CN116768896A - Crystal forms of BTK inhibitor, acid salt thereof and crystal forms of acid salt thereof - Google Patents

Abstract

The application discloses a crystal form of a BTK inhibitor, an acid salt thereof and a crystal form of the acid salt thereof. The crystal forms of the compound of the formula I are a compound free base crystal form A of the formula I, a compound free base crystal form C of the formula I, a compound free base D of the formula I or a compound free base crystal form E of the formula I. The crystal forms of the BTK inhibitor, the acid salt thereof and the crystal forms of the acid salt thereof have the advantages of low hygroscopicity and good stability, and are very important for drug developmentMeaning of interest.

Description

Crystal form of BTK inhibitor and its acid salt and crystal form of its acid salt

This application claims the priority of Chinese patent application No. 202210256052X, filed on March 15, 2022. This application cites the entire text of the above Chinese patent application.

Technical Field

The present invention relates to the field of medical technology, and in particular to a BTK inhibitor crystal form and an acid salt thereof and a crystal form of the acid salt thereof.

Background Art

Bruton's tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine kinases and a key kinase in the B cell antigen receptor (BCR) signaling pathway. Signals sent through the BCR control a series of effector responses, including the activation, proliferation and differentiation of cells that produce mature antibodies. Abnormal BCR-mediated signal transduction 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 heteroimmune diseases. Ibrutinib (trade name Imbmvica) has achieved great success as the first BTK inhibitor to enter the market. However, like many other anticancer drugs, some patients show drug resistance. Studies have found that the C481S mutation of BTK kinase is the main cause of drug resistance. Ibrutinib exerts its pharmacodynamic effect by irreversibly covalently binding to the C481 tryptophan residue of BTK kinase. The C481S mutation converts tryptophan into serine, thereby losing the ability to covalently bind to ibrutinib. Against the above background, the field still needs to develop more efficient inhibitors against BTK.

The crystal structure of active drug ingredients often causes differences in the drug's various physical and chemical properties, such as solubility, dissolution rate, melting point, density, hardness, etc. These differences directly affect the drug's prescription preparation process, storage method, in vivo pharmacokinetic performance, and further affect the drug's bioavailability, clinical efficacy and safety. Therefore, it is of great significance to conduct in-depth research on the polymorphic phenomenon of drugs and find crystal forms with good properties.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the defect that there are few types of BTK inhibitors in the prior art. To this end, a BTK inhibitor crystal form and its acid salt and its acid salt crystal form are provided. The BTK inhibitor crystal form and its acid salt and its acid salt crystal form of the present invention meet the requirements of pharmaceutical use in terms of stability, hygroscopicity, etc., and are of great significance for drug development.

In a first aspect, the present invention provides a free base crystalline form A of a compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles with diffraction peaks at 7.3574±0.2°, 20.0853±0.2°, 26.2299±0.2° and 15.0639±0.2°;

In a preferred embodiment, the free base form A of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 22.5403±0.2°, 10.0156±0.2°, 6.4788±0.2°, 10.8671±0.2° and 19.5949±0.2°.

Preferably, the free base form A of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ angles: 12.0106±0.2°, 25.1097±0.2°, 18.0778±0.2° and 30.3217±0.2°.

In a preferred embodiment, the free base form A of the compound of formula I has an X-ray powder diffraction pattern expressed at 2θ angles as shown in Figure 1.

In a preferred embodiment, the free base form A of the compound of formula I has a thermogravimetric analysis (TGA) diagram in which the weight loss is 2.0%-3.5% (e.g., 3.1%) when initially heated to 200±5°C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the free base form A of the compound of formula I has an endothermic peak at 327.4±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the free base form A of the compound of formula I are substantially as shown in FIG2 .

The second aspect of the present invention further provides a free base crystalline form C of the compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 4.9395±0.2°, 28.0724±0.2°, 11.4647±0.2° and 13.2030±0.2°;

In a preferred embodiment, the free base form C of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 17.2058±0.2°, 14.7891±0.2°, 20.1466±0.2°, 24.5916±0.2° and 21.4712±0.2°.

Preferably, the free base form C of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the free base form C of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles as shown in Figure 49.

In a preferred embodiment, the free base form C of the compound of formula I has a thermogravimetric analysis diagram showing a weight loss of 1%-3% (e.g., 2.7%) when initially heated to 200±5°C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the free base form C of the compound of formula I has an endothermic peak at 329.3±5°C in its differential scanning calorimetry diagram; and/or, an exothermic peak at 311.3±5°C.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the free base form C of the compound of formula I are substantially as shown in FIG. 50 .

The third aspect of the present invention provides a free base crystalline form D of the compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 4.8447±0.2°, 19.3873±0.2°, 12.0794±0.2° and 14.2457±0.2°;

In a preferred embodiment, the free base form D of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 4.3851±0.2°, 15.7673±0.2°, 22.1929±0.2°, 17.9985±0.2° and 24.8383±0.2°.

Preferably, the free base form D of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the X-ray powder diffraction pattern of the free base form D of the compound of formula I expressed in 2θ angles is substantially as shown in Figure 52.

In a preferred embodiment, the free base form D of the compound of formula I has a thermogravimetric analysis chart showing a weight loss of 3%-5% (e.g., 4.1%) when initially heated to 150±5°C, and a weight loss of 6%-8% (e.g., 7.1%) when heated from 150±5°C to 230±5°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the free base 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 diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the free base form D of the compound of formula I are basically as shown in Figure 53.

In a fourth aspect, the present invention provides a free base crystalline form E of the compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles with diffraction peaks at 5.3081±0.2°, 4.9506±0.2°, 20.9925±0.2° and 19.0379±0.2°;

In a preferred embodiment, the free base form E of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 21.2501±0.2°, 17.2819±0.2°, 10.4721±0.2°, 23.0960±0.2° and 28.0729±0.2°.

Preferably, the free base form E of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the X-ray powder diffraction pattern of the free base form E of the compound of formula I expressed in 2θ angles is substantially as shown in Figure 55.

In a preferred embodiment, the free base form E of the compound of formula I has a thermogravimetric analysis chart showing a weight loss of 1%-3% (e.g., 1.8%) when initially heated to 80±5°C, and a weight loss of 16%-18% (e.g., 16.8%) when heated from 80±5°C to 180±5°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the free base crystalline 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 diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the free base 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 the compound of formula I and an acid; the acid is an inorganic acid or an organic acid;

In a preferred embodiment, the molar ratio of the compound of formula I to the acid is 1:(0.5-2), for example 1:0.6, 1:0.7, 1:0.9, 1:1, 1:1.1, 1:1.3 or 1:2.

In a preferred embodiment, the inorganic acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid.

Preferably, the inorganic acid is one or more of hydrochloric acid, phosphoric acid and hydrobromic acid.

In a preferred embodiment, the organic acid is one or more of maleic acid, L-aspartic acid, fumaric acid, L-tartaric acid, citric acid, 1,5-naphthalene disulfonic acid, 1,2-ethane disulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid and malonic acid.

Preferably, the organic acid is one or more of maleic acid, fumaric acid, 1,5-naphthalene disulfonic acid, and p-toluenesulfonic acid.

More preferably, the organic acid is one or more of maleic acid, fumaric acid and p-toluenesulfonic acid.

More preferably, the organic acid is maleic acid.

In a preferred embodiment, the pharmaceutically acceptable salt of the compound of formula I is any of the following pharmaceutically acceptable salts:

(1) The hydrochloride salt 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);

(2) Phosphate salts of the compound of formula I; wherein the molar ratio of the compound of formula I to phosphoric acid is 1:(1-2), for example 1:(1-1.3);

(3) a hydrobromide salt of a compound of formula I; wherein the molar ratio of the compound of formula I to hydrobromic acid is 1:(0.5-1), for example 1:0.9;

(4) a fumarate salt of the compound of formula I; wherein the molar ratio of the compound of formula I to fumaric acid is 1:1;

(5) 1,5-naphthalene disulfonic acid salt of the compound of formula I; wherein the molar ratio of the compound of formula I to 1,5-naphthalene disulfonic acid is 1:(0.5-1), for example 1:0.7;

(6) p-toluenesulfonate of the compound of formula I; wherein the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1;

(7) A 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 pharmaceutically acceptable salt of the compound of formula I can be prepared by a conventional salt-forming reaction in the art. For example, the pharmaceutically acceptable salt of the compound of formula I can be prepared by the following method:

The compound of formula I is reacted with an acid in a solvent to form a salt to obtain a pharmaceutically acceptable salt of the compound of formula I;

Wherein, when the acid is hydrochloric acid, the molar ratio of the compound of formula I to hydrochloric acid is 1:(0.5-2.5), for example 1:(1-2), and for example 1:2;

When the acid is phosphoric acid, the molar ratio of the compound of formula I to phosphoric acid is 1:(0.5-2), for example 1:(0.5-1.5), and for example 1:1;

When the acid is hydrobromic acid, the molar ratio of the compound of formula I to hydrobromic acid is 1:(0.5-2), for example 1:(0.5-1.5), and for example 1:1;

When the acid is fumaric acid, the molar ratio of the compound of formula I to fumaric acid is 1:(0.5-2), for example 1:(0.5-1.5), and for example 1:1;

When the acid is 1,5-naphthalene disulfonic acid, the molar ratio of the compound of formula I to 1,5-naphthalene disulfonic acid is 1:(0.5-2), for example 1:(0.5-1.5), and for example 1:1;

When the acid is p-toluenesulfonic acid, the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:(0.5-2), for example 1:(0.5-1.5), and for example 1:1;

When the acid is maleic acid, the molar ratio of the compound of formula I to maleic acid is 1:(0.5-2), for example 1:(0.5-1.5), and for example 1:1.

In a sixth aspect, the present invention provides a crystalline form A of a hydrochloride of a compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 13.2577±0.2°, 19.0205±0.2°, 26.6619±0.2° and 24.4646±0.2°; the hydrochloride of the compound of formula I is as described above;

In a preferred embodiment, the hydrochloride salt of the compound of formula I is in form A; wherein the molar ratio of the compound of formula I to hydrochloric acid is 1:1.

In a preferred embodiment, the crystalline form A of the hydrochloride salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 25.4625±0.2°, 25.7474±0.2°, 14.8470±0.2°, 10.5627±0.2° and 25.0104±0.2°.

Preferably, the crystalline form A of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the X-ray powder diffraction pattern of the hydrochloride form A of the compound of formula I expressed at 2θ angle is substantially as shown in FIG. 4 .

In a preferred embodiment, the thermogravimetric analysis diagram of Form A of the hydrochloride salt of the compound of Formula I shows a weight loss of 6%-8% (e.g., 7.1%) when initially heated to 110±5°C, and a weight loss of 7%-9% (e.g., 7.9%) when heated from 110±5°C to 200±5°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the hydrochloride form A of the compound of formula I has endothermic peaks at 115.4±5°C and 185.0±5°C in its differential scanning calorimetry diagram; and/or, an exothermic peak at 218.3°C±5°C.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the hydrochloride form A of the compound of formula I are substantially as shown in FIG5 .

In a seventh aspect, the present invention provides a crystalline form B of a hydrochloride of a compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 11.2971±0.2°, 4.1094±0.2°, 16.0047±0.2° and 18.5553±0.2°; the hydrochloride of the compound of formula I is as described above;

In a preferred embodiment, the hydrochloride salt of the compound of formula I is in form B; wherein the molar ratio of the compound of formula I to hydrochloric acid is 1:1.

In a preferred embodiment, the Form B of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 27.3296±0.2°, 17.6049±0.2°, 27.5618±0.2°, 26.3637±0.2° and 25.6428±0.2°.

Preferably, the crystalline form B of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the X-ray powder diffraction pattern of Form B of the hydrochloride salt of the compound of Formula I expressed at 2θ angle is substantially as shown in FIG. 7 .

In a preferred embodiment, the thermogravimetric analysis of Form B of the hydrochloride salt of the compound of Formula I shows a weight loss of 4%-6% (e.g., 4.8%) when initially heated to 150±5°C, and a weight loss of 6.5%-8.5% (e.g., 7.6%) when heated from 150±5°C to 230±5°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the hydrochloride form B of the compound of formula I has an endothermic peak at 223.0±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of Form B of the hydrochloride salt of the compound of Formula I are substantially as shown in FIG8 .

In an eighth aspect, the present invention provides a crystalline form C of a hydrochloride of a compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 21.5443±0.2°, 27.3605±0.2°, 10.0792±0.2° and 18.8112±0.2°; the hydrochloride of the compound of formula I is as described above;

In a preferred embodiment, the hydrochloride salt of the compound of formula I is in 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.

In a preferred embodiment, the Form C of the hydrochloride salt of the compound of Formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 14.1629±0.2°, 8.5449±0.2°, 26.7582±0.2°, 6.8670±0.2° and 17.2037±0.2°.

Preferably, the crystalline form C of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the X-ray powder diffraction pattern of Form C of the hydrochloride salt of the compound of Formula I expressed at 2θ angle is substantially as shown in FIG. 10 .

In a preferred embodiment, the thermogravimetric analysis diagram of Form C of the hydrochloride salt of the compound of Formula I shows a weight loss of 1.5%-3% (e.g., 2.2%) at 150±5°C, and a weight loss of 6.5%-8.5% (e.g., 7.5%) at 150°C to 250°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before the weight loss).

In a preferred embodiment, the hydrochloride salt of the compound of formula I, in form C, has an endothermic peak at 248.2±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of Form C of the hydrochloride salt of the compound of Formula I are substantially as shown in FIG. 11 .

In a ninth aspect, the present invention provides a crystalline form A of the phosphate of the compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 12.8284±0.2°, 21.1193±0.2°, 22.7554±0.2° and 12.4119±0.2°; the phosphate of the compound of formula I is as described above;

In a preferred embodiment, the phosphate salt of the compound of formula I is in form A; wherein the molar ratio of the compound of formula I to phosphoric acid is 1:(1-2), for example 1:1.3.

In a preferred embodiment, the crystalline form A of the phosphate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 24.1820±0.2°, 19.6004±0.2°, 24.9449±0.2°, 17.7015±0.2° and 25.7812±0.2°.

Preferably, the crystalline form A of the phosphate of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 20.4385±0.2°, 14.9572±0.2°, 16.8423±0.2°, 5.2374±0.2° and 31.8376±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of Form A of the phosphate of the compound of Formula I expressed at 2θ angle is substantially as shown in FIG. 13 .

In a preferred embodiment, the thermogravimetric analysis diagram of the crystalline form A of the phosphate salt of the compound of formula I shows a weight loss of 1%-3% (e.g., 2.1%) when initially heated to 65±5°C, and a weight loss of 2%-4% (e.g., 2.8%) when heated from 65±5°C to 125±5°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the crystalline form A of the phosphate of the compound of formula I has endothermic peaks at one or more of 81.7±5°C, 92.1±5°C and 139.2±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the crystalline form A of the phosphate salt of the compound of formula I are substantially as shown in FIG. 14 .

In a tenth aspect, the present invention provides a crystalline form A of a fumarate salt of the compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 5.1732±0.2°, 7.9252±0.2°, 10.2736±0.2° and 18.8307±0.2°; the fumarate salt of the compound of formula I is as described above;

In a preferred embodiment, the fumarate salt of the compound of formula I is in form A; wherein the molar ratio of the compound of formula I to fumaric acid is 1:1.

In a preferred embodiment, the crystalline form A of the fumarate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 24.8824±0.2°, 12.0866±0.2°, 15.4296±0.2°, 23.9878±0.2° and 13.0765±0.2°.

Preferably, the crystalline form A of the fumarate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ angles: 25.7497±0.2°, 27.5661±0.2° and 28.4676±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of the crystalline form A of the fumarate salt of the compound of formula I expressed at 2θ angle is substantially as shown in FIG. 16 .

In a preferred embodiment, the thermogravimetric analysis diagram of the crystalline form A of the fumarate salt of the compound of formula I shows a weight loss of 2%-4% (e.g., 2.6%) when initially heated to 150±5°C, and a weight loss of 19%-22% (e.g., 21.2%) when heated from 150±5°C to 240±5°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, 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 diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the crystalline form A of the fumarate salt of the compound of formula I are substantially as shown in FIG. 17 .

In an eleventh aspect of the present invention, there is provided a crystalline form A of the 1,5-naphthalene disulfonate of the compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 7.7555±0.2°, 9.6043±0.2°, 23.0949±0.2° and 17.5044±0.2°; the 1,5-naphthalene disulfonate of the compound of formula I is as described above;

In a preferred embodiment, the crystalline form A of the 1,5-naphthalene disulfonate of the compound of formula I; wherein the molar ratio of the compound of formula I to methanesulfonic acid is 1:(0.5-1), for example 1:0.7.

In a preferred embodiment, the crystalline form A of the 1,5-naphthalene disulfonate of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 20.2234±0.2°, 22.5424±0.2°, 16.5111±0.2°, 24.1101±0.2° and 11.2117±0.2°.

Preferably, the crystalline form A of the 1,5-naphthalene disulfonate of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ angles: 15.6086±0.2°, 19.5194±0.2°, 12.9255±0.2°, 26.2933±0.2° and 27.8190±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of Form A of the 1,5-naphthalene disulfonate salt of the compound of Formula I expressed at 2θ angle is substantially as shown in FIG. 19 .

In a preferred embodiment, the thermogravimetric analysis of the crystalline form A of the 1,5-naphthalene disulfonate of the compound of formula I shows a weight loss of 2.5%-4.5% (e.g., 3.5%) when initially heated to 130±5°C, and a weight loss of 1.5%-3.5% (e.g., 2.6%) when heated from 130±5°C to 175±5°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the crystalline form A of the 1,5-naphthalene disulfonate of the compound of formula I has endothermic peaks at one or more of 57.7±5°C, 82.9±5°C, 166.9±5°C and 211.1±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the crystalline form A of the 1,5-naphthalene disulfonate of the compound of formula I are substantially as shown in FIG. 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, which has diffraction peaks at 15.0980±0.2°, 20.3818±0.2°, 13.6481±0.2° and 24.7069±0.2° in an X-ray powder diffraction pattern expressed in 2θ angles;

In a preferred embodiment, the crystalline form B of the 1,5-naphthalene disulfonate of the compound of formula I; wherein the molar ratio of the compound of formula I to methanesulfonic acid is 1:(0.5-1), for example 1:0.7.

In a preferred embodiment, the crystalline form B of the 1,5-naphthalene disulfonate of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 15.8095±0.2°, 10.8634±0.2°, 16.7992±0.2°, 26.2961±0.2° and 12.3107±0.2°.

Preferably, the crystalline form B of the 1,5-naphthalene disulfonate of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the X-ray powder diffraction pattern of Form B of the 1,5-naphthalene disulfonate salt of the compound of Formula I expressed at 2θ angle is substantially as shown in FIG. 22 .

In a preferred embodiment, the crystalline form B of the 1,5-naphthalene disulfonate of the compound of formula I has a thermogravimetric analysis diagram showing a weight loss of 3.5%-5.5% (e.g. 4.3%) when initially heated to 200±5°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the crystalline form B of the 1,5-naphthalene disulfonate of the compound of formula I has endothermic peaks at one or more of 57.0±5°C, 82.5±5°C and 276.1±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry diagram and thermogravimetric analysis diagram of Form B of the 1,5-naphthalene disulfonate salt of the compound of Formula I are substantially as shown in FIG. 23 .

In a thirteenth aspect, the present invention provides a crystalline form A of a p-toluenesulfonate salt of the compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 4.0699±0.2°, 20.3148±0.2°, 14.9056±0.2° and 18.3888±0.2°; the p-toluenesulfonate salt of the compound of formula I is as described above;

In a preferred embodiment, the crystalline form A of the p-toluenesulfonate of the compound of formula I; wherein the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1.

In a preferred embodiment, the crystalline form A of the p-toluenesulfonate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 22.0879±0.2°, 25.9320±0.2°, 11.8243±0.2°, 17.2270±0.2° and 24.5224±0.2°.

Preferably, the crystalline form A of the p-toluenesulfonate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the X-ray powder diffraction pattern of Form A of the p-toluenesulfonate salt of the compound of Formula I expressed at 2θ angle is substantially as shown in FIG. 25 .

In a preferred embodiment, the thermogravimetric analysis diagram of the crystalline form A of the p-toluenesulfonate salt of the compound of formula I shows that when initially heated to 75±5°C, the sample loses 3.5%-5.5% (e.g., 4.3%) weight, and when heated from 75±5°C to 120±5°C, the sample loses 5%-7% (e.g., 6.1%) weight (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the crystalline form A of the p-toluenesulfonate of the compound of formula I has an endothermic peak at 111.1±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the crystalline form A of the p-toluenesulfonate salt of the compound of formula I are substantially as shown in FIG. 26 .

In a fourteenth aspect, the present invention provides a crystalline form A of a hydrobromide salt of a compound of formula I, wherein the X-ray powder diffraction pattern expressed in 2θ angles has diffraction peaks at 4.1403±0.2°, 11.1940±0.2°, 27.3198±0.2° and 17.4698±0.2°; the hydrobromide salt of the compound of formula I is as described above;

In a preferred embodiment, the hydrobromide salt of the compound of formula I is in 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.

In a preferred embodiment, the crystalline form A of the hydrobromide salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 20.6495±0.2°, 8.7348±0.2°, 18.5192±0.2°, 16.0192±0.2° and 19.6807±0.2°.

In a preferred embodiment, the crystalline form A of the hydrobromide salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and also has a diffraction peak at the following 2θ angle: 25.5412±0.2°.

In a preferred embodiment, the X-ray powder diffraction pattern of Form A of the hydrobromide salt of the compound of Formula I expressed at 2θ angles is substantially as shown in FIG. 28 .

In a preferred embodiment, the thermogravimetric analysis diagram of the crystalline form A of the hydrobromide salt of the compound of formula I shows a weight loss of 4.5%-6.5% (e.g. 5.6%) when initially heated to 200±5°C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the crystalline form A of the hydrobromide salt of the compound of formula I has an endothermic peak at one or more of 97.7±5°C, 179.4±5°C, 230.7±5°C and 254.9±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the crystalline form A of the hydrobromide salt of the compound of formula I are substantially as shown in FIG. 29 .

In a fifteenth aspect, the present invention provides a crystalline form A of a maleate salt of a compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 4.4590±0.2°, 10.0991±0.2°, 13.6435±0.2° and 20.6462±0.2°; the maleate salt of the compound of formula I is as described above;

In a preferred embodiment, the maleate salt of the compound of formula I is in form A, wherein the molar ratio of the compound of formula I to maleic acid is 1:1.

In a preferred embodiment, the crystalline form A of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 25.9433±0.2°, 17.3036±0.2°, 26.3520±0.2°, 18.2594±0.2° and 17.8271±0.2°.

Preferably, the crystalline form A of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ angles: 15.0805±0.2°, 23.0488±0.2° and 11.6637±0.2°.

In a preferred embodiment, the crystalline form A of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at 2θ angles as shown in Figure 31.

In a preferred embodiment, the thermogravimetric analysis of the crystalline form A of the maleate salt of the compound of formula I shows a weight loss of 2.5%-3.5% (e.g., 2.8%) when initially heated to 150±5°C, and a weight loss of 19%-21% (e.g., 19.3%) when heated from 150°C to 230°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the maleate salt of the compound of formula I, in form A, has an endothermic peak at 200.3±20° C. in its differential scanning calorimetry diagram.

In a preferred embodiment, the maleate salt of the compound of formula I, in form A, has an endothermic peak at 200.3±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of Form A of the maleate salt of the compound of Formula I are substantially as shown in FIG. 32 .

In a sixteenth aspect, the present invention provides a crystalline form E of a maleate salt of a compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 4.4072±0.2°, 13.3026±0.2°, 27.4367±0.2° and 21.9948±0.2°; the maleate salt of the compound of formula I is as described above;

In a preferred embodiment, the maleate salt of the compound of formula I is in form E, wherein the molar ratio of the compound of formula I to maleic acid is 1:1.

In a preferred embodiment, the crystalline form E of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 20.1322±0.2°, 18.1840±0.2°, 12.8549±0.2°, 22.7709±0.2° and 13.6555±0.2°.

Preferably, the crystalline form E of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the crystalline form E of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at 2θ angles as shown in Figure 34.

In a preferred embodiment, the thermogravimetric analysis of the crystalline form E of the maleate salt of the compound of formula I shows a weight loss of 2.5%-4.5% (e.g., 3.4%) when initially heated to 150±5°C, and a weight loss of 19%-21% (e.g., 19.7%) when heated from 150°C to 250°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the maleate salt of the compound of formula I, in form E, has an endothermic peak at 194.2±5° C. in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of Form E of the maleate salt of the compound of Formula I are substantially as shown in FIG. 35 .

In a seventeenth aspect, the present invention provides a crystalline form F of a maleate salt of a compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 10.9668±0.2°, 7.8002±0.2°, 6.1349±0.2° and 12.3076±0.2°; the maleate salt of the compound of formula I is as described above;

In a preferred embodiment, the maleate salt of the compound of formula I is in form F, wherein the molar ratio of the compound of formula I to maleic acid is 1:1.

In a preferred embodiment, the crystalline form F of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 17.6068±0.2°, 16.7364±0.2°, 25.6746±0.2°, 23.5852±0.2° and 20.2850±0.2°.

Preferably, the crystalline form F of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the crystalline form F of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at 2θ angles as shown in Figure 37.

In a preferred embodiment, the thermogravimetric analysis of the crystalline form F of the maleate salt of the compound of formula I shows a weight loss of 2%-4% (e.g., 2.9%) when initially heated to 150±5°C, and a weight loss of 17.5%-19.5% (e.g., 18.7%) when heated from 150°C to 250°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the maleate salt of the compound of formula I, in its crystalline form F, has endothermic peaks at one or more of 65.3±5°C, 81.7±5°C and 180.8±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of Form F of the maleate salt of the compound of Formula I are substantially as shown in FIG. 38 .

In an eighteenth aspect, the present invention provides a crystalline form H of a maleate salt of a compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 4.5619±0.2°, 13.5614±0.2°, 13.0298±0.2° and 10.2862±0.2°; the maleate salt of the compound of formula I is as described above;

In a preferred embodiment, the maleate salt of the compound of formula I is in form H, wherein the molar ratio of the compound of formula I to maleic acid is 1:1.

In a preferred embodiment, the crystalline form H of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 18.3628±0.2°, 25.9556±0.2°, 26.6709±0.2°, 20.7641±0.2° and 12.4688±0.2°.

Preferably, the crystalline form H of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the crystalline form H of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed at 2θ angles as shown in Figure 40.

In a preferred embodiment, the thermogravimetric analysis of the maleate salt of the compound of formula I, Form H, shows a weight loss of 1%-2% (e.g., 1.4%) when initially heated to 150±5°C, and a weight loss of 16.5%-18.5% (e.g., 17.4%) when heated from 150°C to 250°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before the weight loss).

In a preferred embodiment, the maleate salt of the compound of formula I in crystalline form H has an endothermic peak at 188.6±5°C in its differential scanning calorimetry diagram.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of the maleate salt of the compound of formula I in form H are substantially as shown in FIG. 41 .

In a nineteenth aspect, the present invention provides a crystalline form I of a maleate salt of a compound of formula I, wherein the X-ray powder diffraction pattern expressed in 2θ angles has diffraction peaks at 5.4040±0.2°, 9.4028±0.2°, 10.4407±0.2° and 8.8892±0.2°; the maleate salt of the compound of formula I is as described above;

In a preferred embodiment, the maleate salt of the compound of formula I is in form I, wherein the molar ratio of the compound of formula I to maleic acid is 1:1.

In a preferred embodiment, the crystalline form I of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 12.6630±0.2°, 25.4555±0.2°, 13.6954±0.2°, 15.5008±0.2° and 17.6958±0.2°.

Preferably, the crystalline form I of the maleate salt of the compound of formula I, whose X-ray powder diffraction pattern expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the X-ray powder diffraction pattern of Form I of the maleate salt of the compound of Formula I expressed at 2θ angles is substantially as shown in Figure 43.

In a preferred embodiment, the thermogravimetric analysis diagram of the crystalline form I of the maleate salt of the compound of formula I has a weight loss of 2.5%-4.5% (e.g., 3.5%) when heated to 130±5°C, and the weight loss of the sample when heated from 130°C to 250°C is 19%-21% (e.g., 20.2%) (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the crystalline 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 diagram; and/or, an exothermic peak at 161.5±5°C.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of Form I of the maleate salt of the compound of Formula I are substantially as shown in FIG. 44 .

The twentieth aspect of the present invention provides a crystalline form J of a maleate salt of a compound of formula I, which has an X-ray powder diffraction pattern expressed in 2θ angles at 5.4594±0.2°, 25.5787±0.2°, 17.8675±0.2° and 10.5280±0.2°; the maleate salt of the compound of formula I is as described above;

In a preferred embodiment, the maleate salt of the compound of formula I is in form J, wherein the molar ratio of the compound of formula I to maleic acid is 1:1.

In a preferred embodiment, the crystalline form J of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and has diffraction peaks at one or more of the following 2θ angles: 15.7099±0.2°, 27.1774±0.2°, 23.6955±0.2°, 9.4120±0.2° and 8.9158±0.2°;

Preferably, the crystalline form J of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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°.

In a preferred embodiment, the X-ray powder diffraction pattern of Form J of the maleate salt of the compound of Formula I expressed at 2θ angles is substantially as shown in Figure 46.

In a preferred embodiment, the crystalline form J of the maleate salt of the compound of formula I has a thermogravimetric analysis diagram showing a weight loss of 6%-7% (e.g., 6.4%) when initially heated to 150±5°C, and a weight loss of 19.5%-21.5% (e.g., 20.5%) when heated from 150°C to 250°C (the percentage of weight loss is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

In a preferred embodiment, the maleate salt of the compound of formula I, in Form J, has an endothermic peak at 193.7±5°C in its differential scanning calorimetry diagram; and/or, has an exothermic peak at 162.1±5°C.

In a preferred embodiment, the differential scanning calorimetry and thermogravimetric analysis diagram of Form J of the maleate salt of the compound of Formula I are substantially as shown in FIG. 47 .

The crystalline form of the BTK inhibitor of the present invention and the pharmaceutically acceptable salt thereof and the preparation method of the crystalline form of the pharmaceutically acceptable salt thereof can be obtained by many methods known in the art.

The twenty-first aspect of the present invention provides a method for preparing the crystalline form A of the maleate salt of the above-mentioned compound of formula I, which comprises the following steps: crystallizing the compound of formula I and maleic acid in a solvent at 10-70°C to obtain the crystalline 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-methyl pyrrolidone) and/or an ester solvent (preferably ethyl acetate).

The crystallization temperature is preferably 10-30°C or 50-60°C.

The mass volume ratio of the ketone solvent is preferably 30-50 mg/mL, such as 40 mg/mL;

The mass 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 performed under stirring (such as suspension stirring).

After the crystallization is completed, separation can be performed according to conventional operating methods in the art, such as centrifugation or filtration.

The twenty-second aspect of the present invention provides a crystalline form A of a maleate salt obtained by the method for preparing the crystalline form A of a maleate salt of a compound of formula I described above.

The twenty-third aspect of the present invention provides a method for preparing the crystalline form E of the maleate salt of the above-mentioned compound of formula I, which comprises the following steps: dissolving the crystalline form A sample of the maleate salt of the compound of formula I in an ether solvent at 10-30°C, placing the filtrate in an anti-solvent atmosphere for gas-liquid infiltration to obtain the crystalline form E of the maleate 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 an alkyl solvent, preferably n-hexane, n-heptane.

The twenty-fourth aspect of the present invention provides a crystalline form E of a maleate salt obtained by the method for preparing the crystalline form E of a maleate salt of the compound of formula I above.

The twenty-fifth aspect of the present invention provides a method for preparing the crystalline form F of the maleate salt of the compound of formula I mentioned above, which comprises the following steps: at 10-30°C, a sample of the crystalline form A of the maleate salt of the compound of formula I is suspended in a solvent for crystallization to obtain the crystalline 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, 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, such as 22:1.

The twenty-sixth aspect of the present invention provides a crystalline form F of a maleate salt prepared according to the method for preparing the crystalline form F of a maleate salt of a compound of formula I above.

The twenty-seventh aspect of the present invention provides a method for preparing the maleic acid crystalline form H of the compound of formula I, which comprises the following steps: dissolving the maleate crystalline form A sample of the compound of formula I in an ether solvent at 10-30°C, and placing the filtrate in an anti-solvent atmosphere for gas-liquid infiltration to obtain.

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 a maleate salt prepared according to the method for preparing the crystalline form H of a maleate salt of the compound of formula I above.

The twenty-ninth aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically effective dose of substance A and a pharmaceutically acceptable carrier, diluent or excipient; the substance A is a crystalline form of the above-mentioned compound of formula I (one or more of the above-mentioned free base crystalline form A of the above-mentioned compound of formula I, the above-mentioned free base crystalline form C of the above-mentioned compound of formula I, the above-mentioned free base crystalline form D of the above-mentioned compound of formula I and the above-mentioned free base crystalline form E of the above-mentioned compound of formula I), a pharmaceutically acceptable salt of the above-mentioned compound of formula I or a crystalline form of a pharmaceutically acceptable salt of the above-mentioned compound of formula I (the above-mentioned hydrochloride crystalline form A of the above-mentioned compound of formula I, the above-mentioned hydrochloride crystalline form B of the above-mentioned compound of formula I, The invention further comprises one or more of the following: hydrochloride form C, the phosphate form A of the above-mentioned compound of formula I, the fumarate form A of the above-mentioned compound of formula I, the 1,5-naphthalene disulfonate form A of the above-mentioned compound of formula I, the 1,5-naphthalene disulfonate form B of the above-mentioned compound of formula I, the p-toluenesulfonate form A of the above-mentioned compound of formula I, the hydrobromide form A of the above-mentioned compound of formula I, the maleate form A of the above-mentioned compound of formula I, the maleate form E of the above-mentioned compound of formula I, the maleate form F of the above-mentioned compound of formula I, the maleate form H of the above-mentioned compound of formula I, the maleate form I of the above-mentioned compound of formula I and the maleate form J of the above-mentioned compound of formula I).

The thirtieth aspect of the present invention provides a use of a substance B in the preparation of a drug for preventing and/or treating a disease or condition; the substance B is the above-mentioned pharmaceutical composition, the above-mentioned crystalline form of the compound of formula I (one or more of the above-mentioned free base crystalline form A of the compound of formula I, the above-mentioned free base crystalline form C of the compound of formula I, the above-mentioned free base crystalline form D of the compound of formula I and the above-mentioned free base crystalline form E of the compound of formula I), the above-mentioned pharmaceutically acceptable salt of the compound of formula I or the above-mentioned crystalline form of the pharmaceutically acceptable salt of the compound of formula I (the above-mentioned hydrochloride crystalline form A of the compound of formula I, the above-mentioned hydrochloride crystalline form B of the compound of formula I, the above-mentioned hydrochloride crystalline form One or more of the following: crystalline form C, the phosphate crystalline form A of the above-mentioned compound of formula I, the fumarate crystalline form A of the above-mentioned compound of formula I, the 1,5-naphthalene disulfonate crystalline form A of the above-mentioned compound of formula I, the 1,5-naphthalene disulfonate crystalline form B of the above-mentioned compound of formula I, the p-toluenesulfonate crystalline form A of the above-mentioned compound of formula I, the hydrobromide crystalline form A of the above-mentioned compound of formula I, the maleate crystalline form A of the above-mentioned compound of formula I, the maleate crystalline form E of the above-mentioned compound of formula I, the maleate crystalline form F of the above-mentioned compound of formula I, the maleate crystalline form H of the above-mentioned compound of formula I, the maleate crystalline form I of the above-mentioned compound of formula I and the maleate crystalline form J of the above-mentioned compound of formula I).

The disease or disorder is associated with BTK and/or is associated with abnormal B cell activation.

The dosage of substance B is an effective therapeutic dosage.

The thirty-first aspect of the present invention provides the use of the crystalline form of the compound of formula I and its acid salt and the crystalline form of its acid salt or the pharmaceutical composition in the preparation of BTK inhibitors.

In a preferred embodiment, the crystalline form of the compound of formula I and its acid salt and the crystalline form of its acid salt are present in a pharmaceutical composition or medicine in a therapeutically and/or preventively effective amount.

In a preferred embodiment, the disease or disorder is selected from the group consisting of heteroimmune diseases, autoimmune diseases, inflammatory diseases, and cancer.

In a preferred embodiment, the heterologous immune disease, autoimmune disease, inflammatory disease can be selected from the following group: rheumatic disease, glomerulonephritis, Goodpasture syndrome, atherosclerosis, autoimmune blood disease, autoimmune gastritis, autoimmune inflammatory bowel disease, irritable bowel syndrome, allogeneic transplant rejection, chronic thyroiditis, Graves' disease, Sjögren'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, uveitis, conjunctivitis, otitis media, periodontal disease, Parkinson's disease, Alzheimer's disease, septic shock, pulmonary fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis, chronic inflammatory lung disease and other inflammatory or obstructive diseases of the airways.

In a preferred embodiment, the cancer is leukemia or lymphoma.

In a preferred embodiment, the cancer can be selected from the following group: small lymphocytic lymphoma (SLL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, chronic myeloid 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's lymphoma.

Definitions and explanations of terms

All documents cited in the present invention are incorporated herein by reference in their entirety, and if the meanings expressed in these documents are inconsistent with the present invention, the description of the present invention shall prevail. In addition, the various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

The polymorphs of the compound of formula 1 of the present invention have characteristic X-ray powder diffraction peaks expressed in 2θ angles, wherein "±0.20°" is the allowable measurement error range.

The polymorphs of the compound of formula I of the present invention may be used in combination with other active ingredients as long as it does not produce other adverse effects such as allergic reactions.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Those skilled in the art can use known pharmaceutical carriers to prepare suitable pharmaceutical compositions from the polymorphs of the compound of formula I of the present invention. The pharmaceutical compositions can be specially formulated in solid or liquid form for oral administration, parenteral injection or rectal administration.

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 injectable dry powders that can be used immediately after adding a drug solvent before injection).

As used herein, the term "therapeutically and/or prophylactically effective amount" is that amount of a drug or pharmaceutical preparation that elicits the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other person.

When used for the above-mentioned treatment and/or prevention purposes, the total daily dosage of the polymorphs and pharmaceutical compositions of the compound of formula I of the present invention shall be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level shall be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the administration time, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concurrently with the specific compound used; and similar factors known in the medical field. For example, it is practiced in the art to start the dosage of the compound from a level lower than that required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained.

As used herein, "polymorph" or "polymorph" refers to a crystal form having 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 have different packing and geometric arrangements and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate and the like. Depending on their temperature-stability relationship, two polymorphs can be monotropic or tautotropic. For a monotropic system, the relative stability between the two solid phases remains unchanged when the temperature changes. In contrast, in a tautotropic system, there is a transition temperature at which the stability of the two phases is reversed ((Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids" (1999) ISBN:)-8247-0237). This phenomenon of a compound existing in different crystal structures is called pharmaceutical polymorphism.

As used herein, the term "room temperature" or "RT" refers to an ambient temperature of 20 to 25°C (68-77°F).

Abbreviations: MeOH: methanol; 2-MeTHF: 2-methyltetrahydrofuran; EtOH: ethanol; 1,4-Dioxane: 1,4-dioxane; IPA: isopropanol; 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: methyl tert-butyl ether; DMAc: dimethylacetamide; THF: tetrahydrofuran; NMP: N-methylpyrrolidone.

On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive and progressive effect of the present invention is that the BTK inhibitor crystal form and its acid salt and the crystal form of its acid salt of the present invention have the advantages of high activity, low hygroscopicity and good stability, which is of great significance for drug development.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an XRPD spectrum of the free base form A of the compound of formula I.

FIG2 is a TGA/DSC spectrum of the free base form A of the compound of formula I.

FIG3 is a ¹ H NMR spectrum of the free base form A of the compound of formula I.

FIG4 is an XRPD spectrum of the hydrochloride salt form A of the compound of formula I.

FIG5 is a TGA/DSC spectrum of the hydrochloride salt form A of the compound of formula I.

FIG6 is a ¹ H NMR spectrum of hydrochloride form A of the compound of formula I.

FIG. 7 is an XRPD spectrum of the hydrochloride salt form B of the compound of formula I.

FIG8 is a TGA/DSC spectrum of the hydrochloride salt form B of the compound of formula I.

FIG. 9 is a ¹ H NMR spectrum of the hydrochloride salt form B of the compound of formula I.

FIG10 is an XRPD spectrum of the hydrochloride salt form C of the compound of formula I.

FIG. 11 is a TGA/DSC spectrum of the hydrochloride salt form C of the compound of formula I.

FIG. 12 is a ¹ H NMR spectrum of hydrochloride form C of the compound of formula I.

FIG. 13 is an XRPD spectrum of the phosphate crystal form A of the compound of formula I.

FIG. 14 is a TGA/DSC spectrum of the phosphate crystal form A of the compound of formula I.

FIG. 15 is a ¹ H NMR spectrum of the phosphate crystal form A of the compound of formula I.

FIG. 16 is an XRPD spectrum of the fumarate crystalline form A of the compound of Formula I.

FIG. 17 is a TGA/DSC spectrum of the fumarate crystalline form A of the compound of Formula I.

FIG. 18 is a ¹ H NMR spectrum of the fumarate crystalline form A of the compound of formula I.

FIG. 19 is an XRPD spectrum of Form A of 1,5-naphthalene disulfonate salt of the compound of Formula I.

FIG20 is a TGA/DSC spectrum of Form A of 1,5-naphthalene disulfonate salt of the compound of Formula I.

FIG. 21 is a ¹ H NMR spectrum of Form A of 1,5-naphthalene disulfonate salt of the compound of Formula I.

FIG. 22 is an XRPD spectrum of Form B of 1,5-naphthalene disulfonate salt of the compound of Formula I.

FIG. 23 is a TGA/DSC spectrum of Form B of 1,5-naphthalene disulfonate salt of the compound of Formula I.

FIG. 24 is a ¹ H NMR spectrum of Form B of 1,5-naphthalene disulfonate salt of the compound of Formula I.

FIG. 25 is an XRPD spectrum of Form A of the p-toluenesulfonate salt of the compound of Formula I.

FIG26 is a TGA/DSC spectrum of the p-toluenesulfonate crystalline form A of the compound of Formula I.

FIG. 27 is a ¹ H NMR spectrum of Form A of the p-toluenesulfonate salt of the compound of Formula I.

FIG. 28 is an XRPD spectrum of Form A of the hydrobromide salt of the compound of Formula I.

FIG29 is a TGA/DSC spectrum of the hydrobromide salt form A of the compound of formula I.

FIG30 is a ¹ H NMR spectrum of the hydrobromide salt form A of the compound of formula I.

Figure 31 is an XRPD spectrum of maleate salt Form A of the compound of Formula I.

FIG32 is a TGA/DSC spectrum of maleate salt Form A of the compound of Formula I.

FIG. 33 is a ¹ H NMR spectrum of maleate salt Form A of the compound of Formula I.

Figure 34 is an XRPD spectrum of maleate salt Form E of the compound of Formula I.

FIG35 is a TGA/DSC spectrum of maleate salt Form E of the compound of Formula I.

FIG. 36 is a ¹ H NMR spectrum of maleate salt Form E of the compound of Formula I.

Figure 37 is an XRPD spectrum of maleate salt Form F of the compound of Formula I.

FIG38 is a TGA/DSC spectrum of maleate salt Form F of the compound of Formula I.

FIG. 39 is a ¹ H NMR spectrum of 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.

FIG41 is a TGA/DSC spectrum of maleate salt Form H of the compound of Formula I.

FIG. 42 is a ¹ H NMR spectrum of maleate salt Form H of the compound of Formula I.

Figure 43 is the XRPD spectrum of maleate salt Form I of the compound of Formula I.

Figure 44 is a TGA/DSC spectrum of maleate salt Form I of the compound of Formula I.

FIG. 45 is a ¹ H NMR spectrum of maleate salt Form I of the compound of Formula I.

Figure 46 is an XRPD spectrum of maleate salt Form J of the compound of Formula I.

FIG47 is a TGA/DSC spectrum of maleate salt Form J of the compound of Formula I.

FIG. 48 is a ¹ H NMR spectrum of maleate salt Form J of the compound of Formula I.

Figure 49 is an XRPD spectrum of the free base Form C of the compound of Formula I.

Figure 50 is a TGA/DSC spectrum of the free base form C of the compound of Formula I.

FIG51 is a ¹ H NMR spectrum of the free base Form C of the compound of Formula I.

Figure 52 is an XRPD spectrum of the free base form D of the compound of Formula I.

FIG53 is a TGA/DSC spectrum of the free base form D of the compound of Formula I.

FIG. 54 is a ¹ H NMR spectrum of the free base form D of the compound of Formula I.

Figure 55 is an XRPD spectrum of the free base Form E of the compound of Formula I.

FIG56 is a TGA/DSC spectrum of the free base Form E of the compound of Formula I.

FIG. 57 is a ¹ H NMR spectrum of the free base Form E of the compound of Formula I.

Figure 58 is a DVS spectrum of maleate salt form A of the compound of formula I.

Figure 59 is an XRPD overlay of maleate salt Form A of the compound of Formula I before and after pressure stability.

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.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

Instruments and methods

The solid samples were analyzed by various detection and analysis methods, such as powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic water sorption (DVS), and hydrogen spectroscopy liquid nuclear magnetic resonance ( ¹ HSolution NMR).

(1) Powder X-ray Diffraction (XRPD): XRPD results were collected on an X-ray powder diffraction analyzer produced by PANalytical. The scanning parameters are shown in the table.

Table 1 XRPD test parameters (I/II)

(2) Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC): TGA and DSC images were collected on a TA Discovery 5500 thermogravimetric analyzer and a TA Discovery 2500 differential scanning calorimeter, respectively. The test parameters are listed in the table.

Table 2 TGA and DSC test parameters

(3) Dynamic moisture sorption (DVS): Dynamic moisture sorption (DVS) curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was calibrated using the deliquescent point of LiCl, Mg(NO ₃ ) ₂ and KCl. The DVS test parameters are listed in the table.

Table 3 DVS test parameters

(4) ¹ H Solution NMR: 1 H Solution NMR spectra were collected on a Bruker 400M NMR instrument using DMSO-d ₆ as solvent.

(5) High Performance Liquid Chromatography (HPLC): Purity and solubility were tested by Agilent 1260 High Performance Liquid Chromatography. The analysis conditions are shown in the table.

Table 4 HPLC test conditions for purity test

(7) Ion chromatography (IC): ThermoFisher ICS-1100 ion chromatograph was used to analyze the ion content. The specific conditions are shown in the table.

Table 5 Ion chromatography conditions and parameters

IC ThermoFisher ICS-1100 Chromatographic columns IonPac AS18 Analytical Column(4×250mm) Mobile phase 25mM NaOH Injection volume 25μL Flow rate 1.0mL/min Sample cell temperature 35℃ Column temperature 35℃ Current 80mA Run time 7.0min(Cl ^- ); 15.0min(Br ^- ); 40.0min(PO ₄ ^3- )

It is understood that other types of instruments with the same function as the above-mentioned instruments or using different test conditions from those used in the present invention may result in other values, and therefore, the quoted values should not be regarded as absolute values. Due to instrument errors or differences in operators, those skilled in the art will understand that the above parameters for characterizing the physical properties of the crystals may have slight differences, so the above parameters are only used to assist in characterizing the polymorphs provided by the present invention, and cannot be regarded as limitations on the polymorphs of the present invention.

Preparation Example 1 Preparation of Compound of Formula I

Step 1: (S)-2-(Hydroxymethyl)-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoic acid deuterated methyl ester (500 mg, 1.14 mmol) was dissolved in acetonitrile (15 mL), and silver (II) oxide (3.97 g, 17.15 mmol) and deuterated iodomethane (2.49 g, 17.15 mmol) were added, and the reaction was stirred at 35 ° C for 48 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo to give (S)-deuterated methyl 2-(((methoxy-d3)methyl)-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (520 mg, 1.14 mmol, yield 100%) as a yellow solid. ES-API: [M+H] ⁺ =455.1.

Step 2: (S)-2-(((methoxy-d3)methyl)-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoic acid deuterated methyl ester (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. After the reaction solution was cooled to room temperature, it was filtered with diatomaceous earth, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo, and the crude product was purified by flash silica gel column (ethyl acetate/petroleum ether: 0-100%) to give (S)-2-((methoxy-d3)methyl)-2-(methyl-d3)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (350 mg, 0.87 mmol, yield 78%) as a light yellow solid. ES-API: [M+H] ⁺ = 393.2.

Step 3: (S)-2-((Methoxy-d3)methyl)-2-(methyl-d3)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (350 mg, 0.87 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (2 mL) and water (0.8 mL), sodium hydroxide (250 mg, 6.24 mmol) was added, and the reaction was stirred at 65°C for 6 hours. After the reaction solution was cooled to room temperature, it was adjusted to pH = 8 with dilute hydrochloric acid (1.0 M), and then 20 mL of saturated sodium bicarbonate solution was added and extracted with ethyl acetate (100 mL). The organic phase was washed once with saturated sodium bicarbonate solution (20 mL) and twice with saturated brine (20 mL), dried and concentrated to give (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, yield 100%) as a white solid. ES-API: [M+H] ⁺ = 253.1.

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), the reaction was cooled to 0°C, and potassium hydroxide (350 mg, 6.24 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH = 8 with dilute hydrochloric acid (1.0 M) and ethyl acetate was added. The organic phase was washed with saturated brine (30 mL), dried and concentrated, and the crude product was purified by flash silica gel column (methanol/dichloromethane: 0-8%) to give (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 (200 mg, 0.412 mmol, yield 46%) as a light yellow solid. ES-API: [M+H] ⁺ = 485.1.

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 (200 mg, 0.412 mmol) was dissolved in tetrahydrofuran (5 mL) and water (0.5 mL). 2,3-dichloro-5,6-dicyano-p-benzoquinone (281 mg, 1.24 mmol) was added at room temperature and the reaction was stirred at room temperature for 2 hours. Saturated sodium sulfite solution (1 0mL) and saturated sodium bicarbonate solution (10mL) were used to quench the reaction, and then extracted with ethyl acetate (50mL). The organic phase was washed with saturated sodium bicarbonate solution (20mL) and saturated brine (20mL) in sequence, dried and concentrated, and the crude product was purified by preparative HPLC to give (S)-9-(2-chloro-4-phenoxybenzoyl)-2-(methoxy-d3)methyl)-2-(methyl-d3)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine-3-one (compound of formula I, 76 mg, yield 38%) as a white solid. ¹ H 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 = 8.5 Hz, 1H), 7.48 (t, J = 8.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.20–7.16 (m, 3H), 7.02 (dd, J = 8.5, 2.5 Hz, 1H), 3.64 (d, J = 9.5 Hz, 1H), 3.47 (d, J = 9.5 Hz, 1H). ES-API: [M+H] ⁺ = 483.1. XPRD characterization showed that the product was amorphous. Its XPRD results are shown in Figure 60.

Single crystal cultivation: Weigh a sample of the compound of formula I (100 mg), heat the sample in ethanol/water (1:1) solvent to dissolve the sample, and slowly evaporate it at room temperature to obtain a single crystal. X-ray single crystal diffraction test was performed using a Bruker D8 Venture instrument. The results are shown in Table 6 and Figure 61 below.

Table 6

Biological Testing

Test Example 1: BTK and BTK C481S Enzyme Assay

Use DMSO to prepare a 1000X compound 3-fold gradient concentration stock solution, use reaction buffer (50mM HEPES, pH7.5, 0.0015% Briji-35, 2mM DTT, 10mM MgCl ₂ ) to dilute 100 times to 10X compound stock solution, and transfer the 10X compound stock solution to a 384-well plate. Use BTK Kinase Enzyme System (Promega Catalog # V2941) or BTK (C481S) Kinase Enzyme System (Promega Catalog # VA7033) to establish an enzymatic reaction. First, prepare a 2X enzyme solution with reaction buffer and add it to the plate. The enzyme solution contains 10nM BTK or 10nM BTK C481S and incubate with the compound for 10 minutes. Then, 2.5X substrate solution was prepared with reaction buffer and added to the plate. The substrate solution contained ATP (125 μM) and Poly (Glu4, Tyr1) (0.05 μg/μL) and reacted at 20°C for 90 minutes. Finally, the kinase activity was detected according to the experimental steps provided by the ADP-GloTM kinase Assay kit (Promega, #V9101), and the luminescence value was finally read. DMSO was used as the maximum signal value, and no enzyme was used as the minimum signal value. The inhibition rate of the compound (%) was calculated as (maximum signal value-compound signal value)/(maximum signal value-minimum signal value)×100%, and the XLFit four-parameter method was used to fit the compound gradient dilution concentration and the corresponding enzyme activity inhibition rate to calculate the IC ₅₀ value. As a result, the compound of formula I has a high inhibitory activity against BTK or BTK(C481S) kinase, with an _IC50 value of 10.6 nM for BTK and an _IC50 value of 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 them, and inoculate 2E6 cells in a 10cm culture dish and culture overnight. Day 2: Use 1000μL Opti-MEM to prepare a mixture containing 6ug WT-BTK/C481S-BTK plasmid and 18μL FuGENE HD transfection reagent, let it stand at room temperature for 10 minutes, and then use a pipette to slowly add the mixture to the culture dish and culture overnight. Day 3: Take out the culture dish, digest the cells with EDTA, collect and count them, and inoculate 1E4 cells in a 96-well cell culture plate and culture overnight. Use DMSO to prepare a 1000X compound 3.16-fold gradient concentration stock solution and place it at room temperature. Day 4: Take out the prepared 1000X compound stock solution, dilute it 200 times with culture medium to 5× compound stock solution, add 5× compound stock solution to each cell culture well, the final concentration is 1×, and the DMSO content is 0.1%. Use DMSO as an experimental control. After adding the compound and culturing for two hours, remove the remaining culture medium. Add 100μL cell lysis buffer to each well, let it stand on ice for 30 minutes, and ultrasonically lyse it in ice water for 5 minutes. After diluting the cell lysate in proportion, transfer 80μL of the mixed solution to the ELISA plate, and add 80μL of cell lysis buffer to the blank well. After incubating in a 37℃ incubator for 2 hours, take out the plate and complete the antibody incubation and color termination operation according to the PathScan P-Btk(Y223)Sandwich ELISA Kit(Cell signaling#23843CA) instructions, and finally read the OD value. The inhibitory rate of the compound (%) was calculated as (OD _{control -} OD _compound ) / (OD _{control -} OD _blank ) × 100%, and the compound gradient dilution concentration and the corresponding cell proliferation inhibition rate were fitted using the Prism 8 four-parameter method to calculate the IC ₅₀ value. As a result, the compound of formula I had a 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 BTK (C481S) phosphorylation.

Test Example 3: TMD-8 proliferation inhibition experiment

TMD-8 cells are human diffuse large B lymphoma (Mingzhou Bio, MZ-0832), cultured in 10% FBS + 1% PS1640 medium. On the first day, cells in the logarithmic growth phase were taken, counted and inoculated into 600 TMD-8 cells in a 384-well cell culture plate and cultured overnight. On the second day, 400X compound 3-fold gradient concentration stock solution was prepared using DMSO, and the compound stock solution was diluted 40 times to 10× using culture medium. 10× compound stock solution was added to each cell culture well, with a final concentration of 1× and a DMSO content of 0.25%. DMSO was used as an experimental control and culture medium as a blank control. After adding the compound, the culture was continued for three days. On the fifth day, 25μL ADP-Glo was added to each well, mixed and incubated for 10 minutes, and the chemiluminescence value (RLU value) was read. Calculate the cell proliferation inhibition rate (%) = (RLU _{control -} RLU _compound ) / (RLU _{control -} RLU _blank ) × 100%, use XLFit four-parameter method to fit the compound gradient dilution concentration and the corresponding cell proliferation inhibition rate, and calculate the IC ₅₀ value. As a result, the compound of the present invention has a high inhibitory activity against TMD-8, and the IC ₅₀ value for TMD-8 is 72.77nM.

Example 1 Preparation of Free Base Form A of Compound of Formula I

About 20 mg of the compound of formula I sample (obtained from Preparation Example 1) was weighed into an HPLC vial, and 0.5 mL of acetonitrile/water (19:1, v/v) was added. After stirring at room temperature for 3 days, the solid was separated by centrifugation and vacuum dried overnight at room temperature to obtain the free base crystal form A of the compound of formula I. The XRPD, TGA/DSC and 1H NMR characterization results are shown in Figures 1, 2 and 3. The TGA results showed that the sample had a 3.1% weight loss when heated to 200°C; the DSC results showed that the sample observed an endothermic peak at 327.4°C (peak temperature). The X-ray powder diffraction data of the free base crystal form A of the compound of formula I are shown in Table 7 below.

Table 7

Example 2 Preparation of Hydrochloride Form A of Compound of Formula I

About 20 mg of the compound of formula I sample (prepared in Preparation Example 1) and 37% hydrochloric acid (1:2, molar ratio of feed amount) were weighed into an HPLC vial, 0.5 mL of ethyl acetate was added, and after stirring at room temperature for 3 days, the solid was separated by centrifugation and vacuum dried overnight at room temperature to obtain the hydrochloride form A of the compound of formula I; the XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 4, 5 and 6. The TGA results show that the sample loses 7.1% of its weight when heated to 110°C, and loses 7.9% of its weight when heated from 110°C to 200°C; DSC shows that the sample has two endothermic peaks observed at 115.4°C and 185.0°C (peak temperature), and one exothermic peak observed at 218.3°C (peak temperature). IC/HPLC test results show that the molar ratio of hydrochloric acid to free state is 1.0:1. The hydrochloride form A of the compound of formula I, its X-ray powder diffraction data are shown in Table 8 below.

Table 8

Example 3 Preparation of Hydrochloride Form B of Compound of Formula I

Weigh about 20 mg of the compound of formula I sample (prepared in Preparation Example 1) and 37% hydrochloric acid (1:2, molar ratio of feed amount) into an HPLC vial, add 0.5 mL of acetone, stir at room temperature overnight, centrifuge and separate the solid, and vacuum dry it at room temperature overnight to obtain the hydrochloride crystal form B of the compound of formula I; the XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 7, 8 and 9, respectively. The TGA results show that when the temperature is raised to 150°C, the sample loses 4.8% of its weight, and when it is heated from 150°C to 230°C, the sample loses 7.6% of its weight; DSC shows that the sample observes an endothermic peak at 223.0°C (peak temperature). IC/HPLC test results show that the molar ratio of hydrochloric acid to free state is 1.0:1. The hydrochloride crystal form B of the compound of formula I, its X-ray powder diffraction data are shown in Table 9 below.

Table 9

Example 4 Preparation of Hydrochloride Form C of Formula I Compound

About 20 mg of the compound of formula I (prepared in Preparation Example 1) and 1N hydrochloric acid (1:2, molar ratio of feed amount) were weighed into an HPLC vial, 0.5 mL of acetone was added, and after stirring at room temperature overnight, the solid was separated by centrifugation and dried in vacuum at room temperature overnight to obtain the hydrochloride crystal form C of the compound of formula I. The characterization results of XRPD, TGA/DSC and ¹ H NMR are shown in Figures 10, 11 and 12, respectively. The TGA results show that when the temperature is raised to 150°C, the sample loses 2.2% of its weight, and when heated from 150°C to 250°C, the sample loses 7.5% of its weight; DSC shows that the sample observes an endothermic peak at 248.2°C (peak temperature). The IC/HPLC test results show that the molar ratio of hydrochloric acid to the 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.

Table 10

Example 5 Preparation of Phosphate Form A of Compound of Formula I

About 20 mg of the compound of formula I (obtained from Preparation Example 1) and an equimolar amount of phosphoric acid were weighed into an HPLC vial, 0.5 mL of ethyl acetate was added, and after stirring at room temperature for 3 days, the solid was separated by centrifugation and dried overnight in vacuum at room temperature to obtain the phosphate crystal form A of the compound of formula I. The XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 13, 14 and 15, respectively. The TGA results showed that the sample lost 2.1% of its weight when heated to 65°C, and lost 2.8% of its weight when heated from 65°C to 125°C; DSC showed that the sample observed 3 endothermic peaks at 81.7°C, 92.1°C and 139.2°C (peak temperature). The ¹ H NMR results showed that the molar ratio of phosphoric acid to free state was 1.3:1. The X-ray powder diffraction data of the phosphate crystal form A of the compound of formula I are shown in Table 11 below.

Table 11

Example 6 Preparation of Fumarate Crystalline Form A of Compound of Formula I

About 20 mg of the compound of formula I (obtained from Preparation Example 1) and an equimolar amount of fumaric acid were weighed into an HPLC vial, 0.5 mL of ethyl acetate was added, and after stirring at room temperature for 3 days, the solid was separated by centrifugation and dried overnight in vacuum at room temperature to obtain the fumarate form A of the compound of formula I; the XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 16, 17 and 18, respectively. The TGA results showed that the sample lost 2.6% of its weight when heated to 150°C, and lost 21.2% of its weight when heated from 150°C to 240°C; DSC showed that the sample observed an endothermic peak at 224.7°C (peak temperature). The ¹ H NMR results showed that the molar ratio of fumaric acid to free state in the sample was about 1.0:1. The X-ray powder diffraction data of the fumarate form A of the compound of formula I are shown in Table 12 below.

Table 12

Example 7 Preparation of 1,5-naphthalene disulfonate salt of Formula I compound Form A

About 20 mg of the compound of formula I (obtained from Preparation Example 1) and an equimolar amount of 1,5-naphthalene disulfonic acid were weighed into an HPLC vial, and 0.5 mL of acetonitrile/water (19:1, v/v) was added. After stirring at room temperature for 3 days, the solid was separated by centrifugation and vacuum dried overnight at room temperature to obtain 1,5-naphthalene disulfonic acid salt form A of the compound of formula I. The XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 19, 20 and 21, respectively. The TGA results showed that the sample lost 3.5% of its weight when heated to 130°C, and lost 2.6% of its weight when heated from 130°C to 175°C; DSC showed that the sample observed 4 endothermic peaks at 57.7°C, 82.9°C, 166.9°C and 211.1°C (peak temperature). The ¹ H NMR results showed that the molar ratio of 1,5-naphthalene disulfonic acid to the free state in the sample was about 0.7:1, and no acetonitrile solvent residue was observed. The X-ray powder diffraction data of 1,5-naphthalene disulfonate form A of the compound of formula I are shown in Table 13 below.

Table 13

Example 8 Preparation of 1,5-naphthalene disulfonate salt of Formula I compound Form B

About 20 mg of the compound of formula I (obtained from Preparation Example 1) and an equimolar amount of 1,5-naphthalenedisulfonic acid were weighed into an HPLC vial, 0.5 mL of acetone was added, and after stirring at room temperature for 3 days, the solid was separated by centrifugation and vacuum dried overnight at room temperature to obtain the 1,5-naphthalenedisulfonate crystal form B of the compound of formula I. The XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 22, 23 and 24, respectively. The TGA results show that the sample loses 4.3% weight when the temperature is raised to 200°C; DSC shows that the sample observes three endothermic peaks at 57.0°C, 82.5°C and 276.1°C (peak temperature). The ¹ H NMR results show that the molar ratio of 1,5-naphthalenedisulfonic acid to the free state in the sample is about 0.7:1, and no acetonitrile solvent residue is observed. The X-ray powder diffraction data of the 1,5-naphthalenedisulfonate crystal form B of the compound of formula I are shown in Table 14 below.

Table 14

Example 9 Preparation of p-toluenesulfonate salt of Formula I compound Form A

About 20 mg of the compound of formula I (obtained from Preparation Example 1) and an equimolar amount of p-toluenesulfonic acid were weighed into an HPLC vial, and 0.5 mL of acetonitrile/water (19:1, v/v) was added. After stirring at room temperature for 3 days, the solid was separated by centrifugation and dried overnight in vacuum at room temperature to obtain p-toluenesulfonate crystalline form A of the compound of formula I. The characterization results of XRPD, TGA/DSC and ¹ H NMR are shown in Figures 25, 26 and 27, respectively. The TGA results show that the sample loses 4.3% of its weight when heated to 75°C, and loses 6.1% of its weight when heated from 75°C to 120°C; DSC shows that the sample observes an endothermic peak at 111.1°C (peak temperature). The ¹ H NMR results show that the molar ratio of p-toluenesulfonic acid to the free state in the sample is 1.0:1, and no residual acetonitrile solvent is observed. The p-toluenesulfonate crystalline form A of the compound of formula I, its X-ray powder diffraction data are shown in Table 15 below.

Table 15

Example 10 Preparation of Hydrobromide Form A of Compound I

About 20 mg of the compound of formula I (obtained from Preparation Example 1) and an equimolar amount of hydrobromic acid were weighed into an HPLC vial, 0.5 mL of ethyl acetate was added, and after stirring at room temperature for 3 days, the solid was separated by centrifugation and dried overnight in vacuum at room temperature to obtain hydrobromide salt form A. The XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 28, 29 and 30, respectively. The TGA results showed that the sample lost 5.6% of its weight when the temperature was raised to 200°C; DSC showed that the sample observed 4 endothermic peaks at 97.7°C, 179.4°C, 230.7°C and 254.9°C (peak temperature). The IC/HPLC test results showed that the molar ratio of hydrobromic acid to the free state was 0.9:1. The X-ray powder diffraction data of the hydrobromide salt form A of the compound of formula I are shown in Table 16 below.

Table 16

Example 11 Preparation of Maleate Salt Form A of Formula I Compound

About 20 mg of the compound of formula I (obtained from Preparation Example 1) and an equimolar amount of maleic acid were weighed into an HPLC vial, 0.5 mL of acetone solution was added, and after stirring at room temperature for 3 days, the solid was separated by centrifugation and dried overnight in vacuum at room temperature to obtain the maleate crystalline form A of the compound of formula I. The characterization results of XRPD, TGA/DSC and ¹ H NMR are shown in Figures 31, 32 and 33. The TGA results show that the sample loses 2.8% of its weight when heated to 150°C, and loses 19.3% of its weight when heated from 150°C to 230°C; DSC shows that the sample observes an endothermic peak at 200.3°C (peak temperature). The ¹ H NMR results show that the molar ratio of maleic acid to free state in the sample is about 1.0:1. The X-ray powder diffraction data of the maleate crystalline form A of the compound of formula I are shown in Table 17 below.

Table 17

Example 12 Preparation of Maleate Salt Form E of Compound of Formula I

Weigh 20 mg of maleate crystal form A sample (prepared in Example 11) into a 3 mL vial, add 0.2-1.8 mL of tetrahydrofuran solvent to dissolve, take another 20 mL vial and add about 4 mL of n-heptane antisolvent thereto, place the 3 mL vial containing the filtrate in the 20 mL vial, seal the 20 mL vial and let it stand at room temperature. When solid precipitation is observed, collect the solid to obtain maleate crystal form E of the compound of formula I. XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 34, 35 and 36, respectively. TGA results show that the sample loses 3.4% of its weight when heated from room temperature to 150°C, and loses 19.7% of its weight when heated from 150°C to 250°C. DSC results show that an endothermic peak is observed at 194.2°C (peak temperature) for the sample. The ¹ H NMR results showed that the molar ratio of maleic acid to free form in the sample was 1.0:1. The X-ray powder diffraction data of maleate crystalline form E of the compound of formula I are shown in Table 18 below.

Table 18

Example 13 Preparation of Maleate Salt Form F of Compound of Formula I

Weigh 20 mg of maleate salt form A sample (prepared in Example 11) into an HPLC vial, add 0.5 mL of tetrahydrofuran/water (957:43, v/v) solvent, place the resulting suspension under magnetic stirring at room temperature for about 7 days, centrifuge and separate the solid to obtain maleate salt form F of the compound of formula I. XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 37, 38 and 39, respectively. TGA results show that the sample loses 2.9% of its weight when heated from room temperature to 150°C, and loses 18.7% of its weight when heated from 150°C to 250°C. DSC results show that three endothermic peaks are observed at 65.3°C, 81.7°C and 180.8°C (peak temperature) for the sample. ¹ H NMR results show that the molar ratio of maleic acid to free state in the sample is 1.0:1. X-ray powder diffraction data of maleate salt form F of the compound of formula I are shown in Table 19 below.

Table 19

Example 14 Preparation of Maleate Salt Form H of Formula I Compound

Weigh 20 mg of maleate crystal form A sample (prepared in Example 11) into a 3 mL vial, add 0.2-1.8 mL of tetrahydrofuran solvent to dissolve, take another 20 mL vial and add about 4 mL of methyl tert-butyl ether antisolvent thereto, place the 3 mL vial containing the filtrate in the 20 mL vial, seal the 20 mL vial and let it stand at room temperature. When solid precipitation is observed, collect the solid to obtain maleate crystal form H of the compound of formula I. XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 40, 41 and 42, respectively. TGA results show that the sample loses 1.4% of its weight when heated from room temperature to 150°C, and loses 17.4% of its weight when heated from 150°C to 250°C. DSC results show that an endothermic peak is observed at 188.6°C (peak temperature) for the sample. ¹ H NMR (results show that the molar ratio of maleic acid to free state in the sample is 1.0:1. The maleate crystalline form H was identified by VT-XRPD. The sample was purged under N ₂ for 20 min, heated to 150° C. and then cooled to 30° C., and no crystalline change was observed. The X-ray powder diffraction data of the maleate crystalline form H of the compound of formula I are shown in Table 20 below.

Table 20

Example 15 Preparation of Maleate Salt Form I of Compound of Formula I

A maleate salt form A sample (1 g, prepared by Example 11) and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask, and the system was refluxed to dissolve. Naturally cooled to room temperature, solid precipitated. Rotary evaporation was concentrated until ~20 mL of tetrahydrofuran remained. The oil bath was heated to 80°C and stirred for 0.5 hours, naturally cooled to room temperature, and stirred overnight. Filtered and dried to obtain 780 mg of off-white solid, which was maleate salt form I of the compound of formula I. XRPD, TGA/DSC and 1H NMR characterization results are shown in Figures 43, 44 and 45, respectively. TGA results show that the sample loses 3.5% of its weight when heated from room temperature to 130°C, and loses 20.2% of its weight when heated from 130°C to 250°C. DSC results show that two endothermic peaks are observed at 112.9°C and 202.5°C (peak temperature) and one exothermic peak is observed at 161.5°C (peak temperature). The ¹ H NMR result showed that the molar ratio of maleic acid to free state in the sample was 1.0:1. The X-ray powder diffraction data of maleate crystalline form I of the compound of formula I are shown in Table 21 below.

Table 21

Example 16 Preparation of Maleate Salt Form J of Formula I Compound

The maleate salt form I (prepared in Example 15) was heated to 130°C, cooled 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 Figures 46, 47 and 48, respectively. The TGA results showed that the sample lost 6.4% of its weight when heated from room temperature to 150°C, and lost 20.5% of its weight when heated from 150°C to 250°C. The DSC results showed that an endothermic peak was observed at 193.7°C (peak temperature) and an exothermic peak was observed at 162.1°C (peak temperature). The ¹ H NMR results showed that the molar ratio of maleic acid to free state in the sample was 1.0:1. The maleate salt form J was subjected to a humidity induction test. After the maleate salt form J was placed under 80% RH overnight, the crystal form did not change, indicating that the maleate salt form J was relatively stable under high humidity conditions. The X-ray powder diffraction data of maleate salt form J of the compound of formula I are shown in Table 22 below.

Table 22

Example 17 Preparation of Free Base Form C of Compound of Formula I

Weigh 20 mg of maleate crystal form A sample (prepared in Example 11) into a 20 mL vial, dissolve it with 0.2-3.0 mL of methanol solvent (the undissolved system is filtered into another vial using a 0.45 μm PTFE filter), add water antisolvent to the clear solution, and stir while adding dropwise until solid precipitates, or when the total amount of antisolvent is added to 10.0 mL, the sample without solid precipitation is transferred to 5°C for magnetic stirring. If there is still no solid precipitation, it is transferred to room temperature for volatilization. Centrifuge to separate the precipitated solid to obtain free base crystal form C of the compound of formula I. XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 49, 50 and 51. TGA results show that the sample has a 2.7% weight loss when heated to 200°C; DSC results show that the sample has an endothermic peak at 329.3°C (peak temperature) and an exothermic peak at 311.3°C (peak temperature). The X-ray powder diffraction data of the free base form C of the compound of formula I are shown in Table 23 below.

Table 23

Example 18 Preparation of Free Base Form D of Compound of Formula I

Weigh 20 mg of maleate salt form A sample (prepared in Example 11) into a 3 mL vial, add 0.2-1.8 mL of dimethylacetamide solvent to dissolve, take another 20 mL vial and add about 4 mL of water anti-solvent thereto, place the 3 mL vial containing the filtrate in the 20 mL vial, seal the 20 mL vial and let it stand at room temperature. When solid precipitation is observed, collect the solid to obtain free base form D of the compound of formula I. XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 52, 53 and 54, respectively. TGA results show that the sample loses 4.1% of its weight when heated from room temperature to 150°C, and loses 7.1% of its weight when heated from 150°C to 230°C. DSC results show that two endothermic peaks are observed at 175.3°C and 328.9°C (peak temperature) of the sample. X-ray powder diffraction data of free base form D of the compound of formula I are shown in Table 24 below.

Table 24

Example 19 Preparation of Free Base Form E of Compound of Formula I

Weigh 20 mg of maleate crystal form A sample (prepared in Example 11) into an HPLC vial, add 0.5 mL of 1,4-dioxane/water (1:2, v/v) solvent, and suspend and stir at 50°C for 3 days to obtain free base crystal form E of the compound of formula I. The XRPD, TGA/DSC and ¹ H NMR characterization results are shown in Figures 55, 56 and 57, respectively. The TGA results show that the sample loses 1.8% of its weight when heated from room temperature to 80°C; and loses 16.8% of its weight when heated from 80°C to 180°C. The DSC results show that two endothermic peaks are observed at 144.5°C and 329.1°C (peak temperature) of the sample. The X-ray powder diffraction data of free base crystal form E of the compound of formula I are shown in Table 25 below.

Table 25

Example 20 Preparation of Maleate Salt Form A of Formula I Compound

The compound of formula I (7.4 g, obtained in Preparation Example 1) and ethyl acetate (100 mL) were added to a 250 mL round-bottom flask and stirred at room temperature; a solution of maleic acid (1.86 g) in ethyl acetate (50 mL) was added dropwise to obtain a suspension, which was stirred at room temperature for 4 hours; the reaction solution was filtered and the filter cake was dried to obtain 8.8 g of an off-white solid, which was characterized by XRPD and TGA/DSC, and each spectrum was basically the same as that in Example 11. Therefore, the obtained solid is the maleate crystalline form A of the compound of formula I.

Example 21 Preparation of Maleate Salt Form A of Formula I Compound

Add the compound of formula I (570 g, obtained in Preparation Example 1) and ethyl acetate (17 L) to the reaction kettle and stir at room temperature; add a solution of maleic acid (144 g) in ethyl acetate (2.85 L) dropwise to obtain a suspension, heat to 50-60° C., and stir the suspension for 4-5 hours; stop heating, naturally cool to room temperature with stirring, stir for 16-24 hours, filter, and dry the filter cake to obtain 678 g of off-white solid, which is characterized by XRPD and TGA/DSC, and each spectrum is basically the same as the spectrum in Example 11. Therefore, the obtained solid is the maleate crystalline form A of the compound of formula I.

Hygroscopicity

The hygroscopicity of the maleate salt form A sample (obtained in Example 21) of the compound of Formula I was evaluated by DVS testing 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 salt 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.

Pressure stability

The pressure stability test of the maleate crystal form A sample of the compound of formula I (obtained in Example 20) was carried out using a SYP-5BS manual tablet press, and the specific steps are as follows: weigh ~100 mg of the maleate crystal form A sample in the press mold, use ~350MPa pressure for tableting and maintain for 1min, and then take the sample for XRPD testing. The XRPD of the sample before and after pressure stability is shown in Figure 59, and the results show that the crystal form of the maleate crystal form A does not change before and after pressure stability.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (13)

1. A crystalline form of a compound of formula I, characterized in that it is a compound of formula I free base form a, a compound of formula I free base form C, a compound of formula I free base form D, or a compound of formula I free base form E;

the free base crystal form A of the compound of the formula I has diffraction peaks at 7.3574 +/-0.2 degrees, 20.0853 +/-0.2 degrees, 26.2299 +/-0.2 degrees and 15.0639 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by 2 theta angles;

The free base crystal form C of the compound of the formula I has diffraction peaks at 4.9395 +/-0.2 DEG, 28.0724 +/-0.2 DEG, 11.4647 +/-0.2 DEG and 13.2030 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the free base crystal form D of the compound of the formula I has diffraction peaks at 4.8447 +/-0.2 degrees, 19.3873 +/-0.2 degrees, 12.0794 +/-0.2 degrees and 14.2457 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by 2 theta angles;

the free base crystal form E of the compound of the formula I has diffraction peaks at 5.3081 +/-0.2 DEG, 4.9506 +/-0.2 DEG, 20.9925 +/-0.2 DEG and 19.0379 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle.

2. A crystalline form of a compound of formula I as claimed in claim 1,

when the crystal form of the compound of the formula I is a free base crystal form A of the compound of the formula I, the free base crystal form A of the compound of the formula I meets the following 1 or more conditions:

(1) The free base form A of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 22.5403 + -0.2 °, 10.0156 + -0.2 °, 6.4788 + -0.2 °, 10.8671 + -0.2 ° and 19.5949 + -0.2 °;

(2) The free base form A of the compound of formula I has a thermogravimetric analysis of 2.0% -3.5%, for example 3.1% loss in weight when initially heated to 200+ -5deg.C;

(3) The differential scanning calorimeter diagram of the free base crystal form A of the compound shown in the formula I has an endothermic peak at 327.4+/-5 ℃;

when the crystal form of the compound of the formula I is a free base crystal form C of the compound of the formula I, the free base crystal form C of the compound of the formula I meets the following 1 or more conditions:

(1) The free base form C of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 17.2058 + -0.2 °, 14.7891 + -0.2 °, 20.1466 + -0.2 °, 24.5916 + -0.2 ° and 21.4712 + -0.2 °;

(2) The free base form C of the compound of formula I has a thermogravimetric analysis of 1% -3%, for example 2.7% loss in weight when initially heated to 200±5 ℃;

(3) The differential scanning calorimeter of the free base crystal form C of the compound shown in the formula I has an endothermic peak at 329.3 +/-5 ℃; and/or an exothermic peak at 311.3+ -5deg.C;

when the crystal form of the compound of the formula I is a free base crystal form D of the compound of the formula I, the free base crystal form D of the compound of the formula I meets the following 1 or more conditions:

(1) The free base form D of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ, and further has diffraction peaks at one or more of the following 2θ angles: 4.3851 + -0.2 °, 15.7673 + -0.2 °, 22.1929 + -0.2 °, 17.9985 + -0.2 ° and 24.8383 + -0.2 °;

(2) The free base form D of the compound of formula I has a thermogravimetric analysis of 3% -5%, for example 4.1% loss in weight when initially heated to 150±5 ℃; heating from 150±5 ℃ to 230±5 ℃, the sample weight loss is 6% -8%, such as 7.1%;

(3) The free base crystal form D of the compound of the formula I has an endothermic peak at 175.3+/-5 ℃ and/or 328.9 +/-5 ℃ in a differential scanning calorimetry chart;

when the crystal form of the compound of the formula I is a free base crystal form E of the compound of the formula I, the free base crystal form E of the compound of the formula I meets the following 1 or more conditions:

(1) The free base form E of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 21.2501 + -0.2 °, 17.2819 + -0.2 °, 10.4721 + -0.2 °, 23.0960 + -0.2 ° and 28.0729 + -0.2 °;

(2) The free base form E of the compound of formula I has a thermogravimetric analysis of 1% -3%, for example 1.8% loss in weight when initially heated to 80±5 ℃; heating from 80±5 ℃ to 180±5 ℃ with a sample weight loss of 16% -18%, such as 16.8%;

(3) The free base crystal form E of the compound of the formula I has an endothermic peak at 144.5+/-5 ℃ and/or 329.1+/-5 ℃ in a differential scanning calorimetry chart.

3. A crystalline form of a compound of formula I as claimed in claim 2,

when the crystal form of the compound of the formula I is a free base crystal form A of the compound of the formula I, the free base crystal form A of the compound of the formula I meets the following conditions (1) and/or (2):

(1) The free base form A of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and further has diffraction peaks at one or more of the following 2 theta angles: 12.0106 + -0.2 °, 25.1097 + -0.2 °, 18.0778 + -0.2 ° and 30.3217 + -0.2 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 1;

(2) The differential scanning thermogram and thermogravimetric analysis of the free base form a of the compound of formula I is substantially as shown in figure 2;

or alternatively, the first and second heat exchangers may be,

when the crystal form of the compound of the formula I is a free base crystal form C of the compound of the formula I, the free base crystal form C of the compound of the formula I meets the following conditions (1) and/or (2):

(1) The free base form C of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and further has diffraction peaks at one or more of the following 2 theta 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 °; preferably, the X-ray powder diffraction pattern in terms of 2θ is substantially as shown in fig. 49;

(2) The differential scanning thermogram and thermogravimetric analysis of the free base form C of the compound of formula I is substantially as shown in figure 50;

or alternatively, the first and second heat exchangers may be,

when the crystal form of the compound of the formula I is a free base crystal form D of the compound of the formula I, the free base crystal form D of the compound of the formula I meets the following conditions (1) and/or (2):

(1) The free base form D of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ, and further has diffraction peaks at one or more of the following 2θ angles: 22.3605 + -0.2 °, 18.9570 + -0.2 °, 18.3427 + -0.2 °, 23.7387 + -0.2 °, 28.1120 + -0.2 ° and 24.2673 + -0.2 °; preferably, the X-ray powder diffraction pattern in terms of 2θ is substantially as shown in fig. 52;

(2) The differential scanning thermogram and thermogravimetric analysis of the free base form D of the compound of formula I is substantially as shown in figure 53;

or alternatively, the first and second heat exchangers may be,

when the crystal form of the compound of the formula I is a free base crystal form E of the compound of the formula I, the free base crystal form E of the compound of the formula I meets the following conditions (1) and/or (2):

(1) The free base form E of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and further has diffraction peaks at one or more of the following 2 theta 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 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 55;

(2) The differential scanning thermogram and thermogravimetric analysis of the free base form E of the compound of formula I is substantially as shown in figure 56.

4. A pharmaceutically acceptable salt of a compound of formula I, wherein the pharmaceutically acceptable salt is a salt of the compound of formula I with an acid; the acid is inorganic acid or organic acid;

5. the pharmaceutically acceptable salt of the compound of formula I according to claim 4, wherein 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;

and/or the inorganic acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid; preferably, the inorganic acid is one or more of hydrochloric acid, phosphoric acid and hydrobromic acid;

and/or the organic acid is one or more of maleic acid, L-aspartic acid, fumaric acid, L-tartaric acid, citric acid, 1, 5-naphthalene disulfonic acid, 1, 2-ethane disulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid and malonic acid; preferably, the organic acid is one or more of maleic acid, fumaric acid, 1, 5-naphthalene disulfonic acid and p-toluenesulfonic acid; more preferably, the organic acid is one or more of maleic acid, fumaric acid and p-toluenesulfonic acid; more preferably, the organic acid is maleic acid.

6. A pharmaceutically acceptable salt of a compound of formula I according to claim 4, wherein the pharmaceutically acceptable salt of the compound of formula I is any one of the following pharmaceutically acceptable salts:

(1) A hydrochloride salt of a compound of formula I; wherein the molar ratio of the compound of formula I to hydrochloric acid is 1: (0.5-2), e.g., 1 (0.9-1.0);

(2) Phosphates of the compounds of formula I; wherein the molar ratio of the compound of formula I to phosphoric acid is 1: (1-2), such as 1 (1-1.3);

(3) A hydrobromide salt of a compound of formula I; wherein the molar ratio of the compound of formula I to hydrobromic acid is 1 (0.5-1), e.g. 1:0.9;

(4) A fumarate salt of a compound of formula I; wherein the molar ratio of the compound of formula I to fumaric acid is 1:1;

(5) 1, 5-naphthalene disulfonate of a compound of formula I; wherein the molar ratio of the compound of formula I to 1, 5-naphthalenedisulfonic acid is 1 (0.5-1), e.g. 1:0.7;

(6) P-toluenesulfonate of a compound of formula I; wherein the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1;

(7) Maleate salts of compounds of formula I; wherein the molar ratio of the compound of formula I to maleic acid is 1:1.

7. A crystal form of a pharmaceutically acceptable salt of the compound of formula I, wherein the crystal form of the pharmaceutically acceptable salt of the compound of formula I is a hydrochloride crystal form a of the compound of formula I, a hydrochloride crystal form B of the compound of formula I, a hydrochloride crystal form C of the compound of formula I, a phosphate crystal form a of the compound of formula I, a fumarate crystal form a of the compound of formula I, a 1, 5-naphthalene disulfonate crystal form B of the compound of formula I, a p-toluene sulfonate crystal form a of the compound of formula I, a hydrobromide crystal form a of the compound of formula I, a maleate crystal form E of the compound of formula I, a maleate crystal form F of the compound of formula I, a maleate crystal form H of the compound of formula I, a maleate crystal form I of the compound of formula I, or a maleate crystal form J of the compound of formula I;

The hydrochloride crystal form A of the compound of the formula I has diffraction peaks at 13.2577 +/-0.2 degrees, 19.0205 +/-0.2 degrees, 26.6619 +/-0.2 degrees and 24.4646 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the hydrochloride crystal form B of the compound of the formula I has diffraction peaks at 11.2971 +/-0.2 degrees, 4.1094 +/-0.2 degrees, 16.0047 +/-0.2 degrees and 18.5553 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the hydrochloride crystal form C of the compound of the formula I has diffraction peaks at 21.5443 +/-0.2 DEG, 27.3605 +/-0.2 DEG, 10.0792 +/-0.2 DEG and 18.8112 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the phosphate crystal form A of the compound of the formula I has diffraction peaks at 12.8284 +/-0.2 degrees, 21.1193 +/-0.2 degrees, 22.7554 +/-0.2 degrees and 12.4119 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the fumarate salt of the compound of the formula I has a crystal form A, and an X-ray powder diffraction pattern expressed by a 2 theta angle has diffraction peaks at 5.1732 +/-0.2 DEG, 7.9252 +/-0.2 DEG, 10.2736 +/-0.2 DEG and 18.8307 +/-0.2 DEG;

the 1, 5-naphthalene disulfonate crystal form A of the compound of the formula I has diffraction peaks at 7.7555 +/-0.2 DEG, 9.6043 +/-0.2 DEG, 23.0949 +/-0.2 DEG and 17.5044 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

The 1, 5-naphthalene disulfonate crystal form B of the compound of the formula I has diffraction peaks at 15.0980 +/-0.2 DEG, 20.3818 +/-0.2 DEG, 13.6481 +/-0.2 DEG and 24.7069 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the p-toluenesulfonate crystal form A of the compound of the formula I has diffraction peaks at 4.0699 +/-0.2 DEG, 20.3148 +/-0.2 DEG, 14.9056 +/-0.2 DEG and 18.3888 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the hydrobromide crystal form A of the compound of the formula I has diffraction peaks at 4.1403 +/-0.2 DEG, 11.1940 +/-0.2 DEG, 27.3198 +/-0.2 DEG and 17.4698 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the maleate crystal form A of the compound of the formula I has diffraction peaks at 4.4590 +/-0.2 degrees, 10.0991 +/-0.2 degrees, 13.6435 +/-0.2 degrees and 20.6462 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the maleate crystal form E of the compound of the formula I has diffraction peaks at 4.4072 +/-0.2 DEG, 13.3026 +/-0.2 DEG, 27.4367 +/-0.2 DEG and 21.9948 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the maleate crystal form F of the compound of the formula I has diffraction peaks at 10.9668 +/-0.2 DEG, 7.8002 +/-0.2 DEG, 6.1349 +/-0.2 DEG and 12.3076 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

The maleate crystal form H of the compound of the formula I has diffraction peaks at 4.5619 +/-0.2 DEG, 13.5614 +/-0.2 DEG, 13.0298 +/-0.2 DEG and 10.2862 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the maleate crystal form I of the compound of the formula I has diffraction peaks at 5.4040 +/-0.2 DEG, 9.4028 +/-0.2 DEG, 10.4407 +/-0.2 DEG and 8.8892 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle;

the maleate crystal form J of the compound of the formula I has diffraction peaks at 5.4594 +/-0.2 DEG, 25.5787 +/-0.2 DEG, 17.8675 +/-0.2 DEG and 10.5280 +/-0.2 DEG in an X-ray powder diffraction pattern expressed by a 2 theta angle.

8. A crystalline form of a pharmaceutically acceptable salt of a compound of formula I as claimed in claim 7,

when the pharmaceutically acceptable salt of the compound of formula I is in form a hydrochloride of the compound of formula I, the hydrochloride of the compound of formula I satisfies one or more of the following conditions:

(1) The hydrochloride crystal form A of the compound of the formula I has an X-ray powder diffraction pattern expressed by 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 25.4625 + -0.2 °, 25.7474 + -0.2 °, 14.8470 + -0.2 °, 10.5627 + -0.2 ° and 25.0104 + -0.2 °;

(2) The hydrochloride crystal form A of the compound of the formula I has a thermogravimetric analysis chart with a weight loss of 6-8%, such as 7.1%, when the temperature is initially heated to 110+/-5 ℃; heating from 110±5 ℃ to 200±5 ℃ with a sample weight loss of 7% -9%, such as 7.9%;

(3) The hydrochloride crystal form A of the compound of the formula I has endothermic peaks at 115.4+/-5 ℃ and 185.0+/-5 ℃ in a differential scanning calorimetry chart; and/or, an exothermic peak at 218.3 ℃ ± 5 ℃;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in form B, the hydrochloride of the compound of formula I satisfies one or more of the following conditions:

(1) The hydrochloride crystal form B of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 27.3296 + -0.2 °, 17.6049 + -0.2 °, 27.5618 + -0.2 °, 26.3637 + -0.2 ° and 25.6428 + -0.2 °;

(2) The hydrochloride crystal form B of the compound of the formula I has a thermogravimetric analysis chart with a weight loss of 4% -6%, such as 4.8%, when the temperature is initially heated to 150+/-5 ℃; heating from 150±5 ℃ to 230±5 ℃, the sample weight loss being 6.5% -8.5%, for example 7.6%;

(3) The hydrochloride crystal form B of the compound of the formula I has an endothermic peak at 223.0+/-5 ℃ in a differential scanning calorimeter diagram;

Or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in form C, the hydrochloride of the compound of formula I satisfies one or more of the following conditions:

(1) The hydrochloride crystal form C of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 14.1629 + -0.2 °, 8.5449 + -0.2 °, 26.7582 + -0.2 °, 6.8670 + -0.2 ° and 17.2037 + -0.2 °;

(2) The hydrochloride crystal form C of the compound of the formula I has a thermogravimetric analysis of 1.5% -3%, such as 2.2% of the weight loss at 150+/-5 ℃; a weight loss of 6.5% -8.5%, e.g. 7.5%, at 150 ℃ to 250 ℃;

(3) The hydrochloride crystal form C of the compound of the formula I has an endothermic peak at 248.2+/-5 ℃ in a differential scanning calorimeter diagram;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in form a of the phosphate salt of the compound of formula I, the phosphate salt of the compound of formula I satisfies one or more of the following conditions:

(1) The phosphate crystal form A of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 24.1820 + -0.2 °, 19.6004 + -0.2 °, 24.9449 + -0.2 °, 17.7015 + -0.2 ° and 25.7812 + -0.2 °;

(2) The phosphate form A of the compound of formula I has a thermogravimetric analysis with a weight loss of 1% -3%, for example 2.1%, when initially heated to 65+ -5deg.C; heating from 65±5 ℃ to 125±5 ℃ with a sample weight loss of 2% -4%, such as 2.8%;

(3) The differential scanning calorimetry diagram of the phosphate crystal form A of the compound of the formula I has endothermic peaks at one or more of 81.7+/-5 ℃, 92.1+/-5 ℃ and 139.2+/-5 ℃;

or alternatively, the first and second heat exchangers may be,

when the crystalline form of the pharmaceutically acceptable salt of the compound of formula I is the fumarate salt crystalline form a of the compound of formula I, the fumarate salt crystalline form a of the compound of formula I satisfies one or more of the following conditions:

(1) The fumarate salt of the compound of formula I has a crystal form A, an X-ray powder diffraction pattern expressed by 2 theta angles and diffraction peaks at one or more of the following 2 theta angles: 24.8824 + -0.2 °, 12.0866 + -0.2 °, 15.4296 + -0.2 °, 23.9878 + -0.2 ° and 13.0765 + -0.2 °;

(2) The fumarate salt of the compound of formula I in form a has a thermogravimetric analysis of 2% -4%, for example 2.6% loss in weight when initially heated to 150±5 ℃; heating from 150±5 ℃ to 240±5 ℃ with a sample weight loss of 19% -22%, such as 21.2%;

(3) The fumarate crystal form A of the compound shown in the formula I has an endothermic peak at 224.7+/-5 ℃ in a differential scanning calorimeter;

Or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is crystalline form a of the 1, 5-naphthalene disulfonate of the compound of formula I, the 1, 5-naphthalene disulfonate of the compound of formula I satisfies one or more of the following conditions:

(1) The 1, 5-naphthalene disulfonate crystal form A of the compound of the formula I has an X-ray powder diffraction pattern expressed by 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 20.2234 + -0.2 °, 22.5424 + -0.2 °, 16.5111 + -0.2 °, 24.1101 + -0.2 ° and 11.2117 + -0.2 °;

(2) The 1, 5-naphthalene disulfonate crystalline form A of the compound of formula I has a thermogravimetric analysis of 2.5% to 4.5%, for example 3.5% loss in weight when initially heated to 130.+ -. 5 ℃; heating from 130±5 ℃ to 175±5 ℃ and sample weight loss of 1.5% -3.5%, for example 2.6%;

(3) The 1, 5-naphthalene disulfonate crystal form A of the compound of the formula I has an endothermic peak at one or more of 57.7+/-5 ℃, 82.9+/-5 ℃, 166.9+/-5 ℃ and 211.1+/-5 ℃ in a differential scanning calorimeter diagram;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is crystalline form B of the 1, 5-naphthalene disulfonate of the compound of formula I, the 1, 5-naphthalene disulfonate of the compound of formula I satisfies one or more of the following conditions:

(1) The 1, 5-naphthalene disulfonate crystal form B of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 15.8095 + -0.2 °, 10.8634 + -0.2 °, 16.7992 + -0.2 °, 26.2961 + -0.2 ° and 12.3107 + -0.2 °;

(2) The 1, 5-naphthalene disulfonate crystalline form B of the compound of formula I has a thermogravimetric analysis with a weight loss of 3.5% to 5.5%, for example 4.3%, at initial heating to 200±5 ℃;

(3) The crystal form B of the 1, 5-naphthalene disulfonate of the compound of the formula I has a Differential Scanning Calorimetry (DSC) chart with endothermic peaks at one or more of 57.0+/-5 ℃, 82.5+/-5 ℃ and 276.1 +/-5 ℃;

or alternatively, the first and second heat exchangers may be,

when the crystal form of the pharmaceutically acceptable salt of the compound of formula I is the p-toluenesulfonate crystal form a of the compound of formula I, the p-toluenesulfonate crystal form a of the compound of formula I satisfies one or more of the following conditions:

(1) The p-toluenesulfonate crystal form A of the compound of the formula I has an X-ray powder diffraction pattern expressed by 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 22.0879 + -0.2 °, 25.9320 + -0.2 °, 11.8243 + -0.2 °, 17.2270 + -0.2 ° and 24.5224 + -0.2 °;

(2) The p-toluenesulfonate crystal form A of the compound of the formula I has a thermogravimetric analysis chart which is heated to 75+/-5 ℃ at the beginning, and the weight loss of a sample is 3.5% -5.5%, such as 4.3%; heating from 75±5 ℃ to 120±5 ℃, the sample weight loss of 5% -7%, such as 6.1%;

(3) The p-toluenesulfonate crystal form A of the compound of the formula I has an endothermic peak at 111.1+/-5 ℃ in a differential scanning calorimeter diagram;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in form a of the hydrobromide salt of the compound of formula I, the hydrobromide salt of the compound of formula I satisfies one or more of the following conditions:

(1) The hydrobromide crystalline form A of the compound of formula I, which has an X-ray powder diffraction pattern expressed in terms of 2 theta angles, also has diffraction peaks at one or more of the following 2 theta angles: 20.6495 + -0.2 °, 8.7348 + -0.2 °, 18.5192 + -0.2 °, 16.0192 + -0.2 ° and 19.6807 + -0.2 °;

(2) The hydrobromide crystalline form a of the compound of formula I has a thermogravimetric analysis of 4.5% to 6.5%, for example 5.6% loss of weight when initially heated to 200±5 ℃;

(3) The hydrobromide crystal form A of the compound of the formula I has a differential scanning calorimeter with endothermic peaks at one or more of 97.7+/-5 ℃, 179.4+/-5 ℃, 230.7+/-5 ℃ and 254.9+/-5 ℃;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in form a maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies one or more of the following conditions:

(1) The maleate salt of the compound of formula I, form A, has an X-ray powder diffraction pattern expressed in terms of 2 theta angles, and also has diffraction peaks at one or more of the following 2 theta angles: 25.9433 + -0.2 °, 17.3036 + -0.2 °, 26.3520 + -0.2 °, 18.2594 + -0.2 ° and 17.8271 + -0.2 °;

(2) The maleate salt of the compound of formula I, form A, has a thermogravimetric analysis of 2.5% to 3.5%, for example 2.8%, loss of weight when initially heated to 150+ -5deg.C; heating from 150 ℃ to 230 ℃ with a sample weight loss of 19% -21%, such as 19.3%;

(3) The maleate crystal form A of the compound of the formula I has an endothermic peak at 200.3+/-20 ℃ in a differential scanning calorimeter diagram;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is crystalline form E of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies one or more of the following conditions:

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 20.1322 + -0.2 °, 18.1840 + -0.2 °, 12.8549 + -0.2 °, 22.7709 + -0.2 ° and 13.6555 + -0.2 °;

(2) The maleate salt of the compound of formula I has a thermogravimetric analysis of 2.5% to 4.5%, for example 3.4% loss of weight when initially heated to 150±5 ℃; heating from 150 ℃ to 250 ℃ with a sample weight loss of 19% -21%, such as 19.7%;

(3) The maleate crystal form E of the compound of the formula I has an endothermic peak at 194.2+/-5 ℃ in a differential scanning calorimeter diagram;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is crystalline form F of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies one or more of the following conditions:

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 17.6068 + -0.2 °, 16.7364 + -0.2 °, 25.6746 + -0.2 °, 23.5852 + -0.2 ° and 20.2850 + -0.2 °;

(2) The maleate salt of the compound of formula I has a thermogravimetric analysis of 2% to 4%, for example 2.9%, loss of weight at initial heating to 150±5 ℃; heating from 150 ℃ to 250 ℃ with a sample weight loss of 17.5% -19.5%, e.g. 18.7%;

(3) The maleate crystal form F of the compound of the formula I has a differential scanning calorimeter with endothermic peaks at one or more of 65.3+/-5 ℃, 81.7+/-5 ℃ and 180.8 +/-5 ℃;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in the form of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies one or more of the following conditions:

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 18.3628 + -0.2 °, 25.9556 + -0.2 °, 26.6709 + -0.2 °, 20.7641 + -0.2 ° and 12.4688 + -0.2 °;

(2) The maleate salt of the compound of formula I has a thermogravimetric analysis of 1% -2%, for example 1.4% loss in weight when initially heated to 150±5 ℃; heating from 150 ℃ to 250 ℃ with a sample weight loss of 16.5% -18.5%, for example 17.4%;

(3) The maleate crystal form H of the compound of the formula I has an endothermic peak at 188.6+/-5 ℃ in a differential scanning calorimeter diagram;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in the form I of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies one or more of the following conditions:

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles, and also has diffraction peaks at one or more of the following 2 theta angles: 12.6630 + -0.2 °, 25.4555 + -0.2 °, 13.6954 + -0.2 °, 15.5008 + -0.2 ° and 17.6958 + -0.2 °;

(2) The maleate salt of the compound of formula I has a thermogravimetric analysis of 2.5% to 4.5% loss of weight, for example 3.5%, when heated to 130±5 ℃; heating from 130 ℃ to 250 ℃ with a sample weight loss of 19% -21%, such as 20.2%;

(3) The maleate crystal form I of the compound of the formula I has endothermic peaks at 112.9+/-5 ℃ and 202.5+/-5 ℃ in a differential scanning calorimeter diagram; and/or, an exothermic peak at 161.5±5 ℃;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is crystalline form J of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies one or more of the following conditions:

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ angles, and also has diffraction peaks at one or more of the following 2θ angles: 15.7099 + -0.2 °, 27.1774 + -0.2 °, 23.6955 + -0.2 °, 9.4120 + -0.2 ° and 8.9158 + -0.2 °;

(2) The maleate salt of the compound of formula I, form J, has a thermogravimetric analysis of 6% to 7% weight loss, e.g. 6.4%, when initially heated to 150±5 ℃; heating from 150 ℃ to 250 ℃ with a sample weight loss of 19.5% -21.5%, for example 20.5%;

(3) The maleate crystal form J of the compound of the formula I has a differential scanning calorimeter with an endothermic peak at 193.7+/-5 ℃; and/or, there is an exothermic peak at 162.1.+ -. 5 ℃.

9. A crystalline form of a pharmaceutically acceptable salt of a compound of formula I as claimed in claim 7,

When the pharmaceutically acceptable salt of the compound of formula I is in form a hydrochloride of the compound of formula I, the hydrochloride of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The hydrochloride crystal form A of the compound of the formula I has an X-ray powder diffraction pattern expressed by 2 theta angles, and further has diffraction peaks at one or more of the following 2 theta 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 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 4;

(2) The hydrochloride crystal form A of the compound of the formula I is basically shown in the figure 5, and the differential scanning thermogram and thermogravimetric analysis chart of the hydrochloride crystal form A are shown in the figure;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in form B, the hydrochloride of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The hydrochloride crystal form B of the compound of the formula I has an X-ray powder diffraction pattern expressed by 2 theta angles, and further has diffraction peaks at one or more of the following 2 theta 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 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 7;

(2) The hydrochloride crystal form B of the compound of the formula I is basically shown in figure 8 in a differential scanning thermogram and a thermogravimetric analysis chart;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in form C, the hydrochloride of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The hydrochloride crystal form C of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles, and further has diffraction peaks at one or more of the following 2 theta 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 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 10;

(2) The hydrochloride crystal form C of the compound of the formula I is basically shown in figure 11 in a differential scanning thermogram and a thermogravimetric analysis chart;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in the form of the phosphate form a of the compound of formula I, the phosphate form a of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The phosphate crystal form A of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and also has diffraction peaks at one or more of the following 2 theta angles: 20.4385 + -0.2 °, 14.9572 + -0.2 °, 16.8423 + -0.2 °, 5.2374 + -0.2 ° and 31.8376 + -0.2 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 13;

(2) The differential scanning thermogram and thermogravimetric analysis of the phosphate form a of the compound of formula I is substantially as shown in figure 14;

or alternatively, the first and second heat exchangers may be,

when the crystalline form of the pharmaceutically acceptable salt of the compound of formula I is the fumarate salt crystalline form a of the compound of formula I, the fumarate salt crystalline form a of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The fumarate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles, and further has diffraction peaks at one or more of the following 2 theta angles: 25.7497 + -0.2 °, 27.5661 + -0.2 ° and 28.4676 + -0.2 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 16;

(2) The fumarate salt crystal form A of the compound of the formula I has a differential scanning thermogram and a thermogravimetric analysis chart which are basically shown in figure 17;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is crystalline form a of the 1, 5-naphthalene disulfonate of the compound of formula I, the 1, 5-naphthalene disulfonate of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The 1, 5-naphthalene disulfonate crystal form A of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and further has diffraction peaks at one or more of the following 2 theta angles: 15.6086 + -0.2 °, 19.5194 + -0.2 °, 12.9255 + -0.2 °, 26.2933 + -0.2 ° and 27.8190 + -0.2 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 19;

(2) The 1, 5-naphthalene disulfonate crystal form A of the compound of the formula I is basically shown in figure 20 in a differential scanning thermogram and a thermogravimetric analysis chart;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is crystalline form B of the 1, 5-naphthalene disulfonate of the compound of formula I, the 1, 5-naphthalene disulfonate of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The 1, 5-naphthalene disulfonate crystal form B of the compound of the formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles and further has diffraction peaks at one or more of the following 2 theta 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 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 22;

(2) The differential scanning calorimetry chart and thermogravimetric analysis chart of the 1, 5-naphthalene disulfonate crystal form B of the compound of the formula I are basically shown in figure 23;

or alternatively, the first and second heat exchangers may be,

when the crystal form of the pharmaceutically acceptable salt of the compound of formula I is the p-toluenesulfonate crystal form a of the compound of formula I, the p-toluenesulfonate crystal form a of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The p-toluenesulfonate crystal form A of the compound of the formula I has an X-ray powder diffraction pattern expressed by 2 theta angles and further has diffraction peaks at one or more of the following 2 theta 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 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 25;

(2) The p-toluenesulfonate crystal form A of the compound of the formula I is basically shown in figure 26 in a differential scanning thermogram and a thermogravimetric analysis chart;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in the form of the hydrobromide salt of the compound of formula I, form a of the hydrobromide of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The hydrobromide crystal form A of the compound of the formula I has an X-ray powder diffraction pattern expressed by a 2 theta angle and also has diffraction peaks at the following 2 theta angles: 25.5412 + -0.2 °; preferably, the X-ray powder diffraction pattern in terms of 2θ is substantially as shown in fig. 28;

(2) The hydrobromide crystalline form a of the compound of formula I has a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 29;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in the form of maleate form a of the compound of formula I, the maleate form a of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles, and further has diffraction peaks at one or more of the following 2 theta angles: 15.0805 + -0.2 °, 23.0488 + -0.2 ° and 11.6637 + -0.2 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 31;

(2) The maleate salt crystal form A of the compound of the formula I has a differential scanning thermogram and a thermogravimetric analysis chart which are basically shown in figure 32;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in the form of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 34;

(2) The maleate salt crystal form E of the compound of the formula I has a differential scanning thermogram and a thermogravimetric analysis chart substantially shown in figure 35;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is crystalline form F of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 37;

(2) The maleate salt of the compound of formula I, form F, has a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 38;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in the form of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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 °; preferably, the X-ray powder diffraction pattern in terms of 2θ is substantially as shown in fig. 40;

(2) The maleate salt crystal form H of the compound of the formula I is basically shown in figure 41 in a differential scanning thermogram and a thermogravimetric analysis chart;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is in the form I of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles, and also has diffraction peaks at one or more of the following 2 theta 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 °; preferably, the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 43;

(2) The maleate salt of the compound of formula I is in form I, and the differential scanning thermogram and thermogravimetric analysis of the maleate salt is substantially as shown in figure 44;

or alternatively, the first and second heat exchangers may be,

when the pharmaceutically acceptable salt of the compound of formula I is crystalline form J of the maleate salt of the compound of formula I, the maleate salt of the compound of formula I satisfies the following conditions (1) and/or (2):

(1) The maleate salt of the compound of formula I has an X-ray powder diffraction pattern expressed in terms of 2θ angles, and further has diffraction peaks at one or more of the following 2θ 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 °; preferably, the X-ray powder diffraction pattern in terms of 2θ is substantially as shown in fig. 46;

(2) The maleate salt of the compound of formula I, form J, has a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 47.

10. A process for the preparation of a crystalline form of a pharmaceutically acceptable salt of a compound of formula I according to any one of claims 7 to 9, characterized in that it is a process for the preparation of the maleate salt form a, the maleate salt form E, the maleate salt form F or the sulfate salt form H of the compound of formula I; wherein,

The preparation method of the maleate crystal form A of the compound of the formula I comprises the following steps: crystallizing the compound of the formula I and maleic acid in a solvent at the temperature of 10-70 ℃ to obtain a maleate crystal form A of the compound of the formula I;

the preparation method of the maleate crystal form E of the compound of the formula I comprises the following steps: dissolving the maleate crystal form A sample of the compound of the formula I in an ether solvent at the temperature of 10-30 ℃, and then placing filtrate in an anti-solvent atmosphere for gas-liquid permeation to obtain a maleate crystal form E of the compound of the formula I;

the preparation method of the maleic acid crystal form F of the compound of the formula I comprises the following steps: forming a suspension of a maleate crystal form A sample of the compound of the formula I in a solvent at the temperature of 10-30 ℃ for crystallization to obtain a maleate crystal form F of the compound of the formula I;

the preparation method of the maleic acid crystal form H of the compound of the formula I comprises the following steps: and (3) dissolving the maleate crystal form A sample of the compound of the formula I in an ether solvent at the temperature of 10-30 ℃, and then placing filtrate in an anti-solvent atmosphere for gas-liquid permeation to obtain the compound.

11. A process for the preparation of a crystalline form of a pharmaceutically acceptable salt of a compound of formula I as claimed in claim 10,

When the preparation method of the crystal form is the preparation method of the maleate crystal form A of the compound of the formula I, the solvent is a ketone solvent and/or an ester solvent; the ketone solvent is preferably acetone, 2-butanone, methyl isobutyl ketone or N-methyl pyrrolidone; the ester solvent is preferably ethyl acetate; the mass volume ratio of the ketone solvent is preferably 30-50mg/mL, for example 40mg/mL; the mass volume ratio of the ester solvent is preferably 30-80mg/mL, for example 34mg/mL or 74mg/mL;

or, when the preparation method of the crystal form is the preparation method of the maleate crystal form E of the compound of the formula I, the ether solvent is preferably methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 1, 4-dioxane and anisole; the antisolvent is preferably an alkyl solvent, preferably n-hexane or n-heptane;

or, when the preparation method of the crystal form is the preparation method of the maleate crystal form F of the compound of the 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, and the ether solvent is preferably tetrahydrofuran, 2-methyltetrahydrofuran; the mass volume ratio of the mixed solvent of the ether solvent and the water is preferably 30-50mg/mL, for example 40mg/mL; the volume ratio (v/v) of the ether solvent to water is preferably 10 to 25:1, e.g., 22:1;

Or when the preparation method of the crystal form is the preparation method of the maleate crystal form H of the compound of the formula I, the ether solvent is preferably methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 1, 4-dioxane and anisole; the antisolvent is preferably an ether solvent, preferably methyl tert-butyl ether.

12. A pharmaceutical composition comprising a therapeutically effective dose of substance a and a pharmaceutically acceptable carrier, diluent or excipient; substance a is a crystalline form of a compound of formula I as defined in any one of claims 1 to 3, a pharmaceutically acceptable salt of a compound of formula I as defined in any one of claims 4 to 6 or a crystalline form of a pharmaceutically acceptable salt of a compound of formula I as defined in any one of claims 7 to 9.

13. Use of a substance B in the preparation of a medicament or BTK inhibitor for the prophylaxis and/or treatment of a disease or condition, said substance B being a crystalline form of a compound of formula I according to any one of claims 1 to 3, a pharmaceutically acceptable salt of a compound of formula I according to any one of claims 4 to 6, a crystalline form of a pharmaceutically acceptable salt of a compound of formula I according to any one of claims 7 to 9 or a pharmaceutical composition according to claim 12;

Preferably, the disease or condition is selected from: heterologous immune diseases, autoimmune diseases, inflammatory diseases, and cancers.