WO2022052950A1 - 一种降解btk化合物的盐及其晶型和在医药上的用途 - Google Patents

一种降解btk化合物的盐及其晶型和在医药上的用途 Download PDF

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WO2022052950A1
WO2022052950A1 PCT/CN2021/117174 CN2021117174W WO2022052950A1 WO 2022052950 A1 WO2022052950 A1 WO 2022052950A1 CN 2021117174 W CN2021117174 W CN 2021117174W WO 2022052950 A1 WO2022052950 A1 WO 2022052950A1
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compound
formula
crystal form
ray powder
powder diffraction
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PCT/CN2021/117174
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English (en)
French (fr)
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张晨
廖雨亭
王健民
黄龙彬
祝国智
李瑶
严庞科
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海思科医药集团股份有限公司
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Priority to MX2023002816A priority Critical patent/MX2023002816A/es
Priority to KR1020237009665A priority patent/KR20230091088A/ko
Priority to CA3192125A priority patent/CA3192125A1/en
Priority to EP21866003.3A priority patent/EP4212534A1/en
Priority to AU2021341998A priority patent/AU2021341998A1/en
Priority to JP2023515240A priority patent/JP2023541140A/ja
Priority to CN202180055214.7A priority patent/CN116528870A/zh
Priority to US18/025,390 priority patent/US20240018147A1/en
Priority to IL301156A priority patent/IL301156A/en
Publication of WO2022052950A1 publication Critical patent/WO2022052950A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 relates to the field of medicine, in particular, to a crystal form of a salt of a degraded BTK compound and its preparation and application.
  • BTK Bruton's tyrosine kinase
  • BCR B cell antigen receptor
  • BTK mutations cause downstream tumor cell proliferation, differentiation, and activation of signaling pathways such as angiogenesis, leading to X-linked agammaglobulinemia, non-Hodgkin lymphoma (NHL), and many B-cell malignancies, including chronic lymphoid malignancies.
  • CLL Cellular leukemia
  • mantle cell lymphoma mantle cell lymphoma
  • diffuse large B-cell lymphoma Since it is mainly expressed in B cells and myeloid cells, BTK is a target with better targeting and safety.
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • the purpose of the present invention is to provide a BTK-degrading compound with novel structure and good efficacy, its pharmaceutical composition and its use in the field of anti-tumor.
  • the BTK-degrading compound of the present invention has good stability (including chemical stability and crystal form stability), convenient oral administration, good solubility and bioavailability.
  • the object of the present invention is to provide a pharmaceutically acceptable salt of a BTK-degrading compound with novel structure and good efficacy or a crystal of the BTK-degrading compound and its pharmaceutically acceptable salt, its pharmaceutical composition and its use in the field of anti-tumor .
  • the crystal of the present invention has easy processing and crystallization, handling, good stability, convenient oral administration, good solubility and bioavailability.
  • Another object of the present invention is to provide a method for preparing the BTK-degrading compound or/and crystal.
  • Another object of the present invention is to provide a pharmaceutical composition containing the BTK-degrading compound or/and crystal.
  • Another object of the present invention is to provide the application of the compound or/and crystal for degrading BTK.
  • the present invention provides a pharmaceutically acceptable salt of a compound represented by formula (I),
  • Cy1 or Cy2 are each independently selected from piperidinyl or azetidinyl.
  • Cy1 or Cy2 are each independently selected from
  • the pharmaceutically acceptable salt of the compound represented by formula (I) is selected from maleate, fumarate, hydrohalide (preferably hydrobromide and hydrochloride), sulfuric acid Salt, Phosphate, L-Tartrate, Citrate, L-Malate, Hippurate, D-glucuronate, Glycolate, Mucate, Succinate, Lactate, Whey acid salts, palmitate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, pentamethylene acid salt, triphenylacetate, L-proline, ferulate, 2-hydroxyethanesulfonate, mandelate, nitrate, mesylate, malonate, gentisic acid Salt, salicylates, oxalates or glutarates.
  • hydrohalide preferably hydrobromide and hydrochloride
  • sulfuric acid Salt
  • the hydrohalide salt is a hydrobromide salt or a hydrochloride salt.
  • the molar ratio of the compound of formula (I) (free base) to different acids is about 1:1, 1:1.5, 1:2, 1:2.5, or 1:3.
  • the present invention also provides a pharmaceutically acceptable salt of the compound represented by the following formula (Ia) or (Ib),
  • the pharmaceutically acceptable salt of the compound shown in (Ia) or (Ib) is selected from the group consisting of maleate, fumarate, hydrohalide (preferably hydrobromide and hydrochloride) ), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucate, succinate, lactate , orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionic acid salt, valerate, triphenylacetate, L-proline, ferulate, 2-hydroxyethanesulfonate, mandelate, nitrate, mesylate, malonate, gentisate, salicylate, oxalate or glutarate, preferably maleate, fumarate, L-tartrate,
  • the pharmaceutically acceptable salt of the compound of formula (Ia) is selected from the maleate salt, and the molar ratio of the compound of formula (Ia) to the maleate salt is about 1:1, 1:1.5 , 1:2, 1:2.5 or 1:3.
  • the pharmaceutically acceptable salt of the compound of formula (I) has the structure of formula (II).
  • the present invention also provides the compound represented by the following formula (II),
  • the present invention also provides the crystalline form I of the compound represented by formula (II), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.96° ⁇ 0.2°, 9.30° ⁇ 0.2° , 11.86° ⁇ 0.2°, 15.80° ⁇ 0.2°, 21.75° ⁇ 0.2° and 23.93° ⁇ 0.2°.
  • the compound represented by the formula (II) of the present invention is crystal form I, and the X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 3.98° ⁇ 0.2°, 7.65° ⁇ 0.2°, 10.87° ⁇ 0.2°, 16.88° ⁇ 0.2°, 17.89° ⁇ 0.2° and 26.21° ⁇ 0.2°.
  • the compound represented by the formula (II) of the present invention is in the crystal form I, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 15.29° ⁇ 0.2° , 17.33° ⁇ 0.2°, 18.55° ⁇ 0.2°, 19.21° ⁇ 0.2°, 19.91° ⁇ 0.2° and 22.41° ⁇ 0.2°.
  • the compound represented by the formula (II) of the present invention is in the crystal form I, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 4.72° ⁇ 0.2° , 9.58° ⁇ 0.2°, 9.92° ⁇ 0.2°, 12.85° ⁇ 0.2°, 13.37° ⁇ 0.2°, 13.75° ⁇ 0.2°, 14.45° ⁇ 0.2°, 27.37° ⁇ 0.2°, 28.43° ⁇ 0.2°, 30.27 ° ⁇ 0.2°, 31.51° ⁇ 0.2° and 34.21° ⁇ 0.2°.
  • the compound represented by formula (II) described in the present invention is crystal form I, and its X-ray powder diffraction pattern is substantially as shown in FIG. 28 .
  • the compound represented by the formula (II) of the present invention is crystal form I, and its differential scanning calorimetry (DSC) curve is shown in Figure 29 or the thermogravimetric analysis curve is shown in Figure 30 shown.
  • DSC differential scanning calorimetry
  • the present invention also provides the amorphous form of the compound represented by the formula (II), which is irradiated with Cu-K ⁇ , and the X-ray powder diffraction pattern thereof is substantially as shown in FIG.
  • the amorphous form of the compound represented by formula (II) described in the present invention has a differential scanning calorimetry (DSC) curve as shown in FIG. 32 or a thermogravimetric analysis curve as shown in FIG. 33 Show.
  • DSC differential scanning calorimetry
  • the present invention also provides the crystal form II of the compound represented by formula (II), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 3.98° ⁇ 0.2°, 6.35° ⁇ 0.2° , 8.10° ⁇ 0.2°, 9.66° ⁇ 0.2°, 12.21° ⁇ 0.2°, 15.79° ⁇ 0.2°, 16.75° ⁇ 0.2° and 19.39° ⁇ 0.2°.
  • the compound represented by the formula (II) of the present invention is crystal form II, and the X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 12.78° ⁇ 0.2°, 16.33° ⁇ 0.2°, 17.13° ⁇ 0.2°, 17.41° ⁇ 0.2°, 20.45° ⁇ 0.2°, 21.43° ⁇ 0.2°, 23.23° ⁇ 0.2°, 24.65° ⁇ 0.2° and 25.75° ⁇ 0.2°.
  • the compound represented by formula (II) described in the present invention is crystal form II, and its X-ray powder diffraction pattern is substantially as shown in FIG. 34 .
  • the compound represented by formula (II) described in the present invention is crystal form II, and its differential scanning calorimetry (DSC) curve is shown in Figure 35 or the thermogravimetric analysis curve is shown in Figure 36 shown.
  • the present invention also provides the amorphous form of the compound represented by formula (Ia), which is irradiated with Cu-K ⁇ , and its X-ray powder diffraction pattern is basically as shown in FIG. 1 .
  • the amorphous form of the compound represented by the formula (Ia) of the present invention has a differential scanning calorimetry (DSC) curve as shown in Figure 2 or a thermogravimetric analysis curve as shown in Figure 3 .
  • DSC differential scanning calorimetry
  • the present invention also provides that the compound represented by the formula (Ia) is in crystal form I, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 8.32° ⁇ 0.2°, 15.69° ° ⁇ 0.2°, 16.41° ⁇ 0.2°, 17.57° ⁇ 0.2°, 18.89° ⁇ 0.2° and 19.75° ⁇ 0.2°.
  • the compound represented by the formula (Ia) of the present invention is crystal form I, and the X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 10.94° ⁇ 0.2°, 11.90° ⁇ 0.2°, 13.30° ⁇ 0.2°, 14.39° ⁇ 0.2°, 16.67° ⁇ 0.2°, 17.24° ⁇ 0.2°, 18.00° ⁇ 0.2°, 21.25° ⁇ 0.2°, 22.27° ⁇ 0.2°, 23.85° ⁇ 0.2° and 26.45° ⁇ 0.2°.
  • the compound represented by formula (Ia) described in the present invention is crystal form I, and its X-ray powder diffraction pattern is substantially as shown in FIG. 4 .
  • the compound represented by formula (Ia) described in the present invention is crystal form I, and its differential scanning calorimetry (DSC) curve is shown in Figure 5 or the thermogravimetric analysis curve is shown in Figure 6 shown.
  • DSC differential scanning calorimetry
  • the present invention also provides the crystal form II of the compound represented by formula (Ia), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.98° ⁇ 0.2°, 7.86° ⁇ 0.2° , 13.72° ⁇ 0.2°, 17.65° ⁇ 0.2° and 20.01° ⁇ 0.2°.
  • the compound represented by the formula (Ia) of the present invention is crystal form II, and the X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 5.48° ⁇ 0.2°, 13.43° ⁇ 0.2°, 14.93° ⁇ 0.2°, 15.90° ⁇ 0.2°, 16.57° ⁇ 0.2°, 16.95° ⁇ 0.2°, 21.29° ⁇ 0.2°, 22.05° ⁇ 0.2°, 24.97° ⁇ 0.2° and 25.77° ⁇ 0.2°.
  • the compound represented by formula (Ia) described in the present invention is in crystal form II, and its X-ray powder diffraction pattern is substantially as shown in FIG. 7 .
  • the compound represented by formula (Ia) described in the present invention is crystal form II, and its differential scanning calorimetry (DSC) curve is shown in Figure 8 or the thermogravimetric analysis curve is shown in Figure 9 shown.
  • the present invention also provides the crystal form III of the compound represented by formula (Ia), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.02° ⁇ 0.2°, 8.04° ⁇ 0.2° , 16.91° ⁇ 0.2°, 17.23° ⁇ 0.2°, 18.19° ⁇ 0.2°, 19.41° ⁇ 0.2° and 20.03° ⁇ 0.2°.
  • the crystal form III of the compound represented by formula (Ia), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 12.36° ⁇ 0.2°, 14.60° ⁇ 0.2°, 15.03° ⁇ 0.2°, 15.73° ⁇ 0.2°, 20.57° ⁇ 0.2°, 21.31° ⁇ 0.2° and 25.45° ⁇ 0.2°.
  • the crystal form III of the compound represented by formula (Ia) uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 5.19° ⁇ 0.2°, 16.32° ⁇ 0.2° , 18.75° ⁇ 0.2°, 19.73° ⁇ 0.2°, 21.91° ⁇ 0.2°, 22.41° ⁇ 0.2°, 23.48° ⁇ 0.2°, 23.95° ⁇ 0.2° and 26.33° ⁇ 0.2°.
  • the crystal form III of the compound represented by formula (Ia), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 10.34° ⁇ 0.2°, 24.85° ⁇ 0.2° , 26.93° ⁇ 0.2°, 27.57° ⁇ 0.2°, 28.41° ⁇ 0.2°, 29.59° ⁇ 0.2°, 30.19° ⁇ 0.2°, 31.77° ⁇ 0.2°, 33.13° ⁇ 0.2° and 35.75° ⁇ 0.2°.
  • the compound represented by formula (Ia) described in the present invention is crystal form III, and its X-ray powder diffraction pattern is substantially as shown in FIG. 10 .
  • the compound represented by the formula (Ia) of the present invention is the crystal form III, and its differential scanning calorimetry (DSC) curve is shown in Figure 11 or the thermogravimetric analysis curve is shown in Figure 12 shown.
  • DSC differential scanning calorimetry
  • the present invention also provides that the compound represented by the formula (Ib) is in the crystal form I, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.38° ⁇ 0.2°, 8.66° ° ⁇ 0.2°, 13.06° ⁇ 0.2°, 14.34° ⁇ 0.2°, 18.18° ⁇ 0.2°, 20.28° ⁇ 0.2° and 21.82° ⁇ 0.2°.
  • the crystal form I of the compound represented by formula (Ib), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 11.92° ⁇ 0.2°, 12.74° ⁇ 0.2° and 17.44° ⁇ 0.2°.
  • the crystal form I of the compound represented by formula (Ib), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 9.76° ⁇ 0.2°, 11.26° ⁇ 0.2° , 14.14° ⁇ 0.2°, 17.04° ⁇ 0.2°, 23.23° ⁇ 0.2°, 24.06° ⁇ 0.2°, 25.26° ⁇ 0.2° and 26.42° ⁇ 0.2°.
  • the compound represented by formula (Ib) described in the present invention is crystal form I, and its X-ray powder diffraction pattern is substantially as shown in Figure 13-1 and/or Figure 13-2.
  • the compound represented by the formula (Ib) of the present invention is a crystal form I, and its differential scanning calorimetry (DSC) curve is shown in Figure 14 or the thermogravimetric analysis curve is shown in Figure 15 shown.
  • DSC differential scanning calorimetry
  • the present invention also provides the crystal form II of the compound represented by formula (Ib), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.12° ⁇ 0.2°, 6.68° ⁇ 0.2° , 16.50° ⁇ 0.2° and 20.18° ⁇ 0.2°.
  • the crystal form II of the compound represented by formula (Ib) of the present invention using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 9.98° ⁇ 0.2°, 13.44° ° ⁇ 0.2°, 13.86° ⁇ 0.2°, 15.34° ⁇ 0.2°, 22.40° ⁇ 0.2° and 23.12° ⁇ 0.2°.
  • the crystal form II of the compound represented by the formula (Ib) of the present invention using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 15.76° ⁇ 0.2°, 20.99° ⁇ 0.2°, 24.14° ⁇ 0.2° and 26.28° ⁇ 0.2°.
  • the compound represented by formula (Ib) described in the present invention is in crystal form II, and its X-ray powder diffraction pattern is substantially as shown in Figure 16-1 and/or Figure 16-2.
  • the compound represented by the formula (Ib) of the present invention is a crystal form II, and its differential scanning calorimetry (DSC) curve is shown in Figure 17 or the thermogravimetric analysis curve is shown in Figure 18 shown.
  • DSC differential scanning calorimetry
  • the present invention also provides the crystal form III of the compound represented by formula (Ib), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.48° ⁇ 0.2°, 12.24° ⁇ 0.2° , 20.50° ⁇ 0.2° and 25.77° ⁇ 0.2°.
  • the crystal form III of the compound represented by formula (Ib) of the present invention using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 15.59° ⁇ 0.2°, 18.74° ° ⁇ 0.2° and 23.85° ⁇ 0.2°.
  • the crystal form III of the compound represented by the formula (Ib) of the present invention using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 14.95° ⁇ 0.2°, 16.18° ⁇ 0.2°, 16.70° ⁇ 0.2°, 19.00° ⁇ 0.2° and 21.39° ⁇ 0.2°.
  • the compound represented by formula (Ib) described in the present invention is crystal form III, and its X-ray powder diffraction pattern is substantially as shown in Figure 19-1 and/or Figure 19-2.
  • the compound represented by the formula (Ib) of the present invention is a crystal form III, and its differential scanning calorimetry (DSC) curve is shown in Figure 20 or the thermogravimetric analysis curve is shown in Figure 21 shown.
  • DSC differential scanning calorimetry
  • the present invention also provides the crystal form IV of the compound represented by formula (Ib), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 3.92° ⁇ 0.2°, 8.7° ⁇ 0.2° , 15.54° ⁇ 0.2° and 18.22° ⁇ 0.2°.
  • the crystal form IV of the compound represented by the formula (Ib) of the present invention using Cu-K ⁇ radiation, its X-ray powder diffraction pattern further has characteristic diffraction peaks at the following 2 ⁇ positions: 7.76° ⁇ 0.2°, 10.48° ° ⁇ 0.2°, 12.46° ⁇ 0.2°, 16.79° ⁇ 0.2°, 18.94° ⁇ 0.2° and 19.67° ⁇ 0.2°.
  • the compound represented by the formula (Ib) of the present invention is a crystal form IV, and its X-ray powder diffraction pattern is substantially as shown in Figure 22-1 and/or Figure 22-2.
  • the compound represented by the formula (Ib) of the present invention is the crystal form IV, and its differential scanning calorimetry (DSC) curve is shown in Figure 23 or the thermogravimetric analysis curve is shown in Figure 24 shown.
  • DSC differential scanning calorimetry
  • the present invention also provides the amorphous form of the compound represented by the formula (Ib), the X-ray powder diffraction pattern of which is irradiated with Cu-K ⁇ , and the X-ray powder diffraction pattern is substantially as shown in FIG. 25 .
  • the amorphous form of the compound represented by the formula (Ib) of the present invention has a differential scanning calorimetry (DSC) curve as shown in Figure 26 or a thermogravimetric analysis curve as shown in Figure 27 .
  • DSC differential scanning calorimetry
  • the present invention also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by formula (I), wherein the method comprises: the step of forming a salt with the compound represented by formula (I) and an acid.
  • the solvent used is selected from C 1-6 halogenated alkane solvents, C 2-6 ester solvents, C 2-6 ether solvents, One or more of C 1-6 alcohol solvents or water, preferably one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, ether, tetrahydrofuran and water or more, more preferably one or more of dichloromethane, methanol, ethanol and water.
  • the method comprises: the step of forming a salt with the compound represented by the formula (Ia) and an acid; the acid is selected from maleic acid, Fumaric acid, hydrohalic acid (preferably hydrobromic acid and hydrochloric acid), sulfuric acid, phosphoric acid, L-tartaric acid, citric acid, L-malic acid, hippuric acid, D-glucuronic acid, glycolic acid, mucic acid, succinic acid , lactic acid, orotic acid, pamoic acid, glycine, alanine, arginine, cinnamic acid, benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, valeric acid, triphenylacetic acid, L - Proline, ferulic acid, 2-hydroxyethanesulfonic acid, mandelic acid, nitric acid, me
  • the method comprises: forming a salt with the compound represented by the formula (Ia) and maleic acid to prepare the formula (II) ) compounds shown.
  • the present invention also provides a method for preparing a crystal form of a compound represented by formula (Ia), (Ib) or (II), wherein the method comprises the steps of: preparing any crystal form of formula (II), (Ia) , (Ib) compound or amorphous compound shown in formula (II), (Ia), (Ib) are prepared by recrystallization or beating; wherein the solvent of recrystallization or beating is selected from C 2-6 ester solvent, C One or more mixed solvents of 2-6 ether solvents, C 1-6 alcohol solvents, C 1-6 nitrile solvents, alkane solvents and water, the solvent for recrystallization or beating is preferably ethyl acetate One or more mixed solvents of ester, isopropyl acetate, n-heptane, acetonitrile, tetrahydrofuran, trifluoroethanol, methanol, ethanol and water.
  • the recrystallization or beating temperature is 4 to 100°C, preferably room temperature to 90°C, more preferably 40 ⁇ 90°C.
  • the method comprises the steps of: mixing the compound represented by formula (II) with a suitable solvent to form a suspension, heating Stirring and beating, static crystallization, filtration and separation; the solvent is preferably ethanol; the beating temperature is preferably 90°C.
  • the method comprises the steps of: mixing the amorphous compound of formula (Ia) with a suitable solvent, heating, stirring and beating, It is obtained by filtration and separation; the solvent is preferably an acetonitrile/water mixed solvent; the beating temperature is preferably 40°C.
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of the compound or crystal according to any one of the above-mentioned items of the present invention, and a pharmaceutically acceptable adjuvant.
  • the present invention also provides the pharmaceutically acceptable salt of the compound represented by formula (I) or the crystal and pharmaceutical composition of the compound represented by formula (Ia), (Ib) and (II) in preparation for treatment and/or Or the use in the medicine to prevent tumor.
  • the present invention also provides a method for treating and/or preventing tumors, the method comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of the compound represented by formula (I) or formula (Ia), (Ib) , crystals and pharmaceutical compositions of the compounds shown in (II).
  • the X-ray powder diffraction patterns, DSC patterns, and TGA patterns disclosed in the present invention which are substantially the same as the X-ray powder diffraction patterns, also belong to the scope of the present invention.
  • a “therapeutically effective amount” refers to the amount of a compound that causes the physiological or medical translation of a tissue, system, or subject that is sought, including one or more of a compound that, when administered in a subject, is sufficient to prevent the disorder or condition being treated. The amount of compound at which several symptoms occur or are alleviated to some extent.
  • IC50 refers to the half inhibitory concentration, the concentration at which half of the maximal inhibitory effect is achieved.
  • ether solvent in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include but are not limited to: tetrahydrofuran, diethyl ether, propylene glycol methyl ether , methyl tert-butyl ether, isopropyl ether or 1,4-dioxane.
  • the "alcoholic solvent” in the present invention refers to a group derived from one or more "hydroxyl groups” substituted for one or more hydrogen atoms on "C 1-6 alkyl", the "hydroxyl group” and “C 1-6 alkyl group” are derived from 1-6 Alkyl” is as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.
  • ester solvent in the present invention refers to the combination of a lower organic acid with 1 to 4 carbon atoms and a lower alcohol with 1 to 6 carbon atoms, and specific examples include but are not limited to: acetic acid Ethyl, isopropyl acetate or butyl acetate.
  • keton solvent refers to a compound in which a carbonyl group (-C(O)-) is connected with two hydrocarbon groups. According to the difference of the hydrocarbon groups in the molecule, ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic Saturated and unsaturated ketones, specific examples include, but are not limited to: acetone, acetophenone, 4-methyl-2-pentanone.
  • nitrile solvent in the present invention refers to a group derived from one or more "cyano groups” substituted for one or more hydrogen atoms on "C 1-6 alkyl", the "cyano group” and “C 1-6 alkyl” is as defined above, and specific examples include, but are not limited to: acetonitrile or propionitrile.
  • halogenated hydrocarbon solvent in the present invention refers to a group derived from one or more "halogen atoms" substituted for one or more hydrogen atoms on a "C 1-6 alkyl group", and the "halogen atom”" and “C 1-6 alkyl” are as defined above, and specific examples include, but are not limited to: dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride.
  • crystal of the present invention As used in the present invention, “crystal of the present invention”, “crystalline form of the present invention”, “polymorph of the present invention” and the like are used interchangeably.
  • room temperature in the present invention generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • the crystalline structure of the present invention can be analyzed using various analytical techniques known to those of ordinary skill in the art, including, but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and/or thermogravimetric analysis (Thermogravimetric Analysis, TGA). Thermogravimetric Analysis (TGA), also known as Thermogravimetry (TG).
  • the X-ray powder diffractometer (XRD) used in the present invention is Bruker D8 Advance diffractometer, and the copper target wavelength is K ⁇ radiation (40Kv, 40mA), ⁇ -2 ⁇ goniometer, Mo monochromator, Lynxeye detector, calibration material Al 2 O 3 , acquisition software is Diffrac Plus XRD Commander, analysis software is MDI Jade 6; method parameters: none
  • the specification of the reflective sample plate is 24.6mm diameter x1.0mm Thickness
  • the manufacturer of the non-reflective sample plate is MTI corporation
  • the manufacturer of the variable temperature heating table is Shanghai Micrograph Instrument Technology Development Co., Ltd.
  • the sample plate of the variable temperature heating table is copper plate, the detection angle: 3 -40° 2 ⁇ /3-30° 2 ⁇ (hot stage XRPD), step size: 0.02° 2 ⁇ .
  • the differential thermal analysis scanner (DSC) used in the present invention is TA Instruments Q200 DSC or DSC 3, nitrogen protection, and gas flow rate is 50mL/min.
  • thermogravimetric analyzer used in the present invention is TA Instruments Q500 TGA or TGA/DSC 3 + , nitrogen protection, and the gas flow rate is 40 mL/min or 50 mL/min.
  • the "2 ⁇ or 2 ⁇ angle" in the present invention refers to the diffraction angle, ⁇ is the Bragg angle, the unit is ° or degree, and the error range of the 2 ⁇ can be ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1.
  • crystal forms of the present invention are not limited to the characteristic patterns that are exactly the same as those described in the accompanying drawings disclosed in the present invention, such as XRD, DSC, TGA, and which patterns are substantially the same as those described in the accompanying drawings or Any crystalline form having substantially the same characteristic pattern falls within the scope of the present invention.
  • the melting peak heights of DSC curves depend on many factors related to sample preparation and instrument geometry, while peak positions are relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline compounds of the present invention are characterized by DSC patterns having characteristic peak positions having substantially the same properties as the DSC patterns provided in the accompanying drawings of the present invention, with a tolerance of ⁇ 3°C.
  • crystal forms disclosed in the present invention can be prepared by the following common methods for preparing crystal forms:
  • the volatilization experiment is to volatilize the clear solution of the sample at different temperatures until the solvent is dry.
  • the crystal slurry experiment is to stir the supersaturated solution (with insoluble solids) of the sample at a certain temperature in different solvent systems.
  • the anti-solvent test is to take the sample and dissolve it in a good solvent, add anti-solvent, and filter the precipitated solid immediately after stirring for a short time.
  • the cooling crystallization experiment is to dissolve a certain amount of sample into the corresponding solvent at high temperature, and then directly stir and crystallize at room temperature or low temperature.
  • the polymer template experiment is to add different kinds of polymer materials to the sample clarification solution, and leave it open to volatilize at room temperature until the solvent is dry.
  • the thermal method experiment is to treat the sample according to certain thermal method crystallization conditions and cool it to room temperature.
  • the water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature.
  • Figure 1 is the XRD pattern of Compound 1 amorphous.
  • Figure 2 is the DSC spectrum of Compound 1 amorphous.
  • Figure 3 is the TGA spectrum of Compound 1 amorphous.
  • FIG. 4 is the XRD pattern of compound 1 crystal form I.
  • Figure 5 is the DSC spectrum of Compound 1, Form I.
  • FIG. 6 is the TGA spectrum of Compound 1, Form I.
  • FIG. 7 is the XRD pattern of compound 1 crystal form II.
  • Figure 8 is the DSC spectrum of Compound 1, Form II.
  • FIG. 9 is the TGA spectrum of compound 1 crystal form II.
  • FIG. 10 is the XRD pattern of compound 1 crystal form III.
  • Figure 11 is the DSC spectrum of Compound 1, Form III.
  • Figure 12 is the TGA spectrum of Compound 1, Form III.
  • Figure 13-1 is the XRD pattern of Compound 2 Form I.
  • Figure 13-2 is the XRD pattern of Compound 2 Form I.
  • Figure 14 is the DSC spectrum of Compound 2 Form I.
  • Figure 15 is the TGA spectrum of Compound 2 Form I.
  • Figure 16-1 is the XRD pattern of Compound 2 Form II.
  • Figure 16-2 is the XRD pattern of compound 2 crystal form II.
  • Figure 17 is the DSC spectrum of Compound 2, Form II.
  • Figure 18 is the TGA spectrum of Compound 2, Form II.
  • Fig. 19-1 is the XRD pattern of compound 2 crystal form III.
  • Figure 19-2 is the XRD pattern of compound 2 crystal form III.
  • Figure 20 is the DSC spectrum of Compound 2, Form III.
  • Figure 21 is the TGA spectrum of Compound 2, Form III.
  • Fig. 22-1 is the XRD pattern of compound 2 crystal form IV.
  • Figure 22-2 is the XRD pattern of Compound 2, Form IV.
  • Figure 23 is the DSC spectrum of Compound 2, Form IV.
  • Figure 24 is the TGA spectrum of Compound 2, Form IV.
  • Figure 25 is the XRD pattern of Compound 2 amorphous.
  • Figure 26 is the DSC spectrum of Compound 2 amorphous.
  • Figure 27 is the TGA spectrum of Compound 2 amorphous.
  • Figure 28 is the XRD pattern of Compound 3 Form I.
  • Figure 29 is the DSC spectrum of Compound 3 Form I.
  • Figure 30 is the TGA spectrum of Compound 3 Form I.
  • FIG. 31 is the XRD pattern of compound 3 amorphous.
  • Figure 32 is the DSC spectrum of Compound 3 amorphous.
  • Figure 33 is the TGA spectrum of Compound 3 amorphous.
  • FIG. 34 is the XRD pattern of compound 3 crystal form II.
  • Figure 35 is the DSC spectrum of Compound 3, Form II.
  • Figure 36 is the TGA spectrum of Compound 3, Form II.
  • reaction solution was cooled to room temperature, sodium triacetoxyborohydride (12.1 g, 57.1 mmol) was added, and the reaction was performed at room temperature overnight after the addition was complete. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 9-10.
  • reaction solution was cooled to room temperature, sodium triacetoxyborohydride (5.57 g, 26.3 mmol) was added, and the reaction was performed at room temperature overnight after the addition was complete. Saturated sodium bicarbonate solution was added dropwise to the reaction to adjust pH to 9-10.
  • Cyclobutan-1-yl]azetidine-1-carboxylic acid tert-butyl ester (1d) (3.60 g, 6.03 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction solution was concentrated under reduced pressure, 20 mL of dichloromethane was added to the residue, and the pH was adjusted to 9-10 with saturated sodium bicarbonate solution, and the layers were separated.
  • Step 5 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1- Piperidinyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3- Diketone (Compound 1)
  • compound 1 crystal form I (yellow solid).
  • Compound 1 crystal form I was characterized by XRD, DSC and TGA, see Figures 4, 5 and 6.
  • Extract combine the organic phases, wash the organic layer with 15% aqueous sodium chloride solution (500 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3-(4-phenoxyphenyl)-1-[1- (4-Piperidinyl)-4-piperidinyl]pyrazolo[3,4-d]pyrimidin-4-amine (2b) (29.3 g, yield: 82%).
  • Step 4 1-(1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-phenoxyphenyl)-1H -Pyrazolo[3,4-d]pyrimidin-4-amine (2d)
  • reaction solution was concentrated under reduced pressure to obtain an oily substance, 200 mL of methyl tert-butyl ether was added under stirring, and a white solid was gradually precipitated, which was stirred and crystallized at room temperature for 1 h, filtered, and concentrated under reduced pressure to obtain 1-(1'-( Azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] Pyrimidine-4-amine trifluoroacetate (2d) (50 g, yield: 99%).
  • Step 5 5-(3-(4-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1 ,4'-Bipiperidin-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Diketone (Compound 2)
  • the compound of the present invention is tested by X-ray powder diffraction according to the following method.
  • the test parameters of the amorphous, crystal form I, crystal form II and crystal form III of compound 1 are shown in Table 1-1, and the crystal forms I and II of compound 2 are shown in Table 1-1.
  • III, IV and amorphous test parameters are shown in Table 1-1, and the crystal forms I, II and amorphous test parameters of Compound 3 are shown in Table 1-2, and the test results are shown in Figures 1, 4, 7, 10, 13-1, 13-2, 16-1, 16-2, 19-1, 19-2, 22-1, 22-2, 25, 28, 31 and 34.
  • the DSC spectra were collected on TA Instruments Q200 DSC and DSC 3 differential thermal analysis scanners.
  • the test parameters of compound 1 and compound 2 are shown in Table 2-1, and the test parameters of compound 3 are shown in Table 2-2.
  • the test results are shown in Table 2-1. 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32 and 35.
  • TGA spectrum was collected on TA Instruments Q500 TGA and TGA/DSC 3 + thermogravimetric analyzer.
  • the test parameters of compound 1 and compound 2 are shown in Table 3-1, and the test parameters of compound 3 are shown in Table 3-2.
  • the test results are shown in Figures 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36.
  • the X-ray powder diffraction pattern (XRD) of the crystal form I of compound 1 is shown in FIG. 4 .
  • the specific peaks are shown in Table 4.
  • the X-ray powder diffraction pattern (XRD) of the crystal form II of compound 1 is shown in FIG. 7 .
  • the specific peaks are shown in Table 5.
  • the X-ray powder diffraction pattern (XRD) of the crystal form III of compound 1 is shown in FIG. 10 .
  • the specific peaks are shown in Table 6.
  • the X-ray powder diffraction pattern (XRD) of the crystal form I of compound 3 is shown in FIG. 28 .
  • the specific peaks are shown in Table 11.
  • the X-ray powder diffraction pattern (XRD) of the crystal form II of compound 3 is shown in FIG. 34 .
  • the specific peaks are shown in Table 12.
  • Amorphous and crystalline form III of compound 1, and pharmaceutically acceptable salts of compound 1 (such as crystalline form I of compound 3, compound 5, and compound 9) have good chemical stability.
  • crystal form III is the most stable crystal form of compound 1 at room temperature
  • crystal form I is the most stable crystal form of compound 3 at room temperature. type.
  • Compound 1 and its pharmaceutically acceptable salts have certain solubility in water at 25°C.
  • the solubility of the pharmaceutically acceptable salts of compound 1 (such as the crystal form I of compound 3, compound 4, compound 5, compound 7, compound 9) is significantly improved compared with that of compound 1, by more than 15 times.
  • Mino human mantle cell lymphoma cell line purchased from ATCC, culture conditions: RPMI-1640+15% FBS+1% double antibody, cultured at 37°C, 5% CO 2 incubator. Cells were plated in 6-well plates, 5 ⁇ 10 5 cells/well. After plating, different concentrations of compounds were added and incubated for 48 hours in a 37°C, 5% CO 2 incubator. After the incubation, the cells were collected, lysed on ice for 15 minutes by adding RIPA lysis buffer (beyotime, Cat.P0013B), centrifuged at 12,000 rpm and 4°C for 10 minutes, and the supernatant protein samples were collected by BCA kit (Beyotime, Cat.P0009).
  • RIPA lysis buffer beyotime, Cat.P0013B
  • BTK CST, Cat. 8547S
  • internal reference BTK and internal reference were detected using an automatic western blot quantitative analyzer (Proteinsimple) using a kit (Protein simple, Cat. SM-W004).
  • Expression of ⁇ -actin CST, Cat. 3700S
  • the expression level of BTK relative to the internal reference was calculated using compass software and the DC 50 value was calculated according to formula (1) using Origen9.2 software.
  • BTK administration is the expression of BTK in different dosage groups
  • BTK vehicle is the expression of BTK in the vehicle control group.
  • BTK% BTK administration/BTK vehicle ⁇ 100% Formula (1)
  • mice Female ICR mice, 6-8 weeks old, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., and the experiment was started after 3 days of adaptation. After 3 consecutive days of intragastric administration of different doses of compounds, the mouse spleen was taken, spleen cells were collected, RIPA lysis buffer (beyotime, Cat. P0013B) was added, lysed on ice for 15 minutes, centrifuged at 12000 rpm for 10 minutes at 4°C, and collected. The supernatant protein sample was quantified with BCA kit (Beyotime, Cat. P0009), the protein was diluted to 0.25 mg/mL, and BTK (CST, Cat.
  • BTK administration is the expression of BTK in different dosage groups
  • BTK vehicle is the expression of BTK in the vehicle control group.
  • BTK% BTK administration /BTK vehicle ⁇ 100% Formula (2)
  • BTK wt (Carna, Cat. No 08-180) and BTK C481S (Carna, Cat. No 08-547) were prepared as 2.5 ⁇ kinase solutions, and the substrate FAM-P2 (GL Biochem, Cat. No. 112394) was mixed with ATP ((Sigma, Cat. No. A7699-1G) was prepared as a 2.5 ⁇ substrate solution.
  • Inhibition rate% (max-conversion)/(max-min)*100%.
  • Compound 1 has a significant inhibitory effect on BTK wt/C481S kinase.
  • test substance was administered to Beagle dogs by a single dose of intravenous and intragastric administration, the concentration of the test substance in the dog's plasma was determined, and the pharmacokinetic characteristics and bioavailability of the test substance in dogs were evaluated.
  • Test animals male Beagle dogs, about 8-11 kg, 0.5-1 week old, 6 dogs/compound. Purchased from Beijing Masi Biotechnology Co., Ltd.
  • Test method see Table 23. On the test day, 6 Beagle dogs were randomly divided into groups according to their body weight. One day before administration, fasting for 14-18 hours, and 4 hours after administration.
  • Time points of plasma collection in G1&G2 groups 0, 5min, 15min, 30min, 1, 2, 4, 6, 8, 10, 12, 24h.

Abstract

提供了一种降解BTK的化合物的盐和/或晶型及制备和应用。所述如式(I)所示化合物的可药用盐及晶型，其中，可药用盐选自马来酸盐、富马酸盐、氢卤酸盐(优选为氢溴酸盐和盐酸盐)、硫酸盐、磷酸盐、L-酒石酸盐、柠檬酸盐、L-苹果酸盐、马尿酸盐、D-葡萄糖醛酸盐、乙醇酸盐、粘酸盐、琥珀酸盐、乳酸盐、乳清酸盐、帕莫酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、肉桂酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、乙酸盐、丙酸盐、戊酸盐、三苯基乙酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、扁桃酸盐、硝酸盐、甲磺酸盐、丙二酸盐、龙胆酸盐、水杨酸盐、草酸盐或戊二酸盐：

Description

一种降解BTK化合物的盐及其晶型和在医药上的用途 技术领域
本发明涉及医药领域，具体的说，是涉及一种降解BTK化合物的盐的晶型及制备和应用。
背景技术
布鲁顿酪氨酸蛋白激酶(BTK,Bruton’s tyrosine kinase)是非受体蛋白酪氨酸激酶Tec家族的成员，是B细胞抗原受体(BCR)信号通路中的关键调节因子，分布在淋巴系统、造血及血液系统中。BTK突变会引起下游肿瘤细胞的增殖、分化以及血管生成等信号通路的激活，会导致X连锁无丙种球蛋白血症、非霍奇金淋巴瘤(NHL)与许多B细胞恶性肿瘤，包括慢性淋巴细胞性白血病(CLL)、套细胞淋巴瘤以及弥漫大B细胞淋巴瘤。由于主要在B细胞和髓细胞中表达，BTK是一种靶向性和安全性较好的靶点。
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物，此类化合物能够诱导靶蛋白被细胞的蛋白酶体识别，引起靶向蛋白的降解，能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体，使PROTAC技术应用于各种疾病的治疗成为可能，该技术近年来同时得到了广泛的关注。
发明内容
本发明的目的是提供一种结构新颖、药效好的降解BTK的化合物，其药物组合物以及其在抗肿瘤领域的用途。本发明降解BTK的化合物具有稳定性好(包括化学稳定性和晶型稳定性)、便于口服、较好的溶解度和生物利用度。
本发明的目的是提供一种结构新颖、药效好的降解BTK的化合物的可药用盐或降解BTK的化合物及其可药用盐的晶体，其药物组合物以及其在抗肿瘤领域的用途。
本发明的晶体具有易于加工和结晶、处理、稳定性好、便于口服、较好的溶解度和生物利用度。
本发明的另一目的在于提供所述降解BTK的化合物或/和晶体的制备方法。
本发明的另一目的在于提供含有所述降解BTK的化合物或/和晶体的药物组合物。
本发明的再一目的在于提供所述降解BTK的化合物或/和晶体的应用。
本发明提供一种式(I)所示化合物的可药用盐，
Figure PCTCN2021117174-appb-000001
在一些实施方案中，Cy1或Cy2各自独立地选自哌啶基或氮杂环丁基。
在一些实施方案中，Cy1或Cy2各自独立地选自
Figure PCTCN2021117174-appb-000002
在一些实施方案中，所述式(I)所示化合物的可药用盐选自马来酸盐、富马酸盐、氢卤酸盐(优选为氢溴酸盐和盐酸盐)、硫酸盐、磷酸盐、L-酒石酸盐、柠檬酸盐、L-苹果酸盐、马尿酸盐、D-葡萄糖醛酸盐、乙醇酸盐、粘酸盐、琥珀酸盐、乳酸盐、乳清酸盐、帕莫酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、肉桂酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、乙酸盐、丙酸盐、戊酸盐、三苯基乙酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、扁桃酸盐、硝酸盐、甲磺酸盐、丙二酸盐、龙胆酸盐、水杨酸盐、草酸盐或戊二酸盐。
在一些实施方案中，所述氢卤酸盐为氢溴酸盐或盐酸盐。
在一些实施方案中，所述式(I)所示化合物(游离碱)与不同酸的摩尔比例为约1:1、1:1.5、1:2、1:2.5或1:3。
本发明还提供了下述式(Ia)或(Ib)所示化合物的可药用盐，
Figure PCTCN2021117174-appb-000003
在一些实施方案中，所述(Ia)或(Ib)所示化合物的可药用盐选自马来酸盐、富马酸盐、氢卤酸盐(优选为氢溴酸盐和盐酸盐)、硫酸盐、磷酸盐、L-酒石酸盐、柠檬酸盐、L-苹果酸盐、马尿酸盐、D-葡萄糖醛酸盐、乙醇酸盐、粘酸盐、琥珀酸盐、乳酸盐、乳清酸盐、帕莫酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、肉桂酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、乙酸盐、丙 酸盐、戊酸盐、三苯基乙酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、扁桃酸盐、硝酸盐、甲磺酸盐、丙二酸盐、龙胆酸盐、水杨酸盐、草酸盐或戊二酸盐，优选马来酸盐、富马酸盐、L-酒石酸盐、柠檬酸盐、L-苹果酸盐、水杨酸盐或草酸盐。
在一些实施方案中，式(Ia)所示化合物的可药用盐选自马来酸盐，且式(Ia)所示化合物与马来酸盐的摩尔比例为约1:1、1:1.5、1:2、1:2.5或1:3。
在一些实施方案中，式(I)所示化合物的可药用盐具有式(II)所示的结构。
本发明还提供了下述式(II)所示化合物，
Figure PCTCN2021117174-appb-000004
本发明还提供了式(II)所示化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：5.96°±0.2°、9.30°±0.2°、11.86°±0.2°、15.80°±0.2°、21.75°±0.2°和23.93°±0.2°。
优选地，本发明所述的式(II)所示的化合物为晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：3.98°±0.2°、7.65°±0.2°、10.87°±0.2°、16.88°±0.2°、17.89°±0.2°和26.21°±0.2°。
更优选地，本发明所述的式(II)所示的化合物为晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：15.29°±0.2°、17.33°±0.2°、18.55°±0.2°、19.21°±0.2°、19.91°±0.2°和22.41°±0.2°。
更优选地，本发明所述的式(II)所示的化合物为晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：4.72°±0.2°、9.58°±0.2°、9.92°±0.2°、12.85°±0.2°、13.37°±0.2°、13.75°±0.2°、14.45°±0.2°、27.37°±0.2°、28.43°±0.2°、30.27°±0.2°、31.51°±0.2°和34.21°±0.2°。
在一些实施方案中，本发明所述的式(II)所示的化合物为晶型I，其X-射线粉末衍射图谱基本如附图28所示。
在一些实施方案中，本发明所述的式(II)所示的化合物为晶型I，其差示扫描量热分析曲线(DSC)如附图29所示或热重分析曲线如附图30所示。
本发明还提供了式(II)所示化合物的无定型，使用Cu-Kα辐射，其X-射线粉末衍射图谱基本如附图31所示。
在一些实施方案中，本发明所述的式(II)所示的化合物的无定型，其差示扫描量热分析曲线(DSC)如附图32所示或热重分析曲线如附图33所示。
本发明还提供了式(II)所示化合物的晶型II，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：3.98°±0.2°、6.35°±0.2°、8.10°±0.2°、9.66°±0.2°、12.21°±0.2°、15.79°±0.2°、16.75°±0.2°和19.39°±0.2°。
优选地，本发明所述的式(II)所示的化合物为晶型II，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：12.78°±0.2°、16.33°±0.2°、17.13°±0.2°、17.41°±0.2°、20.45°±0.2°、21.43°±0.2°、23.23°±0.2°、24.65°±0.2°和25.75°±0.2°。
在一些实施方案中，本发明所述的式(II)所示的化合物为晶型II，其X-射线粉末衍射图谱基本如附图34所示。
在一些实施方案中，本发明所述的式(II)所示的化合物为晶型II，其差示扫描量热分析曲线(DSC)如附图35所示或热重分析曲线如附图36所示。
本发明还提供了式(Ia)所示化合物的无定型，使用Cu-Kα辐射，其X-射线粉末衍射图谱基本如附图1所示。
在一些实施方案中，本发明所述的式(Ia)所示化合物的无定型，其差示扫描量热分析曲线(DSC)如附图2所示或热重分析曲线如附图3所示。
本发明还提供了所述的式(Ia)所示的化合物为晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：8.32°±0.2°、15.69°±0.2°、16.41°±0.2°、17.57°±0.2°、18.89°±0.2°和19.75°±0.2°。
优选地，本发明所述的式(Ia)所示的化合物为晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：10.94°±0.2°、11.90°±0.2°、13.30°±0.2°、14.39°±0.2°、16.67°±0.2°、17.24°±0.2°、18.00°±0.2°、21.25°±0.2°、22.27°±0.2°、23.85°±0.2°和26.45°±0.2°。
在一些实施方案中，本发明所述的式(Ia)所示的化合物为晶型I，其X-射线粉末衍射图谱基本如附图4所示。
在一些实施方案中，本发明所述的式(Ia)所示的化合物为晶型I，其差示扫描量热分析曲线(DSC)如附图5所示或热重分析曲线如附图6所示。
本发明还提供了式(Ia)所示化合物的晶型II，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：4.98°±0.2°、7.86°±0.2°、13.72°±0.2°、17.65°±0.2°和20.01°±0.2°。
优选地，本发明所述的式(Ia)所示的化合物为晶型II，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：5.48°±0.2°、13.43°±0.2°、14.93°±0.2°、15.90°±0.2°、16.57°±0.2°、16.95°±0.2°、21.29°±0.2°、22.05°±0.2°、24.97°±0.2°和25.77°±0.2°。
在一些实施方案中，本发明所述的式(Ia)所示的化合物为晶型II，其X-射线粉末衍射图谱基本如附图7所示。
在一些实施方案中，本发明所述的式(Ia)所示的化合物为晶型II，其差示扫描量热分析曲线(DSC)如附图8所示或热重分析曲线如附图9所示。
本发明还提供了式(Ia)所示化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：5.02°±0.2°、8.04°±0.2°、16.91°±0.2°、17.23°±0.2°、18.19°±0.2°、19.41°±0.2°和20.03°±0.2°。
优选地，式(Ia)所示化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：12.36°±0.2°、14.60°±0.2°、15.03°±0.2°、15.73°±0.2°、20.57°±0.2°、21.31°±0.2°和25.45°±0.2°。
更优选地，式(Ia)所示化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：5.19°±0.2°、16.32°±0.2°、18.75°±0.2°、19.73°±0.2°、21.91°±0.2°、22.41°±0.2°、23.48°±0.2°、23.95°±0.2°和26.33°±0.2°。
更优选地，式(Ia)所示化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：10.34°±0.2°、24.85°±0.2°、26.93°±0.2°、27.57°±0.2°、28.41°±0.2°、29.59°±0.2°、30.19°±0.2°、31.77°±0.2°、33.13°±0.2°和35.75°±0.2°。
在一些实施方案中，本发明所述的式(Ia)所示的化合物为晶型III，其X-射线粉末衍射图谱基本如附图10所示。
在一些实施方案中，本发明所述的式(Ia)所示的化合物为晶型III，其差示扫描量热分析曲线(DSC)如附图11所示或热重分析曲线如附图12所示。
本发明还提供了所述的式(Ib)所示的化合物为晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：4.38°±0.2°、8.66°±0.2°、13.06°±0.2°、14.34°±0.2°、18.18°±0.2°、20.28°±0.2°和21.82°±0.2°。
优选地，式(Ib)所示化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在 以下2θ位置具有特征衍射峰：11.92°±0.2°、12.74°±0.2°和17.44°±0.2°。
更优选地，式(Ib)所示化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：9.76°±0.2°、11.26°±0.2°、14.14°±0.2°、17.04°±0.2°、23.23°±0.2°、24.06±0.2°、25.26°±0.2°和26.42±0.2°。在一些实施方案中，本发明所述的式(Ib)所示的化合物为晶型I，其X-射线粉末衍射图谱基本如附图13-1和/或附图13-2所示。
在一些实施方案中，本发明所述的式(Ib)所示的化合物为晶型I，其差示扫描量热分析曲线(DSC)如附图14所示或热重分析曲线如附图15所示。
本发明还提供了式(Ib)所示化合物的晶型II，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：5.12°±0.2°、6.68°±0.2°、16.50°±0.2°和20.18°±0.2°。
优选地，本发明所述的式(Ib)所示化合物的晶型II，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：9.98°±0.2°、13.44°±0.2°、13.86°±0.2°、15.34°±0.2°、22.40°±0.2°和23.12°±0.2°。
更优选地，本发明所述的式(Ib)所示化合物的晶型II，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：15.76°±0.2°、20.99°±0.2°、24.14°±0.2°和26.28°±0.2°。
在一些实施方案中，本发明所述的式(Ib)所示的化合物为晶型II，其X-射线粉末衍射图谱基本如附图16-1和/或附图16-2所示。
在一些实施方案中，本发明所述的式(Ib)所示的化合物为晶型II，其差示扫描量热分析曲线(DSC)如附图17所示或热重分析曲线如附图18所示。
本发明还提供了式(Ib)所示化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：7.48°±0.2°、12.24°±0.2°、20.50°±0.2°和25.77°±0.2°。
优选地，本发明所述的式(Ib)所示化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：15.59°±0.2°、18.74°±0.2°和23.85°±0.2°。
更优选地，本发明所述的式(Ib)所示化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：14.95°±0.2°、16.18°±0.2°、16.70°±0.2°、19.00°±0.2°和21.39°±0.2°。
在一些实施方案中，本发明所述的式(Ib)所示的化合物为晶型III，其X-射线粉末衍射图谱基本如附图19-1和/或附图19-2所示。
在一些实施方案中，本发明所述的式(Ib)所示的化合物为晶型III，其差示扫描量热分析曲线(DSC)如附图20所示或热重分析曲线如附图21所示。
本发明还提供了式(Ib)所示化合物的晶型IV，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：3.92°±0.2°、8.7°±0.2°、15.54°±0.2°和18.22°±0.2°。
优选地，本发明所述的式(Ib)所示化合物的晶型IV，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：7.76°±0.2°、10.48°±0.2°、12.46°±0.2°、16.79°±0.2°、18.94°±0.2°和19.67°±0.2°。
在一些实施方案中，本发明所述的式(Ib)所示的化合物为晶型IV，其X-射线粉末衍射图谱基本如附图22-1和/或附图22-2所示。
在一些实施方案中，本发明所述的式(Ib)所示的化合物为晶型IV，其差示扫描量热分析曲线(DSC)如附图23所示或热重分析曲线如附图24所示。
本发明还提供了式(Ib)所示化合物的无定型，使用Cu-Kα辐射，其X-射线粉末衍射图谱基本如附图25所示。
在一些实施方案中，本发明所述的式(Ib)所示化合物的无定型，其差示扫描量热分析曲线(DSC)如附图26所示或热重分析曲线如附图27所示。
本发明还提供一种式(I)所示化合物的可药用盐的制备方法，其中，所述方法包括：以式(I)所示化合物和酸成盐的步骤。
本发明所述的式(I)所示化合物的制备方法的一些实施方案中，所用溶剂选自C 1-6卤代烷烃类溶剂、C 2-6酯类溶剂、C 2-6醚类溶剂、C 1-6醇类溶剂或水中的一种或多种，优选二氯甲烷、1,2-二氯乙烷、乙酸乙酯、甲醇、乙醇、异丙醇、乙醚、四氢呋喃和水中的一种或多种，更优选二氯甲烷、甲醇、乙醇和水中的一种或多种。
本发明所述的式(I)所示化合物的制备方法的一些实施方案中，所述方法包括：以式(Ia)所示化合物和酸成盐的步骤；所述酸选自马来酸、富马酸、氢卤酸(优选为氢溴酸和盐酸)、硫酸、磷酸、L-酒石酸、柠檬酸、L-苹果酸、马尿酸、D-葡萄糖醛酸、乙醇酸、粘酸、琥珀酸、乳酸、乳清酸、帕莫酸、甘氨酸、丙氨酸、精氨酸、肉桂酸、苯甲酸、苯磺酸、对甲苯磺酸、乙酸、丙酸、戊酸、三苯基乙酸、L-脯氨酸、阿魏酸、2-羟基乙磺酸、扁桃酸、硝酸、甲磺酸、丙二酸、龙胆酸、水杨酸、草酸或戊二酸。
本发明所述的式(I)所示化合物的马来酸盐制备方法的一些实施方案中，所述方法包括：以式(Ia)所示化合物和马来酸成盐，制备得到式(II)所示化合物。
本发明还提供一种式(Ia)、(Ib)或(II)所示化合物的晶型的制备方法，其中，所述方法包括如下步骤：将任意晶型的式(II)、(Ia)、(Ib)化合物或无定型的式(II)、(Ia)、(Ib)所示化合物采用重结晶或打浆制备得到；其中重结晶或打浆的溶剂选自C 2-6酯类溶剂、C 2-6醚类溶剂、C 1-6醇类溶剂、C 1-6腈类溶剂、烷烃类溶剂和水中的一种或两种以上的混合溶剂，所述重结晶或打浆的溶剂优选乙酸乙酯、乙酸异丙酯、正庚烷、乙腈、四氢呋喃、三氟乙醇、甲醇、乙醇和水中的一种或两种以上的混合溶剂。
本发明所述式(Ia)、(Ib)或(II)所示化合物的晶型的制备方法的一些实施方案中，重结晶或打浆温度为4～100℃，优选室温～90℃，更优选40～90℃。
本发明所述式(II)所示化合物的晶型I的制备方法的一些实施方案中，所述方法包括如下步骤：将式(II)所示化合物与适当的溶剂混合形成悬浊液，加热搅拌打浆，静止析晶，过滤分离得到；所述溶剂优选乙醇；所述打浆温度优选90℃。
本发明所述式(Ia)化合物的晶型III的制备方法的一些实施方案中，所述方法包括如下步骤：将无定型的式(Ia)所示化合物与适当的溶剂混合，加热搅拌打浆，过滤分离得到；所述溶剂优选乙腈/水混合溶剂；所述打浆温度优选40℃。
又一方面，本发明还提供了一种药物组合物，其中，所述药物组合物含有治疗有效量的本发明上面任意一项所述的化合物或晶体、及药学上可接受的辅料。
再一方面，本发明还提供了式(I)所示化合物的可药用盐或式(Ia)、(Ib)、(II)所示化合物的晶体和药物组合物在制备用于治疗和/或预防肿瘤的药物中的用途。
再一方面，本发明还提供了一种治疗和/或预防肿瘤的方法，所述方法包括给予治疗有效量的式(I)所示化合物的可药用盐或式(Ia)、(Ib)、(II)所示化合物的晶体和药物组合物。
其中可以理解的是，本发明所述的“优选地，……，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰”，或者“更优选地，……，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰”等等诸如此类的表达，是指在前面所述2θ位置具有特征衍射峰的基础上，进一步还在所述的“以下2θ位置”具有特征衍射峰。
本发明公开的X-射线粉末衍射或DSC图、TGA图，与其实质上相同的也属于本发明的范围。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
“治疗有效量”指引起组织、系统或受试者生理或医学翻译的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻 至某种程度的化合物的量。
“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。
本发明所述的“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。
本发明所述的“酮类溶剂”是指羰基(-C(O)-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、苯乙酮、4-甲基-2-戊酮。
本发明所述的“腈类溶剂”是指一个或多个“氰基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“氰基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：乙腈或丙腈。
本发明所述的“卤代烃类溶剂”是指一个或多个“卤素原子”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：二氯甲烷、1,2-二氯乙烷、氯仿或四氯化碳。
如本发明所用，“本发明的晶体”、“本发明的晶型”、“本发明的多晶型物”等可互换使用。
本发明所述“室温”一般指4-30℃，优选地指20±5℃。
本发明晶型结构可以使用本领域普通技术人员已知的各种分析技术分析，包括但不限于，X-射线粉末衍射(XRD)、示差扫描热法(DSC)和/或热重分析(Thermogravimetric Analysis，TGA)。热重分析(Thermogravimetric Analysis，TGA)，又叫热重法(Thermogravimetry，TG)。
本发明使用的X-射线粉末衍射仪(XRD)为Bruker D8 Advance diffractometer，铜靶波长为
Figure PCTCN2021117174-appb-000005
的Kαradiation(40Kv,40mA)，θ-2θ测角仪，Mo单色仪，Lynxeye探测器，校准物质Al 2O 3，采集软件为Diffrac Plus XRD Commander，分析软件为MDI Jade 6；方法参数：无反射样品板规格为24.6mm diameter x1.0mm Thickness，无反射样品板厂家为MTI corporation，变温热台厂家为上海微图仪器科技发展有限公司，变温热台样品板为铜板，检测角度：3-40° 2θ/3-30°2θ(热台XRPD)，步长：0.02°2θ。
本发明使用的差热分析扫描仪(DSC)为TA Instruments Q200 DSC或DSC 3，氮气保护，气体流速为50mL/分钟。
本发明使用的热重分析仪(TGA)为TA Instruments Q500 TGA或TGA/DSC 3 +，氮气保护，气体流速为40mL/分钟或50mL/分钟。
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，所述2θ的误差范围可以是±0.3、±0.2或±0.1。
可以理解的是，本发明描述的和保护的数值为近似值。数值内的变化可能归因于设备的校准、设备误差、晶体的纯度、晶体大小、样本大小以及其他因素。
可以理解的是，本发明的晶型不限于与本发明公开的附图中描述的特征图谱完全相同的特征图谱，比如XRD、DSC、TGA，具有与附图中描述的哪些图谱基本上相同或本质上相同的特征图谱的任何晶型均落入本发明的范围内。
可以理解的是，差示扫描量热(DSC)领域中所熟知的，DSC曲线的熔融峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明的结晶化合物的特征在于具有特征峰位置的DSC图，具有与本发明附图中提供的DSC图实质上相同的性质，误差容限为±3℃。
本发明公开的晶型可以经如下的常见的制备晶型的方法制备：
1、挥发实验是将样品澄清溶液在不同温度下敞口挥发至溶剂干。
2、晶浆实验是将样品的过饱和溶液(有不溶固体存在)在不同溶剂体系中某个温度下进行搅拌。
3、抗溶剂实验是取样品溶解在良溶剂中，加入抗溶剂，析出固体短时搅拌后立即过滤处理。
4、冷却结晶实验是在高温下将一定量的样品溶解到相应溶剂中，然后直接在室温或低温搅拌析晶。
5、高分子模板实验是在样品澄清溶液中加入不同种类的高分子材料，置于室温下敞口挥发至溶剂干。
6、热方法实验是将样品按一定热方法结晶条件处理并冷却至室温。
7、水汽扩散实验是将样品在室温下一定湿度环境中放置。
附图说明
图1为化合物1无定型的XRD谱图。
图2为化合物1无定型的DSC谱图。
图3为化合物1无定型的TGA谱图。
图4为化合物1晶型I的XRD谱图。
图5为化合物1晶型I的DSC谱图。
图6为化合物1晶型I的TGA谱图。
图7为化合物1晶型II的XRD谱图。
图8为化合物1晶型II的DSC谱图。
图9为化合物1晶型II的TGA谱图。
图10为化合物1晶型III的XRD谱图。
图11为化合物1晶型III的DSC谱图。
图12为化合物1晶型III的TGA谱图。
图13-1为化合物2晶型I的XRD谱图。
图13-2为化合物2晶型I的XRD谱图。
图14为化合物2晶型I的DSC谱图。
图15为化合物2晶型I的TGA谱图。
图16-1为化合物2晶型II的XRD谱图。
图16-2为化合物2晶型II的XRD谱图。
图17为化合物2晶型II的DSC谱图。
图18为化合物2晶型II的TGA谱图。
图19-1为化合物2晶型III的XRD谱图。
图19-2为化合物2晶型III的XRD谱图。
图20为化合物2晶型III的DSC谱图。
图21为化合物2晶型III的TGA谱图。
图22-1为化合物2晶型IV的XRD谱图。
图22-2为化合物2晶型IV的XRD谱图。
图23为化合物2晶型IV的DSC谱图。
图24为化合物2晶型IV的TGA谱图。
图25为化合物2无定型的XRD谱图。
图26为化合物2无定型的DSC谱图。
图27为化合物2无定型的TGA谱图。
图28为化合物3晶型I的XRD谱图。
图29为化合物3晶型I的DSC谱图。
图30为化合物3晶型I的TGA谱图。
图31为化合物3无定型的XRD谱图。
图32为化合物3无定型的DSC谱图。
图33为化合物3无定型的TGA谱图。
图34为化合物3晶型II的XRD谱图。
图35为化合物3晶型II的DSC谱图。
图36为化合物3晶型II的TGA谱图。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。
实施例1：化合物1的制备
5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1，也称为式(Ia)化合物)
5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione
Figure PCTCN2021117174-appb-000006
Figure PCTCN2021117174-appb-000007
第一步：3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-甲酸叔丁酯(1b)
tert-butyl 3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidine-1-carboxylate
Figure PCTCN2021117174-appb-000008
将3-(4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1a)(合成方法见J.Med.Chem.2015,58,9625-9638)(11.0g,28.5mmol)溶解在100mL 1,2-二氯乙烷中，依次加入3-氧代氮杂环丁-1-甲酸叔丁酯(9.74g,56.9mmol)和冰醋酸(3.42g,57.0mmol)，加完后65℃反应3h。反应液冷却至室温，加入三乙酰氧基硼氢化钠(12.1g,57.1mmol)，加完后室温反应过夜。向反应液中滴加饱和碳酸氢钠溶液调pH至9-10，减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝100:0-19:1)，得到3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-甲酸叔丁酯(1b)(7.20g，产率：47％)。
LCMS m/z＝542.3[M+1] +
第二步：1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(1c)
1-[1-(azetidin-3-yl)-4-piperidyl]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine
Figure PCTCN2021117174-appb-000009
将3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-甲酸叔丁酯(1b)(7.20g,13.3mmol)溶解在15mL二氯甲烷中，加入50mL 4N盐酸乙酸乙酯溶液和10mL无水甲醇，室温搅拌2h。反应液减压浓缩后残留物加入20mL二氯甲烷，用饱和碳酸氢钠溶液调pH至9-10，分液，水层用甲醇/二氯甲烷(v/v＝1:10)萃取(100mL x 3)，合并有机层，无水硫酸钠干燥，减压浓缩，得1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(1c)(5.80g,产率：99％)。
LCMS m/z＝442.2[M+1] +
第三步：3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-甲酸叔丁酯(1d)
tert-butyl 3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidine-1-carboxylate
Figure PCTCN2021117174-appb-000010
将1-[1-(氮杂环丁-3-基)-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(1c)(5.80g,13.1mmol)溶解在25mL 1,2-二氯乙烷中，依次加入3-氧代氮杂环丁-1-甲酸叔丁酯(4.50g,26.3mmol)和冰醋酸(1.58g,26.3mmol)，加完后65℃反应3h。反应液冷却至室温，加入三乙酰氧基硼氢化钠(5.57g,26.3mmol)，加完后室温反应过夜。向反应液滴加饱和碳酸氢钠溶液调pH至9-10，减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝100:0-19:1)，得到3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-甲酸叔丁酯(1d)(3.60g,产率：46％)。
LCMS m/z＝597.3[M+1] +
第四步：1-[1-[1-(氮杂环丁-3-基)氮杂环丁-3-基]-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(1e)
1-[1-[1-(azetidin-3-yl)azetidin-3-yl]-4-piperidyl]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine
Figure PCTCN2021117174-appb-000011
将3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-甲酸叔丁酯(1d)(3.60g,6.03mmol)溶解在5mL二氯甲烷中，加入5mL三氟乙酸，室温搅拌2h。反应液减压浓缩后残留物加入20mL二氯甲烷，用饱和碳酸氢钠溶液调pH至9-10，分液，水层再用100mL二氯甲烷萃取，合并有机层，无水硫酸钠干燥，减压浓缩，得粗品1-[1-[1-(氮杂环丁-3-基)氮杂环丁-3-基]-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(1e)(3.0g)。
LCMS m/z＝497.3[M+1] +
第五步：5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1)
5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione
Figure PCTCN2021117174-appb-000012
将上述粗品1-[1-[1-(氮杂环丁-3-基)氮杂环丁-3-基]-4-哌啶基]-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-4-胺(1e)(3.00g)溶解在15mL二甲亚砜中，依次加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(2.00g,7.25mmol)和二异丙基乙胺(3.90g,30.2mmol)，加完后90℃反应2h。反应液冷却至室温，慢慢滴加10mL水，过滤，滤饼用50mL二氯甲烷溶解，再用15mL饱和氯化钠溶液洗涤，分液，有机层用无水硫酸钠干燥，减压浓缩后粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝100:0-19:1)，将过柱所得纯品溶液直接减压浓缩得到5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1)(2.90g，从化合物1d算两步产率：64％)。
使用XRD、DSC和TGA分析，为化合物1的无定型(黄色固体)，见图1、2和3。
1H NMR(400MHz,CDCl 3)δ9.99(s,1H),8.39(s,1H),7.72–7.57(m,3H),7.45–7.32(m,2H),7.21–7.11(m,3H),7.10–7.04(m,2H),6.78(d,1H),6.52(dd,1H),5.81(brs,2H),4.92(dd, 1H),4.87–4.71(m,1H),4.08–3.99(m,2H),3.94–3.83(m,2H),3.76–3.65(m,1H),3.64–3.49(m,2H),3.20–3.04(m,3H),3.00–2.64(m,5H),2.52–2.34(m,2H),2.18–1.89(m,5H).
LCMS m/z＝377.3[M/2+1] +
实施例2：化合物1晶型I的制备
向实施例1制备的化合物1的无定型(40mg)中加入8mL乙酸乙酯，溶清，将溶液置于40℃下敞口挥发，得化合物1晶型I(黄色固体)。通过XRD、DSC和TGA表征化合物1晶型I，见图4、5、6。
实施例3：化合物1晶型II的制备
向实施例1制备的化合物1的无定型(200mg)中加入6mL乙醇，室温晶浆3天，离心后固体室温真空干燥过夜，得化合物1晶型II(黄色固体)。通过XRD、DSC和TGA表征化合物1晶型II，见图7、8、9。
实施例4：化合物1晶型III的制备
向实施例1制备的化合物1的无定型(400mg)中加入6mL乙腈和6mL水，于40℃搅拌72h，抽滤，收集滤饼，将滤饼于40℃真空干燥过夜，得化合物1晶型III(黄色固体)。通过XRD、DSC和TGA表征化合物1晶型III，见图10、11、12。
实施例5：化合物2的制备
5-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-联哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物2，也称为式(Ib)化合物)
5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure PCTCN2021117174-appb-000013
第一步：4-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]哌啶-1-甲酸叔丁酯(2a)
tert-butyl 4-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]piperidine-1-carboxylate
Figure PCTCN2021117174-appb-000014
将3-(4-苯氧基苯基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1a)(合成方法见J.Med.Chem.2015,58,9625-9638)(10.42g,26.97mmol)溶解于200mL 1,2-二氯乙烷中，依次加入4-氧代哌啶-1-甲酸叔丁酯(13.43g，67.42mmol)、冰醋酸(4.2g,67.42mmol)，加热至65℃搅拌2小时。降至室温，加入三乙酰氧基硼氢化钠(34.29g,161.79mmol)，室温搅拌反应16小时。TLC监测反应完后静置，加入2M的氢氧化钠水溶液50mL,用饱和碳酸氢钠水溶液调节pH＝8-9，静置分层，水相用二氯甲烷(200mL x 3)萃取，合并有机相，用饱和食盐水(300mL)洗涤一次,无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品柱层析纯化(200-300目硅胶，二氯甲烷/甲醇(v/v)＝100/1-15/1)得4-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]哌啶-1-甲酸叔丁酯(2a)(10.72g，收率：70％)。
第二步：3-(4-苯氧基苯基)-1-[1-(4-哌啶基)-4-哌啶基]吡唑并[3,4-d]嘧啶-4-胺(2b)
3-(4-phenoxyphenyl)-1-[1-(4-piperidyl)-4-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine
Figure PCTCN2021117174-appb-000015
将4-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]哌啶-1-甲酸叔丁酯(2a)(45g，92.48mmol)加入反应瓶中，加入410mL二氯甲烷，搅拌溶解后，加入80mL三氟乙酸，室温搅拌反应过夜。反应完后减压浓缩反应液，得油状物，加入500mL二氯甲烷，搅拌下慢慢滴加2mol/L氢氧化钠溶液调pH为10，分液，水相用二氯甲烷(400mL x3)萃取,合并有机相，有机层用15％氯化钠水溶液(500mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得3-(4-苯氧基苯基)-1-[1-(4-哌啶基)-4-哌啶基]吡唑并[3,4-d]嘧啶-4-胺(2b)(29.3g，收率：82％)。
第三步：3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-联哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(2c)
tert-butyl 3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'- bipiperidin]-1'-yl)azetidine-1-carboxylate
Figure PCTCN2021117174-appb-000016
将3-(4-苯氧基苯基)-1-[1-(4-哌啶基)-4-哌啶基]吡唑并[3,4-d]嘧啶-4-胺(2b)(29.3g，0.076mol)加入到1,2-二氯乙烷(0.5L)中，然后依次加入1-Boc-3-氮杂环丁酮(37.7g，0.189mol)、乙酸(11.4g，0.189mol)和无水硫酸钠(30g)，加完后慢慢加入三乙酰氧基硼氢化钠(96.3g，0.45mol)，室温搅拌反应2h。倒入2L的塑料烧杯中，加入冰块，加入2M的氢氧化钠水溶液调节pH＝12-13，静置分层，水相用二氯甲烷(400mL x 3)萃取，合并有机相，用饱和食盐水(600mL)洗涤,无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品柱层析纯化(200-300目硅胶，二氯甲烷/甲醇(v/v)＝100/0-12/1)，得3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-联哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(2c)(35g，收率：81％)。
第四步：1-(1'–(氮杂环丁-3-基)-[1,4'-联哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(2d)
1-(1'-(azetidin-3-yl)-[1,4'-bipiperidin]-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
Figure PCTCN2021117174-appb-000017
将3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-联哌啶]-1'-基)氮杂环丁-1-甲酸叔丁酯(2c)(25g,0.04mol)加入反应瓶中，加入125mL二氯甲烷，慢慢滴加50mL三氟乙酸，加完后室温搅拌反应2h。反应完后减压浓缩反应液，得油状物，在搅拌下加入200mL甲基叔丁基醚，逐渐析出白色固体，室温搅拌析晶1h，过滤，减压浓缩，得1-(1'–(氮杂环丁-3-基)-[1,4'-联哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺三氟乙酸盐(2d)(50g，收率：99％)。
第五步：5-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-联哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物2)
5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-[1,4'-bipiperidin]-1'-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure PCTCN2021117174-appb-000018
向1-(1'–(氮杂环丁-3-基)-[1,4'-联哌啶]-4-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺三氟乙酸盐(2d)(48g，0.031mol)中依次加入2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(10.3g，0.037mol)、N,N′-二异丙基乙胺(40g，0.31mol)和二甲亚砜(0.2L)，于120℃搅拌反应3h。将反应液冰水冷却至室温，搅拌下将反应液加入水(0.2L)，析出大量固体，继续搅拌30min，过滤，抽干，滤饼用0.5L二氯甲烷搅拌溶解，浓氨水洗涤(200mL x 3)，无水硫酸钠干燥，过滤，减压浓缩滤液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝100/0-94/6)，收集产品。向上述过柱产品中加入乙酸乙酯(0.28L)，搅拌打浆20h，过滤，滤饼于45℃真空干燥92h，得5-(3-(4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-[1,4'-联哌啶]-1'-基)氮杂环丁-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(化合物2)(17g，收率：72％)。
使用XRD、DSC和TGA分析，为化合物2的晶型I(黄色固体)，见图13-1、13-2、14、15。
1H NMR(400MHz,CDCl 3)δ10.22(brs,1H),8.39(s,1H),7.67–7.60(m,3H),7.42–7.34(m,2H),7.19–7.10(m,3H),7.10–7.04(m,2H),6.78(d,1H),6.51(dd,1H),5.89(brs,2H),4.96–4.88(m,1H),4.83–4.70(m,1H),4.14–4.04(m,2H),3.92–3.84(m,2H),3.39–3.30(m,1H),3.18–3.04(m,2H),3.00–2.91(m,2H),2.90–2.65(m,3H),2.56–2.32(m,5H),2.16–2.01(m,3H),2.01–1.84(m,4H),1.73–1.59(m,2H)。
LC-MS m/z＝781.4[M+1] +。
实施例6：化合物2晶型II的制备
往化合物2的晶型I(210mg)中加入2.8mL四氢呋喃和1.4mL水，于60℃加热搅拌溶清，转至4℃搅拌过夜，析出固体，减压抽滤，室温真空干燥约3h，得到化合物2晶型II(黄色固体)。通过XRD、DSC和TGA表征化合物2晶型II，见图16-1、16-2、17、18。
实施例7：化合物2晶型III的制备
往化合物2的晶型I(210mg)中加入14mL水和1.4mL四氢呋喃，4℃晶浆3天，减压抽滤干，得到化合物2晶型III(黄色固体)。通过XRD、DSC和TGA表征化合物2晶型III，见图19-1、19-2、20、21。
实施例8：化合物2晶型IV的制备
往化合物2的晶型I(30mg)中加入1mL乙酸异丙酯和1mL正庚烷，室温晶浆3天，离心，样品在室温真空下干燥约5h，得到化合物2晶型IV(黄色固体)。通过XRD、DSC和TGA表征化合物2晶型IV，见图22-1、22-2、23、24。
实施例9：化合物2无定型的制备
往化合物2的晶型I(400mg)加入5mL二氯甲烷加热溶清，过滤，滤液在40℃下减压浓缩干，得到化合物2无定型(黄色固体)。通过XRD、DSC和TGA表征化合物2无定型，见图25、26、27。
实施例10：化合物3的制备
5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)]吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮二马来酸盐(化合物3，也称为式(II)化合物)
5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione dimaleate
Figure PCTCN2021117174-appb-000019
向5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1)(1.0g，1.33mmol)中加入二氯甲烷(10mL)，室温搅拌至溶清，滴入马来酸(0.309g，2.66mmol)的甲醇(1mL)溶液，加入过程中逐渐析出固体，室温继续搅拌3h后减压抽滤，滤饼用10mL二氯甲烷洗涤，将收集的滤饼于40℃下减压浓缩除去残留溶剂，得0.96g粗品。向上述粗品中加入20mL乙 醇，于90℃加热搅拌打浆0.5h。将混悬液冷却至室温析晶2h，减压抽滤，滤饼用10mL乙醇洗涤，将收集的滤饼于40℃下减压浓缩除去残留溶剂，得5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)]吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮二马来酸盐(化合物3)(0.62g，产率：47％)。
使用XRD、DSC和TGA分析，为化合物3的晶型I(黄色固体)，见图28、29、30。
1H NMR(400MHz,DMSO-d 6)δ11.06(s,1H),8.27(s,1H),7.72–7.63(m,3H),7.48–7.41(m,2H),7.24–7.09(m,5H),6.86(d,1H),6.72(dd,1H),6.15(s,4H),5.06(dd,1H),5.01–4.86(m,1H),4.24–4.12(m,2H),4.11–3.93(m,3H),3.92–3.79(m,2H),3.77–3.59(m,3H),3.37–3.22(m,2H),2.98–2.68(m,3H),2.65–2.51(m,2H),2.46–2.31(m,2H),2.18–2.06(m,2H),2.06–1.96(m,1H).
实施例11：化合物3的无定型制备
向化合物3(300mg)(晶型I)中依次加入50mL三氟乙醇和50mL二氯甲烷，溶清，40℃下减压浓缩干，得到化合物3的无定型(黄色固体)。
使用XRD、DSC和TGA分析，为化合物3的无定型，见图31、32、33。
实施例12：化合物3的晶型II制备
向化合物3(150mg)(晶型I)中加入6.0mL甲醇和4.0mL水，置于70℃水浴中溶清，置于4℃环境下搅拌过夜，析出固体，减压抽滤，室温真空干燥过夜，得到化合物3的晶型II(黄色固体)。
使用XRD、DSC和TGA分析，为化合物3的晶型II，见图34、35、36。
实施例13：
5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮L-苹果酸盐(化合物4)
5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione L-malate
Figure PCTCN2021117174-appb-000020
Figure PCTCN2021117174-appb-000021
向5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1)(0.40g，0.531mmol)中加入二氯甲烷(8mL)，室温搅拌至溶清，滴入L-苹果酸(0.28g，2.09mmol)的甲醇(0.5mL)溶液，加入过程中逐渐析出粘稠状固体，继续室温搅拌2h后于40℃减压浓缩，向残留物中加入乙醇(10mL)，加热至90℃搅拌1h，然后冷却至室温搅拌2h，抽滤，滤饼于50℃真空干燥18h，得5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮L-苹果酸盐(化合物4)(黄色固体)(0.41g，收率：81％)。
1H NMR(400MHz,DMSO-d 6)δ11.05(s,1H),8.24(s,1H),7.70–7.61(m,3H),7.48–7.40(m,2H),7.23–7.08(m,5H),6.80(d,1H),6.67(dd,1H),5.05(dd,1H),4.77–4.64(m,1H),4.21(dd,1.5H),4.11–4.02(m,2H),3.88–3.80(m,2H),3.76–3.66(m,1H),3.55–3.46(m,2H),3.16–3.04(m,3H),3.00–2.80(m,3H),2.65–2.52(m,3H),2.49–2.38(m,2H),2.31–2.07(m,4H),2.06–1.89(m,3H).
实施例14：
5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮柠檬酸盐(化合物5)
5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione citrate
Figure PCTCN2021117174-appb-000022
向5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮 杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1)(0.40g，0.531mmol)中加入二氯甲烷(8mL)，室温搅拌至溶清，滴入柠檬酸一水合物(0.45g，2.14mmol)的甲醇(0.7mL)溶液，加入过程中逐渐析出粘稠状固体，继续室温搅拌2h后于40℃减压浓缩，向残留物中加入乙醇(10mL)，加热至90℃搅拌1h，然后冷却至室温搅拌2h，抽滤，滤饼于50℃真空干燥18h，得5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮柠檬酸盐(化合物5)(黄色固体)(0.48g，收率：87％)。
1H NMR(400MHz,DMSO-d 6)δ11.06(s,1H),8.25(s,1H),7.70–7.63(m,3H),7.48–7.40(m,2H),7.23–7.09(m,5H),6.82(d,1H),6.68(dd,1H),5.06(dd,1H),4.83–4.71(m,1H),4.15–4.04(m,2H),3.91–3.74(m,3H),3.64–3.53(m,2H),3.33–3.20(m,3H),3.09–2.96(m,2H),2.94–2.82(m,1H),2.79–2.53(m,8H),2.40–2.20(m,4H),2.07–1.91(m,3H).
实施例15：
5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮富马酸盐(化合物6)
5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione fumarate
Figure PCTCN2021117174-appb-000023
将5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1)(0.500g，0.664mmol)溶解在二氯甲烷(5mL)中，依次加入无水甲醇(1.25mL)和富马酸(0.616g，5.31mmol)，室温搅拌7h后过滤，收集滤饼，向滤饼中加入无水乙醇(15mL)，升温至80℃搅拌2h。冷却至室温，过滤，滤饼于50℃真空干燥16h，得到5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4- d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮富马酸盐(化合物6)(黄色固体)(0.400g，产率：69％)。
1H NMR(400MHz,DMSO-d 6)δ11.05(s,1H),8.23(s,1H),7.70–7.60(m,3H),7.47–7.40(m,2H),7.23–7.09(m,5H),6.79(d,1H),6.66(dd,1H),6.62(s,2H),5.05(dd,1H),4.74–4.62(m,1H),4.09–4.01(m,2H),3.86–3.78(m,2H),3.71–3.62(m,1H),3.50–3.40(m,2H),3.08–2.97(m,3H),2.94–2.82(m,3H),2.64–2.46(m,2H),2.29–2.14(m,2H),2.12–1.86(m,5H).
实施例16：
5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮L-酒石酸盐(化合物7)
5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione L-tartrate
Figure PCTCN2021117174-appb-000024
将5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1)(0.500g，0.664mmol)溶解在二氯甲烷(5mL)中，依次加入无水甲醇(0.75ml)和L-酒石酸(0.399g，2.66mmol)，室温搅拌4h后过滤，收集滤饼，向滤饼中加入无水乙醇(15mL)，升温至80℃搅拌2h。冷却至室温，过滤，滤饼于50℃真空干燥16h，得到5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮L-酒石酸盐(化合物7)(黄色固体)(0.510g，产率：79％)。
1H NMR(400MHz,DMSO-d 6)δ11.06(s,1H),8.24(s,1H),7.70–7.61(m,3H),7.48–7.40(m,2H),7.23–7.09(m,5H),6.80(d,1H),6.67(dd,1H),5.06(dd,1H),4.78–4.65(m,1H),4.28(s,3H),4.11–4.02(m,2H),3.88–3.79(m,2H),3.76–3.66(m,1H),3.56–3.40(m,2H),3.18–3.04 (m,3H),2.98–2.80(m,3H),2.65–2.46(m,2H),2.35–1.87(m,7H).
实施例17：
5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮水杨酸盐(化合物8)
5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione salicylate
Figure PCTCN2021117174-appb-000025
向5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1)(0.400g，0.531mmol)中加入10mL乙醇/水(v/v)＝4:1的混合溶剂，加热至80℃使其完全溶解，加入水杨酸(0.293g，2.12mmol)，继续在80℃下搅拌至溶液澄清，降温至60℃搅拌1h，随后冷却至室温搅拌2h析晶，抽滤，收集滤饼，向滤饼中加入10mL乙醇/水(v/v)＝4/1的混合溶剂，加热至80℃搅拌至固体溶解，再冷却至室温搅拌2h析晶，过滤，收集滤饼，滤饼于50℃真空干燥16h，得到5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮水杨酸盐(化合物8)(黄色固体)(0.140g，产率：30％)。
1H NMR(400MHz,DMSO-d 6)δ11.05(s,1H),8.24(s,1H),7.78–7.59(m,4H),7.48–7.40(m,2H),7.39–7.31(m,1H),7.24–7.08(m,5H),6.85–6.74(m,3H),6.65(dd,1H),5.06(dd,1H),4.87–4.73(m,1H),4.15–4.04(m,2H),3.95–3.77(m,3H),3.70–3.58(m,2H),3.41–3.28(m,3H),3.14–3.01(m,2H),2.95–2.81(m,1H),2.65–2.46(m,2H),2.45–2.22(m,4H),2.07–1.94(m,3H).
实施例18：
5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮的草酸盐(化合物9)
5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]azetidin-1-yl]azetidin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione oxalate
将5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮(化合物1)(0.500g，0.664mmol)溶解在二氯甲烷(10mL)中，慢慢滴加草酸二水合物(0.335g，2.66mmol)的甲醇溶液(2mL)，室温搅拌4h后过滤，收集滤饼，向滤饼中加入无水乙醇(12mL)，升温至80℃搅拌2h。冷却至室温，过滤，收集滤饼，滤饼于50℃真空干燥16h，得到5-[3-[3-[4-[4-氨基-3-(4-苯氧基苯基)吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]氮杂环丁-1-基]氮杂环丁-1-基]-2-(2,6-二氧代-3-哌啶基)异二氢吲哚-1,3-二酮的草酸盐(化合物9)(黄色固体)(0.480g)。
1H NMR(400MHz,DMSO-d 6)δ11.06(s,1H),8.26(s,1H),7.71–7.62(m,3H),7.49–7.39(m,2H),7.24–7.09(m,5H),6.84(d,1H),6.70(dd,1H),5.06(dd,1H),4.95–4.83(m,1H),4.21–4.09(m,2H),4.06–3.91(m,3H),3.88–3.74(m,2H),3.70–3.55(m,3H),3.30–3.16(m,2H),2.96–2.81(m,1H),2.74–2.46(m,4H),2.44–2.28(m,2H),2.15–1.94(m,3H)。
测试例
1.化合物1、2、3的XRD测试
将本发明化合物按照如下方法进行X-射线粉末衍射测试，化合物1的无定型、晶型I、晶型II及晶型III测试参数如表1-1所示，化合物2的晶型I、II、III、IV和无定型测试参数如表1-1所示，化合物3的晶型I、II和无定型测试参数如表1-2所示，测试结果见图1、4、7、10、13-1、13-2、16-1、16-2、19-1、19-2、22-1、22-2、25、28、31和34。
表1-1 XRD测试参数
Figure PCTCN2021117174-appb-000026
Figure PCTCN2021117174-appb-000027
表1-2 XRD测试参数
Figure PCTCN2021117174-appb-000028
2.化合物1、2、3的DSC测试
DSC图谱在TA Instruments Q200 DSC和DSC 3差热分析扫描仪上采集，化合物1和化合物2的测试参数如表2-1所示，化合物3的测试参数如表2-2所示，测试结果见图2、5、8、11、14、17、20、23、26、29、32和35。
表2-1 DSC测试参数
Figure PCTCN2021117174-appb-000029
表2-2 DSC测试参数
Figure PCTCN2021117174-appb-000030
3.化合物1、2、3的TGA测试
TGA图谱在TA Instruments Q500 TGA和TGA/DSC 3 +热重分析仪上采集，化合物1和化合物2的测试参数如表3-1所示，化合物3的的测试参数如表3-2所示，测试结果见图3、6、9、12、15、18、21、24、27、30、33和36。
表3-1 TGA测试参数
Figure PCTCN2021117174-appb-000031
表3-2 TGA测试参数
Figure PCTCN2021117174-appb-000032
4.化合物1、2、3的XRD测试的具体峰值表征结果
化合物1的晶型I的X-射线粉末衍射图谱(XRD)附图4所示。具体峰值如表4所示。
表4
2-Theta d BG Height I％ Area I％ FWHM
8.323 10.6149 669 2324 57.2 23926 50.1 0.175
10.245 8.6272 577 140 3.4 647 1.4 0.079
10.942 8.0791 577 1554 38.3 23713 49.6 0.26
11.903 7.4289 553 673 16.6 6101 12.8 0.154
13.304 6.6497 524 891 21.9 9265 19.4 0.177
14.386 6.1517 523 511 12.6 7603 15.9 0.253
15.686 5.6449 732 1715 42.2 18578 38.9 0.184
16.407 5.3984 702 1404 34.6 25605 53.6 0.31
16.667 5.3147 716 715 17.6 15844 33.1 0.377
17.243 5.1383 672 224 5.5 3107 6.5 0.236
17.568 5.0441 675 1408 34.7 17676 37 0.214
18.003 4.9232 679 363 8.9 3830 8 0.179
18.888 4.6944 881 4062 100 42818 89.6 0.179
19.747 4.492 828 2841 69.9 47795 100 0.286
20.187 4.3951 707 438 10.8 11036 23.1 0.429
21.249 4.1779 577 650 16 9218 19.3 0.241
21.62 4.107 586 80 2 671 1.4 0.143
22.271 3.9884 581 2283 56.2 26904 56.3 0.2
23.849 3.7279 538 1167 28.7 25991 54.4 0.379
24.83 3.5829 488 190 4.7 3040 6.4 0.272
25.269 3.5216 470 514 12.7 8436 17.7 0.279
26.45 3.367 435 1518 37.4 26092 54.6 0.292
27.123 3.2849 435 83 2 3142 6.6 0.644
27.589 3.2305 415 68 1.7 856 1.8 0.214
28.285 3.1525 372 148 3.6 2321 4.9 0.267
29.45 3.0304 327 71 1.7 586 1.2 0.14
30.111 2.9654 318 323 8 5231 10.9 0.275
31.07 2.8761 314 141 3.5 2229 4.7 0.269
31.649 2.8247 292 74 1.8 1424 3 0.327
32.01 2.7937 262 76 1.9 1421 3 0.318
33.694 2.6578 254 369 9.1 7891 16.5 0.364
35.169 2.5496 227 121 3 1866 3.9 0.262
36.154 2.4824 214 76 1.9 953 2 0.213
36.997 2.4277 210 59 1.5 1205 2.5 0.347
37.625 2.3887 208 61 1.5 499 1 0.139
化合物1的晶型II的X-射线粉末衍射图谱(XRD)附图7所示。具体峰值如表5所示。
表5
2-Theta d BG Height I％ Area I％ FWHM
4.979 17.7336 1214 8900 100 87065 100 0.166
5.479 16.117 1135 3492 39.2 36750 42.2 0.179
7.859 11.2407 735 3518 39.5 33929 39 0.164
10.944 8.078 583 613 6.9 10168 11.7 0.282
11.407 7.7507 583 586 6.6 6779 7.8 0.197
11.945 7.4028 581 109 1.2 584 0.7 0.091
12.685 6.9724 605 145 1.6 1192 1.4 0.14
13.425 6.5899 630 2024 22.7 44754 51.4 0.376
13.724 6.4472 644 3852 43.3 56786 65.2 0.251
14.247 6.2115 730 180 2 645 0.7 0.061
14.927 5.9302 663 2359 26.5 29085 33.4 0.21
15.204 5.8227 656 751 8.4 11837 13.6 0.268
15.902 5.5686 768 850 9.6 8216 9.4 0.164
16.565 5.347 823 2445 27.5 34850 40 0.242
16.946 5.2279 812 1197 13.4 12636 14.5 0.18
17.646 5.0221 776 4534 50.9 46966 53.9 0.176
18.751 4.7283 577 152 1.7 2342 2.7 0.262
19.589 4.528 634 325 3.7 8890 10.2 0.465
20.007 4.4344 590 2610 29.3 40346 46.3 0.263
20.603 4.3074 680 324 3.6 2205 2.5 0.116
21.288 4.1704 607 942 10.6 33012 37.9 0.596
22.047 4.0285 586 1705 19.2 45071 51.8 0.45
23.049 3.8555 437 175 2 3277 3.8 0.318
23.988 3.7067 400 68 0.8 1079 1.2 0.27
24.969 3.5633 475 789 8.9 16036 18.4 0.346
25.768 3.4545 593 981 11 12591 14.5 0.218
27.332 3.2603 385 224 2.5 8099 9.3 0.615
27.651 3.2234 383 406 4.6 13554 15.6 0.568
27.989 3.1852 395 294 3.3 7071 8.1 0.409
28.693 3.1087 352 229 2.6 2724 3.1 0.202
29.629 3.0126 331 87 1 796 0.9 0.156
30.154 2.9613 335 85 1 1152 1.3 0.23
30.557 2.9231 323 66 0.7 1460 1.7 0.376
32.223 2.7757 251 62 0.7 764 0.9 0.21
32.708 2.7356 262 136 1.5 1641 1.9 0.205
33.458 2.676 250 94 1.1 2578 3 0.466
33.91 2.6414 235 107 1.2 2828 3.2 0.449
37.353 2.4054 200 77 0.9 1822 2.1 0.402
化合物1的晶型III的X-射线粉末衍射图谱(XRD)附图10所示。具体峰值如表6所示。
表6
2-Theta d BG Height I％ Area I％ FWHM
5.017 17.5993 1189 3030 47.7 49913 97.5 0.28
5.181 17.0438 1156 2438 38.4 23296 45.5 0.153
8.042 10.9853 743 6351 100 51190 100 0.137
10.042 8.8012 578 180 2.8 1655 3.2 0.156
10.343 8.5457 565 686 10.8 6708 13.1 0.166
10.993 8.0414 556 114 1.8 776 1.5 0.116
12.362 7.1542 526 1039 16.4 9628 18.8 0.158
13.352 6.6256 500 90 1.4 757 1.5 0.143
14.602 6.0613 575 1704 26.8 10243 20 0.102
15.026 5.8911 605 1725 27.2 17629 34.4 0.174
15.563 5.6891 687 1078 17 8808 17.2 0.139
15.725 5.631 723 1908 30 12761 24.9 0.114
16.322 5.4262 873 676 10.6 2780 5.4 0.07
16.588 5.3398 817 512 8.1 3731 7.3 0.124
16.905 5.2404 692 3370 53.1 29024 56.7 0.146
17.228 5.1427 714 5157 81.2 50079 97.8 0.165
17.446 5.0791 740 866 13.6 19679 38.4 0.386
18.189 4.8733 593 3405 53.6 23288 45.5 0.116
18.746 4.7296 592 526 8.3 5266 10.3 0.17
19.405 4.5704 854 4526 71.3 29764 58.1 0.112
19.728 4.4964 901 976 15.4 7699 15 0.134
20.029 4.4295 603 3291 51.8 32507 63.5 0.168
20.345 4.3614 1045 645 10.2 2976 5.8 0.074
20.568 4.3146 901 2278 35.9 30207 59 0.226
21.311 4.1659 559 2693 42.4 19069 37.3 0.12
21.505 4.1287 538 980 15.4 11540 22.5 0.188
21.907 4.0538 507 467 7.4 4704 9.2 0.171
22.41 3.9639 452 435 6.8 3508 6.9 0.137
22.846 3.8893 432 148 2.3 931 1.8 0.107
23.026 3.8593 428 252 4 2573 5 0.174
23.484 3.7851 416 508 8 5576 10.9 0.187
23.953 3.7121 402 659 10.4 4741 9.3 0.122
24.195 3.6754 392 228 3.6 3468 6.8 0.259
24.412 3.6432 383 292 4.6 2984 5.8 0.174
24.847 3.5805 366 364 5.7 3496 6.8 0.163
25.249 3.5243 352 514 8.1 9114 17.8 0.302
25.449 3.497 345 857 13.5 10768 21 0.214
26.03 3.4203 336 84 1.3 491 1 0.099
26.328 3.3823 327 637 10 6787 13.3 0.181
26.934 3.3076 331 361 5.7 3068 6 0.145
27.568 3.2329 296 443 7 3894 7.6 0.149
28.409 3.1391 264 326 5.1 4278 8.4 0.223
29.176 3.0583 257 165 2.6 1458 2.8 0.15
29.587 3.0167 258 242 3.8 4832 9.4 0.34
29.79 2.9967 242 180 2.8 2773 5.4 0.262
30.191 2.9577 250 250 3.9 2737 5.3 0.186
31.171 2.8669 233 162 2.6 1331 2.6 0.14
31.772 2.814 239 249 3.9 3365 6.6 0.23
32.049 2.7904 238 255 4 3324 6.5 0.222
32.472 2.755 226 102 1.6 1597 3.1 0.266
33.135 2.7014 220 210 3.3 2073 4 0.168
34.068 2.6295 215 100 1.6 1059 2.1 0.18
34.416 2.6037 207 161 2.5 2267 4.4 0.239
35.754 2.5092 219 196 3.1 3196 6.2 0.277
36.747 2.4437 225 87 1.4 868 1.7 0.17
37.101 2.4212 195 57 0.9 511 1 0.152
37.938 2.3697 178 113 1.8 1350 2.6 0.203
化合物2的晶型I的X-射线粉末衍射图谱(XRD)附图13-1和13-2所示。具体峰值如表7所示。
表7
2-Theta d Height I％ Area I％
4.377 20.1693 1741 100 17639 100
8.023 11.0103 66 3.8 737 4.2
8.663 10.1993 1030 59.2 14242 80.7
9.762 9.0531 151 8.7 1098 6.2
10.845 8.1509 100 5.7 593 3.4
11.262 7.8502 133 7.6 1213 6.9
11.922 7.4173 252 14.5 2371 13.4
12.742 6.9415 577 33.1 8200 46.5
13.061 6.7727 843 48.4 11391 64.6
14.144 6.2565 188 10.8 6934 39.3
14.343 6.1704 453 26 8216 46.6
14.897 5.942 74 4.3 207 1.2
15.31 5.7827 64 3.7 1110 6.3
15.605 5.6738 85 4.9 1941 11
16.319 5.4272 75 4.3 623 3.5
17.041 5.1988 141 8.1 1246 7.1
17.442 5.0802 219 12.6 3443 19.5
18.18 4.8756 347 19.9 6360 36.1
19.524 4.543 72 4.1 599 3.4
20.282 4.3748 490 28.1 10772 61.1
21.823 4.0692 559 32.1 14868 84.3
23.23 3.8258 87 5 814 4.6
24.061 3.6955 106 6.1 1320 7.5
25.262 3.5226 136 7.8 2239 12.7
26.423 3.3703 86 4.9 2148 12.2
26.799 3.324 54 3.1 1126 6.4
29.503 3.0251 55 3.2 813 4.6
39.228 2.2947 35 2 337 1.9
化合物2的晶型II的X-射线粉末衍射图谱(XRD)附图16-1和16-2所示。具体峰值如表8所示。
表8
2-Theta d Height I％ Area I％
5.116 17.2585 514 41.8 6102 41.8
6.682 13.218 1230 100 14607 100
9.986 8.8505 169 13.7 2115 14.5
11.036 8.0108 45 3.7 636 4.4
13.441 6.5823 232 18.9 3725 25.5
13.863 6.3829 206 16.7 2553 17.5
15.341 5.7711 201 16.3 3304 22.6
15.762 5.6176 148 12 2952 20.2
16.503 5.3673 424 34.5 5827 39.9
18.976 4.6729 63 5.1 650 4.4
20.182 4.3963 575 46.7 10939 74.9
20.988 4.2293 97 7.9 980 6.7
21.255 4.1766 62 5 612 4.2
22.399 3.966 204 16.6 2155 14.8
23.121 3.8436 242 19.7 5358 36.7
24.14 3.6837 82 6.7 1954 13.4
24.54 3.6245 41 3.3 538 3.7
26.281 3.3883 110 8.9 3092 21.2
26.595 3.3489 56 4.6 2211 15.1
27.321 3.2616 47 3.8 814 5.6
27.574 3.2322 40 3.3 815 5.6
28.283 3.1528 56 4.6 864 5.9
28.538 3.1252 42 3.4 879 6
30.409 2.937 35 2.8 381 2.6
31.342 2.8517 40 3.3 512 3.5
化合物2的晶型III的X-射线粉末衍射图谱(XRD)附图19-1和19-2所示。具体峰值如表9所示。
表9
2-Theta d Height I％ Area I％
3.996 22.0947 148 5.8 847 4.8
7.475 11.816 2550 100 17651 100
9.313 9.4881 75 2.9 564 3.2
11.431 7.7343 54 2.1 362 2.1
11.776 7.5089 191 7.5 1545 8.8
12.242 7.2237 770 30.2 5762 32.6
13.322 6.6406 156 6.1 1162 6.6
14.511 6.099 49 1.9 348 2
14.948 5.9219 213 8.4 1091 6.2
15.585 5.6813 298 11.7 3871 21.9
16.176 5.4749 272 10.7 3225 18.3
16.437 5.3885 159 6.2 738 4.2
16.701 5.3038 157 6.2 736 4.2
17.687 5.0105 106 4.2 1521 8.6
18.742 4.7307 373 14.6 5292 30
19.001 4.6668 264 10.4 2993 17
20.246 4.3825 107 4.2 919 5.2
21.385 4.1517 151 5.9 3600 20.4
21.624 4.1062 104 4.1 3292 18.7
21.845 4.0652 122 4.8 2466 14
22.503 3.9478 997 39.1 9765 55.3
22.842 3.89 123 4.8 2515 14.2
23.102 3.8468 91 3.6 855 4.8
23.845 3.7286 343 13.5 3284 18.6
24.331 3.6552 93 3.6 2279 12.9
25.038 3.5536 47 1.8 201 1.1
25.765 3.4549 452 17.7 4944 28
27.825 3.2036 128 5 2406 13.6
29.364 3.0391 87 3.4 1335 7.6
化合物2的晶型IV的X-射线粉末衍射图谱(XRD)附图22-1和22-2所示。具体峰值如表10所示。
表10
2-Theta d Height I％ Area I％
3.918 22.5314 331 60.2 3600 38.7
7.762 11.3801 146 26.5 1419 15.3
8.7 10.1553 550 100 9302 100
10.136 8.7195 66 12 1716 18.4
10.481 8.4337 145 26.4 3370 36.2
12.048 7.3398 54 9.8 1454 15.6
12.46 7.0979 190 34.5 2852 30.7
13.914 6.3592 56 10.2 1100 11.8
15.542 5.6967 224 40.7 3615 38.9
16.785 5.2777 139 25.3 1469 15.8
17.508 5.0613 87 15.8 1830 19.7
18.221 4.8649 205 37.3 4139 44.5
18.943 4.681 143 26 1862 20
19.665 4.5107 183 33.3 3792 40.8
23.639 3.7605 72 13.1 1363 14.7
化合物3的晶型I的X-射线粉末衍射图谱(XRD)附图28所示。具体峰值如表11所示。
表11
2-Theta d Height I％ Area I％
3.982 22.171 1341 24.9 12956 26.1
4.717 18.7191 212 3.9 2332 4.7
5.961 14.8149 4110 76.2 48450 97.5
6.183 14.2819 1080 20 12242 24.6
7.645 11.5541 633 11.7 5532 11.1
9.302 9.4998 1257 23.3 16176 32.5
9.578 9.2265 467 8.7 5600 11.3
9.921 8.908 451 8.4 4411 8.9
10.866 8.1354 693 12.8 7712 15.5
11.161 7.9208 192 3.6 3691 7.4
11.861 7.4553 5395 100 49258 99.1
12.605 7.0167 432 8 3167 6.4
12.845 6.8859 442 8.2 3326 6.7
13.366 6.6189 322 6 2465 5
13.745 6.4371 508 9.4 5537 11.1
14.447 6.1259 368 6.8 3491 7
15.004 5.8997 179 3.3 1285 2.6
15.287 5.7912 467 8.7 5870 11.8
15.804 5.603 1491 27.6 16385 33
16.202 5.466 113 2.1 714 1.4
16.604 5.3347 641 11.9 5691 11.4
16.884 5.2468 1193 22.1 11488 23.1
17.325 5.1144 1072 19.9 8684 17.5
17.885 4.9554 855 15.8 8847 17.8
18.246 4.8581 841 15.6 12818 25.8
18.546 4.7802 958 17.8 13140 26.4
19.207 4.6171 402 7.5 5519 11.1
19.91 4.4558 862 16 30956 62.3
20.167 4.3995 899 16.7 12343 24.8
20.444 4.3406 1060 19.6 13328 26.8
21.326 4.163 238 4.4 1531 3.1
21.749 4.0829 2558 47.4 27358 55
22.166 4.0071 978 18.1 24665 49.6
22.409 3.9642 1003 18.6 17207 34.6
22.749 3.9056 204 3.8 1848 3.7
23.927 3.716 3166 58.7 49712 100
24.616 3.6136 188 3.5 1593 3.2
25.306 3.5165 248 4.6 2013 4
25.77 3.4542 542 10 3586 7.2
26.21 3.3973 1085 20.1 18055 36.3
26.707 3.3351 244 4.5 1638 3.3
27.369 3.2559 361 6.7 5116 10.3
2-Theta d Height I％ Area I％
27.689 3.2191 723 13.4 12127 24.4
27.952 3.1894 477 8.8 12761 25.7
28.431 3.1367 353 6.5 4167 8.4
28.988 3.0777 175 3.2 3531 7.1
29.195 3.0563 219 4.1 3535 7.1
29.77 2.9986 428 7.9 10655 21.4
30.269 2.9503 531 9.8 5579 11.2
30.826 2.8983 75 1.4 212 0.4
31.13 2.8706 104 1.9 2031 4.1
31.512 2.8367 581 10.8 12473 25.1
32.586 2.7456 91 1.7 800 1.6
34.209 2.619 218 4 2492 5
34.912 2.5678 86 1.6 1384 2.8
化合物3的晶型II的X-射线粉末衍射图谱(XRD)附图34所示。具体峰值如表12所示。
表12
2-Theta d Height I％ Area I％
3.982 22.1703 4212 100 73527 100
6.345 13.9191 1726 41 19664 26.7
8.103 10.9026 1208 28.7 12546 17.1
9.661 9.1473 1086 25.8 13129 17.9
10.473 8.4399 95 2.3 436 0.6
12.205 7.246 4062 96.4 48626 66.1
12.784 6.9191 901 21.4 12703 17.3
14.882 5.9481 245 5.8 1714 2.3
15.346 5.7689 208 4.9 964 1.3
15.785 5.6096 1143 27.1 11201 15.2
16.325 5.4252 959 22.8 5761 7.8
16.747 5.2895 1406 33.4 23883 32.5
17.127 5.1728 1068 25.4 30246 41.1
17.407 5.0904 704 16.7 22768 31
18.446 4.806 226 5.4 1473 2
18.948 4.6797 183 4.3 3450 4.7
19.388 4.5746 1225 29.1 22320 30.4
20.449 4.3394 665 15.8 8048 10.9
21.427 4.1435 383 9.1 5700 7.8
22.308 3.9819 91 2.2 1544 2.1
23.227 3.8264 1225 29.1 26339 35.8
23.547 3.7751 532 12.6 17218 23.4
24.649 3.6088 768 18.2 10917 14.8
25.749 3.457 698 16.6 17885 24.3
26.77 3.3274 160 3.8 2917 4
27.091 3.2887 322 7.6 7139 9.7
27.608 3.2283 194 4.6 1590 2.2
2-Theta d Height I％ Area I％
28.31 3.1498 582 13.8 12038 16.4
28.871 3.0899 210 5 6754 9.2
29.433 3.0322 143 3.4 2317 3.2
31.015 2.881 139 3.3 1867 2.5
31.69 2.8211 95 2.3 1678 2.3
33.072 2.7064 145 3.4 3709 5
33.45 2.6767 90 2.1 1869 2.5
5、化合物1及其可药用盐的化学稳定性数据
取样品分别在高温(40℃)和高湿(RH92.5％)条件下进行试验，HPLC检测纯度(百分数表示)，实验结果见表16。
供试品溶液制备方法及HPLC检测纯度条件见表13、14、15；
表13供试品溶液制备方法1
Figure PCTCN2021117174-appb-000033
表14供试品溶液制备方法2
Figure PCTCN2021117174-appb-000034
表15 HPLC检测纯度条件
Figure PCTCN2021117174-appb-000035
Figure PCTCN2021117174-appb-000036
表16化合物1不同种类的盐及晶型在不同条件下的化学稳定性
(采用HPLC测定含量)
Figure PCTCN2021117174-appb-000037
结论：化合物1的无定型和晶型III、化合物1的可药用盐(如化合物3的晶型I、化合物5、化合物9)具有较好的化学稳定性。
6.化合物1、3的晶型稳定性数据
6.1.化合物1和化合物3的晶型稳定性。见表17。
表17化合物1和化合物3晶型稳定性
Figure PCTCN2021117174-appb-000038
Figure PCTCN2021117174-appb-000039
结论：化合物1的无定型、晶型I、II、III和化合物3的无定型、晶型I、晶型II稳定性较好。
6.2.化合物1晶型I、II、III室温竞争实验，考察室温下晶型在乙酸异丙酯和水/乙腈(v/v＝1:1)溶剂中的晶型稳定性；化合物3晶型I、II室温竞争实验，考察室温下晶型在乙醇/水(v/v＝1:1)和丙酮/水(v/v＝1:1)溶剂中的晶型稳定性，具体内容见表18。
表18化合物1和化合物3晶型竞争晶浆实验
Figure PCTCN2021117174-appb-000040
由上述化合物1晶型竞争晶浆实验可知，晶型III为化合物1在室温下最稳定晶型；由上述化合物3晶型竞争晶浆实验可知，晶型I为化合物3在室温下最稳定晶型。
7. 25℃水中溶解度数据
表19化合物1不同种类的可药用盐在25℃水中的溶解度
Figure PCTCN2021117174-appb-000041
结论：化合物1及其可药用盐在25℃水中具有一定的溶解度。化合物1的可药用盐(如化合物3的晶型I、化合物4、化合物5、化合物7、化合物9)相比于化合物1的溶解度具有明显的提高，提高了约15倍以上。
8.Mino细胞中BTK降解检测
Mino人套细胞淋巴瘤细胞株，购自于ATCC，培养条件：RPMI-1640+15％FBS+1％双抗，培养于37℃，5％CO 2孵箱中。细胞铺板6孔板，5×10 5个/孔。铺板后，加入不同浓度化合物，37 ℃，5％CO 2孵箱中培养48小时。培养结束后，收集细胞，加入RIPA裂解液(beyotime,Cat.P0013B)于冰上裂解15分钟后，12000rpm，4℃离心10分钟，收集上清蛋白样品，用BCA试剂盒(Beyotime,Cat.P0009)进行蛋白定量后，将蛋白稀释为0.25mg/mL，使用全自动蛋白质印迹定量分析仪(Proteinsimple)运用试剂盒(Protein simple,Cat.SM-W004)检测BTK(CST,Cat.8547S)和内参β-actin(CST,Cat.3700S)的表达。使用compass软件计算BTK相对于内参的表达量并使用Origen9.2软件根据式(1)计算DC 50值。其中BTK给药为不同剂量给药组BTK表达量，BTK溶媒为溶媒对照组BTK表达量。
BTK％＝BTK给药/BTK溶媒×100％      式(1)
表20 Mino细胞中BTK降解的DC 50值
序号 化合物编号 DC 50(nM)
1 化合物2 22.9
2 化合物1 10.9
结论：化合物1和化合物2对Mino细胞中的BTK有显著的降解作用。
9.小鼠脾脏BTK蛋白降解检测
雌性ICR小鼠，6-8周龄，购自于北京维通利华实验动物技术有限公司，适应3天后开始实验。连续3天灌胃给于不同剂量的化合物后，取小鼠脾脏，收集脾脏细胞，加入RIPA裂解液(beyotime,Cat.P0013B)于冰上裂解15分钟后，12000rpm，4℃离心10分钟，收集上清蛋白样品，用BCA试剂盒(Beyotime,Cat.P0009)进行蛋白定量后，将蛋白稀释为0.25mg/mL，使用全自动蛋白质印迹定量分析仪(Proteinsimple)检测BTK(CST,Cat.8547S)和内参β-actin(CST,Cat.3700S)的表达。使用compass软件计算BTK相对于内参的表达量并使用Origen9.2软件根据式(2)计算DD 50值。其中BTK 给药为不同剂量给药组BTK表达量，BTK 溶媒为溶媒对照组BTK表达量。
BTK％＝BTK 给药/BTK 溶媒×100％   式(2)
表21化合物小鼠脾脏BTK蛋白降解的DD 50值
序号 化合物编号 DD 50(mg/kg)
1 化合物2 3.8
2 化合物1 3.8
结论：化合物1和化合物2对小鼠脾脏BTK蛋白有显著的降解作用。
10.体外激酶检测
激酶BTK wt(Carna,Cat.No 08-180)和BTK C481S(Carna,Cat.No 08-547)配制成2.5×的激酶溶液，底物FAM-P2(GL Biochem,Cat.No.112394)与ATP((Sigma,Cat.No.A7699-1G)配制成2.5×的底物溶液。在384孔板中加入5μL不同浓度的化合物，加入10μL 2.5×的激酶溶液， 室温孵育10分钟。加入10μL 2.5×的底物溶液，于28℃孵育适当时间后，加入30μL终止液终止反应，使用Caliper EZ reader2仪器检测。运用XLFit excel add-in version 5.4.0.8软件计算IC 50值。抑制率计算公式见式(3)，其中max为DMSO对照读数，min为阴性对照读数，conversion为化合物读数
抑制率％＝(max-conversion)/(max-min)*100％.  式(3)
其结果见表22：
表22抑制BTK wt/C481S激酶的IC 50值
序号 化合物编号 BTK C481S IC 50(nM) BTK wt IC 50(nM)
1 化合物1 8 6.3
结论：化合物1对BTK wt/C481S激酶有显著的抑制作用。
11.犬药代动力学测试
实验目的：本试验通过单剂量静脉和灌胃给予受试物于Beagle犬，测定犬血浆中受试物的浓度，评价受试物在犬体内药代特征和生物利用度。
试验动物：雄性Beagle犬，8～11kg左右，0.5～1周龄，6只/化合物。购于北京玛斯生物技术有限公司。
试验方法：见表23，试验当天，6只Beagle犬按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。
表23
Figure PCTCN2021117174-appb-000042
*剂量以游离碱计。
取样：于给药前及给药后经颈静脉取血1.0ml，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。
G1&G2组采集血浆时间点：0,5min,15min,30min,1,2,4,6,8,10,12,24h。
分析检测前，所有样品存于-80℃。用HPLC-MS/MS对样品进行检测。
表24化合物在犬血浆中药代动力学参数
Figure PCTCN2021117174-appb-000043
*注：i.g.(灌胃)给予化合物；
结论：化合物1及其可药用盐在犬体内具有一定的口服吸收。化合物3的晶型I，化合物5，化合物7和化合物9相比于化合物1的口服暴露量有明显提高，提高了2倍以上。

Claims (33)

  1. 式(I)所示化合物的可药用盐，
    Figure PCTCN2021117174-appb-100001
    其中：
    Cy1或Cy2各自独立地选自哌啶基或氮杂环丁基；
    所述可药用盐选自马来酸盐、富马酸盐、氢卤酸盐(优选为氢溴酸盐和盐酸盐)、硫酸盐、磷酸盐、L-酒石酸盐、柠檬酸盐、L-苹果酸盐、马尿酸盐、D-葡萄糖醛酸盐、乙醇酸盐、粘酸盐、琥珀酸盐、乳酸盐、乳清酸盐、帕莫酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、肉桂酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、乙酸盐、丙酸盐、戊酸盐、三苯基乙酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、扁桃酸盐、硝酸盐、甲磺酸盐、丙二酸盐、龙胆酸盐、水杨酸盐、草酸盐或戊二酸盐。
  2. 根据权利要求1所述的可药用盐，式(I)所示化合物选自式(Ia)或(Ib)，其中，
    Figure PCTCN2021117174-appb-100002
    所述可药用盐选自马来酸盐、富马酸盐、氢卤酸盐(优选为氢溴酸盐和盐酸盐)、硫酸盐、磷酸盐、L-酒石酸盐、柠檬酸盐、L-苹果酸盐、马尿酸盐、D-葡萄糖醛酸盐、乙醇酸盐、粘酸盐、琥珀酸盐、乳酸盐、乳清酸盐、帕莫酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、肉桂酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、乙酸盐、丙酸盐、戊酸盐、三苯基乙酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、扁桃酸盐、硝酸盐、甲磺酸盐、丙二酸盐、龙胆酸盐、水杨酸盐、 草酸盐或戊二酸盐。
  3. 根据权利要求2所述的可药用盐，其中，所述可药用盐选自马来酸盐、富马酸盐、L-酒石酸盐、柠檬酸盐、L-苹果酸盐、水杨酸盐或草酸盐。
  4. 根据权利要求1所述的可药用盐，其中，式(I)所述的化合物的可药用盐选自式(II)，
    Figure PCTCN2021117174-appb-100003
  5. 一种式(II)所示化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：5.96°±0.2°、9.30°±0.2°、11.86°±0.2°、15.80°±0.2°、21.75°±0.2°和23.93°±0.2°。
  6. 根据权利要求5所述的式(II)化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：3.98°±0.2°、7.65°±0.2°、10.87°±0.2°、16.88°±0.2°、17.89°±0.2°和26.21°±0.2°。
  7. 根据权利要求6所述的式(II)化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：15.29°±0.2°、17.33°±0.2°、18.55°±0.2°、19.21°±0.2°、19.91°±0.2°和22.41°±0.2°。
  8. 根据权利要求7所述的式(II)化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱更进一步在以下2θ位置具有特征衍射峰：4.72°±0.2°、9.58°±0.2°、9.92°±0.2°、12.85°±0.2°、13.37°±0.2°、13.75°±0.2°、14.45°±0.2°、27.37°±0.2°、28.43°±0.2°、30.27°±0.2°、31.51°±0.2°和34.21°±0.2°。
  9. 根据权利要求8所述的式(II)化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱如图28所示。
  10. 根据权利要求8所述的式(II)化合物的晶型I，其特征在于，其差示扫描量热分析曲线如图29所示或热重分析曲线如图30所示。
  11. 一种式(Ia)所示化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ 位置具有特征衍射峰：5.02°±0.2°、8.04°±0.2°、16.91°±0.2°、17.23°±0.2°、18.19°±0.2°、19.41°±0.2°和20.03°±0.2°，
    Figure PCTCN2021117174-appb-100004
  12. 根据权利要求11所述的式(Ia)化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：12.36°±0.2°、14.60°±0.2°、15.03°±0.2°、15.73°±0.2°、20.57°±0.2°、21.31°±0.2°和25.45°±0.2°。
  13. 根据权利要求12所述的式(Ia)化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：5.19°±0.2°、16.32°±0.2°、18.75°±0.2°、19.73°±0.2°、21.91°±0.2°、22.41°±0.2°、23.48°±0.2°、23.95°±0.2°和26.33°±0.2°。
  14. 根据权利要求13所述的式(Ia)化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱更进一步在以下2θ位置具有特征衍射峰：10.34°±0.2°、24.85°±0.2°、26.93°±0.2°、27.57°±0.2°、28.41°±0.2°、29.59°±0.2°、30.19°±0.2°、31.77°±0.2°、33.13°±0.2°和35.75°±0.2°。
  15. 根据权利要求14所述的式(Ia)化合物的晶型III，使用Cu-Kα辐射，其X-射线粉末衍射图谱如图10所示。
  16. 根据权利要求14所述的式(Ia)化合物的晶型III，其特征在于，其差示扫描量热分析曲线如图11所示或热重分析曲线如图12所示。
  17. 一种式(Ib)所示化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：4.38°±0.2°、8.66°±0.2°、13.06°±0.2°、14.34°±0.2°、18.18°±0.2°、20.28°±0.2°和21.82°±0.2°，
    Figure PCTCN2021117174-appb-100005
  18. 根据权利要求17所述的式(Ib)化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射 图谱进一步在以下2θ位置具有特征衍射峰：11.92°±0.2°、12.74°±0.2°和17.44°±0.2°。
  19. 根据权利要求18所述的式(Ib)化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：9.76°±0.2°、11.26°±0.2°、14.14°±0.2°、17.04°±0.2°、23.23°±0.2°、24.06±0.2°、25.26°±0.2°和26.42±0.2°。
  20. 根据权利要求19所述的式(Ib)化合物的晶型I，使用Cu-Kα辐射，其X-射线粉末衍射图谱基本如附图13-1和/或附图13-2所示。
  21. 根据权利要求19所述的式(Ib)化合物的晶型I，其特征在于，其差示扫描量热分析曲线(DSC)如附图14所示或热重分析曲线如附图15所示。
  22. 一种权利要求1所述的可药用盐的制备方法，其中，所述方法包括：以式(I)所示化合物和酸成盐的步骤。
  23. 根据权利要求22所述的制备方法，其中，所用溶剂选自C 1-6卤代烷烃类溶剂、C 2-6酯类溶剂、C 2-6醚类溶剂、C 1-6醇类溶剂或水中的一种或多种。
  24. 根据权利要求23所述的制备方法，其中，所用溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸乙酯、甲醇、乙醇、异丙醇、乙醚、四氢呋喃和水中的一种或多种。
  25. 根据权利要求24所述的制备方法，其中，所用溶剂选自二氯甲烷、甲醇、乙醇和水中的一种或多种。
  26. 根据权利要求23所述的制备方法，其中，所述方法包括：以式(Ia)所示化合物和马来酸为原料，制备得到式(II)所示化合物。
  27. 一种式(Ia)、(Ib)或(II)所示化合物的晶型的制备方法，其中，所述方法包括如下步骤：将任意晶型的式(II)、(Ia)、(Ib)化合物或无定型的式(II)、(Ia)、(Ib)所示化合物采用重结晶或打浆制备得到，其中重结晶或打浆的溶剂选自C 2-6酯类溶剂、C 2-6醚类溶剂、C 1-6醇类溶剂、C 1- 6腈类溶剂、烷烃类溶剂和水中的一种或两种以上的混合溶剂。
  28. 根据权利要求27所述的制备方法，其中，重结晶或打浆的溶剂选自乙酸乙酯、乙酸异丙酯、正庚烷、乙腈、四氢呋喃、三氟乙醇、甲醇、乙醇和水中的一种或两种以上的混合溶剂。
  29. 根据权利要求27所述的制备方法，其中，重结晶或打浆温度为4～100℃，优选室温～90℃，更优选40～90℃。
  30. 根据权利要求29所述的制备方法，其中所述晶型为式(II)化合物的晶型I，以及所述方法包括如下步骤：将式(II)所示化合物与适当的溶剂混合形成悬浊液，加热搅拌打浆，静止析晶，过滤分离得到；所述溶剂选自乙醇。
  31. 根据权利要求29所述的制备方法，其中所述晶型为式(Ia)化合物的晶型III，以及所述方法包括如下步骤：将无定型的式(Ia)所示化合物与适当的溶剂混合，加热搅拌打浆，过滤分离得到；所述溶剂选自乙腈/水混合溶剂。
  32. 一种药物组合物，其中，所述药物组合物含有治疗有效量的权利要求1～4任意一项所述的化合物的可药用盐或者权利要求5-21任意一项所述的晶体、及药学上可接受的辅料。
  33. 权利要求1～4任意一项所述的化合物的可药用盐或者权利要求5、11或17所述的晶体或者权利要求32所述的药物组合物在制备用于治疗和/或预防肿瘤或癌症的药物中的用途。
PCT/CN2021/117174 2020-09-09 2021-09-08 一种降解btk化合物的盐及其晶型和在医药上的用途 WO2022052950A1 (zh)

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