WO2023174300A1 - Btk抑制剂的晶型及其酸式盐和其酸式盐的晶型 - Google Patents

Btk抑制剂的晶型及其酸式盐和其酸式盐的晶型 Download PDF

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WO2023174300A1
WO2023174300A1 PCT/CN2023/081427 CN2023081427W WO2023174300A1 WO 2023174300 A1 WO2023174300 A1 WO 2023174300A1 CN 2023081427 W CN2023081427 W CN 2023081427W WO 2023174300 A1 WO2023174300 A1 WO 2023174300A1
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compound
formula
crystal form
ray powder
angle
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French (fr)
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赵金柱
曹煜东
周福生
朱林东
刘祥超
兰炯
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劲方医药科技(上海)有限公司
浙江劲方药业有限公司
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Definitions

  • the present invention relates to the field of medical technology, and specifically relates to a crystal form of a BTK inhibitor and its acid salt and the crystal form of its acid salt.
  • Bruton's tyrosine kinase is a member of the Tec family of non-receptor tyrosine kinases and is a key kinase in the B cell antigen receptor (BCR) signaling pathway. Signaling through the BCR controls a range of effector responses, including activation, proliferation, and differentiation of mature antibody-producing cells. Abnormal BCR-mediated signaling can cause misregulated B cell activation and/or the formation of pathogenic autoantibodies, leading to a variety of human diseases, including cancer, autoimmune diseases, and xenoimmune diseases. Ibrutinib (trade name: Imbmvica) was the first BTK inhibitor to enter the market and achieved great success.
  • the crystal structure of active pharmaceutical ingredients often causes differences in various physical and chemical properties of the drug, such as solubility, dissolution rate, melting point, density, hardness, etc. These differences directly affect the drug's formulation process, storage method, and in vivo pharmacokinetics. performance, thereby affecting the bioavailability, clinical efficacy and safety of the drug. Therefore, it is of great significance to deeply study the polymorphism phenomenon of drugs and find crystal forms with good properties.
  • the technical problem to be solved by the present invention is to overcome the shortcoming of a small number of types of BTK inhibitors in the prior art.
  • a crystal form of a BTK inhibitor and its acid salt and its acid salt are provided.
  • the crystal form of the BTK inhibitor of the present invention, its acid salt, and the crystal form of its acid salt meet pharmaceutical requirements in terms of stability, hygroscopicity, etc., and are of very important significance for drug development.
  • the first aspect of the present invention provides a free base crystal form A of the compound of formula I, whose X-ray powder is expressed in 2 ⁇ angle
  • the final diffraction pattern has diffraction peaks at 7.3574 ⁇ 0.2°, 20.0853 ⁇ 0.2°, 26.2299 ⁇ 0.2° and 15.0639 ⁇ 0.2°;
  • the free base crystal form A of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more 2 ⁇ angles as follows: 22.5403 ⁇ 0.2° , 10.0156 ⁇ 0.2°, 6.4788 ⁇ 0.2°, 10.8671 ⁇ 0.2° and 19.5949 ⁇ 0.2°.
  • the free base crystal form A of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 12.0106 ⁇ 0.2°, 25.1097 ⁇ 0.2 °, 18.0778 ⁇ 0.2° and 30.3217 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the free base crystal form A of the compound of formula I is basically as shown in Figure 1.
  • the free base crystal form A of the compound of formula I has a thermogravimetric analysis (TGA) weight loss of 2.0%-3.5% (for example, 3.1%) when initially heated to 200 ⁇ 5°C (The weight loss percentage is the weight loss of the sample as a percentage of the weight of the sample before this weight loss).
  • TGA thermogravimetric analysis
  • the free base crystal form A of the compound of formula I has an endothermic peak at 327.4 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning heat map and thermogravimetric analysis chart of the free base crystal form A of the compound of formula I are basically as shown in Figure 2.
  • the second aspect of the present invention also provides a free base crystal form C of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2 ⁇ angle is 4.9395 ⁇ 0.2°, 28.0724 ⁇ 0.2°, 11.4647 ⁇ 0.2° and 13.2030 ⁇ There is a diffraction peak at 0.2°;
  • the free base crystal form C of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 17.2058 ⁇ 0.2° ,14.7891 ⁇ 0.2°, 20.1466 ⁇ 0.2°, 24.5916 ⁇ 0.2° and 21.4712 ⁇ 0.2°.
  • the free base crystal form C of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 9.0935 ⁇ 0.2°, 19.4096 ⁇ 0.2 °, 18.2149 ⁇ 0.2°, 22.5487 ⁇ 0.2°, 26.6034 ⁇ 0.2° and 22.9264 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the free base crystal form C of the compound of formula I is basically as shown in Figure 49.
  • the free base crystal form C of the compound of formula I has a weight loss of 1%-3% (for example, 2.7%) (for example, 2.7%) in the thermogravimetric analysis when initially heated to 200 ⁇ 5°C.
  • the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the free base crystal form C of the compound of formula I has an endothermic peak at 329.3 ⁇ 5°C in its differential scanning calorimetry; and/or has an exothermic peak at 311.3 ⁇ 5°C. peak.
  • the differential scanning heat map and thermogravimetric analysis chart of the free base crystal form C of the compound of formula I are basically as shown in Figure 50.
  • the third aspect of the present invention provides a free base crystal form D of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2 ⁇ angle is 4.8447 ⁇ 0.2°, 19.3873 ⁇ 0.2°, 12.0794 ⁇ 0.2° and 14.2457 ⁇ 0.2°. There are diffraction peaks everywhere;
  • the free base crystal form D of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more 2 ⁇ angles as follows: 4.3851 ⁇ 0.2° , 15.7673 ⁇ 0.2°, 22.1929 ⁇ 0.2°, 17.9985 ⁇ 0.2° and 24.8383 ⁇ 0.2°.
  • the free base crystal form D of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 22.3605 ⁇ 0.2°, 18.9570 ⁇ 0.2 °, 18.3427 ⁇ 0.2°, 23.7387 ⁇ 0.2°, 28.1120 ⁇ 0.2° and 24.2637 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the free base crystal form D of the compound of formula I is basically as shown in Figure 52.
  • thermogravimetric analysis chart of the free base crystalline form D of the compound of formula I has a weight loss of 3%-5% (for example, 4.1%) when initially heated to 150 ⁇ 5°C.
  • the weight loss of the sample is 6%-8% (example Such as 7.1%) (the weight loss percentage is the percentage of the weight loss of the sample and the weight of the sample before this weight loss).
  • the free base crystal form D of the compound of formula I has an endothermic peak at 175.3 ⁇ 5°C and/or 328.9 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning heat diagram and thermogravimetric analysis diagram of the free base crystal form D of the compound of formula I are basically as shown in Figure 53.
  • the fourth aspect of the present invention provides a free base crystal form E of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2 ⁇ angle is 5.3081 ⁇ 0.2°, 4.9506 ⁇ 0.2°, 20.9925 ⁇ 0.2° and 19.0379 ⁇ 0.2°. There are diffraction peaks everywhere;
  • the free base crystal form E of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 21.2501 ⁇ 0.2° , 17.2819 ⁇ 0.2°, 10.4721 ⁇ 0.2°, 23.0960 ⁇ 0.2° and 28.0729 ⁇ 0.2°.
  • the free base crystal form E of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has diffraction peaks at one or more of the following 2 ⁇ angles: 12.5909 ⁇ 0.2°, 13.8832 ⁇ 0.2 °, 14.9003 ⁇ 0.2°, 8.6259 ⁇ 0.2°, 7.3206 ⁇ 0.2° and 15.9004 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the free base crystal form E of the compound of formula I is basically as shown in Figure 55.
  • thermogravimetric analysis chart of the free base crystal form E of the compound of formula I has a weight loss of 1%-3% (for example, 1.8%) when initially heated to 80 ⁇ 5°C, and the weight loss is from 80 ⁇ 5°C to 80 ⁇ 5°C.
  • the weight loss of the sample is 16%-18% (for example, 16.8%) (the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the free base crystal form E of the compound of formula I has an endothermic peak at 144.5 ⁇ 5°C and/or 329.1 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning heat diagram and thermogravimetric analysis diagram of the free base crystal form E of the compound of formula I are basically as shown in Figure 56.
  • the fifth aspect of the present invention provides a pharmaceutically acceptable salt of a compound of formula I;
  • the pharmaceutically acceptable salt is a salt formed by a compound of formula I and an acid;
  • the acid is an inorganic acid or an organic acid;
  • the molar ratio of the compound of formula I to the acid is 1:(0.5-2), such as 1:0.6, 1:0.7, 1:0.9, 1:1, 1:1.1 , 1:1.3 or 1:2.
  • the inorganic acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid.
  • the inorganic acid is one or more of hydrochloric acid, phosphoric acid and hydrobromic acid.
  • the organic acid is maleic acid, L-aspartic acid, fumaric acid, L-tartaric acid, citric acid, 1,5-naphthalenedisulfonic acid, 1,2-ethylenediamine
  • sulfonic acid p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid and malonic acid.
  • the organic acid is one or more of maleic acid, fumaric acid, 1,5-naphthalenedisulfonic acid, and p-toluenesulfonic acid.
  • the organic acid is one or more of maleic acid, fumaric acid and p-toluenesulfonic acid.
  • the organic acid is maleic acid.
  • the pharmaceutically acceptable salt of the compound of formula I is any of the following pharmaceutically acceptable salts:
  • Hydrochloride of the compound of formula I wherein, the molar ratio of the compound of formula I to hydrochloric acid is 1: (0.5-2), for example, 1: (0.9-1.0);
  • 1,5-naphthalene disulfonate of the compound of formula I wherein, the molar ratio of the compound of formula I and 1,5-naphthalenedisulfonic acid is 1:(0.5-1), for example, 1:0.7;
  • the pharmaceutically acceptable salt of the compound of formula I can be prepared by conventional salt-forming reactions in the art.
  • the pharmaceutically acceptable salt of the compound of formula I can be prepared by the following method:
  • the compound of formula I is subjected to a salt-forming reaction with an acid in a solvent to obtain a pharmaceutically acceptable salt of the compound of formula I;
  • the molar ratio of the compound of formula I to hydrochloric acid is 1:(0.5-2.5), such as 1:(1-2), another example is 1:2;
  • the molar ratio of the compound of formula I to phosphoric acid is 1:(0.5-2), such as 1:(0.5-1.5), another example is 1:1;
  • the molar ratio of the compound of formula I to hydrobromic acid is 1:(0.5-2), such as 1:(0.5-1.5), another example is 1:1;
  • the molar ratio of the compound of formula I to fumaric acid is 1:(0.5-2), such as 1:(0.5-1.5), another example is 1:1;
  • the molar ratio of the compound of formula I to 1,5-naphthalene disulfonic acid is 1:(0.5-2), such as 1:(0.5-1.5), and For example 1:1;
  • the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:(0.5-2), such as 1:(0.5-1.5), another example is 1:1;
  • the molar ratio of the compound of formula I to maleic acid is 1:(0.5-2), such as 1:(0.5-1.5), another example is 1:1.
  • the sixth aspect of the present invention provides a crystal form A of the hydrochloride of the compound of formula I, whose X-ray powder diffraction pattern expressed at 2 ⁇ angle is 13.2577 ⁇ 0.2°, 19.0205 ⁇ 0.2°, 26.6619 ⁇ 0.2° and 24.4646 There is a diffraction peak at ⁇ 0.2°; the hydrochloride of the compound represented by Formula I is as described above;
  • the hydrochloride salt of the compound of formula I is Form A; wherein the molar ratio of the compound of formula I to hydrochloric acid is 1:1.
  • the crystal form A of the hydrochloride of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 25.4625 ⁇ 0.2°, 25.7474 ⁇ 0.2°, 14.8470 ⁇ 0.2°, 10.5627 ⁇ 0.2° and 25.0104 ⁇ 0.2°.
  • the crystal form A of the hydrochloride of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 24.6922 ⁇ 0.2°, 20.9024 ⁇ 0.2°, 18.2234 ⁇ 0.2°, 11.6824 ⁇ 0.2°, 21.1980 ⁇ 0.2° and 16.9518 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystal form A of the hydrochloride of the compound of formula I is basically as shown in Figure 4.
  • thermogravimetric analysis chart of the crystal form A of the hydrochloride of the compound of formula I has a weight loss of 6%-8% (for example, 7.1%) when initially heated to 110 ⁇ 5°C.
  • the weight loss of the sample is 7%-9% (for example, 7.9%) (the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the crystal form A of the hydrochloride of the compound of formula I has endothermic peaks at 115.4 ⁇ 5°C and 185.0 ⁇ 5°C in its differential scanning calorimetry; and/or, at There is an exothermic peak at 218.3°C ⁇ 5°C.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the hydrochloride of the compound of formula I is basically as shown in Figure 5.
  • the seventh aspect of the present invention provides a crystal form B of the hydrochloride of the compound of formula I, whose X-ray powder diffraction pattern expressed at 2 ⁇ angle is 11.2971 ⁇ 0.2°, 4.1094 ⁇ 0.2°, 16.0047 ⁇ 0.2° and 18.5553 There is a diffraction peak at ⁇ 0.2°; the hydrochloride of the compound represented by Formula I is as described above;
  • the hydrochloride salt of the compound of formula I is crystal form B; wherein, the molar ratio of the compound of formula I to hydrochloric acid is 1:1.
  • the crystal form B of the hydrochloride of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 27.3296 ⁇ 0.2°, 17.6049 ⁇ 0.2°, 27.5618 ⁇ 0.2°, 26.3637 ⁇ 0.2° and 25.6428 ⁇ 0.2°.
  • the crystal form B of the hydrochloride of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 21.4646 ⁇ 0.2°, 20.6275 ⁇ 0.2°, 12.7357 ⁇ 0.2°, 20.3279 ⁇ 0.2°, 24.8169 ⁇ 0.2° and 24.1245 ⁇ 0.2°.
  • the crystal form B of the hydrochloride of the compound of formula I has an X-ray
  • the line powder diffraction pattern is basically as shown in Figure 7.
  • thermogravimetric analysis chart of the crystal form B of the hydrochloride of the compound of formula I has a weight loss of 4%-6% (for example, 4.8%) when initially heated to 150 ⁇ 5°C.
  • the weight loss of the sample is 6.5%-8.5% (for example, 7.6%) (the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the crystal form B of the hydrochloride of the compound of formula I has an endothermic peak at 223.0 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form B of the hydrochloride of the compound of formula I is basically as shown in Figure 8.
  • the eighth aspect of the present invention provides a crystal form C of the hydrochloride of the compound of formula I, whose X-ray powder diffraction pattern expressed at 2 ⁇ angle is 21.5443 ⁇ 0.2°, 27.3605 ⁇ 0.2°, 10.0792 ⁇ 0.2° and 18.8112 There is a diffraction peak at ⁇ 0.2°; the hydrochloride of the compound represented by Formula I is as described above;
  • the hydrochloride salt of the compound of formula I is Form C; wherein, the molar ratio of the compound of formula I to hydrochloric acid is 1: (0.9-1.0); for example, 1:0.9.
  • the crystal form C of the hydrochloride of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 14.1629 ⁇ 0.2°, 8.5449 ⁇ 0.2°, 26.7582 ⁇ 0.2°, 6.8670 ⁇ 0.2° and 17.2037 ⁇ 0.2°.
  • the crystal form C of the hydrochloride of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 25.7895 ⁇ 0.2°, 15.3903 ⁇ 0.2°, 22.6726 ⁇ 0.2°, 14.7930 ⁇ 0.2°, 29.4042 ⁇ 0.2° and 15.8036 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystal form C of the hydrochloride of the compound of formula I is basically as shown in Figure 10.
  • thermogravimetric analysis of the crystal form C of the hydrochloride of the compound of formula I shows a weight loss of 1.5%-3% (for example, 2.2%) at 150 ⁇ 5°C, and a weight loss of 1.5%-3% (for example, 2.2%) at 150°C to 250°C.
  • the weight loss at °C is 6.5%-8.5% (for example, 7.5%) (the weight loss percentage is the percentage of the weight loss of the sample and the weight of the sample before this weight loss).
  • the crystalline form C of the hydrochloride of the compound of formula I has an endothermic peak at 248.2 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form C of the hydrochloride of the compound of formula I is basically as shown in Figure 11.
  • the ninth aspect of the present invention provides a crystalline form A of the phosphate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed at 2 ⁇ angle is 12.8284 ⁇ 0.2°, 21.1193 ⁇ 0.2°, 22.7554 ⁇ 0.2° and There is a diffraction peak at 12.4119 ⁇ 0.2°; the phosphate of the compound represented by Formula I is as described above;
  • the crystalline form A of the phosphate salt of the compound of formula I is; wherein, the molar ratio of the compound of formula I to phosphoric acid is 1:(1-2), for example, 1:1.3.
  • the crystal form A of the phosphate of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 24.1820 ⁇ 0.2°, 19.6004 ⁇ 0.2°, 24.9449 ⁇ 0.2°, 17.7015 ⁇ 0.2° and 25.7812 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed in 2 ⁇ angle of the phosphate crystal form A of the compound of formula I also has diffraction peaks at one or more of the following 2 ⁇ angles: 20.4385 ⁇ 0.2°, 14.9572 ⁇ 0.2°, 16.8423 ⁇ 0.2°, 5.2374 ⁇ 0.2° and 31.8376 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystal form A of the phosphate of the compound of formula I is basically as shown in Figure 13.
  • thermogravimetric analysis chart of the crystal form A of the phosphate salt of the compound of formula I has a weight loss of 1%-3% (for example, 2.1%) when initially heated to 65 ⁇ 5°C, from When heated from 65 ⁇ 5°C to 125 ⁇ 5°C, the weight loss of the sample is 2%-4% (for example, 2.8%) (the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the crystalline form A of the phosphate of the compound of formula I has a differential scanning calorimetry at one or more of 81.7 ⁇ 5°C, 92.1 ⁇ 5°C and 139.2 ⁇ 5°C. Endothermic peak.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the phosphate of the compound of formula I is basically as shown in Figure 14.
  • the tenth aspect of the present invention provides a crystal form A of the fumarate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed at a 2 ⁇ angle is 5.1732 ⁇ 0.2°, 7.9252 ⁇ 0.2°, and 10.2736 ⁇ 0.2 There are diffraction peaks at 18.8307 ⁇ 0.2°; the fumarate salt of the compound represented by Formula I is as described above;
  • the fumarate salt of the compound of formula I is crystal form A; wherein, the molar ratio of the compound of formula I to fumaric acid is 1:1.
  • the crystal form A of the fumarate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 24.8824 ⁇ 0.2°, 12.0866 ⁇ 0.2°, 15.4296 ⁇ 0.2°, 23.9878 ⁇ 0.2° and 13.0765 ⁇ 0.2°.
  • the crystal form A of the fumarate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 25.7497 ⁇ 0.2° , 27.5661 ⁇ 0.2° and 28.4676 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystalline form A of the fumarate salt of the compound of formula I is basically as shown in Figure 16.
  • thermogravimetric analysis chart of the crystalline form A of the fumarate salt of the compound of formula I has a weight loss of 2%-4% (for example, 2.6%) when initially heated to 150 ⁇ 5°C. , heated from 150 ⁇ 5°C to 240 ⁇ 5°C, the weight loss of the sample is 19%-22% (for example, 21.2%) (the weight loss percentage is the weight loss of the sample and the weight of the sample before this weight loss) .
  • the crystalline form A of the fumarate salt of the compound of formula I has an endothermic peak at 224.7 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the fumarate salt of the compound of formula I are basically as shown in Figure 17.
  • the eleventh aspect of the present invention provides a crystalline form A of the 1,5-naphthalene disulfonate of the compound of formula I, whose X-ray powder diffraction pattern expressed at a 2 ⁇ angle is 7.7555 ⁇ 0.2°, 9.6043 ⁇ There are diffraction peaks at 0.2°, 23.0949 ⁇ 0.2° and 17.5044 ⁇ 0.2°; the 1,5-naphthalene disulfonate of the compound represented by formula I is as described above;
  • the crystal form A of the 1,5-naphthalene disulfonate of the compound of formula I is; wherein, the molar ratio of the compound of formula I to methanesulfonic acid is 1:(0.5-1), for example 1:0.7.
  • the crystal form A of the 1,5-naphthalene disulfonate of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has one or more of the following 2 ⁇ angles There are diffraction peaks at: 20.2234 ⁇ 0.2°, 22.5424 ⁇ 0.2°, 16.5111 ⁇ 0.2°, 24.1101 ⁇ 0.2° and 11.2117 ⁇ 0.2°.
  • the crystal form A of the 1,5-naphthalene disulfonate of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles. : 15.6086 ⁇ 0.2°, 19.5194 ⁇ 0.2°, 12.9255 ⁇ 0.2°, 26.2933 ⁇ 0.2° and 27.8190 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystal form A of the 1,5-naphthalene disulfonate of the compound of formula I is basically as shown in Figure 19.
  • thermogravimetric analysis chart of the crystal form A of the 1,5-naphthalene disulfonate of the compound of formula I has a weight loss of 2.5%-4.5% when initially heated to 130 ⁇ 5°C. (for example, 3.5%), when heated from 130 ⁇ 5°C to 175 ⁇ 5°C, the weight loss of the sample is 1.5%-3.5% (for example, 2.6%) (the weight loss percentage is the weight loss of the sample and the weight of the sample before this weight loss. percentage of weight).
  • the crystal form A of the 1,5-naphthalene disulfonate of the compound of formula I has a differential scanning calorimetry diagram at 57.7 ⁇ 5°C, 82.9 ⁇ 5°C, and 166.9 ⁇ 5°C. There is an endothermic peak at one or more places between 211.1 ⁇ 5°C.
  • the differential scanning heat map and thermogravimetric analysis chart of the crystal form A of the 1,5-naphthalene disulfonate of the compound of formula I are basically as shown in Figure 20.
  • the twelfth aspect of the present invention provides a crystalline form B of the 1,5-naphthalene disulfonate of the compound of formula I, whose X-ray powder diffraction pattern expressed at a 2 ⁇ angle is 15.0980 ⁇ 0.2°, 20.3818 ⁇ There are diffraction peaks at 0.2°, 13.6481 ⁇ 0.2° and 24.7069 ⁇ 0.2°;
  • the crystalline form B of the 1,5-naphthalene disulfonate of the compound of formula I is; wherein, the molar ratio of the compound of formula I to methanesulfonic acid is 1:(0.5-1), for example 1:0.7.
  • the crystal form B of the 1,5-naphthalene disulfonate of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has one or more of the following 2 ⁇ angles There are diffraction peaks at: 15.8095 ⁇ 0.2°, 10.8634 ⁇ 0.2°, 16.7992 ⁇ 0.2°, 26.2961 ⁇ 0.2° and 12.3107 ⁇ 0.2°.
  • the crystal form B of the 1,5-naphthalene disulfonate of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles. : 18.9746 ⁇ 0.2°, 5.0796 ⁇ 0.2°, 25.1466 ⁇ 0.2°, 23.3711 ⁇ 0.2°, 27.3657 ⁇ 0.2° and 32.3061 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystalline form B of the 1,5-naphthalene disulfonate of the compound of formula I is basically as shown in Figure 22.
  • thermogravimetric analysis chart of the crystal form B of the 1,5-naphthalene disulfonate of the compound of formula I has a weight loss of 3.5%-5.5% when initially heated to 200 ⁇ 5°C. (For example, 4.3%) (The percentage of weight loss is the percentage of the weight loss of the sample and the weight of the sample before this weight loss).
  • the crystalline form B of the 1,5-naphthalene disulfonate of the compound of formula I has a differential scanning calorimetry diagram at 57.0 ⁇ 5°C, 82.5 ⁇ 5°C and 276.1 ⁇ 5°C. There are endothermic peaks at one or more places.
  • the differential scanning calorimetry and thermogravimetric analysis diagrams of the crystal form B of the 1,5-naphthalene disulfonate of the compound of formula I are basically as shown in Figure 23.
  • the thirteenth aspect of the present invention provides a crystal form A of the p-toluenesulfonate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed at a 2 ⁇ angle is 4.0699 ⁇ 0.2°, 20.3148 ⁇ 0.2°, 14.9056 There are diffraction peaks at ⁇ 0.2° and 18.3888 ⁇ 0.2°; the p-toluenesulfonate salt of the compound represented by Formula I is as described above;
  • the crystal form A of the p-toluenesulfonate of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles : 22.0879 ⁇ 0.2°, 25.9320 ⁇ 0.2°, 11.8243 ⁇ 0.2°, 17.2270 ⁇ 0.2° and 24.5224 ⁇ 0.2°.
  • the crystal form A of the p-toluenesulfonate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 12.2243 ⁇ 0.2 °, 25.3151 ⁇ 0.2°, 9.5171 ⁇ 0.2°, 23.7569 ⁇ 0.2°, 29.9444 ⁇ 0.2° and 28.8866 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystal form A of the p-toluenesulfonate of the compound of formula I is basically as shown in Figure 25.
  • thermogravimetric analysis chart of the crystal form A of the p-toluenesulfonate of the compound of formula I is initially heated to 75 ⁇ 5°C, and the sample weight loss is 3.5%-5.5% (for example, 4.3 %), heated from 75 ⁇ 5°C to 120 ⁇ 5°C, the weight loss of the sample is 5%-7% (for example, 6.1%) (the weight loss percentage is the weight of the sample reduced by the weight of the sample before this weight loss) percentage).
  • the crystal form A of the p-toluenesulfonate salt of the compound of formula I has an endothermic peak at 111.1 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning heat map and thermogravimetric analysis chart of the crystal form A of the p-toluenesulfonate salt of the compound of formula I are basically as shown in Figure 26.
  • the fourteenth aspect of the present invention provides a crystal form A of the hydrobromide salt of the compound of formula I, whose X-ray powder diffraction pattern expressed at 2 ⁇ angle is 4.1403 ⁇ 0.2°, 11.1940 ⁇ 0.2°, and 27.3198 ⁇ 0.2°. There are diffraction peaks at 17.4698 ⁇ 0.2°; the hydrobromide salt of the compound represented by Formula I is as described above;
  • the hydrobromide salt of the compound of formula I is crystal form A; wherein, the molar ratio of the compound of formula I to hydrobromic acid is 1: (0.5-1), for example, 1:0.9.
  • the crystal form A of the hydrobromide salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 20.6495 ⁇ 0.2°, 8.7348 ⁇ 0.2°, 18.5192 ⁇ 0.2°, 16.0192 ⁇ 0.2° and 19.6807 ⁇ 0.2°.
  • the crystal form A of the hydrobromide salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at the following 2 ⁇ angle: 25.5412 ⁇ 0.2° .
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystal form A of the hydrobromide salt of the compound of formula I is basically as shown in Figure 28.
  • thermogravimetric analysis chart of the hydrobromide crystal form A of the compound of formula I has a weight loss of 4.5%-6.5% (for example, 5.6%) when initially heated to 200 ⁇ 5°C. (The weight loss percentage is the weight loss of the sample as a percentage of the weight of the sample before this weight loss).
  • the crystal form A of the hydrobromide salt of the compound of formula I has a differential scanning calorimetry diagram at 97.7 ⁇ 5°C, 179.4 ⁇ 5°C, 230.7 ⁇ 5°C and 254.9 ⁇ 5°C. There are endothermic peaks at one or more places.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the hydrobromide salt of the compound of formula I is basically as shown in Figure 29.
  • the fifteenth aspect of the present invention provides a crystal form A of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed at 2 ⁇ angle is 4.4590 ⁇ 0.2°, 10.0991 ⁇ 0.2°, and 13.6435 ⁇ 0.2°. There are diffraction peaks at 20.6462 ⁇ 0.2°; the maleate salt of the compound represented by Formula I is as described above;
  • the crystalline form A of the maleate salt of the compound of formula I wherein the molar ratio of the compound of formula I and maleic acid is 1:1.
  • the crystal form A of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 25.9433 ⁇ 0.2°, 17.3036 ⁇ 0.2°, 26.3520 ⁇ 0.2°, 18.2594 ⁇ 0.2° and 17.8271 ⁇ 0.2°.
  • the crystal form A of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 15.0805 ⁇ 0.2° , 23.0488 ⁇ 0.2° and 11.6637 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystal form A of the maleate salt of the compound of formula I is basically as shown in Figure 31.
  • thermogravimetric analysis chart of crystalline form A of the maleate salt of the compound of formula I has a weight loss of 2.5%-3.5% (for example, 2.8%) when initially heated to 150 ⁇ 5°C. , when heated from 150°C to 230°C, the weight loss of the sample is 19%-21% (for example, 19.3%) (the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the crystal form A of the maleate salt of the compound of formula I has an endothermic peak at 200.3 ⁇ 20°C in its differential scanning calorimetry.
  • the crystal form A of the maleate salt of the compound of formula I has an endothermic peak at 200.3 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form A of the maleate salt of the compound of formula I is basically as shown in Figure 32.
  • the sixteenth aspect of the present invention provides a crystal form E of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed at 2 ⁇ angle is 4.4072 ⁇ 0.2°, 13.3026 ⁇ 0.2°, and 27.4367 ⁇ 0.2°. There are diffraction peaks at 21.9948 ⁇ 0.2°; the maleate salt of the compound represented by Formula I is as described above;
  • the crystalline form E of the maleate salt of the compound of formula I wherein the molar ratio of the compound of formula I to maleic acid is 1:1.
  • the crystal form E of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 20.1322 ⁇ 0.2°, 18.1840 ⁇ 0.2°, 12.8549 ⁇ 0.2°, 22.7709 ⁇ 0.2° and 13.6555 ⁇ 0.2°.
  • the crystal form E of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 28.9010 ⁇ 0.2° , 15.5372 ⁇ 0.2°, 16.2816 ⁇ 0.2°, 10.1536 ⁇ 0.2°, 26.7355 ⁇ 0.2° and 12.1903 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystalline form E of the maleate salt of the compound of formula I is basically as shown in Figure 34.
  • thermogravimetric analysis chart of crystalline form E of the maleate salt of the compound of formula I has a weight loss of 2.5%-4.5% (for example, 3.4%) when initially heated to 150 ⁇ 5°C. , heated from 150°C to 250°C, the sample weight loss is 19%- 21% (for example, 19.7%) (the weight loss percentage is the weight loss of the sample and the weight of the sample before this weight loss).
  • the crystalline form E of the maleate salt of the compound of formula I has an endothermic peak at 194.2 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystalline form E of the maleate salt of the compound of formula I is basically as shown in Figure 35.
  • the seventeenth aspect of the present invention provides a crystal form F of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed at 2 ⁇ angle is 10.9668 ⁇ 0.2°, 7.8002 ⁇ 0.2°, and 6.1349 ⁇ 0.2°. There are diffraction peaks at 12.3076 ⁇ 0.2°; the maleate salt of the compound represented by Formula I is as described above;
  • the crystalline form F of the maleate salt of the compound of formula I wherein the molar ratio of the compound of formula I to maleic acid is 1:1.
  • the crystal form F of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 17.6068 ⁇ 0.2°, 16.7364 ⁇ 0.2°, 25.6746 ⁇ 0.2°, 23.5852 ⁇ 0.2° and 20.2850 ⁇ 0.2°.
  • the crystal form F of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 9.9869 ⁇ 0.2° , 19.9375 ⁇ 0.2°, 23.2431 ⁇ 0.2°, 22.4598 ⁇ 0.2°, 22.7746 ⁇ 0.2° and 24.7937 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystalline form F of the maleate salt of the compound of formula I is basically as shown in Figure 37.
  • thermogravimetric analysis chart of crystalline form F of the maleate salt of the compound of formula I has a weight loss of 2%-4% (for example, 2.9%) when initially heated to 150 ⁇ 5°C. , when heated from 150°C to 250°C, the weight loss of the sample is 17.5%-19.5% (for example, 18.7%) (the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the crystal form F of the maleate salt of the compound of formula I has a differential scanning calorimetry diagram at one or more of 65.3 ⁇ 5°C, 81.7 ⁇ 5°C and 180.8 ⁇ 5°C. There are endothermic peaks everywhere.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form F of the maleate salt of the compound of formula I is basically as shown in Figure 38.
  • the eighteenth aspect of the present invention provides a crystalline form H of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2 ⁇ angle is 4.5619 ⁇ 0.2°, 13.5614 ⁇ 0.2°, and 13.0298 ⁇ 0.2°. There are diffraction peaks at 10.2862 ⁇ 0.2°; the maleate salt of the compound represented by Formula I is as described above;
  • the crystalline form H of the maleate salt of the compound of formula I wherein the molar ratio of the compound of formula I to maleic acid is 1:1.
  • the crystal form H of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 18.3628 ⁇ 0.2°, 25.9556 ⁇ 0.2°, 26.6709 ⁇ 0.2°, 20.7641 ⁇ 0.2° and 12.4688 ⁇ 0.2°.
  • the crystal form H of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 15.9640 ⁇ 0.2° , 8.9876 ⁇ 0.2°, 27.2853 ⁇ 0.2°, 19.2049 ⁇ 0.2°, 23.2406 ⁇ 0.2° and 28.2446 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystalline form H of the maleate salt of the compound of formula I is basically as shown in Figure 40.
  • thermogravimetric analysis chart of crystalline form H of the maleate salt of the compound of formula I has a weight loss of 1%-2% (for example, 1.4%) when initially heated to 150 ⁇ 5°C. , when heated from 150°C to 250°C, the weight loss of the sample is 16.5%-18.5% (for example, 17.4%) (the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the crystalline form H of the maleate salt of the compound of formula I has an endothermic peak at 188.6 ⁇ 5°C in its differential scanning calorimetry.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystalline form H of the maleate salt of the compound of formula I is basically as shown in Figure 41.
  • the nineteenth aspect of the present invention provides a crystal form I of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed at 2 ⁇ angle is 5.4040 ⁇ 0.2°, 9.4028 ⁇ 0.2°, and 10.4407 ⁇ 0.2°. There are diffraction peaks at 8.8892 ⁇ 0.2°;
  • the maleate salt of the compound represented by Formula I is as described above;
  • the crystalline form I of the maleate salt of the compound of formula I wherein the molar ratio of the compound of formula I to maleic acid is 1:1.
  • the crystal form I of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 12.6630 ⁇ 0.2°, 25.4555 ⁇ 0.2°, 13.6954 ⁇ 0.2°, 15.5008 ⁇ 0.2° and 17.6958 ⁇ 0.2°.
  • the crystal form I of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 17.4174 ⁇ 0.2°, 11.3412 ⁇ 0.2°, 23.4711 ⁇ 0.2°, 27.0913 ⁇ 0.2°, 20.1842 ⁇ 0.2° and 6.0958 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystalline form I of the maleate salt of the compound of formula I is basically as shown in Figure 43.
  • thermogravimetric analysis chart of the maleic acid salt form I of the compound of formula I has a weight loss of 2.5%-4.5% (for example, 3.5%) when heated to 130 ⁇ 5°C.
  • the weight loss of the sample is 19%-21% (for example, 20.2%) (the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the crystal form I of the maleate salt of the compound of formula I has endothermic peaks at 112.9 ⁇ 5°C and 202.5 ⁇ 5°C in its differential scanning calorimetry; and/or, There is an exothermic peak at 161.5 ⁇ 5°C.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form I of the maleate salt of the compound of formula I are basically as shown in Figure 44.
  • a twentieth aspect of the present invention provides a crystal form J of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2 ⁇ angle is 5.4594 ⁇ 0.2°, 25.5787 ⁇ 0.2°, and 17.8675 ⁇ 0.2°. There are diffraction peaks at 10.5280 ⁇ 0.2°; the maleate salt of the compound represented by Formula I is as described above;
  • the crystal form J of the maleate salt of the compound of formula I wherein the molar ratio of the compound of formula I to maleic acid is 1:1.
  • the crystal form J of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and also has a diffraction peak at one or more of the following 2 ⁇ angles: 15.7099 ⁇ 0.2°, 27.1774 ⁇ 0.2°, 23.6955 ⁇ 0.2°, 9.4120 ⁇ 0.2° and 8.9158 ⁇ 0.2°;
  • the crystal form J of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at a 2 ⁇ angle, and further has a diffraction peak at one or more of the following 2 ⁇ angles: 20.4902 ⁇ 0.2° , 29.5595 ⁇ 0.2°, 28.3910 ⁇ 0.2°, 12.7045 ⁇ 0.2°, 20.9226 ⁇ 0.2° and 13.7795 ⁇ 0.2°.
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle of the crystal form J of the maleate salt of the compound of formula I is basically as shown in Figure 46.
  • thermogravimetric analysis chart of crystalline form J of the maleate salt of the compound of formula I has a value of 6%-7% (for example, 6.4%) when initially heated to 150 ⁇ 5°C.
  • Weight loss when heated from 150°C to 250°C, the weight loss of the sample is 19.5%-21.5% (for example, 20.5%) (the weight loss percentage is the weight loss of the sample divided by the weight of the sample before this weight loss).
  • the crystal form J of the maleate salt of the compound of formula I has an endothermic peak at 193.7 ⁇ 5°C in its differential scanning calorimetry; and/or, at 162.1 ⁇ 5°C There are exothermic peaks everywhere.
  • the differential scanning thermogram and thermogravimetric analysis diagram of the crystal form J of the maleate salt of the compound of formula I is basically as shown in Figure 47.
  • Preparation methods of the crystalline form of the BTK inhibitor of the present invention and its pharmaceutically acceptable salts and the crystalline form of its pharmaceutically acceptable salts can be obtained by many methods as known in the art.
  • the twenty-first aspect of the present invention provides a method for preparing crystal form A of the maleate salt of the compound of formula I, which includes the following steps: mixing the compound of formula I and maleate at 10-70°C.
  • the maleic acid is crystallized in a solvent to obtain crystal form A of the maleate salt of the compound of formula I.
  • the solvent is a ketone solvent (preferably acetone, 2-butanone, methyl isobutyl ketone, N-methylpyrrolidone) and/or an ester solvent (preferably ethyl acetate).
  • ketone solvent preferably acetone, 2-butanone, methyl isobutyl ketone, N-methylpyrrolidone
  • ester solvent preferably ethyl acetate
  • the crystallization temperature is preferably 10-30°C or 50-60°C.
  • the mass-to-volume ratio of the ketone solvent is preferably 30-50 mg/mL, such as 40 mg/mL;
  • the mass-to-volume ratio of the ester solvent is preferably 30-80 mg/mL, such as 34 mg/mL or 74 mg/mL.
  • the crystallization method can be carried out under stirring (such as suspension stirring).
  • separation can be carried out according to conventional operating methods in the art, such as centrifugation or filtration.
  • the twenty-second aspect of the present invention provides a maleate salt crystal form A prepared according to the preparation method of the maleate salt crystal form A of the compound of formula I mentioned above.
  • the twenty-third aspect of the present invention provides a method for preparing the crystalline form E of the maleate salt of the compound of formula I, which includes the following steps: at 10-30°C, the maleate of the compound of formula I is prepared. After the acid salt crystal form A sample is dissolved in an ether solvent, the filtrate is placed in an antisolvent atmosphere for gas-liquid permeation to obtain crystal form E of the maleic acid salt of the compound of formula I.
  • the ether solvent is preferably methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, anisole; the anti-solvent is preferably alkyl.
  • the solvent is preferably n-hexane or n-heptane.
  • the twenty-fourth aspect of the present invention provides a crystalline form E of the maleate salt prepared according to the preparation method of the crystalline form E of the maleate salt of the compound of formula I.
  • the twenty-fifth aspect of the present invention provides a method for preparing crystalline form F of the maleate salt of the compound of formula I according to the above, which includes the following steps: at 10-30°C, the maleic acid of the compound of formula I is prepared.
  • the salt crystal form A sample is formed into a suspension in a solvent and crystallized to obtain the crystal form F of the maleate salt of the compound of formula I.
  • the solvent is preferably an ether solvent or a mixed solvent of an ether solvent and water, preferably a mixed solvent of an ether solvent and water.
  • the ether solvent is preferably tetrahydrofuran or 2-methyltetrahydrofuran.
  • the mass volume ratio of the mixed solvent of the ether solvent and water is preferably 30-50 mg/mL, such as 40 mg/mL; the volume ratio (v/v) of the ether solvent and water is preferably 10-25:1 , for example 22:1.
  • the twenty-sixth aspect of the present invention provides a crystalline form F of the maleate salt prepared according to the preparation method of the maleate salt form F of the compound of formula I mentioned above.
  • the twenty-seventh aspect of the present invention provides a method for preparing crystalline form H of maleic acid of the compound of formula I, which includes the following steps: at 10-30°C, the maleate salt of the compound of formula I is After the crystal form A sample is dissolved in an ether solvent, the filtrate is placed in an antisolvent atmosphere for gas-liquid permeation.
  • the ether solvent is preferably methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, anisole;
  • the anti-solvent is preferably an ether solvent , preferably methyl tert-butyl ether.
  • the twenty-eighth aspect of the present invention provides a crystalline form H of the maleate salt prepared according to the preparation method of the crystalline form H of the maleate salt of the compound of formula I.
  • the twenty-ninth aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective dose of substance A and a drug.
  • a scientifically acceptable carrier, diluent or excipient; the substance A is the crystal form of the above-mentioned compound of formula I (the above-mentioned free base crystal form A of the above-mentioned compound of formula I, the above-mentioned free base crystal form C of the compound of formula I , one or more of the above-mentioned free base crystal form D of the compound of formula I and the above-mentioned free base crystal form E of the compound of formula I), a pharmaceutically acceptable salt of the above-mentioned compound of formula I or a pharmaceutically acceptable salt of the above-mentioned compound of formula I
  • the crystal forms of pharmaceutically acceptable salts (the above-mentioned compound of formula I hydrochloride crystal form A, the above-mentioned compound of formula I hydrochloride crystal form B, the above-mentioned compound of
  • the thirtieth aspect of the present invention provides the use of substance B in the preparation of medicines for preventing and/or treating diseases or conditions;
  • the substance B is the above-mentioned pharmaceutical composition, the crystal form of the above-mentioned compound of formula I (the above-mentioned One or more of the free base crystal form A of the compound of formula I, the free base crystal form C of the above-mentioned compound of formula I, the free base crystal form D of the above-mentioned compound of formula I, and the free base crystal form E of the above-mentioned compound of formula I) , the pharmaceutically acceptable salt of the above-mentioned compound of formula I or the crystal form of the pharmaceutically acceptable salt of the above-mentioned compound of formula I (the above-mentioned compound of formula I hydrochloride crystal form A, the above-mentioned compound of formula I hydrochloride Crystal Form B, the above-mentioned compound of formula I hydrochloride crystal form C, the above-mentioned compound of
  • the disease or disorder is associated with BTK and/or associated with abnormal B cell activation.
  • the dosage of substance B is an effective therapeutic amount.
  • the thirty-first aspect of the present invention provides the crystal form of the compound of formula I and its acid salt and the crystal form of its acid salt or the use of the pharmaceutical composition in the preparation of BTK inhibitors.
  • the thirty-second aspect of the present invention provides the use of substance B in preventing and/or treating diseases or conditions, and the substance B is as described above.
  • the thirty-second aspect of the present invention provides a method for inhibiting BTK kinase, or preventing and/or treating diseases, including the steps of: administering substance B to a subject in need;
  • the disease or disorder is related to BTK and/or related to abnormal B cell activation, and the substance B is as described above.
  • the crystalline form of the compound of formula I, its acid salt, and the crystalline form of its acid salt are present in the pharmaceutical composition or medicine in a therapeutically and/or preventively effective amount.
  • the disease or condition is selected from the group consisting of heteroimmune diseases, autoimmune diseases, inflammatory diseases, and cancer.
  • the heteroimmune diseases, autoimmune diseases, and inflammatory diseases can be selected from the following group: rheumatic diseases, glomerulonephritis, Goodpasture syndrome, atherosclerosis, autoimmune blood diseases, Autoimmune gastritis, autoimmune inflammatory bowel disease, irritable bowel syndrome, allograft rejection, chronic thyroiditis, Graves' disease, Sjogren's disease, scleroderma, diabetes, hepatitis, pancreatitis, Primary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, dermatomyositis, contact dermatitis, eczema, vasculitis, chronic renal insufficiency, Stevens-Johnson syndrome , inflammatory pain, idiopathic diarrhea, cachexia, sarcoidosis, Guillain-Barre syndrome, u
  • the cancer is leukemia or lymphoma.
  • the cancer may be selected from the group consisting of small lymphocytic lymphoma (SLL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia Myeloid leukemia (CML), acute promyelocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Waldenstrom's macroglobulinemia , follicular lymphoma, multiple myeloma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), non-Hodgkin lymphoma.
  • SLL small lymphocytic lymphoma
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • AML acute myelogenous leukemia
  • CML chronic lymphocy
  • the polymorphic form of the compound of Formula 1 of the present invention has an X-ray powder diffraction characteristic peak expressed at an angle of 2 ⁇ , where “ ⁇ 0.20°” is the allowable measurement error range.
  • the polymorphic form of the compound of formula I according to the invention can be used in combination with other active ingredients, as long as it does not produce other adverse effects, such as allergic reactions.
  • composition as used herein is meant to include products containing specified amounts of each of the specified ingredients, as well as any product resulting directly or indirectly from the combination of specified amounts of each specified ingredient.
  • compositions may be particularly specially formulated for oral administration, for parenteral injection, or for rectal administration in solid or liquid form.
  • the pharmaceutical composition can be formulated into a variety of dosage forms for easy administration, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions) , or an injectable dry powder that can be used immediately after adding the drug solvent before injection).
  • oral preparations such as tablets, capsules, solutions or suspensions
  • injectable preparations such as injectable solutions or suspensions
  • injectable dry powder that can be used immediately after adding the drug solvent before injection.
  • terapéuticaally and/or prophylactically effective amount is an amount of a drug or pharmaceutical formulation that elicits the biological or medical response in a tissue, system, animal or human sought by a researcher, veterinarian, physician or other person.
  • the total daily dosage of the polymorphs and pharmaceutical compositions of the compound of formula I of the present invention must be determined by the attending physician within the scope of reliable medical judgment.
  • the specific therapeutically effective dosage level will be determined by a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; The patient's age, weight, general health, sex, and diet; the timing, route of administration, and excretion rate of the specific compound employed; the duration of treatment; medications used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical field. For example, it is common practice in the art to start dosages of a compound at levels lower than those required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.
  • Polymorph or “polymorph” as used in the present invention refers to crystalline forms that have the same chemical composition but different spatial arrangements of the molecules, atoms and/or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in packing and geometric arrangement and may exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution velocity and similar properties. Depending on their temperature-stability relationship, two polymorphs can be monotropic or tautotropic. For a unidenaturing system, the relative stability between the two solid phases remains unchanged when the temperature changes.
  • room temperature or "RT” as used herein refers to an ambient temperature of 20 to 25°C (68-77°F).
  • MeOH methanol
  • 2-MeTHF 2-methyltetrahydrofuran
  • EtOH ethanol
  • 1,4-Dioxane 1,4-dioxane
  • IPA isopropyl alcohol
  • ACN acetonitrile
  • Acetone acetone
  • DCM dichloromethane
  • MIBK methyl isobutyl ketone: Toluene: toluene
  • EtOAc ethyl acetate
  • n-Heptane n-heptane
  • IPAc isopropyl acetate
  • DMSO dimethyl sulfoxide
  • MTBE methane tert-butyl ether
  • DMAc dimethylacetamide
  • THF tetrahydrofuran
  • NMP N-methylpyrrolidone.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the crystal form of the BTK inhibitor of the present invention and its acid salt and the crystal form of its acid salt have the advantages of high activity, low hygroscopicity and good stability, which are very important for drug development. significance.
  • Figure 1 is the XRPD spectrum of the free base crystal form A of the compound of formula I.
  • Figure 2 is a TGA/DSC spectrum of the free base crystal form A of the compound of formula I.
  • Figure 3 is a 1 H NMR spectrum of the free base crystal form A of the compound of formula I.
  • Figure 4 is the XRPD spectrum of the hydrochloride salt form A of the compound of formula I.
  • Figure 5 is a TGA/DSC spectrum of the hydrochloride crystal form A of the compound of formula I.
  • Figure 6 is a 1 H NMR spectrum of the hydrochloride salt form A of the compound of formula I.
  • Figure 7 is the XRPD spectrum of the hydrochloride salt form B of the compound of formula I.
  • Figure 8 is a TGA/DSC spectrum of the hydrochloride salt form B of the compound of formula I.
  • Figure 9 is a 1 H NMR spectrum of the hydrochloride salt form B of the compound of formula I.
  • Figure 10 is the XRPD spectrum of the hydrochloride salt form C of the compound of formula I.
  • Figure 11 is a TGA/DSC spectrum of the hydrochloride salt form C of the compound of formula I.
  • Figure 12 is a 1 H NMR spectrum of the hydrochloride salt form C of the compound of formula I.
  • Figure 13 is the XRPD spectrum of the phosphate crystal form A of the compound of formula I.
  • Figure 14 is a TGA/DSC spectrum of the phosphate crystal form A of the compound of formula I.
  • Figure 15 is a 1 H NMR spectrum of the phosphate crystal form A of the compound of formula I.
  • Figure 16 is the XRPD spectrum of the fumarate salt form A of the compound of formula I.
  • Figure 17 is a TGA/DSC spectrum of the fumarate crystal form A of the compound of formula I.
  • Figure 18 is a 1 H NMR spectrum of the fumarate salt form A of the compound of formula I.
  • Figure 19 is the XRPD spectrum of the 1,5-naphthalene disulfonate crystal form A of the compound of formula I.
  • Figure 20 is a TGA/DSC spectrum of the 1,5-naphthalene disulfonate crystal form A of the compound of formula I.
  • Figure 21 is a 1 H NMR spectrum of the 1,5-naphthalene disulfonate crystal form A of the compound of formula I.
  • Figure 22 is the XRPD spectrum of the 1,5-naphthalene disulfonate crystal form B of the compound of formula I.
  • Figure 23 is a TGA/DSC spectrum of the 1,5-naphthalene disulfonate crystal form B of the compound of formula I.
  • Figure 24 is a 1 H NMR spectrum of the 1,5-naphthalene disulfonate crystal form B of the compound of formula I.
  • Figure 25 is the XRPD spectrum of the p-toluenesulfonate crystal form A of the compound of formula I.
  • Figure 26 is a TGA/DSC spectrum of the p-toluenesulfonate crystal form A of the compound of formula I.
  • Figure 27 is a 1 H NMR spectrum of the p-toluenesulfonate crystal form A of the compound of formula I.
  • Figure 28 is an XRPD spectrum of the hydrobromide salt form A of the compound of formula I.
  • Figure 29 is a TGA/DSC spectrum of the hydrobromide salt form A of the compound of formula I.
  • Figure 30 is a 1 H NMR spectrum of the hydrobromide salt form A of the compound of formula I.
  • Figure 31 is the XRPD spectrum of the maleate salt form A of the compound of formula I.
  • Figure 32 is a TGA/DSC spectrum of the maleate salt form A of the compound of formula I.
  • Figure 33 is a 1 H NMR spectrum of the maleate salt form A of the compound of formula I.
  • Figure 34 is an XRPD spectrum of the maleate salt form E of the compound of formula I.
  • Figure 35 is a TGA/DSC spectrum of the maleate salt form E of the compound of formula I.
  • Figure 36 is a 1 H NMR spectrum of the maleate salt form E of the compound of formula I.
  • Figure 37 is an XRPD spectrum of the maleate salt form F of the compound of formula I.
  • Figure 38 is a TGA/DSC spectrum of the maleate salt form F of the compound of formula I.
  • Figure 39 is a 1 H NMR spectrum of the maleate salt form F of the compound of formula I.
  • Figure 40 is an XRPD spectrum of the maleate salt form H of the compound of formula I.
  • Figure 41 is a TGA/DSC spectrum of the maleate salt form H of the compound of formula I.
  • Figure 42 is a 1 H NMR spectrum of the maleate salt form H of the compound of formula I.
  • Figure 43 is an XRPD spectrum of the maleate salt form I of the compound of formula I.
  • Figure 44 is a TGA/DSC spectrum of the maleate salt form I of the compound of formula I.
  • Figure 45 is a 1 H NMR spectrum of the maleate salt form I of the compound of formula I.
  • Figure 46 is an XRPD spectrum of the maleate salt form J of the compound of formula I.
  • Figure 47 is a TGA/DSC spectrum of the maleate salt form J of the compound of formula I.
  • Figure 48 is a 1 H NMR spectrum of the maleate salt form J of the compound of formula I.
  • Figure 49 is the XRPD spectrum of the free base crystal form C of the compound of formula I.
  • Figure 50 is a TGA/DSC spectrum of the free base crystal form C of the compound of formula I.
  • Figure 51 is a 1 H NMR spectrum of the free base crystal form C of the compound of formula I.
  • Figure 52 is the XRPD spectrum of the free base crystal form D of the compound of formula I.
  • Figure 53 is a TGA/DSC spectrum of the free base crystal form D of the compound of formula I.
  • Figure 54 is a 1 H NMR spectrum of the free base crystal form D of the compound of formula I.
  • Figure 55 is the XRPD spectrum of the free base crystal form E of the compound of formula I.
  • Figure 56 is a TGA/DSC spectrum of the free base crystal form E of the compound of formula I.
  • Figure 57 is a 1 H NMR spectrum of the free base crystal form E of the compound of formula I.
  • Figure 58 is a DVS spectrum of the maleate salt form A of the compound of formula I.
  • Figure 59 is an XRPD stack before and after pressure stabilization of the maleate salt form A of the compound of formula I.
  • Figure 60 is the XRPD spectrum of the compound of formula I obtained in Preparation Example 1.
  • Figure 61 is the X-ray single crystal diffraction spectrum of the compound of formula I obtained in Preparation Example 1.
  • the obtained solid samples were analyzed using a variety of detection and analysis methods, such as powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), dynamic moisture adsorption (DVS), hydrogen spectroscopy Liquid NMR ( 1 H Solution NMR).
  • Powder X-ray diffraction (XRPD) XRPD results were collected on an X-ray powder diffraction analyzer produced by PANalytical. The scanning parameters are as shown in the table.
  • TGA and DSC charts were obtained on TA Discovery 5500 Collected on a thermogravimetric analyzer and TA Discovery 2500 differential scanning calorimeter, the test parameters are listed in the table.
  • Dynamic moisture adsorption (DVS) The dynamic moisture adsorption (DVS) curve was collected on the DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C is corrected using the deliquescent points of LiCl, Mg(NO 3 ) 2 and KCl. DVS test parameters are listed in the table.
  • HPLC High performance liquid chromatography
  • Ion chromatography The ThermoFisher ICS-1100 ion chromatograph was used to analyze the ion content in the test. The specific conditions are shown in the table.
  • Step 1 (S)-2-(hydroxymethyl)-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino )
  • Deuterated methyl propionate 500 mg, 1.14 mmol
  • acetonitrile 15 mL
  • silver (II) oxide 3.97 g, 17.15 mmol
  • deuterated methyl iodide (2.49 g, 17.15 mmol) were added, and the reaction was carried out at 35°C Stir for 48 hours.
  • the reaction solution was cooled to room temperature and filtered through Celite, and the filter cake was washed with ethyl acetate (20 mL).
  • Step 2 (S)-2-(((methoxy-d3)methyl)-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b] Pyridin-4-yl)amino)deuterated methyl propionate (520 mg, 1.14 mmol) was dissolved in acetic acid (10 mL), iron powder (447 mg, 8.01 mmol) was added, and the reaction was stirred at 90°C for 2 hours. The reaction solution was cooled to room temperature. Afterwards, it was filtered with diatomaceous earth, and the filter cake was washed with ethyl acetate (20 mL).
  • Step 4 (S)-2-(((methoxy-d3)methyl)-2-(methyl-d3)-1,2,4,7-tetrahydro-3H-pyrrolo[3', 2':5,6]pyrido[3,4-b]pyrazin-3-one (225 mg, 0.89 mmol) and 2-chloro-4-phenoxybenzaldehyde (622 mg, 2.68 mmol) were dissolved in methanol (10 mL ), cool the reaction to 0°C, and add potassium hydroxide (350 mg, 6.24 mmol). The reaction is stirred at room temperature for 16 hours.
  • Step 5 (2S)-9-(((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-((methoxy-d3)methyl)-2-(methyl -d3)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (200mg, 0.412mmol ) was dissolved in tetrahydrofuran (5 mL) and water (0.5 mL) and 2,3-dichloro-5,6-dicyanobenzoquinone (281 mg, 1.24 mmol) was added at room temperature, and the reaction was stirred at room temperature for 2 hours.
  • Test Example 1 BTK and BTK C481S enzymatic experiments
  • DMSO DMSO to prepare a 3-fold gradient concentration stock solution of 1000X compound
  • reaction buffer 50mM HEPES, pH7.5, 0.0015% Briji-35, 2mM DTT, 10mM MgCl 2
  • reaction buffer 50mM HEPES, pH7.5, 0.0015% Briji-35, 2mM DTT, 10mM MgCl 2
  • BTK Kinase Enzyme System Promega Catalog #V2941
  • BTK (C481S) Kinase Enzyme System Promega Catalog #VA7033
  • the substrate solution contains ATP (125 ⁇ M) and Poly(Glu4, Tyr1) (0.05 ⁇ g/ ⁇ L), and react at 20°C for 90 minutes.
  • ATP 125 ⁇ M
  • Poly(Glu4, Tyr1) 0.05 ⁇ g/ ⁇ L
  • DMSO DMSO as the maximum signal value and no enzyme as the minimum signal value.
  • the compound of formula I has high inhibitory activity against BTK or BTK(C481S) kinase, with an IC 50 value of 10.6 nM for BTK and 12.5 nM for BTK(C481S).
  • Test example 2 p-BTK cell experiment
  • Day 1 Take HEK293 cells (ADDEXBIO, T0011001) in the logarithmic growth phase, digest the cells with EDTA, collect and count, inoculate 2E6 cells into a 10cm culture dish, and culture overnight.
  • the next day Use 1000 ⁇ L Opti-MEM to prepare a mixture containing 6ug of WT-BTK/C481S-BTK plasmid and 18 ⁇ L of FuGENE HD transfection reagent. After letting it stand at room temperature for 10 minutes, use a pipette to slowly add the mixture to the culture medium. dish and incubate overnight.
  • Day 3 Take out the culture dish and digest the cells with EDTA.
  • the compound of formula I has high inhibitory activity on the phosphorylation level of BTK or BTK(C481S), with an IC 50 value of 17.00 nM for BTK and an IC 50 value of 39.20 nM for phosphorylation of BTK(C481S).
  • TMD-8 cells are human diffuse large B lymphoma (Mingzhou Biotechnology, MZ-0832), cultured in 10% FBS + 1% PS1640 medium.
  • cells in the logarithmic growth phase were collected, counted and seeded with 600 TMD-8 cells in a 384-well cell culture plate, and cultured overnight.
  • the next day use DMSO to prepare a 3-fold gradient concentration stock solution of 400X compound, dilute it 40 times with culture medium to 10X compound stock solution, add 10X compound stock solution to each cell culture well, the final concentration is 1X, DMSO content is 0.25%.
  • DMSO was used as experimental control, and culture medium was used as blank control. Incubation was continued for three days after compound addition.
  • the compound of the present invention has high inhibitory activity against TMD-8, and the IC 50 value for TMD-8 is 72.77 nM.
  • TGA results show that when the temperature is raised to 150°C, the sample loses weight by 2.2%, and when heated from 150°C to 250°C, the sample loses weight by 7.5%; DSC shows that the sample observes an endothermic peak at 248.2°C (peak temperature).
  • IC/HPLC test results show that the molar ratio of hydrochloric acid to free state is 0.9:1.
  • the X-ray powder diffraction data of the hydrochloride crystal form C of the compound of formula I are shown in Table 10 below.
  • the TGA results show that when the temperature is raised to 130°C, the weight loss of the sample is 3.5%, and when heated from 130°C to 175°C, the weight loss of the sample is 2.6%; DSC shows that the sample is observed at 57.7°C, 82.9°C, 166.9°C and 211.1°C (peak temperature) to 4 endothermic peaks.
  • the 1 H NMR results showed that the molar ratio of 1,5-naphthalenedisulfonic acid to the free state in this sample was approximately 0.7:1, and no acetonitrile solvent residue was observed.
  • the X-ray powder diffraction data of the 1,5-naphthalene disulfonate crystal form A of the compound of formula I are shown in Table 13 below.
  • the TGA results showed that when the temperature was raised to 200°C, the weight loss of the sample was 4.3%; DSC showed that three endothermic peaks were observed in the sample at 57.0°C, 82.5°C and 276.1°C (peak temperature).
  • the 1 H NMR results showed that the molar ratio of 1,5-naphthalenedisulfonic acid to the free state in this sample was approximately 0.7:1, and no acetonitrile solvent residue was observed.
  • the X-ray powder diffraction data of the 1,5-naphthalene disulfonate crystal form B of the compound of formula I are shown in Table 14 below.
  • the TGA results showed that when the temperature was raised to 75°C, the sample lost weight by 4.3%, and when heated from 75°C to 120°C, the sample lost weight by 6.1%; DSC showed that the sample observed an endothermic peak at 111.1°C (peak temperature).
  • the 1 H NMR results showed that the molar ratio of p-toluenesulfonic acid to the free state in this sample was 1.0:1, and no solvent residue of acetonitrile was observed.
  • the X-ray powder diffraction data of the p-toluenesulfonate crystal form A of the compound of formula I are shown in Table 15 below.
  • the TGA results show that when the sample is heated from room temperature to 150°C, the sample weight loss is 1.4%, and when heated from 150°C to 250°C, the sample weight loss is 17.4%.
  • DSC results show that an endothermic peak was observed in this sample at 188.6°C (peak temperature).
  • 1 H NMR (results show that the molar ratio of maleic acid to free state in this sample is 1.0:1.
  • the maleate crystal form H was identified by VT-XRPD, and the sample was purged under N 20min . When heated to 150°C and lowered to 30°C, no change in crystal form was observed.
  • the maleate salt crystal form H of the compound of formula I has X-ray powder diffraction data as shown in Table 20 below.
  • the TGA results show that when the sample is heated from room temperature to 130°C, the sample weight loss is 3.5%, and when heated from 130°C to 250°C, the sample weight loss is 20.2%.
  • the DSC results show that two endothermic peaks were observed at 112.9°C and 202.5°C (peak temperature), and one exothermic peak was observed at 161.5°C (peak temperature).
  • 1 H NMR results showed that the molar ratio of maleic acid to free state in this sample was 1.0:1.
  • the X-ray powder diffraction data of the maleate salt form I of the compound of formula I are shown in Table 21 below.
  • the maleate salt crystal form I (prepared in Example 15) was heated to 130°C, lowered to room temperature and exposed to air to obtain the maleate salt form J of the compound of formula I.
  • the XRPD, TGA/DSC and 1 H NMR characterization results are shown in Figure 46, Figure 47 and Figure 48 respectively.
  • the TGA results show that when the sample is heated from room temperature to 150°C, the sample weight loss is 6.4%, and when heated from 150°C to 250°C, the sample weight loss is 20.5%.
  • the DSC results show that this sample has an endothermic peak observed at 193.7°C (peak temperature) and an exothermic peak at 162.1°C (peak temperature).
  • 1 H NMR results showed that the molar ratio of maleic acid to free state in this sample was 1.0:1.
  • the maleate crystal form J was subjected to a humidity induction test. After the maleate crystal form J was placed under 80% RH overnight, the crystal form did not change, indicating that the maleate crystal form J was relatively stable under high humidity conditions. Stablize.
  • the X-ray powder diffraction data of the maleate salt of the compound of formula I, Form J, are shown in Table 22 below.
  • the XRPD, TGA/DSC and 1 H NMR characterization results are shown in Figure 49, Figure 50 and Figure 51.
  • the TGA results showed that the sample had a weight loss of 2.7% when heated to 200°C; the DSC results showed that an endothermic peak was observed at 329.3°C (peak temperature) and an exothermic peak was observed at 311.3°C (peak temperature).
  • the X-ray powder diffraction data of the free base crystal form C of the compound of formula I are shown in Table 23 below.
  • the hygroscopicity of the maleate salt form A sample of the compound of formula I (obtained in Example 21) was evaluated by the DVS test between 0% RH and 95% RH at 25°C. The DVS test results are shown in Figure 58. The results show that the moisture adsorption of the maleate crystal form A sample at 25°C/80% RH is ⁇ 0.13%, indicating that it has almost no hygroscopicity, and the crystal form of the sample before and after the DVS test is consistent.
  • a SYP-5BS manual tablet press was used to conduct a pressure stability test on the maleate crystal form A sample of the compound of formula I (obtained in Example 20). The specific steps are as follows: Weigh ⁇ 100 mg of the maleate crystal form A sample. In the press mold, use ⁇ 350MPa pressure to press the tablet and maintain it for 1 minute, and then take the sample for XRPD testing. The XRPD of the sample before and after pressure stabilization is shown in Figure 59. The results show that the crystal form of maleate crystal form A remains unchanged before and after pressure stabilization.

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Abstract

本发明公开了一种BTK抑制剂的晶型及其酸式盐和其酸式盐的晶型。本发明中所述的式I化合物的晶型为式I化合物游离碱晶型A、式I化合物游离碱晶型C、式I化合物游离碱D或式I化合物游离碱晶型E。本发明的BTK抑制剂的晶型及其酸式盐和其酸式盐的晶型具有引湿性低和稳定性好优点，对于药物开发具有非常重要的意义。

Description

BTK抑制剂的晶型及其酸式盐和其酸式盐的晶型
本申请要求申请日为2022年3月15日的中国专利申请202210256052X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及医药技术领域，具体涉及一种BTK抑制剂的晶型及其酸式盐和其酸式盐的晶型。
背景技术
布鲁顿酪氨酸激酶(BTK)是非受体酪氨酸激酶Tec家族的一个成员，是B细胞抗原受体(BCR)信号通路中的关键激酶。通过BCR发出的信号控制着一系列效应器反应，包括产生成熟抗体的细胞的激活、增殖和分化。异常的BCR介导的信号转导可引起错误调节的B细胞活化和/或病原性自身抗体的形成，从而导致多种人类疾病，包括癌症、自身免疫疾病和异种免疫性疾病。依鲁替尼(Ibrutinib，商品名Imbmvica)作为第一个进入市场的BTK抑制剂取得极大的成功。然而与许多其他抗癌药物一样，部分患者对药物表现出耐药性。研究发现，BTK激酶的C481S突变是导致耐药的主要原因，依鲁替尼是通过与BTK激酶的C481色氨酸残基的不可逆共价结合而发生药效作用的，C481S突变将色氨酸变成丝氨酸从而失去与依鲁替尼共价结合的能力。在上述背景下，本领域仍需要开发更多针对BTK的高效抑制剂。
药物活性成分的晶型结构往往会引起该药物各种理化性质的差异，如溶解度、溶出速率、熔点、密度、硬度等，这些差异直接影响药物的处方制剂工艺、储存方法、体内药代动力学表现，进而影响到药物的生物利用度、临床疗效和安全性。因此深入研究药物的多晶型现象并找到具备良好性质的晶型具有十分重要的意义。
发明内容
本发明所要解决技术问题是克服现有技术中BTK抑制剂种类较少的缺陷，为此，提供一种BTK抑制剂的晶型及其酸式盐和其酸式盐的晶型。本发明的BTK抑制剂的晶型及其酸式盐和其酸式盐的晶型在稳定性、引湿性等方面符合药用的要求，对于药物开发具有非常重要的意义。
本发明第一方面提供了一种式I化合物游离碱晶型A，其以2θ角度表示的X-射线粉 末衍射图在7.3574±0.2°、20.0853±0.2°、26.2299±0.2°和15.0639±0.2°处有衍射峰；
在某一优选方案中，所述的式I化合物游离碱晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.5403±0.2°、10.0156±0.2°、6.4788±0.2°、10.8671±0.2°和19.5949±0.2°。
优选，所述的式I化合物游离碱晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：12.0106±0.2°、25.1097±0.2°、18.0778±0.2°和30.3217±0.2°。
在某一优选方案中，所述的式I化合物游离碱晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图1所示。
在某一优选方案中，所述的式I化合物游离碱晶型A，其热重分析图(TGA)在起始加热至200±5℃处失重为2.0％-3.5％(例如3.1％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物游离碱晶型A，其差示扫描量热图在327.4±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物游离碱晶型A，其差示扫描热图和热重分析图基本如图2所示。
本发明第二方面提还供了一种式I化合物游离碱晶型C，其以2θ角度表示的X-射线粉末衍射图在4.9395±0.2°、28.0724±0.2°、11.4647±0.2°和13.2030±0.2°处有衍射峰；
在某一优选方案中，所述的式I化合物游离碱晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.2058±0.2°、14.7891±0.2°、 20.1466±0.2°、24.5916±0.2°和21.4712±0.2°。
优选，所述的式I化合物游离碱晶型C，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：9.0935±0.2°、19.4096±0.2°、18.2149±0.2°、22.5487±0.2°、26.6034±0.2°和22.9264±0.2°。
在某一优选方案中，所述的式I化合物游离碱晶型C，其以2θ角度表示的X-射线粉末衍射图基本如图49所示。
在某一优选方案中，所述的式I化合物游离碱晶型C，其热重分析图在起始加热至200±5℃处失重为1％-3％(例如2.7％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物游离碱晶型C，其差示扫描量热图在329.3±5℃处有吸热峰；和/或，在311.3±5℃处有放热峰。
在某一优选方案中，所述的式I化合物游离碱晶型C，其差示扫描热图和热重分析图基本如图50所示。
本发明第三方面提供了一种式I化合物游离碱晶型D，其以2θ角度表示的X-射线粉末衍射图在4.8447±0.2°、19.3873±0.2°、12.0794±0.2°和14.2457±0.2°处有衍射峰；
在某一优选方案中，所述的式I化合物游离碱晶型D，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：4.3851±0.2°、15.7673±0.2°、22.1929±0.2°、17.9985±0.2°和24.8383±0.2°。
优选，所述的式I化合物游离碱晶型D，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：22.3605±0.2°、18.9570±0.2°、18.3427±0.2°、23.7387±0.2°、28.1120±0.2°和24.2637±0.2°。
在某一优选方案中，所述的式I化合物游离碱晶型D，其以2θ角度表示的X-射线粉末衍射图基本如图52所示。
在某一优选方案中，所述的式I化合物游离碱晶型D，其热重分析图在起始加热至150±5℃处失重为3％-5％(例如4.1％)，从150±5℃加热至230±5℃，样品失重为6％-8％(例 如7.1％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物游离碱晶型D，其差示扫描量热图在175.3±5℃和/或328.9±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物游离碱晶型D，其差示扫描热图和热重分析图基本如图53所示。
本发明第四方面提供了一种式I化合物游离碱晶型E，其以2θ角度表示的X-射线粉末衍射图在5.3081±0.2°、4.9506±0.2°、20.9925±0.2°和19.0379±0.2°处有衍射峰；
在某一优选方案中，所述的式I化合物游离碱晶型E，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.2501±0.2°、17.2819±0.2°、10.4721±0.2°、23.0960±0.2°和28.0729±0.2°。
优选，所述的式I化合物游离碱晶型E，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：12.5909±0.2°、13.8832±0.2°、14.9003±0.2°、8.6259±0.2°、7.3206±0.2°和15.9004±0.2°。
在某一优选方案中，所述的式I化合物游离碱晶型E，其以2θ角度表示的X-射线粉末衍射图基本如图55所示。
在某一优选方案中，所述的式I化合物游离碱晶型E，其热重分析图在起始加热至80±5℃处失重为1％-3％(例如1.8％)，从80±5℃加热至180±5℃，样品失重为16％-18％(例如16.8％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物游离碱晶型E，其差示扫描量热图在144.5±5℃和/或329.1±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物游离碱晶型E，其差示扫描热图和热重分析图基本如图56所示。
本发明第五方面提供了一种式I化合物的药学上可接受的盐；所述的药学上可接受的盐为式I化合物与酸形成的盐；所述的酸为无机酸或有机酸；
在某一优选方案中，所述的式I化合物与所述的酸的摩尔比为1:(0.5-2)，例如1:0.6、1:0.7、1:0.9、1:1、1:1.1、1:1.3或1:2。
在某一优选方案中，所述的无机酸为盐酸、硫酸、磷酸和氢溴酸中的一种或多种。
较佳地，所述的无机酸为盐酸、磷酸和氢溴酸中的一种或多种。
在某一优选方案中，所述的有机酸为马来酸、L-天冬氨酸、富马酸、L-酒石酸、柠檬酸、1,5-萘二磺酸、1,2-乙二磺酸、对甲苯磺酸、甲磺酸、苯磺酸、2-羟基乙磺酸、乙磺酸和丙二酸中的一种或多种。
较佳地，所述的有机酸为马来酸、富马酸、1,5-萘二磺酸、对甲苯磺酸中的一种或多种。
更佳地，所述的有机酸为马来酸、富马酸和对甲苯磺酸中的一种或多种。
更佳地，所述的有机酸为马来酸。
在某一优选方案中，所述的式I化合物的药学上可接受的盐为如下任一药学上可接受的盐：
(1)式I化合物的盐酸盐；其中，式I化合物与盐酸的摩尔比为1：(0.5-2)，例如1:(0.9-1.0)；
(2)式I化合物的磷酸盐；其中，式I化合物与磷酸的摩尔比为1：(1-2)，例如1:(1-1.3)；
(3)式I化合物的氢溴酸盐；其中，式I化合物与氢溴酸的摩尔比为1:(0.5-1)，例如1:0.9；
(4)式I化合物的富马酸盐；其中，式I化合物与富马酸的摩尔比为1:1；
(5)式I化合物的1,5-萘二磺酸盐；其中，式I化合物与1,5-萘二磺酸的摩尔比为1:(0.5-1)，例如1:0.7；
(6)式I化合物的对甲苯磺酸盐；其中，式I化合物与对甲苯磺酸的摩尔比为1:1；
(7)式I化合物的马来酸盐；其中，式I化合物与马来酸的摩尔比为1:1。
所述的式I化合物的药学上可接受的盐可以通过本领域常规的成盐反应制得。例如 所述的式I化合物的药学上可接受的盐可以通过下述方法制得：
将式I化合物与酸在溶剂中进行成盐反应，得到所述的式I化合物的药学上可接受的盐；
其中，当酸为盐酸时，所述的式I化合物与盐酸的摩尔比为1：(0.5-2.5)，例如1:(1-2)，又例如1:2；
当酸为磷酸时，所述的式I化合物与磷酸的摩尔比为1：(0.5-2)，例如1:(0.5-1.5)，又例如1:1；
当酸为氢溴酸时，所述的式I化合物与氢溴酸的摩尔比为1:(0.5-2)，例如1:(0.5-1.5)，又例如1:1；
当酸为富马酸时，所述的式I化合物与富马酸的摩尔比为1:(0.5-2)，例如1:(0.5-1.5)，又例如1:1；
当酸为1,5-萘二磺酸时，所述的式I化合物与1,5-萘二磺酸的摩尔比为1:(0.5-2)，例如1:(0.5-1.5)，又例如1:1；
当酸为对甲苯磺酸时，所述的式I化合物与对甲苯磺酸的摩尔比为1:(0.5-2)，例如1:(0.5-1.5)，又例如1:1；
当酸为马来酸时，所述的式I化合物与马来酸的摩尔比为1:(0.5-2)，例如1:(0.5-1.5)，又例如1:1。
本发明第六方面提供了一种式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在13.2577±0.2°、19.0205±0.2°、26.6619±0.2°和24.4646±0.2°处有衍射峰；所述的如式I所示的化合物的盐酸盐如上所述；
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A；其中，式I化合物与盐酸的摩尔比为1：1。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：25.4625±0.2°、25.7474±0.2°、14.8470±0.2°、10.5627±0.2°和25.0104±0.2°。
优选，所述的式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：24.6922±0.2°、20.9024±0.2°、18.2234±0.2°、11.6824±0.2°、21.1980±0.2°和16.9518±0.2°。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图4所示。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其热重分析图在起始加热至110±5℃处失重为6％-8％(例如7.1％)，从110±5℃加热至200±5℃，样品失重为7％-9％(例如7.9％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其差示扫描量热图在115.4±5℃和185.0±5℃处有吸热峰；和/或，在218.3℃±5℃处有放热峰。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型A，其差示扫描热图和热重分析图基本如图5所示。
本发明第七方面提供了一种式I化合物的盐酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图在11.2971±0.2°、4.1094±0.2°、16.0047±0.2°和18.5553±0.2°处有衍射峰；所述的如式I所示的化合物的盐酸盐如上所述；
在某一优选方案中，所述的式I化合物的盐酸盐的晶型B；其中，式I化合物与盐酸酸的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：27.3296±0.2°、17.6049±0.2°、27.5618±0.2°、26.3637±0.2°和25.6428±0.2°。
优选，所述的式I化合物的盐酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：21.4646±0.2°、20.6275±0.2°、12.7357±0.2°、20.3279±0.2°、24.8169±0.2°和24.1245±0.2°。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型B，其以2θ角度表示的X-射 线粉末衍射图基本如图7所示。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型B，其热重分析图在起始加热至150±5℃处失重为4％-6％(例如4.8％)，从150±5℃加热至230±5℃，样品失重为6.5％-8.5％(例如7.6％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型B，其差示扫描量热图在223.0±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型B，其差示扫描热图和热重分析图基本如图8所示。
本发明第八方面提供了一种式I化合物的盐酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图在21.5443±0.2°、27.3605±0.2°、10.0792±0.2°和18.8112±0.2°处有衍射峰；所述的如式I所示的化合物的盐酸盐如上所述；
在某一优选方案中，所述的式I化合物的盐酸盐的晶型C；其中，式I化合物与盐酸的摩尔比为1:(0.9-1.0)；例如1:0.9。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：14.1629±0.2°、8.5449±0.2°、26.7582±0.2°、6.8670±0.2°和17.2037±0.2°。
优选，所述的式I化合物的盐酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：25.7895±0.2°、15.3903±0.2°、22.6726±0.2°、14.7930±0.2°、29.4042±0.2°和15.8036±0.2°。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型C，其以2θ角度表示的X-射线粉末衍射图基本如图10所示。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型C，其热重分析图在150±5℃处失重1.5％-3％(例如2.2％)，在150℃至250℃处失重为6.5％-8.5％(例如7.5％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型C，其差示扫描量热图在248.2±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的盐酸盐的晶型C，其差示扫描热图和热重分析图基本如图11所示。
本发明第九方面提供了一种上述的式I化合物的磷酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在12.8284±0.2°、21.1193±0.2°、22.7554±0.2°和12.4119±0.2°处有衍射峰；所述的如式I所示的化合物的磷酸盐如上所述；
在某一优选方案中，所述的式I化合物的磷酸盐的晶型A；其中，式I化合物与磷酸的摩尔比为1:(1-2)，例如1:1.3。
在某一优选方案中，所述的式I化合物的磷酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：24.1820±0.2°、19.6004±0.2°、24.9449±0.2°、17.7015±0.2°和25.7812±0.2°。
优选，所述的式I化合物的磷酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.4385±0.2°、14.9572±0.2°、16.8423±0.2°、5.2374±0.2°和31.8376±0.2°。
在某一优选方案中，所述的式I化合物的磷酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图13所示。
在某一优选方案中，所述的式I化合物的磷酸盐的晶型A，其热重分析图在起始加热至65±5℃处失重为1％-3％(例如2.1％)，从65±5℃加热至125±5℃，样品失重为2％-4％(例如2.8％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的磷酸盐的晶型A，其差示扫描量热图在81.7±5℃、92.1±5℃和139.2±5℃的一处或多处有吸热峰。
在某一优选方案中，所述的式I化合物的磷酸盐的晶型A，其差示扫描热图和热重分析图基本如图14所示。
本发明第十方面提供了一种上述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在5.1732±0.2°、7.9252±0.2°、10.2736±0.2°和18.8307±0.2°处有衍射峰；所述的如式I所示的化合物的富马酸盐如上所述；
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A；其中，式I化合物与富马酸的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：24.8824±0.2°、12.0866±0.2°、15.4296±0.2°、23.9878±0.2°和13.0765±0.2°。
优选，所述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：25.7497±0.2°、27.5661±0.2°和28.4676±0.2°。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图16所示。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其热重分析图在起始加热至150±5℃处失重为2％-4％(例如2.6％)，从150±5℃加热至240±5℃，样品失重为19％-22％(例如21.2％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其差示扫描量热图在224.7±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的富马酸盐的晶型A，其差示扫描热图和热重分析图基本如图17所示。
本发明第十一方面提供了一种上述的式I化合物的1,5-萘二磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在7.7555±0.2°、9.6043±0.2°、23.0949±0.2°和17.5044±0.2°处有衍射峰；所述的如式I所示的化合物的1,5-萘二磺酸盐如上所述；
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型A；其中，式I化合物与甲磺酸的摩尔比为1:(0.5-1)，例如1:0.7。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.2234±0.2°、22.5424±0.2°、16.5111±0.2°、24.1101±0.2°和11.2117±0.2°。
优选，所述的式I化合物的1,5-萘二磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：15.6086±0.2°、19.5194±0.2°、12.9255±0.2°、26.2933±0.2°和27.8190±0.2°。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图19所示。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型A，其热重分析图在起始加热至130±5℃处失重为2.5％-4.5％(例如3.5％)，从130±5℃加热至175±5℃，样品失重为1.5％-3.5％(例如2.6％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型A，其差示扫描量热图在57.7±5℃、82.9±5℃、166.9±5℃和211.1±5℃的一处或多处有吸热峰。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型A，其差示扫描热图和热重分析图基本如图20所示。
本发明第十二方面提供了一种上述的式I化合物的1,5-萘二磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图在15.0980±0.2°、20.3818±0.2°、13.6481±0.2°和24.7069±0.2°处有衍射峰；
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型B；其中，式I化合物与甲磺酸的摩尔比为1:(0.5-1)，例如1:0.7。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：15.8095±0.2°、10.8634±0.2°、16.7992±0.2°、26.2961±0.2°和12.3107±0.2°。
优选，所述的式I化合物的1,5-萘二磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：18.9746±0.2°、5.0796±0.2°、25.1466±0.2°、23.3711±0.2°、27.3657±0.2°和32.3061±0.2°。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型B，其以2θ角度表示的X-射线粉末衍射图基本如图22所示。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型B，其热重分析图在起始加热至200±5℃处失重为3.5％-5.5％(例如4.3％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型B，其差示扫描量热图在57.0±5℃、82.5±5℃和276.1±5℃的一处或多处有吸热峰。
在某一优选方案中，所述的式I化合物的1,5-萘二磺酸盐的晶型B，其差示扫描量热图和热重分析图基本如图23所示。
本发明第十三方面提供了一种上述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在4.0699±0.2°、20.3148±0.2°、14.9056±0.2°和18.3888±0.2°处有衍射峰；所述的如式I所示的化合物的对甲苯磺酸盐如上所述；
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A；其中，式I化合物与对甲苯磺酸的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.0879±0.2°、25.9320±0.2°、11.8243±0.2°、17.2270±0.2°和24.5224±0.2°。
优选，所述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：12.2243±0.2°、25.3151±0.2°、9.5171±0.2°、23.7569±0.2°、29.9444±0.2°和28.8866±0.2°。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图25所示。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其热重分析图在起始加热至75±5℃，样品失重为3.5％-5.5％(例如4.3％)，从75±5℃加热至120±5℃，样品失重为5％-7％(例如6.1％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其差示扫描量热图在111.1±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的对甲苯磺酸盐的晶型A，其差示扫描热图和热重分析图基本如图26所示。
本发明第十四方面提供了一种式I化合物的氢溴酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在4.1403±0.2°、11.1940±0.2°、27.3198±0.2°和17.4698±0.2°处有衍射峰；所述的如式I所示的化合物的氢溴酸盐如上所述；
在某一优选方案中，所述的式I化合物的氢溴酸盐的晶型A；其中，式I化合物与氢溴酸的摩尔比为1:(0.5-1)，例如1:0.9。
在某一优选方案中，所述的式I化合物的氢溴酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.6495±0.2°、8.7348±0.2°、 18.5192±0.2°、16.0192±0.2°和19.6807±0.2°。
在某一优选方案中，所述的式I化合物的氢溴酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下2θ角度处有衍射峰：25.5412±0.2°。
在某一优选方案中，所述的式I化合物的氢溴酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图28所示。
在某一优选方案中，所述的式I化合物的氢溴酸盐的晶型A，其热重分析图在起始加热至200±5℃处失重为4.5％-6.5％(例如5.6％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的氢溴酸盐的晶型A，其差示扫描量热图在97.7±5℃、179.4±5℃、230.7±5℃和254.9±5℃的一处或多处有吸热峰。
在某一优选方案中，所述的式I化合物的氢溴酸盐的晶型A，其差示扫描热图和热重分析图基本如图29所示。
本发明第十五方面提供了一种式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图在4.4590±0.2°、10.0991±0.2°、13.6435±0.2°和20.6462±0.2°处有衍射峰；所述的如式I所示的化合物的马来酸盐如上所述；
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其中，式I化合物与马来酸的摩尔比为1：1。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：25.9433±0.2°、17.3036±0.2°、26.3520±0.2°、18.2594±0.2°和17.8271±0.2°。
优选，所述的式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：15.0805±0.2°、23.0488±0.2°和11.6637±0.2°。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其以2θ角度表示的X-射线粉末衍射图基本如图31所示。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其热重分析图在起始加热至150±5℃处失重为2.5％-3.5％(例如2.8％)，从150℃加热至230℃，样品失重为19％-21％(例如19.3％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其差示扫描量热图在200.3±20℃处有吸热峰。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其差示扫描量热图在200.3±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型A，其差示扫描热图和热重分析图基本如图32所示。
本发明第十六方面提供了一种式I化合物的马来酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图在4.4072±0.2°、13.3026±0.2°、27.4367±0.2°和21.9948±0.2°处有衍射峰；所述的如式I所示的化合物的马来酸盐如上所述；
在某一优选方案中，所述的式I化合物的马来酸盐的晶型E，其中，式I化合物与马来酸的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.1322±0.2°、18.1840±0.2°、12.8549±0.2°、22.7709±0.2°和13.6555±0.2°。
优选，所述的式I化合物的马来酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：28.9010±0.2°、15.5372±0.2°、16.2816±0.2°、10.1536±0.2°、26.7355±0.2°和12.1903±0.2°。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型E，其以2θ角度表示的X-射线粉末衍射图基本如图34所示。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型E，其热重分析图在起始加热至150±5℃处失重为2.5％-4.5％(例如3.4％)，从150℃加热至250℃，样品失重为19％- 21％(例如19.7％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型E，其差示扫描量热图在194.2±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型E，其差示扫描热图和热重分析图基本如图35所示。
本发明第十七方面提供了一种式I化合物的马来酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图在10.9668±0.2°、7.8002±0.2°、6.1349±0.2°和12.3076±0.2°处有衍射峰；所述的如式I所示的化合物的马来酸盐如上所述；
在某一优选方案中，所述的式I化合物的马来酸盐的晶型F，其中，式I化合物与马来酸的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.6068±0.2°、16.7364±0.2°、25.6746±0.2°、23.5852±0.2°和20.2850±0.2°。
优选，所述的式I化合物的马来酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：9.9869±0.2°、19.9375±0.2°、23.2431±0.2°、22.4598±0.2°、22.7746±0.2°和24.7937±0.2°。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型F，其以2θ角度表示的X-射线粉末衍射图基本如图37所示。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型F，其热重分析图在起始加热至150±5℃处失重为2％-4％(例如2.9％)，从150℃加热至250℃，样品失重为17.5％-19.5％(例如18.7％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型F，其差示扫描量热图在65.3±5℃、81.7±5℃和180.8±5℃的一处或多处有吸热峰。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型F，其差示扫描热图和热重分析图基本如图38所示。
本发明第十八方面提供了一种式I化合物的马来酸盐的晶型H，其以2θ角度表示的X-射线粉末衍射图在4.5619±0.2°、13.5614±0.2°、13.0298±0.2°和10.2862±0.2°处有衍射峰；所述的如式I所示的化合物的马来酸盐如上所述；
在某一优选方案中，所述的式I化合物的马来酸盐的晶型H，其中，式I化合物与马来酸的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型H，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：18.3628±0.2°、25.9556±0.2°、26.6709±0.2°、20.7641±0.2°和12.4688±0.2°。
优选，所述的式I化合物的马来酸盐的晶型H，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：15.9640±0.2°、8.9876±0.2°、27.2853±0.2°、19.2049±0.2°、23.2406±0.2°和28.2446±0.2°。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型H，其以2θ角度表示的X-射线粉末衍射图基本如图40所示。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型H，其热重分析图在起始加热至150±5℃处失重为1％-2％(例如1.4％)，从150℃加热至250℃，样品失重为16.5％-18.5％(例如17.4％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型H，其差示扫描量热图在188.6±5℃处有吸热峰。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型H，其差示扫描热图和热重分析图基本如图41所示。
本发明第十九方面提供了一种式I化合物的马来酸盐的晶型I，其以2θ角度表示的X-射线粉末衍射图在5.4040±0.2°、9.4028±0.2°、10.4407±0.2°和8.8892±0.2°处有衍射峰； 所述的如式I所示的化合物的马来酸盐如上所述；
在某一优选方案中，所述的式I化合物的马来酸盐的晶型I，其中，式I化合物与马来酸的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型I，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：12.6630±0.2°、25.4555±0.2°、13.6954±0.2°、15.5008±0.2°和17.6958±0.2°。
优选，所述的式I化合物的马来酸盐的晶型I，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.4174±0.2°、11.3412±0.2°、23.4711±0.2°、27.0913±0.2°、20.1842±0.2°和6.0958±0.2°。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型I，其以2θ角度表示的X-射线粉末衍射图基本如图43所示。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型I，其热重分析图在加热至130±5℃时具有2.5％-4.5％的失重(例如3.5％)，从130℃加热至250℃，样品失重为19％-21％(例如20.2％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型I，其差示扫描量热图在112.9±5℃和202.5±5℃处有吸热峰；和/或，在161.5±5℃处有放热峰。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型I，其差示扫描热图和热重分析图基本如图44所示。
本发明第二十方面提供了一种式I化合物的马来酸盐的晶型J，其以2θ角度表示的X-射线粉末衍射图在5.4594±0.2°、25.5787±0.2°、17.8675±0.2°和10.5280±0.2°处有衍射峰；所述的如式I所示的化合物的马来酸盐如上所述；
在某一优选方案中，所述的式I化合物的马来酸盐的晶型J，其中，式I化合物与马来酸的摩尔比为1:1。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型J，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：15.7099±0.2°、27.1774±0.2°、23.6955±0.2°、9.4120±0.2°和8.9158±0.2°；
优选，所述的式I化合物的马来酸盐的晶型J，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：20.4902±0.2°、29.5595±0.2°、28.3910±0.2°、12.7045±0.2°、20.9226±0.2°和13.7795±0.2°。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型J，其以2θ角度表示的X-射线粉末衍射图基本如图46所示。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型J，其热重分析图在起始加热至150±5℃时具有6％-7％(例如6.4％)的失重，从150℃加热至250℃，样品失重为19.5％-21.5％(例如20.5％)(所述的失重的百分比为样品减少的重量与样品在此次失重前的重量的百分比)。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型J，其差示扫描量热图在193.7±5℃处有吸热峰；和/或，在162.1±5℃处有放热峰。
在某一优选方案中，所述的式I化合物的马来酸盐的晶型J，其差示扫描热图和热重分析图基本如图47所示。
本发明的BTK抑制剂的晶型及其药学上可接受的盐和其药学上可接受的盐的晶型的制备方法可以通过如本领域中已知的许多方法来获得结晶形式。
本发明第二十一方面提供了一种上述的式I化合物的马来酸盐的晶型A的制备方法，其包括如下步骤：在10-70℃下，将所述的式I化合物与马来酸在溶剂中进行析晶，得到式I化合物的马来酸盐的晶型A。
所述的溶剂为酮类溶剂(优选丙酮，2-丁酮，甲基异丁酮，N-甲基吡咯烷酮)和/或酯类溶剂(优选乙酸乙酯)。
所述的析晶的温度优选10-30℃或50-60℃。
所述的酮类溶剂的质量体积比优选为30-50mg/mL，例如40mg/mL；
所述的酯类溶剂的质量体积比优选为30-80mg/mL，例如34mg/mL或74mg/mL。
所述的析晶的方式可以在搅拌(例如悬浮搅拌)下进行析晶。
所述的析晶结束后，可按照本领域中的常规操作方法进行分离，例如离心或者过滤。
本发明第二十二方面提供了一种按照上述式I化合物的马来酸盐的晶型A的制备方法制得的马来酸盐的晶型A。
本发明第二十三方面提供了一种上述的式I化合物的马来酸盐的晶型E的制备方法，其包括如下步骤：在10-30℃下，将所述的式I化合物马来酸盐晶型A样品在醚类溶剂中溶清后，将滤液置于反溶剂氛围下进行气液渗透，得到式I化合物的马来酸盐的晶型E。
所述的醚类溶剂优选甲基叔丁基醚，四氢呋喃，2-甲基四氢呋喃，环戊基甲醚，1,4-二氧六环，苯甲醚；所述的反溶剂优选烷基类溶剂，优选为正己烷，正庚烷。
本发明第二十四方面提供了一种按照上述式I化合物的马来酸盐的晶型E的制备方法制得的马来酸盐的晶型E。
本发明第二十五方面提供了一种按照上述的式I化合物的马来酸盐的晶型F的制备方法，其包括如下步骤：在10-30℃下，将式I化合物的马来酸盐晶型A样品在溶剂中形成悬浊液进行析晶得到式I化合物的马来酸盐的晶型F。
所述的溶剂优选为醚类溶剂或醚类溶剂和水的混合溶剂，优选为醚类溶剂和水的混合溶剂，所述的醚类溶剂优选四氢呋喃，2-甲基四氢呋喃。
所述的醚类溶剂和水的混合溶剂的质量体积比优选为30-50mg/mL，例如40mg/mL；所述醚类溶剂和水的体积比(v/v)优选为10-25：1，例如22:1。
本发明第二十六方面提供了一种按照上述式I化合物的马来酸盐的晶型F的制备方法制得的马来酸盐的晶型F。
本发明第二十七方面提供了一种式I化合物的马来酸的晶型H的制备方法，其包括如下步骤：在10-30℃下，将所述的式I化合物的马来酸盐晶型A样品在醚类溶剂中溶清后，将滤液置于反溶剂氛围下进行气液渗透得到。
所述的醚类溶剂优选甲基叔丁基醚，四氢呋喃，2-甲基四氢呋喃，环戊基甲醚，1,4-二氧六环，苯甲醚；所述的反溶剂优选醚类溶剂，优选为甲基叔丁基醚。
本发明第二十八方面提供了一种按照上述式I化合物的马来酸盐的晶型H的制备方法制得的马来酸盐的晶型H。
本发明第二十九方面提供了一种药物组合物，其包含治疗有效剂量的物质A以及药 学上可接受的载体、稀释剂或赋形剂；所述的物质A为上述的式I化合物的晶型(上述的式I化合物游离碱晶型A、上述的式I化合物游离碱晶型C、上述的式I化合物游离碱晶型D和上述的式I化合物游离碱晶型E中的一种或多种)、上述的式I化合物的药学上可接受的盐或上述的式I化合物的药学上可接受的盐的晶型(上述的式I化合物盐酸盐晶型A、上述的式I化合物盐酸盐晶型B、上述的式I化合物盐酸盐晶型C、上述的式I化合物磷酸盐晶型A、上述的式I化合物富马酸盐晶型A、上述的式I化合物1,5-萘二磺酸盐晶型A、上述的式I化合物1,5-萘二磺酸盐晶型B、上述的式I化合物对甲苯磺酸盐晶型A、上述的式I化合物氢溴酸盐晶型A、上述的式I化合物马来酸盐晶型A、上述的式I化合物马来酸盐晶型E、上述的式I化合物马来酸盐晶型F、上述的式I化合物马来酸盐晶型H、上述的式I化合物马来酸盐晶型I和上述的式I化合物马来酸盐晶型J中的一种或多种)。
本发明第三十方面提供了一种物质B在制备预防和/或治疗疾病或病症的药物中的用途；所述的物质B为上述的药物组合物、上述的式I化合物的晶型(上述的式I化合物游离碱晶型A、上述的式I化合物游离碱晶型C、上述的式I化合物游离碱晶型D和上述的式I化合物游离碱晶型E中的一种或多种)、上述的式I化合物的药学上可接受的盐或上述的式I化合物的药学上可接受的盐的晶型(上述的式I化合物盐酸盐晶型A、上述的式I化合物盐酸盐晶型B、上述的式I化合物盐酸盐晶型C、上述的式I化合物磷酸盐晶型A、上述的式I化合物富马酸盐晶型A、上述的式I化合物1,5-萘二磺酸盐晶型A、上述的式I化合物1,5-萘二磺酸盐晶型B、上述的式I化合物对甲苯磺酸盐晶型A、上述的式I化合物氢溴酸盐晶型A、上述的式I化合物马来酸盐晶型A、上述的式I化合物马来酸盐晶型E、上述的式I化合物马来酸盐晶型F、上述的式I化合物马来酸盐晶型H、上述的式I化合物马来酸盐晶型I和上述的式I化合物马来酸盐晶型J中的一种或多种)。
所述疾病或病症与BTK相关和/或与B细胞活化异常相关。
所述的物质B的用量为有效治疗量。
本发明第三十一方面提供了所述的式I化合物的晶型及其酸式盐和其酸式盐的晶型或者所述的药物组合物在制备BTK抑制剂中的用途。
本发明第三十二方面提供了一种物质B在预防和/或治疗疾病或病症中的用途，所述的物质B如前所述。
本发明第三十二方面提供了一种抑制BTK激酶，或者，预防和/或治疗疾病的方法，包括步骤：给需要的对象施用物质B；
所述疾病或病症与BTK相关和/或与B细胞活化异常相关，所述的物质B如前所述。
在某一优选方案中，所述的式I化合物的晶型及其酸式盐和其酸式盐的晶型以治疗和/或预防有效量存在于药物组合物或药物中。
在某一优选方案中，所述疾病或病症选自下组：异种免疫疾病、自身免疫疾病、炎性疾病、癌症。
在某一优选方案中，所述异种免疫疾病、自身免疫疾病、炎性疾病可以选自下组：风湿性疾病、肾小球肾炎、Goodpasture综合征、动脉粥样硬化、自身免疫性血液病、自身免疫性胃炎、自身免疫性炎性肠病、肠易激综合征、同种异体移植排斥、慢性甲状腺炎、格雷夫斯病、舍格伦病、硬皮病、糖尿病、肝炎、胰腺炎、原发性肝硬化、重症肌无力、多发性硬化症、系统性红斑狼疮、牛皮癣、特应性皮炎、皮肌炎、接触性皮炎、湿疹、血管炎、慢性肾功能不全、Stevens-Johnson综合征、炎性疼痛、特发性腹泻、恶病质、结节病、Guillain-Barre综合征、葡萄膜炎、结膜炎、中耳炎、牙周病、帕金森氏病、阿尔茨海默氏病、败血性休克、肺间质纤维化、哮喘、支气管炎、鼻炎、鼻窦炎、尘肺、肺功能不全综合征、肺气肿、肺纤维化、慢性炎性肺病和气道上的其他炎性或阻塞性疾病。
在某一优选方案中，所述癌症为白血病或淋巴瘤。
在某一优选方案中，所述癌症可以选自下组：小淋巴细胞淋巴瘤(SLL)，急性淋巴细胞白血病(ALL)，慢性淋巴细胞白血病(CLL)，急性骨髓性白血病(AML)，慢性骨髓性白血病(CML)，急性早幼粒细胞白血病，慢性粒细胞白血病，弥漫性大B细胞淋巴瘤，血管内大B细胞淋巴瘤，原发性渗出性淋巴瘤，华氏巨球蛋白血症，滤泡性淋巴瘤，多发性骨髓瘤、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、非霍奇金淋巴癌。
术语定义和说明
本发明所引述的所有文献，它们的全部内容通过引用并入本文，并且如果这些文献所表达的含义与本发明不一致时，以本发明的表述为准。此外，本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表述的含义为准。
本发明的式1化合物的多晶型物以2θ角度表示的X-射线粉末衍射特征峰，其中“±0.20°”为允许的测量误差范围。
本发明的式I化合物的多晶型物可以与其它活性成分组合使用，只要它不产生其他不利作用，例如过敏反应。
本发明所用的术语“组合物”意指包括包含指定量的各指定成分的产品，以及直接或间接从指定量的各指定成分的组合产生的任何产品。
本领域技术人员可以使用已知的药物载体，将本发明的式I化合物的多晶型物制备成适合的药物组合物。所述药物组合物可特别专门配制成以固体或液体形式供口服给药、供胃肠外注射或供直肠给药。
所述的药物组合物可配制成多种剂型，便于给药，例如，口服制剂(如片剂、胶囊剂、溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末，在注射前加入药物溶媒后可立即使用)。
本发明所用的术语“治疗和/或预防有效量”是引起研究人员、兽医、医生或其他人所寻求的组织、系统、动物或人的生物学或医学应答的药物或药物制剂的量。
当用于上述治疗和/或预防用途时，本发明式I化合物的多晶型物和药物组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者，具体的治疗有效剂量水平须根据多种因素而定，所述因素包括所治疗的障碍和该障碍的严重程度；所采用的具体化合物的活性；所采用的具体组合物；患者的年龄、体重、一般健康状况、性别和饮食；所采用的具体化合物的给药时间、给药途径和排泄率；治疗持续时间；与所采用的具体化合物组合使用或同时使用的药物；及医疗领域公知的类似因素。例如，本领域的做法是，化合物的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。
本发明所用的“多晶型”或“多晶型物”是指具有相同化学组成，但构成该晶体的分子、原子和/或离子的不同空间排列的晶型。尽管多晶型物具有相同的化学组成，但它们的堆积和几何排列不同，并可能表现出不同的物理性质，如熔点、形状、颜色、密度、硬度、可形变性、稳定性、溶解度、溶出速率和类似性质。根据他们的温度-稳定性关系，两种多晶型物可以是单变性或互变性的。对于单变性体系，在温度变化时，两种固相之间的相对稳定性保持不变。相反，在互变性体系中，存在一个过渡温度，在此两种相的稳定性调换((Theory and Origin of Polymorphism in″Polymorphism in Pharmaceutical Solids″(1999)ISBN：)-8247-0237)。这种化合物以不同晶体结构存在的现象被称作药物多晶型现象。
本文所用的术语″室温″或″RT″是指20至25℃(68-77°F)的环境温度。
缩写说明：MeOH：甲醇；2-MeTHF：2-甲基四氢呋喃；EtOH：乙醇；1,4-Dioxane：1,4-二氧六环；IPA：异丙醇；ACN：乙腈；Acetone：丙酮；DCM:二氯甲烷；MIBK：甲基异丁基酮：Toluene：甲苯；EtOAc：乙酸乙酯；n-Heptane：正庚烷；IPAc：乙酸异丙酯；DMSO：二甲亚砜；MTBE：甲基叔丁基醚；DMAc：二甲基乙酰胺；THF：四氢呋喃；NMP:N-甲基吡咯烷酮。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实 例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的BTK抑制剂的晶型及其酸式盐和其酸式盐的晶型具有活性高、引湿性低和稳定性好优点，对于药物开发具有非常重要的意义。
附图说明
图1为式I化合物的游离碱晶型A的XRPD谱图。
图2为式I化合物的游离碱晶型A的TGA/DSC谱图。
图3为式I化合物的游离碱晶型A的1H NMR谱图。
图4为式I化合物的盐酸盐晶型A的XRPD谱图。
图5为式I化合物的盐酸盐晶型A的TGA/DSC谱图。
图6为式I化合物的盐酸盐晶型A的1H NMR谱图。
图7为式I化合物的盐酸盐晶型B的XRPD谱图。
图8为式I化合物的盐酸盐晶型B的TGA/DSC谱图。
图9为式I化合物的盐酸盐晶型B的1H NMR谱图。
图10为式I化合物的盐酸盐晶型C的XRPD谱图。
图11为式I化合物的盐酸盐晶型C的TGA/DSC谱图。
图12为式I化合物的盐酸盐晶型C的1H NMR谱图。
图13为式I化合物的磷酸盐晶型A的XRPD谱图。
图14为式I化合物的磷酸盐晶型A的TGA/DSC谱图。
图15为式I化合物的磷酸盐晶型A的1H NMR谱图。
图16为式I化合物的富马酸盐晶型A的XRPD谱图。
图17为式I化合物的富马酸盐晶型A的TGA/DSC谱图。
图18为式I化合物的富马酸盐晶型A的1H NMR谱图。
图19为式I化合物的1,5-萘二磺酸盐晶型A的XRPD谱图。
图20为式I化合物的1,5-萘二磺酸盐晶型A的TGA/DSC谱图。
图21为式I化合物的1,5-萘二磺酸盐晶型A的1H NMR谱图。
图22为式I化合物的1,5-萘二磺酸盐晶型B的XRPD谱图。
图23为式I化合物的1,5-萘二磺酸盐晶型B的TGA/DSC谱图。
图24为式I化合物的1,5-萘二磺酸盐晶型B的1H NMR谱图。
图25为式I化合物的对甲苯磺酸盐晶型A的XRPD谱图。
图26为式I化合物的对甲苯磺酸盐晶型A的TGA/DSC谱图。
图27为式I化合物的对甲苯磺酸盐晶型A的1H NMR谱图。
图28为式I化合物的氢溴酸盐晶型A的XRPD谱图。
图29为式I化合物的氢溴酸盐晶型A的TGA/DSC谱图。
图30为式I化合物的氢溴酸盐晶型A的1H NMR谱图。
图31为式I化合物的马来酸盐晶型A的XRPD谱图。
图32为式I化合物的马来酸盐晶型A的TGA/DSC谱图。
图33为式I化合物的马来酸盐晶型A的1H NMR谱图。
图34为式I化合物的马来酸盐晶型E的XRPD谱图。
图35为式I化合物的马来酸盐晶型E的TGA/DSC谱图。
图36为式I化合物的马来酸盐晶型E的1H NMR谱图。
图37为式I化合物的马来酸盐晶型F的XRPD谱图。
图38为式I化合物的马来酸盐晶型F的TGA/DSC谱图。
图39为式I化合物的马来酸盐晶型F的1H NMR谱图。
图40为式I化合物的马来酸盐晶型H的XRPD谱图。
图41为式I化合物的马来酸盐晶型H的TGA/DSC谱图。
图42为式I化合物的马来酸盐晶型H的1H NMR谱图。
图43为式I化合物的马来酸盐晶型I的XRPD谱图。
图44为式I化合物的马来酸盐晶型I的TGA/DSC谱图。
图45为式I化合物的马来酸盐晶型I的1H NMR谱图。
图46为式I化合物的马来酸盐晶型J的XRPD谱图。
图47为式I化合物的马来酸盐晶型J的TGA/DSC谱图。
图48为式I化合物的马来酸盐晶型J的1H NMR谱图。
图49为式I化合物的游离碱晶型C的XRPD谱图。
图50为式I化合物的游离碱晶型C的TGA/DSC谱图。
图51为式I化合物的游离碱晶型C的1H NMR谱图。
图52为式I化合物的游离碱晶型D的XRPD谱图。
图53为式I化合物的游离碱晶型D的TGA/DSC谱图。
图54为式I化合物的游离碱晶型D的1H NMR谱图。
图55为式I化合物的游离碱晶型E的XRPD谱图。
图56为式I化合物的游离碱晶型E的TGA/DSC谱图。
图57为式I化合物的游离碱晶型E的1H NMR谱图。
图58为式I化合物的马来酸盐晶型A的DVS谱图。
图59为式I化合物的马来酸盐晶型A的压力稳定性前后的XRPD叠图。
图60为制备例1得到的式I化合物的XRPD谱图。
图61为制备例1得到的式I化合物的X-射线单晶衍射谱图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
仪器和方法
运用多种检测分析方法对得到的固体样品进行了分析，例如粉末X射线衍射(XRPD)、差示扫描量热法(DSC)和热重分析(TGA)、动态水分吸附(DVS)、氢谱液体核磁(1H Solution NMR)。
(1)粉末X射线衍射(XRPD)：XRPD结果是在PANalytical生产的X射线粉末衍射分析仪上采集，扫描参数如表所示。
表1 XRPD测试参数(I/II)
(2)热重分析(TGA)和差示扫描量热(DSC)：TGA和DSC图分别在TA Discovery 5500 热重分析仪和TA Discovery 2500差示扫描量热仪上采集，表列出了测试参数。
表2 TGA和DSC测试参数
(3)动态水分吸附(DVS)：动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl、Mg(NO3)2和KCl的潮解点校正。DVS测试参数列于表。
表3 DVS测试参数
(4)氢谱液体核磁(1H Solution NMR)：氢谱液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d6作为溶剂。
(5)高效液相色谱(HPLC)：试验中纯度和溶解度由安捷伦1260高效液相色谱仪测试，分析条件如表所示。
表4纯度测试的高效液相色谱测试条件

(7)离子色谱(IC)：试验中使用ThermoFisher ICS-1100离子色谱仪分析离子含量，具体条件见表。
表5离子色谱条件和参数
可以理解的是，使用与上述仪器作用相同的其他类型的仪器或使用不同与本发明中使用的测试条件时，可能会得到另外的数值，因此，所引用的数值不应视为绝对的数值。由于仪器的误差或操作人员的区别，本领域技术人员能理解，以上用于表征晶体的物理性质的参数可能有微小的差别，所以上述的参数仅用于辅助表征本发明提供的多晶型物， 而不能视为是对本发明的多晶型物的限制。
制备例1式I化合物的制备
步骤一：(S)-2-(羟甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸氘代甲酯(500mg，1.14mmol)溶于乙腈(15mL),加入氧化银(II)(3.97g,17.15mmol)和氘代碘甲烷(2.49g,17.15mmol),反应在35℃搅拌48小时。反应液冷却至室温后用硅藻土过滤，滤饼用乙酸乙酯(20mL)洗涤。所得滤液经真空浓缩得到(S)-2-(((甲氧基-d3)甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸氘代甲酯(520mg,1.14mmol,收率100％),黄色固体。ES-API:[M+H]+＝455.1。
步骤二：(S)-2-(((甲氧基-d3)甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸氘代甲酯(520mg,1.14mmol)溶于乙酸(10mL)，加入铁粉(447mg,8.01mmol),反应在90℃搅拌2小时。反应液冷却至室温后用硅藻土过滤，滤饼用乙酸乙酯(20mL)洗涤。滤液真空浓缩,所得粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-100％)得到(S)-2-((甲氧基-d3)甲基)-2-(甲基-d3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(350mg,0.87mmol，收率78％)，浅黄色固体。ES-API:[M+H]+＝393.2。
步骤三：(S)-2-((甲氧基-d3)甲基)-2-(甲基-d3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(350mg,0.87mmol)溶于甲醇(3mL)，四氢呋喃(2mL)和水(0.8mL)，加入氢氧化钠(250mg，6.24mmol)，反应在65℃搅拌6小时。反应液冷却至室温后用稀盐酸(1.0M)调至pH＝8，而后加入20mL饱和碳酸氢钠溶液，用乙酸乙酯(100mL)萃取。有机相依次用饱和碳酸氢钠溶液(20mL)洗涤一次，饱和食盐水(20mL)洗涤两 次，干燥后浓缩得到(S)-2-(((甲氧基-d3)甲基)-2-(甲基-d3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(225mg，0.89mmol,收率100％)，白色固体。ES-API:[M+H]+＝253.1。
步骤四：(S)-2-(((甲氧基-d3)甲基)-2-(甲基-d3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(225mg，0.89mmol)和2-氯-4-苯氧基苯甲醛(622mg，2.68mmol溶于甲醇(10mL)，将反应冷至0℃，加入氢氧化钾(350mg，6.24mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(100mL)萃取。有机相用饱和食盐水(30mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d3)甲基)-2-(甲基-d3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg,0.412mmol,产率46％)，淡黄色固体。ES-API:[M+H]+＝485.1。
步骤五：(2S)-9-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d3)甲基)-2-(甲基-d3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.412mmol)溶于四氢呋喃(5mL)和水(0.5mL)室温下加入2,3-二氯-5,6-二氰对苯醌(281mg，1.24mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL)淬灭反应，而后用乙酸乙酯萃取(50mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(20mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-苯氧基苯甲酰基)-2-(甲氧基-d3)甲基)-2-(甲基-d3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(式I化合物,76mg,产率38％)，白色固体。1H NMR(500MHz,DMSO-d6)δ12.46(s,1H),10.48(s,1H),8.27(s,1H),7.69(s,1H),7.60(s,1H),7.56(d,J＝8.5Hz,1H),7.48(t,J＝8.5Hz,2H),7.25(t,J＝7.5Hz,1H),7.20–7.16(m,3H),7.02(dd,J＝8.5,2.5Hz,1H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H).ES-API:[M+H]+＝483.1。经XPRD表征显示该产品为无定型物。其XPRD结果如图60所示。
单晶培养：称取式I化合物样品(100mg)，乙醇/水(1:1)溶剂加热使样品溶解，放室温缓慢挥发，得到单晶。通过Bruker D8Venture仪器进行X-射线单晶衍射测试。结果见下表6和图61。
表6


生物测试
测试例1：BTK和BTK C481S酶学实验
使用DMSO配制1000X的化合物3倍梯度浓度储液，使用反应缓冲液(50mM HEPES,pH7.5,0.0015％Briji-35,2mM DTT,10mM MgCl2)稀释100倍至10X化合物储液，转移10X化合物储液到384孔板中。用BTK Kinase Enzyme System(Promega Catalog#V2941)或BTK(C481S)Kinase Enzyme System(Promega Catalog#VA7033)来建立酶学反应。首先，用反应缓冲液配制2X酶液加入板内，酶液包含10nM BTK或10nM BTK C481S，与化合物孵育10分钟。然后，用反应缓冲液配制2.5X底物溶液加入板内，底物溶液包含ATP(125μM)，Poly(Glu4,Tyr1)(0.05μg/μL)，在20℃反应90分钟。最后，按照ADP-GloTM kinase Assay试剂盒(Promega,#V9101)提供的实验步骤来检测激酶活性,最终读取luminescence化学发光值。使用DMSO作为最大值信号值,不加酶作为最小值信号值。计算化合物的抑制率(％)＝(最大值信号值–化合物信号值)/(最大值信号值–最小值信号值)×100％，使用XLFit四参数法拟合化合物梯度稀释浓度和对应的酶活抑制率，计算出IC50值。结果，式I化合物对BTK或BTK(C481S)激酶具有较高的抑制活性，对BTK的IC50值为10.6nM，对BTK(C481S)的IC50值为12.5nM。
测试例2：p-BTK细胞实验
第一天：取对数生长期的HEK293细胞(ADDEXBIO,T0011001)，酶EDTA消化细胞收集计数并接种2E6个细胞于10cm培养皿中，培养过夜。第二天：使用1000μL Opti-MEM分别配制含6ug WT-BTK/C481S-BTK质粒和18μL FuGENE HD转染试剂的混合液，室温静置10分钟后，用移液枪把混合液缓慢加入到培养皿中，培养过夜。第三天：取出培养皿酶EDTA消化细胞收集计算并接种1E4个细胞于96孔细胞培养板中，培养过夜。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，室温放置。第四天：取出配制好的1000X化合物储存液，使用培养基稀释200倍至5×化合物储液，每个细胞培养孔加入5×化合物储液，终浓度为1×，DMSO含量为0.1％。使用DMSO作为实验对照。加入化合物培养两小时之后，去除残留的培养基。每孔加入100μL细胞裂解缓冲液,冰上静置30分钟，冰水超声裂解5分钟。按比例稀释细胞裂解液后转移80μL混液至ELISA 板中，空白孔则加入80μL细胞裂解缓冲液。37℃孵育箱中孵育2小时后，取出板子按照PathScan P-Btk(Y223)Sandwich ELISA Kit(Cell signaling#23843CA)说明书完成抗体孵育以及显色终止操作，最后读取OD值。计算化合物的抑制率(％)＝(OD对照–OD化合物)/(OD对照–OD空白)×100％，使用Prism 8四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC50值。结果，式I化合物对BTK或BTK(C481S)磷酸化水平具有较高的抑制活性，对BTK的IC50值为17.00nM，对BTK(C481S)磷酸化的IC50值为39.20nM。
测试例3：TMD-8增殖抑制实验
TMD-8细胞为人弥漫性大B淋巴瘤(明舟生物，MZ-0832)，培养于10％FBS+1％PS1640培养基中。第一天，取对数生长期的细胞，计数并接种600个TMD-8细胞于384孔细胞培养板中，培养过夜。第二天，使用DMSO配制400X的化合物3倍梯度浓度储液，使用培养基稀释40倍至10×化合物储液，每个细胞培养孔加入10×化合物储液，终浓度为1×，DMSO含量为0.25％。使用DMSO作为实验对照,培养基作为空白对照。加入化合物后继续培养三天。在第五天，每孔加入25μL ADP-Glo,混匀孵育10分钟后读取化学发光值(RLU值)。计算细胞增殖抑制率(％)＝(RLU对照-RLU化合物)/(RLU对照-RLU空白)×100％，使用XLFit四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC50值。结果，本发明化合物对TMD-8具有较高的抑制活性，对TMD-8的IC50值为72.77nM。
实施例1式I化合物游离碱晶型A的制备
称量约20mg的式I化合物样品(由制备例1得到)至HPLC小瓶中，加入0.5mL乙腈/水(19:1,v/v)，室温搅拌3天后，离心分离固体在室温下真空干燥过夜后获得式I化合物游离碱晶型A。XRPD和TGA/DSC及1H NMR表征结果如图1、图2和图3所示。TGA结果显示样品加热至200℃时有3.1％的失重；DSC结果显示样品在327.4℃(峰值温度)观察到1个吸热峰。式I化合物游离碱晶型A，其X射线粉末衍射数据如下表7所示。
表7

实施例2式I化合物盐酸盐晶型A的制备
称取约20mg式I化合物样品(由制备例1制备得到)和37％盐酸(1:2,投料量摩尔比)至HPLC小瓶中，加入0.5mL乙酸乙酯，室温搅拌3天后，离心分离固体在室温下真空干燥过夜后获得式I化合物盐酸盐晶型A；XRPD和TGA/DSC及1H NMR表征结果如图4、图5和图6所示。TGA结果显示，升温至110℃，样品失重为7.1％，从110℃加热至200℃，样品失重为7.9％；DSC表明该样品115.4℃和185.0℃(峰值温度)观察到2个吸热峰，在218.3℃(峰值温度)观察到1个放热峰。IC/HPLC测试结果显示盐酸与游离态摩尔比为1.0:1。式I化合物盐酸盐晶型A，其X射线粉末衍射数据如下表8所示。
表8

实施例3式I化合物盐酸盐晶型B的制备
称取约20mg式I化合物样品(由制备例1制备得到)和37％盐酸(1:2,投料量摩尔比)至HPLC小瓶中，加入0.5mL丙酮，室温搅拌过夜后，离心分离固体在室温下真空干燥过夜后获得式I化合物盐酸盐晶型B；XRPD和TGA/DSC及1H NMR表征结果分别如图7、图8和图9所示。TGA结果显示，升温至150℃，样品失重为4.8％，从150℃加热至230℃，样品失重为7.6％；DSC表明该样品在223.0℃(峰值温度)观察到1个吸热峰。IC/HPLC测试结果显示盐酸与游离态摩尔比为1.0:1。式I化合物盐酸盐晶型B，其X射线粉末衍射数据如下表9所示。
表9
实施例4式I化合物盐酸盐晶型C的制备
称取约20mg式I化合物(由制备例1制备得到)和和1N盐酸(1:2,投料量摩尔比)至HPLC小瓶中，加入0.5mL丙酮，室温搅拌过夜后，离心分离固体在室温下真空干燥 过夜后获得式I化合物盐酸盐晶型C。XRPD和TGA/DSC及1H NMR表征结果分别如图10、图和图所示。TGA结果显示，升温至150℃，样品失重为2.2％，从150℃加热至250℃，样品失重为7.5％；DSC表明该样品在248.2℃(峰值温度)观察到1个吸热峰。IC/HPLC测试结果显示盐酸与游离态摩尔比为0.9:1。式I化合物盐酸盐晶型C，其X射线粉末衍射数据如下表10所示。
表10
实施例5式I化合物磷酸盐晶型A的制备
称取约20mg式I化合物(由制备例1得到)和等摩尔量的磷酸至HPLC小瓶中，加入0.5mL乙酸乙酯，室温搅拌3天后，离心分离固体在室温下真空干燥过夜后获得式I化合物磷酸盐晶型A。XRPD和TGA/DSC及1H NMR表征结果分别如图13、图14和图15所示。TGA结果显示，升温至65℃，样品失重为2.1％，从65℃加热至125℃，样品失 重为2.8％；DSC表明该样品在81.7℃，92.1℃和139.2℃(峰值温度)观察到3个吸热峰。1H NMR结果显示磷酸与游离态摩尔比为1.3:1。式I化合物磷酸盐晶型A，其X射线粉末衍射数据如下表11所示。
表11
实施例6式I化合物富马酸盐晶型A的制备
称取约20mg式I化合物(由制备例1得到)和等摩尔量的富马酸至HPLC小瓶中，加入0.5mL乙酸乙酯，室温搅拌3天后，离心分离固体在室温下真空干燥过夜后获得式I化合物富马酸盐晶型A；XRPD和TGA/DSC及1H NMR表征结果分别如图16、图17和图18所示。TGA结果显示，升温至150℃，样品失重为2.6％，从150℃加热至240℃，样品失重为21.2％；DSC表明该样品在224.7℃(峰值温度)观察到1个吸热峰。1H NMR结果显示，该样品中富马酸与游离态的摩尔比约为1.0:1。式I化合物富马酸盐晶型A，其X射线粉末衍射数据如下表12所示。
表12
实施例7式I化合物1,5-萘二磺酸盐晶型A的制备
称取约20mg式I化合物(由制备例1得到)和等摩尔量的1,5-萘二磺酸至HPLC小瓶中，加入0.5mL乙腈/水(19:1，v/v)，室温搅拌3天后，离心分离固体在室温下真空干燥过夜后获得式I化合物的1,5-萘二磺酸盐晶型A。XRPD和TGA/DSC及1H NMR表征结果分别如图19，图20，图21所示。TGA结果显示，升温至130℃，样品失重为3.5％，从130℃加热至175℃，样品失重为2.6％；DSC表明该样品在57.7℃，82.9℃，166.9℃和211.1℃(峰值温度)观察到4个吸热峰。1H NMR结果显示，该样品中1,5-萘二磺酸与游离态的摩尔比约为0.7:1，未观察到乙腈溶剂残留。式I化合物的1,5-萘二磺酸盐晶型A，其X射线粉末衍射数据如下表13所示。
表13
实施例8式I化合物1,5-萘二磺酸盐晶型B的制备
称取约20mg式I化合物(由制备例1得到)和等摩尔量的1,5-萘二磺酸至HPLC小瓶中，加入0.5mL丙酮，室温搅拌3天后，离心分离固体在室温下真空干燥过夜后获得式I化合物的1,5-萘二磺酸盐晶型B。XRPD和TGA/DSC及1H NMR表征结果分别如图22，图23，图24所示。TGA结果显示，升温至200℃，样品失重为4.3％；DSC表明该样品在57.0℃，82.5℃和276.1℃(峰值温度)观察到3个吸热峰。1H NMR结果显示，该样品中1,5-萘二磺酸与游离态的摩尔比约为0.7:1，未观察到乙腈溶剂残留。式I化合物的1,5-萘二磺酸盐晶型B，其X射线粉末衍射数据如下表14所示。
表14

实施例9式I化合物对甲苯磺酸盐晶型A的制备
称取约20mg式I化合物(由制备例1得到)和等摩尔量的对甲苯磺酸至HPLC小瓶中，加入0.5mL乙腈/水(19:1，v/v)，室温搅拌3天后，离心分离固体在室温下真空干燥过夜后获得式I化合物的对甲苯磺酸盐晶型A。XRPD和TGA/DSC及1H NMR表征结果分别如图25，图26，图27所示。TGA结果显示，升温至75℃，样品失重为4.3％，从75℃加热至120℃，样品失重为6.1％；DSC表明该样品在111.1℃(峰值温度)观察到1个吸热峰。1H NMR结果显示，该样品中对甲苯磺酸与游离态的摩尔比为1.0:1，未观察到乙腈的溶剂残留。式I化合物的对甲苯磺酸盐晶型A，其X射线粉末衍射数据如下表15所示。
表15
实施例10式I化合物氢溴酸盐晶型A的制备
称取约20mg式I化合物(由制备例1得到)和等摩尔量的氢溴酸至HPLC小瓶中，加入0.5mL乙酸乙酯，室温搅拌3天后，离心分离固体在室温下真空干燥过夜后获得氢溴酸盐晶型A。XRPD和TGA/DSC及1H NMR表征结果分别如图28，图29，图30所示。 TGA结果显示，升温至200℃，样品失重为5.6％；DSC表明该样品在97.7℃，179.4℃，230.7℃和254.9℃(峰值温度)观察到4个吸热峰。IC/HPLC测试结果显示，氢溴酸与游离态摩尔比为0.9:1。式I化合物的氢溴酸盐晶型A，其X射线粉末衍射数据如下表16所示。
表16
实施例11式I化合物马来酸盐晶型A的制备
称取约20mg式I化合物(由制备例1得到)和等摩尔量的马来酸至HPLC小瓶中，加入0.5mL丙酮溶液，室温搅拌3天后，离心分离固体在室温下真空干燥过夜后获得式I化合物马来酸盐晶型A。XRPD和TGA/DSC及1H NMR表征结果如图31、图32和图33所示。TGA结果显示，升温至150℃，样品失重为2.8％，从150℃加热至230℃，样品失重为19.3％；DSC表明该样品在200.3℃(峰值温度)处观察到1个吸热峰。1H NMR结果显示，该样品中马来酸与游离态的摩尔比约为1.0:1。式I化合物马来酸盐晶型A，其X射线粉末衍射数据如下表17所示。
表17
实施例12式I化合物的马来酸盐晶型E的制备
称取20mg的马来酸盐晶型A样品(由实施例11制备得到)至3mL小瓶中，加入0.2～1.8mL四氢呋喃溶剂溶解，另取20mL的小瓶向其中加入约4mL的正庚烷反溶剂，将装有滤液的3mL小瓶敞口置于20mL小瓶后，密封20mL的小瓶并于室温下静置。当观察到有固体析出时，则收集固体，得到式I化合物的马来酸盐晶型E。XRPD和TGA/DSC及1H NMR表征结果分别如图34，图35，图36所示。TGA结果表明，该样品从室温加热至150℃，样品失重为3.4％，从150℃加热至250℃，样品失重为19.7％。DSC结果表明，该样品在194.2℃(峰值温度)处观察到1个吸热峰。1H NMR结果表明，该样品中马来酸与游离态的摩尔比为1.0:1。式I化合物的马来酸盐晶型E，其X射线粉末衍射数据如下表18所示。
表18
实施例13式I化合物的马来酸盐晶型F的制备
称取20mg的马来酸盐晶型A样品(由实施例11制备得到)至HPLC小瓶中，加入0.5mL四氢呋喃/水(957:43,v/v)溶剂，得到的悬浊液置于室温下磁力搅拌约7天，离心分离固体，得到式I化合物马来酸盐晶型F。XRPD和TGA/DSC及1H NMR表征结果分别如图37，图38，图39所示。TGA结果表明，该样品从室温加热至150℃，样品失重为2.9％，从150℃加热至250℃，样品失重为18.7％。DSC结果表明，该样品在65.3℃, 81.7℃和180.8℃(峰值温度)处观察到3个吸热峰。1H NMR结果表明，该样品中马来酸与游离态的摩尔比为1.0:1。式I化合物马来酸盐晶型F，其X射线粉末衍射数据如下表19所示。
表19
实施例14式I化合物马来酸盐晶型H的制备
称取20mg的马来酸盐晶型A样品(由实施例11制备得到)至3mL小瓶中，加入0.2～1.8mL四氢呋喃溶剂溶解，另取20mL的小瓶向其中加入约4mL的甲基叔丁基醚反溶剂，将装有滤液的3mL小瓶敞口置于20mL小瓶后，密封20mL的小瓶并于室温下静置。当观察到有固体析出时，则收集固体，得到式I化合物马来酸盐晶型H。XRPD和TGA/DSC及1H NMR表征结果分别如图40，图41，图42所示。TGA结果表明，该样品从室温加热至150℃，样品失重为1.4％，从150℃加热至250℃，样品失重为17.4％。DSC结果表明，该样品在188.6℃(峰值温度)处观察到1个吸热峰。1H NMR(结果表明，该样品中马来酸与游离态的摩尔比为1.0:1。通过VT-XRPD对马来酸盐晶型H进行晶型鉴定，将样品在N2下吹扫20min，加热至150℃并降至30℃，均未观察到晶型变化。式I化合物马来酸盐晶型H，其X射线粉末衍射数据如下表20所示。
表20
实施例15式I化合物的马来酸盐晶型I的制备
向100mL圆底烧瓶中加入马来酸盐晶型A样品(1g,由实施例11制备得到)、四氢呋喃(30mL),体系回流溶清。自然冷却至室温，固体析出。旋蒸浓缩至剩余～20mL四氢呋喃。油浴升温至80℃搅拌0.5小时，自然冷却到室温，搅拌过夜。过滤，干燥，得到780mg类白色固体，为式I化合物马来酸盐晶型I。XRPD和TGA/DSC及1H NMR表征结果分别如图43，图44，图45所示。TGA结果表明，该样品从室温加热至130℃，样品失重为3.5％，从130℃加热至250℃，样品失重为20.2％。DSC结果表明，该样品在112.9℃和202.5℃(峰值温度)处观察到2个吸热峰，在161.5℃(峰值温度)处观察到1个放热峰。1H NMR结果表明，该样品中马来酸与游离态的摩尔比为1.0:1。式I化合物马来酸盐晶型I，其X射线粉末衍射数据如下表21所示。
表21

实施例16式I化合物马来酸盐晶型J的制备
将马来酸盐晶型I(由实施例15制备得到)加热至130℃，降至室温并暴露在空气中获得式I化合物马来酸盐晶型J。XRPD和TGA/DSC及1H NMR表征结果分别如图46，图47，图48所示。TGA结果表明，该样品从室温加热至150℃，样品失重为6.4％，从150℃加热至250℃，样品失重为20.5％。DSC结果表明，该样品在193.7℃(峰值温度)处观察到1个吸热峰，在162.1℃(峰值温度)处观察到1个放热峰。1H NMR结果表明，该样品中马来酸与游离态的摩尔比为1.0:1。马来酸盐晶型J进行湿度诱导试验，将马来酸盐晶型J置于80％RH条件下放置过夜后，晶型不变，表明马来酸盐晶型J在高湿条件下相对稳定。式I化合物马来酸盐晶型J，其X射线粉末衍射数据如下表22所示。
表22

实施例17式I化合物游离碱晶型C的制备
称取20mg的马来酸盐晶型A样品(由实施例11制备得到)于20mL小瓶内，用0.2～3.0mL的甲醇溶剂溶解后(未溶清的体系使用0.45μm的PTFE滤头过滤至另一小瓶内)，向该澄清溶液中加入水的反溶剂，边滴加边搅拌至有固体析出，或当反溶剂总量加至10.0mL后，无固体析出的样品转至5℃下磁力搅拌，若仍无固体析出，则转至室温挥发。离心分离析出固体，得到式I化合物游离碱晶型C。XRPD和TGA/DSC及1H NMR表征结果如图49，图50，图51所示。TGA结果显示样品加热至200℃时有2.7％的失重；DSC结果显示样品在329.3℃(峰值温度)处观察到1个吸热峰，在311.3℃(峰值温度)处观察到1个放热峰。式I化合物游离碱晶型C，其X射线粉末衍射数据如下表23所示。
表23
实施例18式I化合物游离碱晶型D的制备
称取20mg马来酸盐晶型A样品(由实施例11制备得到)至3mL小瓶中，加入0.2～1.8mL二甲基乙酰胺溶剂溶解，另取20mL的小瓶向其中加入约4mL水的反溶剂，将装有滤液的3mL小瓶敞口置于20mL小瓶后，密封20mL的小瓶并于室温下静置。当观察到有固体析出时，则收集固体，得到式I化合物游离碱晶型D。XRPD和TGA/DSC及1H NMR表征结果分别如图52，图53，图54所示。TGA结果显示该样品从室温加热 至150℃，样品失重为4.1％，从150℃加热至230℃，样品失重为7.1％。DSC结果显示样品在175.3℃和328.9℃(峰值温度)处观察到2个吸热峰。式I化合物游离碱晶型D，其X射线粉末衍射数据如下表24所示。
表24
实施例19式I化合物游离碱晶型E的制备
称取20mg马来酸盐晶型A样品(由实施例11制备得到)至HPLC小瓶中，分别加入0.5mL 1,4-二氧六环/水(1:2,v/v)的溶剂，50℃条件下悬浮搅拌3天后获得式I化合物游离碱晶型E。XRPD和TGA/DSC及1H NMR表征结果分别如图55，图56，图57所示。TGA结果显示该样品从室温加热至80℃，样品失重为1.8％；从80℃加热至180℃，样品失重为16.8％。DSC结果显示样品在144.5℃和329.1℃(峰值温度)处观察到2个吸热峰。式I化合物游离碱晶型E，其X射线粉末衍射数据如下表25所示。
表25

实施例20式I化合物马来酸盐晶型A的制备
向250mL圆底烧瓶中加入式I化合物(7.4g,由制备例1得到)和乙酸乙酯(100mL)，室温搅拌；滴加马来酸(1.86g)的乙酸乙酯(50mL)溶液，得到混悬液，室温搅拌4小时；反应液过滤，滤饼干燥得到8.8g灰白色固体，对其进行XRPD、TGA/DSC表征，各个图谱基本同实施例11中的图谱。故所得固体为式I化合物马来酸盐晶型A。
实施例21式I化合物马来酸盐晶型A的制备
向反应釜中加入式I化合物(570g,由制备例1得到)和乙酸乙酯(17L)，室温搅拌；滴加马来酸(144g)的乙酸乙酯(2.85L)溶液，得到混悬液，升温至50-60℃，混悬液保温搅拌4-5小时；停止加热，搅拌下自然冷却至室温，搅拌16-24小时，过滤，滤饼干燥得到678g灰白色固体，对其进行XRPD、TGA/DSC表征，各个图谱基本同实施例11中的图谱。故所得固体为式I化合物马来酸盐晶型A。
引湿性
通过25℃下0％RH～95％RH之间的DVS测试对式I化合物的马来酸盐晶型A样品(实施例21得到)的引湿性进行了评估。DVS测试结果见图58。结果表明，马来酸盐晶型A样品在25℃/80％RH的水分吸附为～0.13％，表明其几乎无引湿性，且DVS测试前后样品的晶型一致。
压力稳定性
使用SYP-5BS手动压片机对式I化合物的马来酸盐晶型A样品(实施例20得到)进行了压力稳定性测试，具体步骤如下：称取～100mg马来酸盐晶型A样品于压力机模具中，使用～350MPa压力进行压片并维持1min，后取样品测试XRPD。压力稳定性前后样品的XRPD见图59，结果表明，压力稳定性前后马来酸盐晶型A的晶型不变。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (13)

  1. 一种式I化合物的晶型，其特征在于，其为式I化合物游离碱晶型A、式I化合物游离碱晶型C、式I化合物游离碱晶型D或式I化合物游离碱晶型E；
    所述的式I化合物游离碱晶型A，其以2θ角度表示的X-射线粉末衍射图在7.3574±0.2°、20.0853±0.2°、26.2299±0.2°和15.0639±0.2°处有衍射峰；
    所述的式I化合物游离碱晶型C，其以2θ角度表示的X-射线粉末衍射图在4.9395±0.2°、28.0724±0.2°、11.4647±0.2°和13.2030±0.2°处有衍射峰；
    所述的式I化合物游离碱晶型D，其以2θ角度表示的X-射线粉末衍射图在4.8447±0.2°、19.3873±0.2°、12.0794±0.2°和14.2457±0.2°处有衍射峰；
    所述的式I化合物游离碱晶型E，其以2θ角度表示的X-射线粉末衍射图在5.3081±0.2°、4.9506±0.2°、20.9925±0.2°和19.0379±0.2°处有衍射峰。
  2. 如权利要求1所述的式I化合物的晶型，其特征在于，
    当所述的式I化合物的晶型为式I化合物游离碱晶型A时，所述的式I化合物游离碱晶型A满足如下1个或多个条件：
    (1)所述的式I化合物游离碱晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.5403±0.2°、10.0156±0.2°、6.4788±0.2°、10.8671±0.2°和19.5949±0.2°；
    (2)所述的式I化合物游离碱晶型A，其热重分析图在起始加热至200±5℃处失重为2.0％-3.5％，例如3.1％；
    (3)所述的式I化合物游离碱晶型A，其差示扫描量热图在327.4±5℃处有吸热峰；
    当所述的式I化合物的晶型为式I化合物游离碱晶型C时，所述的式I化合物游离碱晶型C满足如下1个或多个条件：
    (1)所述的式I化合物游离碱晶型C，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.2058±0.2°、14.7891±0.2°、20.1466±0.2°、24.5916±0.2° 和21.4712±0.2°；
    (2)所述的式I化合物游离碱晶型C，其热重分析图在起始加热至200±5℃处失重为1％-3％，例如2.7％；
    (3)所述的式I化合物游离碱晶型C，其差示扫描量热图在329.3±5℃处有吸热峰；和/或在311.3±5℃处有放热峰；
    当所述的式I化合物的晶型为式I化合物游离碱晶型D时，所述的式I化合物游离碱晶型D满足如下1个或多个条件：
    (1)所述的式I化合物游离碱晶型D，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：4.3851±0.2°、15.7673±0.2°、22.1929±0.2°、17.9985±0.2°和24.8383±0.2°；
    (2)所述的式I化合物游离碱晶型D，其热重分析图在起始加热至150±5℃处失重为3％-5％，例如4.1％；从150±5℃加热至230±5℃，样品失重为6％-8％，例如7.1％；
    (3)所述的式I化合物游离碱晶型D，其差示扫描量热图在175.3±5℃和/或328.9±5℃处有吸热峰；
    当所述的式I化合物的晶型为式I化合物游离碱晶型E时，所述的式I化合物游离碱晶型E满足如下1个或多个条件：
    (1)所述的式I化合物游离碱晶型E，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：21.2501±0.2°、17.2819±0.2°、10.4721±0.2°、23.0960±0.2°和28.0729±0.2°；
    (2)所述的式I化合物游离碱晶型E，其热重分析图在起始加热至80±5℃处失重为1％-3％，例如1.8％；从80±5℃加热至180±5℃，样品失重为16％-18％，例如16.8％；
    (3)所述的式I化合物游离碱晶型E，其差示扫描量热图在144.5±5℃和/或329.1±5℃处有吸热峰。
  3. 如权利要求2所述的式I化合物的晶型，其特征在于，
    当所述的式I化合物的晶型为式I化合物游离碱晶型A时，所述的式I化合物游离碱晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物游离碱晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：12.0106±0.2°、25.1097±0.2°、18.0778±0.2°和30.3217±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图1所示；
    (2)所述的式I化合物游离碱晶型A，其差示扫描热图和热重分析图基本如图2所示；
    或，
    当所述的式I化合物的晶型为式I化合物游离碱晶型C时，所述的式I化合物游离碱晶型C满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物游离碱晶型C，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：9.0935±0.2°、19.4096±0.2°、18.2149±0.2°、22.5487±0.2°、26.6034±0.2°和22.9264±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图49所示；
    (2)所述的式I化合物游离碱晶型C，其差示扫描热图和热重分析图基本如图50所示；
    或，
    当所述的式I化合物的晶型为式I化合物游离碱晶型D时，所述的式I化合物游离碱晶型D满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物游离碱晶型D，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：22.3605±0.2°、18.9570±0.2°、18.3427±0.2°、23.7387±0.2°、28.1120±0.2°和24.2673±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图52所示；
    (2)所述的式I化合物游离碱晶型D，其差示扫描热图和热重分析图基本如图53所示；
    或，
    当所述的式I化合物的晶型为式I化合物游离碱晶型E时，所述的式I化合物游离碱晶型E满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物游离碱晶型E，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：12.5909±0.2°、13.8832±0.2°、14.9003±0.2°、8.6259±0.2°、7.3206±0.2°和15.9004±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图55所示；
    (2)所述的式I化合物游离碱晶型E，其差示扫描热图和热重分析图基本如图56所示。
  4. 一种式I化合物的药学上可接受的盐，其特征在于，所述的药学上可接受的盐为式I化合物与酸形成的盐；所述的酸为无机酸或有机酸；
  5. 如权利要求4所述的式I化合物的药学上可接受的盐，其特征在于，所述的式I化合物与所述的酸的摩尔比为1∶(0.5-2)，例如1∶0.6、1∶0.7、1∶0.9、1∶1、1∶1.1、1∶1.3或1∶2；
    和/或，所述的无机酸为盐酸、硫酸、磷酸、氢溴酸中的一种或多种；较佳地，所述的无机酸为盐酸、磷酸和氢溴酸中的一种或多种；
    和/或，所述的有机酸为马来酸、L-天冬氨酸、富马酸、L-酒石酸、柠檬酸、1，5-萘二磺酸、1，2-乙二磺酸、对甲苯磺酸、甲磺酸、苯磺酸、2-羟基乙磺酸、乙磺酸、丙二酸中的一种或多种；较佳地，所述的有机酸为马来酸、富马酸、1，5-萘二磺酸、对甲苯磺酸中的一种或多种；更佳地，所述的有机酸为马来酸、富马酸和对甲苯磺酸中的一种或多种；更佳地，所述的有机酸为马来酸。
  6. 如权利要求4所述的式I化合物的药学上可接受的盐，其特征在于，所述的式I化合物的药学上可接受的盐为如下任一药学上可接受的盐：
    (1)式I化合物的盐酸盐；其中，式I化合物与盐酸的摩尔比为1∶(0.5-2)，例如1∶(0.9-1.0)；
    (2)式I化合物的磷酸盐；其中，式I化合物与磷酸的摩尔比为1∶(1-2)，例如1∶(1-1.3)；
    (3)式I化合物的氢溴酸盐；其中，式I化合物与氢溴酸的摩尔比为1∶(0.5-1)，例如1∶0.9；
    (4)式I化合物的富马酸盐；其中，式I化合物与富马酸的摩尔比为1∶1；
    (5)式I化合物的1，5-萘二磺酸盐；其中，式I化合物与1，5-萘二磺酸的摩尔比为1∶(0.5-1)，例如1∶0.7；
    (6)式I化合物的对甲苯磺酸盐；其中，式I化合物与对甲苯磺酸的摩尔比为1∶1；
    (7)式I化合物的马来酸盐；其中，式I化合物与马来酸的摩尔比为1∶1。
  7. 一种式I化合物的药学上可接受的盐的晶型，其特征在于，所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐晶型A、式I化合物的盐酸盐晶型B、式I化合物的盐酸盐晶型C、式I化合物的磷酸盐晶型A、式I化合物的富马酸盐晶型A、 式I化合物的1，5-萘二磺酸盐晶型A、式I化合物的1，5-萘二磺酸盐晶型B、式I化合物的对甲苯磺酸盐晶型A、式I化合物的氢溴酸盐晶型A、式I化合物的马来酸盐晶型A、式I化合物的马来酸盐晶型E、式I化合物的马来酸盐晶型F、式I化合物的马来酸盐晶型H、式I化合物的马来酸盐晶型I或式I化合物的马来酸盐晶型J；
    所述的式I化合物的盐酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图在13.2577±0.2°、19.0205±0.2°、26.6619±0.2°和24.4646±0.2°处有衍射峰；
    所述的式I化合物的盐酸盐晶型B，其以2θ角度表示的X-射线粉末衍射图在11.2971±0.2°、4.1094±0.2°、16.0047±0.2°和18.5553±0.2°处有衍射峰；
    所述的式I化合物的盐酸盐晶型C，其以2θ角度表示的X-射线粉末衍射图在21.5443±0.2°、27.3605±0.2°、10.0792±0.2°和18.8112±0.2°处有衍射峰；
    所述的式I化合物的磷酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图在12.8284±0.2°、21.1193±0.2°、22.7554±0.2°和12.4119±0.2°处有衍射峰；
    所述的式I化合物的富马酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图在5.1732±0.2°、7.9252±0.2°、10.2736±0.2°和18.8307±0.2°处有衍射峰；
    所述的式I化合物的1，5-萘二磺酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图在7.7555±0.2°、9.6043±0.2°、23.0949±0.2°和17.5044±0.2°处有衍射峰；
    所述的式I化合物的1，5-萘二磺酸盐晶型B，其以2θ角度表示的X-射线粉末衍射图在15.0980±0.2°、20.3818±0.2°、13.6481±0.2°和24.7069±0.2°处有衍射峰；
    所述的式I化合物的对甲苯磺酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图在4.0699±0.2°、20.3148±0.2°、14.9056±0.2°和18.3888±0.2°处有衍射峰；
    所述的式I化合物的氢溴酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图在4.1403±0.2°、11.1940±0.2°、27.3198±0.2°和17.4698±0.2°处有衍射峰；
    所述的式I化合物的马来酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图在4.4590±0.2°、10.0991±0.2°、13.6435±0.2°和20.6462±0.2°处有衍射峰；
    所述的式I化合物的马来酸盐晶型E，其以2θ角度表示的X-射线粉末衍射图在4.4072±0.2°、13.3026±0.2°、27.4367±0.2°和21.9948±0.2°处有衍射峰；
    所述的式I化合物的马来酸盐晶型F，其以2θ角度表示的X-射线粉末衍射图在10.9668±0.2°、7.8002±0.2°、6.1349±0.2°和12.3076±0.2°处有衍射峰；
    所述的式I化合物的马来酸盐晶型H，其以2θ角度表示的X-射线粉末衍射图在4.5619±0.2°、13.5614±0.2°、13.0298±0.2°和10.2862±0.2°处有衍射峰；
    所述的式I化合物的马来酸盐晶型I，其以2θ角度表示的X-射线粉末衍射图在5.4040±0.2°、9.4028±0.2°、10.4407±0.2°和8.8892±0.2°处有衍射峰；
    所述的式I化合物的马来酸盐晶型J，其以2θ角度表示的X-射线粉末衍射图在5.4594±0.2°、25.5787±0.2°、17.8675±0.2°和10.5280±0.2°处有衍射峰。
  8. 如权利要求7所述的式I化合物的药学上可接受的盐的晶型，其特征在于，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐晶型A时，所述的式I化合物的盐酸盐晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的盐酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：25.4625±0.2°、25.7474±0.2°、14.8470±0.2°、10.5627±0.2°和25.0104±0.2°；
    (2)所述的式I化合物的盐酸盐晶型A，其热重分析图在起始加热至110±5℃处失重为6％-8％，例如7.1％；从110±5℃加热至200±5℃，样品失重为7％-9％，例如7.9％；
    (3)所述的式I化合物的盐酸盐晶型A，其差示扫描量热图在115.4±5℃和185.0±5℃处有吸热峰；和/或，在218.3℃±5℃处有放热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐晶型B时，所述的式I化合物的盐酸盐晶型B满足如下1个或多个条件：
    (1)所述的式I化合物的盐酸盐晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：27.3296±0.2°、17.6049±0.2°、27.5618±0.2°、26.3637±0.2°和25.6428±0.2°；
    (2)所述的式I化合物的盐酸盐晶型B，其热重分析图在起始加热至150±5℃处失重为4％-6％，例如4.8％；从150±5℃加热至230±5℃，样品失重为6.5％-8.5％，例如7.6％；
    (3)所述的式I化合物的盐酸盐晶型B，其差示扫描量热图在223.0±5℃处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐晶型C时，所述的式I化合物的盐酸盐晶型C满足如下1个或多个条件：
    (1)所述的式I化合物的盐酸盐晶型C，其以2θ角度表示的X-射线粉末衍射图，还在 如下一个或多个2θ角度处有衍射峰：14.1629±0.2°、8.5449±0.2°、26.7582±0.2°、6.8670±0.2°和17.2037±0.2°；
    (2)所述的式I化合物的盐酸盐晶型C，其热重分析图在150±5℃处失重1.5％-3％，例如2.2％；在150℃至250℃处失重为6.5％-8.5％，例如7.5％；
    (3)所述的式I化合物的盐酸盐晶型C，其差示扫描量热图在248.2±5℃处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的磷酸盐晶型A时，所述的式I化合物的磷酸盐晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的磷酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：24.1820±0.2°、19.6004±0.2°、24.9449±0.2°、17.7015±0.2°和25.7812±0.2°；
    (2)所述的式I化合物的磷酸盐晶型A，其热重分析图在起始加热至65±5℃处失重为1％-3％，例如2.1％；从65±5℃加热至125±5℃，样品失重为2％-4％，例如2.8％；
    (3)所述的式I化合物的磷酸盐晶型A，其差示扫描量热图在81.7±5℃、92.1±5℃和139.2±5℃的一处或多处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的富马酸盐晶型A时，所述的式I化合物的富马酸盐晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的富马酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：24.8824±0.2°、12.0866±0.2°、15.4296±0.2°、23.9878±0.2°和13.0765±0.2°；
    (2)所述的式I化合物的富马酸盐晶型A，其热重分析图在起始加热至150±5℃处失重为2％-4％，例如2.6％；从150±5℃加热至240±5℃，样品失重为19％-22％，例如21.2％；
    (3)所述的式I化合物的富马酸盐晶型A，其差示扫描量热图在224.7±5℃处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的1，5-萘二磺酸盐晶型A时，所述的式I化合物的1，5-萘二磺酸盐晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的1，5-萘二磺酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.2234±0.2°、22.5424±0.2°、16.5111±0.2°、 24.1101±0.2°和11.2117±0.2°；
    (2)所述的式I化合物的1，5-萘二磺酸盐晶型A，其热重分析图在起始加热至130±5℃处失重为2.5％-4.5％，例如3.5％；从130±5℃加热至175±5℃，样品失重为1.5％-3.5％，例如2.6％；
    (3)所述的式I化合物的1，5-萘二磺酸盐晶型A，其差示扫描量热图在57.7±5℃、82.9±5℃、166.9±5℃和211.1±5℃的一处或多处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的1，5-萘二磺酸盐晶型B时，所述的式I化合物的1，5-萘二磺酸盐晶型B满足如下1个或多个条件：
    (1)所述的式I化合物的1，5-萘二磺酸盐晶型B，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：15.8095±0.2°、10.8634±0.2°、16.7992±0.2°、26.2961±0.2°和12.3107±0.2°；
    (2)所述的式I化合物的1，5-萘二磺酸盐晶型B，其热重分析图在起始加热至200±5℃处失重为3.5％-5.5％，例如4.3％；
    (3)所述的式I化合物的1，5-萘二磺酸盐的晶型B，其差示扫描量热图在57.0±5℃、82.5±5℃和276.1±5℃的一处或多处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的对甲苯磺酸盐晶型A时，所述的式I化合物的对甲苯磺酸盐晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的对甲苯磺酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：22.0879±0.2°、25.9320±0.2°、11.8243±0.2°、17.2270±0.2°和24.5224±0.2°；
    (2)所述的式I化合物的对甲苯磺酸盐晶型A，其热重分析图在起始加热至75±5℃，样品失重为3.5％-5.5％，例如4.3％；从75±5℃加热至120±5℃，样品失重为5％-7％，例如6.1％；
    (3)所述的式I化合物的对甲苯磺酸盐晶型A，其差示扫描量热图在111.1±5℃处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的氢溴酸盐晶型A时，所述的式I化合物的氢溴酸盐晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的氢溴酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，还 在如下一个或多个2θ角度处有衍射峰：20.6495±0.2°、8.7348±0.2°、18.5192±0.2°、16.0192±0.2°和19.6807±0.2°；
    (2)所述的式I化合物的氢溴酸盐晶型A，其热重分析图在起始加热至200±5℃处失重为4.5％-6.5％，例如5.6％；
    (3)所述的式I化合物的氢溴酸盐晶型A，其差示扫描量热图在97.7±5℃、179.4±5℃、230.7±5℃和254.9±5℃的一处或多处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型A时，所述的式I化合物的马来酸盐晶型A满足如下1个或多个条件：
    (1)所述的式I化合物的马来酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：25.9433±0.2°、17.3036±0.2°、26.3520±0.2°、18.2594±0.2°和17.8271±0.2°；
    (2)所述的式I化合物的马来酸盐晶型A，其热重分析图在起始加热至150±5℃处失重为2.5％-3.5％，例如2.8％；从150℃加热至230℃，样品失重为19％-21％，例如19.3％；
    (3)所述的式I化合物的马来酸盐晶型A，其差示扫描量热图在200.3±20℃处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型E时，所述的式I化合物的马来酸盐晶型E满足如下1个或多个条件：
    (1)所述的式I化合物的马来酸盐晶型E，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.1322±0.2°、18.1840±0.2°、12.8549±0.2°、22.7709±0.2°和13.6555±0.2°；
    (2)所述的式I化合物的马来酸盐晶型E，其热重分析图在起始加热至150±5℃处失重为2.5％-4.5％，例如3.4％；从150℃加热至250℃，样品失重为19％-21％，例如19.7％；
    (3)所述的式I化合物的马来酸盐晶型E，其差示扫描量热图在194.2±5℃处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型F时，所述的式I化合物的马来酸盐晶型F满足如下1个或多个条件：
    (1)所述的式I化合物的马来酸盐晶型F，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.6068±0.2°、16.7364±0.2°、25.6746±0.2°、 23.5852±0.2°和20.2850±0.2°；
    (2)所述的式I化合物的马来酸盐晶型F，其热重分析图在起始加热至150±5℃处失重为2％-4％，例如2.9％；从150℃加热至250℃，样品失重为17.5％-19.5％，例如18.7％；
    (3)所述的式I化合物的马来酸盐晶型F，其差示扫描量热图在65.3±5℃、81.7±5℃和180.8±5℃的一处或多处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型H时，所述的式I化合物的马来酸盐晶型H满足如下1个或多个条件：
    (1)所述的式I化合物的马来酸盐晶型H，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：18.3628±0.2°、25.9556±0.2°、26.6709±0.2°、20.7641±0.2°和12.4688±0.2°；
    (2)所述的式I化合物的马来酸盐晶型H，其热重分析图在起始加热至150±5℃处失重为1％-2％，例如1.4％；从150℃加热至250℃，样品失重为16.5％-18.5％，例如17.4％；
    (3)所述的式I化合物的马来酸盐晶型H，其差示扫描量热图在188.6±5℃处有吸热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型I时，所述的式I化合物的马来酸盐晶型I满足如下1个或多个条件：
    (1)所述的式I化合物的马来酸盐晶型I，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：12.6630±0.2°、25.4555±0.2°、13.6954±0.2°、15.5008±0.2°和17.6958±0.2°；
    (2)所述的式I化合物的马来酸盐晶型I，其热重分析图在加热至130±5℃时具有2.5％-4.5％的失重，例如3.5％；从130℃加热至250℃，样品失重为19％-21％，例如20.2％；
    (3)所述的式I化合物的马来酸盐晶型I，其差示扫描量热图在112.9±5℃和202.5±5℃处有吸热峰；和/或，在161.5±5℃处有放热峰；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型J时，所述的式I化合物的马来酸盐晶型J满足如下1个或多个条件：
    (1)所述的式I化合物的马来酸盐晶型J，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：15.7099±0.2°、27.1774±0.2°、23.6955±0.2°、9.4120±0.2°和8.9158±0.2°；
    (2)所述的式I化合物的马来酸盐晶型J，其热重分析图在起始加热至150±5℃时具有6％-7％的失重，例如6.4％；从150℃加热至250℃，样品失重为19.5％-21.5％，例如20.5％；
    (3)所述的式I化合物的马来酸盐晶型J，其差示扫描量热图在193.7±5℃处有吸热峰；和/或，在162.1±5℃处有放热峰。
  9. 如权利要求7所述的式I化合物的药学上可接受的盐的晶型，其特征在于，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐晶型A时，所述的式I化合物的盐酸盐晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的盐酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：24.6922±0.2°、20.9024±0.2°、18.2234±0.2°、11.6824±0.2°、21.1980±0.2°和16.9518±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图4所示；
    (2)所述的式I化合物的盐酸盐晶型A，其差示扫描热图和热重分析图基本如图5所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐晶型B时，所述的式I化合物的盐酸盐晶型B满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的盐酸盐晶型B，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：21.4646±0.2°、20.6275±0.2°、12.7357±0.2°、20.3279±0.2°、24.8169±0.2°和24.1245±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图7所示；
    (2)所述的式I化合物的盐酸盐晶型B，其差示扫描热图和热重分析图基本如图8所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的盐酸盐晶型C时，所述的式I化合物的盐酸盐晶型C满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的盐酸盐晶型C，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：25.7895±0.2°、15.3903±0.2°、22.6726±0.2°、14.7930±0.2°、29.4042±0.2°和15.8036±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图10所示；
    (2)所述的式I化合物的盐酸盐晶型C，其差示扫描热图和热重分析图基本如图11所 示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的磷酸盐晶型A时，所述的式I化合物的磷酸盐晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的磷酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：20.4385±0.2°、14.9572±0.2°、16.8423±0.2°、5.2374±0.2°和31.8376±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图13所示；
    (2)所述的式I化合物的磷酸盐晶型A，其差示扫描热图和热重分析图基本如图14所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的富马酸盐晶型A时，所述的式I化合物的富马酸盐晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的富马酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：25.7497±0.2°、27.5661±0.2°和28.4676±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图16所示；
    (2)所述的式I化合物的富马酸盐晶型A，其差示扫描热图和热重分析图基本如图17所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的1，5-萘二磺酸盐晶型A时，所述的式I化合物的1，5-萘二磺酸盐晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的1，5-萘二磺酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：15.6086±0.2°、19.5194±0.2°、12.9255±0.2°、26.2933±0.2°和27.8190±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图19所示；
    (2)所述的式I化合物的1，5-萘二磺酸盐晶型A，其差示扫描热图和热重分析图基本如图20所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的1，5-萘二磺酸盐晶型B时，所述的式I化合物的1，5-萘二磺酸盐晶型B满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的1，5-萘二磺酸盐晶型B，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：18.9746±0.2°、5.0796±0.2°、 25.1466±0.2°、23.3711±0.2°、27.3657±0.2°和32.3061±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图22所示；
    (2)所述的式I化合物的1，5-萘二磺酸盐晶型B，其差示扫描量热图和热重分析图基本如图23所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的对甲苯磺酸盐晶型A时，所述的式I化合物的对甲苯磺酸盐晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的对甲苯磺酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：12.2243±0.2°、25.3151±0.2°、9.5171±0.2°、23.7569±0.2°、29.9444±0.2°和28.8866±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图25所示；
    (2)所述的式I化合物的对甲苯磺酸盐晶型A，其差示扫描热图和热重分析图基本如图26所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的氢溴酸盐晶型A时，所述的式I化合物的氢溴酸盐晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的氢溴酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，还在如下2θ角度处有衍射峰：25.5412±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图28所示；
    (2)所述的式I化合物的氢溴酸盐晶型A，其差示扫描热图和热重分析图基本如图29所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型A时，所述的式I化合物的马来酸盐晶型A满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的马来酸盐晶型A，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：15.0805±0.2°、23.0488±0.2°和11.6637±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图31所示；
    (2)所述的式I化合物的马来酸盐晶型A，其差示扫描热图和热重分析图基本如图32所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型E时， 所述的式I化合物的马来酸盐晶型E满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的马来酸盐晶型E，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：28.9010±0.2°、15.5372±0.2°、16.2816±0.2°、10.1536±0.2°、26.7355±0.2°和12.1903±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图34所示；
    (2)所述的式I化合物的马来酸盐晶型E，其差示扫描热图和热重分析图基本如图35所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型F时，所述的式I化合物的马来酸盐晶型F满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的马来酸盐晶型F，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：9.9869±0.2°、19.9375±0.2°、23.2431±0.2°、22.4598±0.2°、22.7746±0.2°和24.7937±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图37所示；
    (2)所述的式I化合物的马来酸盐晶型F，其差示扫描热图和热重分析图基本如图38所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型H时，所述的式I化合物的马来酸盐晶型H满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的马来酸盐晶型H，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：15.9640±0.2°、8.9876±0.2°、27.2853±0.2°、19.2049±0.2°、23.2406±0.2°和28.2446±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图40所示；
    (2)所述的式I化合物的马来酸盐晶型H，其差示扫描热图和热重分析图基本如图41所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型I时，所述的式I化合物的马来酸盐晶型I满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的马来酸盐晶型I，其以2θ角度表示的X-射线粉末衍射图，还在如下一个或多个2θ角度处有衍射峰：17.4174±0.2°、11.3412±0.2°、23.4711±0.2°、27.0913±0.2°、20.1842±0.2°和6.0958±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图 基本如图43所示；
    (2)所述的式I化合物的马来酸盐晶型I，其差示扫描热图和热重分析图基本如图44所示；
    或，
    当所述的式I化合物的药学上可接受的盐的晶型为式I化合物的马来酸盐晶型J时，所述的式I化合物的马来酸盐晶型J满足如下(1)和/或(2)的条件：
    (1)所述的式I化合物的马来酸盐晶型J，其以2θ角度表示的X-射线粉末衍射图，进一步还在如下一个或多个2θ角度处有衍射峰：20.4902±0.2°、29.5595±0.2°、28.3910±0.2°、12.7045±0.2°、20.9226±0.2°和13.7795±0.2°；优选，其以2θ角度表示的X-射线粉末衍射图基本如图46所示；
    (2)所述的式I化合物的马来酸盐晶型J，其差示扫描热图和热重分析图基本如图47所示。
  10. 一种如权利要求7-9中任一项所述的式I化合物的药学上可接受的盐的晶型的制备方法，其特征在于，其为所述的式I化合物的马来酸盐晶型A的制备方法、所述的式I化合物的马来酸盐晶型E的制备方法、所述的式I化合物的马来酸盐晶型F的制备方法或所述的式I化合物的硫酸盐晶型H的制备方法；其中，
    所述的式I化合物的马来酸盐晶型A的制备方法，其包括如下步骤：在10-70℃下，将所述的式I化合物与马来酸在溶剂中进行析晶，得到式I化合物的马来酸盐晶型A；
    所述的式I化合物的马来酸盐晶型E的制备方法，其包括如下步骤：在10-30℃下，将所述的式I化合物马来酸盐晶型A样品在醚类溶剂中溶清后，将滤液置于反溶剂氛围下进行气液渗透，得到式I化合物的马来酸盐晶型E；
    所述式I化合物的马来酸晶型F的制备方法，其包括如下步骤：在10-30℃下，将式I化合物的马来酸盐晶型A样品在溶剂中形成悬浊液进行析晶，得到式I化合物的马来酸盐晶型F；
    所述式I化合物的马来酸晶型H的制备方法，其包括如下步骤：在10-30℃下，将所述的式I化合物的马来酸盐晶型A样品在醚类溶剂中溶清后，将滤液置于反溶剂氛围下进行气液渗透得到。
  11. 如权利要求10所述的式I化合物的药学上可接受的盐的晶型的制备方法，其特征在于，
    当所述的晶型的制备方法为所述的式I化合物的马来酸盐晶型A的制备方法时，所述的溶剂为酮类溶剂和/或酯类溶剂；所述的酮类溶剂优选丙酮、2-丁酮、甲基异丁酮、 N-甲基吡咯烷酮；所述的酯类溶剂优选乙酸乙酯；所述的酮类溶剂的质量体积比优选为30-50mg/mL，例如40mg/mL；所述的酯类溶剂的质量体积比优选为30-80mg/mL，例如34mg/mL或74mg/mL；
    或，当所述的晶型的制备方法为所述的式I化合物的马来酸盐晶型E的制备方法时，所述的醚类溶剂优选甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、1，4-二氧六环、苯甲醚；所述的反溶剂优选烷基类溶剂，优选为正己烷、正庚烷；
    或，当所述的晶型的制备方法为所述的式I化合物的马来酸盐晶型F的制备方法时，所述的溶剂优选为醚类溶剂或醚类溶剂和水的混合溶剂，优选为醚类溶剂和水的混合溶剂，所述的醚类溶剂优选四氢呋喃，2-甲基四氢呋喃；所述的醚类溶剂和水的混合溶剂的质量体积比优选为30-50mg/mL，例如40mg/mL；所述醚类溶剂和水的体积比(v/v)优选为10-25∶1，例如22∶1；
    或，当所述的晶型的制备方法为所述的式I化合物的马来酸盐晶型H的制备方法时，所述的醚类溶剂优选甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、1，4-二氧六环、苯甲醚；所述的反溶剂优选醚类溶剂，优选为甲基叔丁基醚。
  12. 一种药物组合物，其包含治疗有效剂量的物质A以及药学上可接受的载体、稀释剂或赋形剂；所述的物质A为如权利要求1-3中任一项所述的式I化合物的晶型、如权利要求4-6任一项所述的式I化合物的药学上可接受的盐或如权利要求7-9中任一项所述的式I化合物的药学上可接受的盐的晶型。
  13. 一种物质B在制备预防和/或治疗疾病或病症的药物或BTK抑制剂中的用途，所述的物质B为如权利要求1-3中任一项所述的式I化合物的晶型、如权利要求4-6任一项所述的式I化合物的药学上可接受的盐、如权利要求7-9中任一项所述的式I化合物的药学上可接受的盐的晶型或如权利要求12所述的药物组合物；
    优选地，所述疾病或病症选自：异种免疫疾病、自身免疫疾病、炎性疾病、癌症。
PCT/CN2023/081427 2022-03-15 2023-03-14 Btk抑制剂的晶型及其酸式盐和其酸式盐的晶型 WO2023174300A1 (zh)

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WO2022063101A1 (zh) * 2020-09-23 2022-03-31 劲方医药科技(上海)有限公司 芳甲酰取代的三环化合物及其制法和用途

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