CN (1) CN117915919A (fr)
WO (1) WO2023040876A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017016463A1 (fr) * 2015-07-24 2017-02-02 上海海雁医药科技有限公司 Inhibiteur de l'egfr et sel pharmaceutiquement acceptable et polymorphe de celui-ci, et utilisation associée
WO2017206904A1 (fr) * 2016-06-02 2017-12-07 上海海雁医药科技有限公司 Inhibiteur de pi3k, sel pharmaceutiquement acceptable, forme polycristalline, et leur utilisation
CN110214012A (zh) * 2017-01-20 2019-09-06 艾库斯生物科学有限公司 用于治疗癌症相关疾病的唑嘧啶
WO2019206155A1 (fr) * 2018-04-24 2019-10-31 上海海雁医药科技有限公司 Inhibiteur d'ezh2, sels pharmaceutiquement acceptables, substances polymorphes de celui-ci, et utilisation de l'inhibiteur d'ezh2
WO2019206154A1 (fr) * 2018-04-24 2019-10-31 上海海雁医药科技有限公司 Inhibiteur de cdk4/6, sel pharmaceutiquement acceptable, polymorphe de celui-ci et utilisation associée
WO2020187267A1 (fr) * 2019-03-18 2020-09-24 上海海雁医药科技有限公司 Inhibiteur de btk, sel pharmaceutiquement acceptable, polymorphe et application de celui-ci
WO2021185256A1 (fr) * 2020-03-16 2021-09-23 上海海雁医药科技有限公司 Dérivé de pyrimidine amine ou de pyridine amine substituée, composition et utilisation médicale associées
CN113429410A (zh) * 2020-03-23 2021-09-24 上海海雁医药科技有限公司 多杂环取代的嘧啶或吡啶胺衍生物、其组合物及医药上的用途

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017016463A1 (fr) * 2015-07-24 2017-02-02 上海海雁医药科技有限公司 Inhibiteur de l'egfr et sel pharmaceutiquement acceptable et polymorphe de celui-ci, et utilisation associée
WO2017206904A1 (fr) * 2016-06-02 2017-12-07 上海海雁医药科技有限公司 Inhibiteur de pi3k, sel pharmaceutiquement acceptable, forme polycristalline, et leur utilisation
CN110214012A (zh) * 2017-01-20 2019-09-06 艾库斯生物科学有限公司 用于治疗癌症相关疾病的唑嘧啶
WO2019206155A1 (fr) * 2018-04-24 2019-10-31 上海海雁医药科技有限公司 Inhibiteur d'ezh2, sels pharmaceutiquement acceptables, substances polymorphes de celui-ci, et utilisation de l'inhibiteur d'ezh2
WO2019206154A1 (fr) * 2018-04-24 2019-10-31 上海海雁医药科技有限公司 Inhibiteur de cdk4/6, sel pharmaceutiquement acceptable, polymorphe de celui-ci et utilisation associée
WO2020187267A1 (fr) * 2019-03-18 2020-09-24 上海海雁医药科技有限公司 Inhibiteur de btk, sel pharmaceutiquement acceptable, polymorphe et application de celui-ci
WO2021185256A1 (fr) * 2020-03-16 2021-09-23 上海海雁医药科技有限公司 Dérivé de pyrimidine amine ou de pyridine amine substituée, composition et utilisation médicale associées
CN113429410A (zh) * 2020-03-23 2021-09-24 上海海雁医药科技有限公司 多杂环取代的嘧啶或吡啶胺衍生物、其组合物及医药上的用途

Also Published As

Publication number Publication date
CN117915919A (zh) 2024-04-19

Similar Documents

Publication Publication Date Title
IL212398A (en) 6-oxo-1,6-dihydropyridines and their use in drug preparation
UA79229C2 (en) 3-nitrogen-6,7-dioxygen steroids and uses related thereto
TW201236684A (en) Pharmaceutically acceptable salts of (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide, preparation process and pharmaceutical use there of
JP7406691B2 (ja) トリアゾロピリミジン系化合物の結晶形、塩のタイプおよびその調製方法
JP2018511634A (ja) Ｂ−ｒａｆキナーゼのマレイン酸塩、結晶形、調整方法、及びその使用
JP2020527166A (ja) Ｂｃｌ−２タンパク質を阻害するためのＮ−ベンゼンスルホニルベンズアミド系化合物、その組成物および使用
WO2020228807A1 (fr) Sels d'une classe de composés de pyrimidine, polymorphes et compositions pharmaceutiques de ceux-ci, procédés de préparation correspondants et utilisations associées
JPWO2004035572A1 (ja) Ｎ−｛２−クロロ−４−［（６，７−ジメトキシ−４−キノリル）オキシ］フェニル｝−ｎ’−（５−メチル−３−イソキサゾリル）ウレアの塩の結晶形
JP2015528482A (ja) 結晶性化合物
US20210079021A1 (en) Crystal form and salt form of tgf-bri inhibitor and preparation method therefor
JP2022553833A (ja) エストロゲン受容体調節薬の塩及び形態
WO2023040876A1 (fr) Composé aza-aromatique, polymorphe de sel pharmaceutiquement acceptable de celui-ci, composition pharmaceutique et application
JP2022518605A (ja) ジアリールチオヒダントイン化合物結晶
JP2022528747A (ja) Ｆａｋ阻害剤の塩及び結晶形態
KR102374933B1 (ko) c-Met 억제제의 결정형과 이의 염 형태 및 제조 방법
WO2023040863A1 (fr) Polymorphe et application de dérivé de pyrimidine et sel pharmaceutiquement acceptable associé
WO2020147838A1 (fr) Sel d'un inhibiteur d'egfr, forme cristalline et procédé de préparation associé
JP2019524857A (ja) キナゾリン誘導体の塩の結晶
TWI728404B (zh) 一種1,2,4-三-3-胺類衍生物的晶型及製備方法
WO2020140894A1 (fr) Composé de benzothiophène substitué contenant du fluor, composition pharmaceutique et application de celui-ci
WO2020192762A1 (fr) Forme de sel et forme cristalline d'un antagoniste du récepteur a2a et son procédé de préparation
TW201829398A (zh) 酪胺酸蛋白激酶調節劑、晶型及其用途
CN110903291B (zh) 一种杂芳基并[4,3-c]嘧啶-5-胺类衍生物的盐、盐的晶型及制备方法
CN112334473B (zh) 一种杂芳基并[4,3-c]嘧啶-5-胺类衍生物的晶型及制备方法
WO2022262699A1 (fr) Composé de benzimidazole substitué, composition le contenant et utilisation associée

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: 22869245

Country of ref document: EP

Kind code of ref document: A1