CN116768896A

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

Info

Publication number: CN116768896A
Application number: CN202310243277.6A
Authority: CN
Inventors: 赵金柱; 曹煜东; 周福生; 朱林东; 刘祥超; 兰炯
Original assignee: Genfleet Therapeutics Shanghai Inc; Zhejiang Genfleet Therapeutics Co Ltd
Current assignee: Genfleet Therapeutics Shanghai Inc; Zhejiang Genfleet Therapeutics Co Ltd
Priority date: 2022-03-15
Filing date: 2023-03-14
Publication date: 2023-09-19
Also published as: WO2023174300A1

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 forms of BTK inhibitor, acid salt thereof and crystal forms of acid salt thereof

The application claims priority from China patent application 202210256052X with application date of 2022, 3 and 15. The present application incorporates the entirety of the above-mentioned chinese patent application.

Technical Field

The application relates to the technical field of medicines, in particular to a crystal form of a BTK inhibitor, an acid salt thereof and a crystal form of the acid salt thereof.

Background

Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of non-receptor tyrosine kinases, a key kinase in the B cell antigen receptor (BCR) signaling pathway. The signals emitted by BCR control a range of effector responses including activation, proliferation and differentiation of mature antibody producing cells. Aberrant BCR-mediated signaling can cause deregulated B-cell activation and/or pathogenic autoantibody formation, leading to a variety of human diseases including cancer, autoimmune diseases, and xenogenic immune diseases. Ibrutinib (ibutinib, trade name Imbmvica) has met with great success as the first BTK inhibitor to enter the market. However, as with many other anticancer drugs, some patients exhibit resistance to the drug. It was found that the C481S mutation of BTK kinase is the main cause of drug resistance, ibrutinib is pharmacodynamic through irreversible covalent binding to the C481 tryptophan residue of BTK kinase, and the C481S mutation turns tryptophan into serine and loses the ability to covalently bind ibrutinib. In the above background, there remains a need in the art to develop more potent inhibitors of BTK.

The crystal structure of the active ingredient of the drug often causes the differences of various physicochemical properties of the drug, such as solubility, dissolution rate, melting point, density, hardness and the like, and the differences directly affect the prescription preparation process, storage method and in vivo pharmacokinetic performance of the drug, thereby affecting the bioavailability, clinical curative effect and safety of the drug. Therefore, it is very important to deeply study the polymorphism of the medicine and find the crystal form with good properties.

Disclosure of Invention

The invention aims to solve the technical problem of overcoming the defect of few BTK inhibitor types in the prior art, and provides a crystal form of the BTK inhibitor, an acid salt thereof and a crystal form of the acid salt thereof. The crystal forms of the BTK inhibitor, the acid salt thereof and the crystal forms of the acid salt thereof meet the requirements of medicines in the aspects of stability, hygroscopicity and the like, and have very important significance for medicine development.

In a first aspect the present invention provides a crystalline form a of the free base of a compound of formula I having an X-ray powder diffraction pattern in terms of 2Θ having 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 terms of 2Θ, and further 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 compound of formula I, form a, 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: 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 in terms of 2θ angles substantially 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) of 2.0% to 3.5% (e.g., 3.1%) weight loss when initially heated to 200±5 ℃ (the percentage weight loss is the percentage of the weight of the sample reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the compound of formula I, form A, has a differential scanning calorimetry thermogram with an endotherm at 327.4+ -5deg.C.

In a preferred embodiment, the compound of formula I is in form a as free base, and the differential scanning thermogram and thermogravimetric analysis are substantially as shown in figure 2.

The second aspect of the present invention also provides a crystalline form C of the free base of the compound of formula I, having an X-ray powder diffraction pattern in terms of 2Θ with diffraction peaks 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 terms of 2Θ, and further 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 compound of formula I, form C, 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: 9.0935 ±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 in terms of 2θ angles substantially as shown in figure 49.

In a preferred embodiment, the free base form C of the compound of formula I has a thermogravimetric analysis of 1% to 3% (e.g., 2.7%) weight loss (the percentage of weight loss is the percentage of weight reduced by the sample to the weight of the sample before the weight loss) at 200±5 ℃ at the start of heating.

In a preferred embodiment, the free base form C of the compound of formula I has a differential scanning calorimetry trace with an endotherm at 329.3 ±5 ℃; and/or, an exothermic peak at 311.3.+ -. 5 ℃.

In a preferred embodiment, the free base form C of the compound of formula I is characterized by a differential scanning thermogram and thermogravimetric analysis substantially as depicted in figure 50.

In a third aspect the present invention provides a crystalline form D of the free base of a compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ with diffraction peaks 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 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°.

Preferably, the compound of formula I, form D, 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: 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 free base form D of the compound of formula I has an X-ray powder diffraction pattern in terms of 2θ angles 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 of 3% to 5% (e.g., 4.1%) weight loss at initial heating to 150±5 ℃, and a sample weight loss of 6% to 8% (e.g., 7.1%) from 150±5 ℃ to 230±5 ℃ (the weight loss is the percentage of the weight of the sample reduced to the weight of the sample prior to 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 ℃ and/or 328.9 ±5 ℃ in a differential scanning calorimetry pattern.

In a preferred embodiment, the free base form D of the compound of formula I is characterized by a differential scanning thermogram and thermogravimetric analysis substantially as depicted in figure 53.

In a fourth aspect, the present invention provides a crystalline form E of the free base of a compound of formula I, having an X-ray powder diffraction pattern in terms of 2-theta 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 terms of 2Θ, and further 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 compound of formula I, form E, 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: 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 free base form E of the compound of formula I has an X-ray powder diffraction pattern in terms of 2θ angles 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 of 1% to 3% (e.g., 1.8%) weight loss at initial heating to 80±5 ℃, heating from 80±5 ℃ to 180±5 ℃ and a sample weight loss of 16% to 18% (e.g., 16.8%) (the weight loss is the percentage of weight of sample reduced to the weight of sample prior to this weight loss).

In a preferred embodiment, the free base form E of the compound of formula I has an endothermic peak at 144.5±5 ℃ and/or 329.1±5 ℃ in a differential scanning calorimetry pattern.

In a preferred embodiment, the free base form E of the compound of formula I is characterized by a differential scanning thermogram and thermogravimetric analysis substantially as depicted in figure 56.

In a fifth aspect the invention provides a pharmaceutically acceptable salt of a compound of formula I; the pharmaceutically acceptable salt is a salt formed by a compound of the formula I and acid; the acid is inorganic acid or organic acid;

in a preferred embodiment, the molar ratio of the compound of formula I to the acid is 1 (0.5-2), e.g. 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 mineral 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-toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid, 2-hydroxy ethane sulfonic acid, ethane sulfonic 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 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.

The pharmaceutically acceptable salts of the compounds of formula I may be prepared by conventional salt-forming reactions in the art. For example, the pharmaceutically acceptable salts of the compounds of formula I may be prepared by:

carrying out salt forming reaction on a compound of the formula I and acid in a solvent to obtain pharmaceutically acceptable salts of the compound of the 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), e.g. 1 (1-2), and further e.g. 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), e.g., 1 (0.5-1.5), and further e.g., 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), e.g., 1 (0.5-1.5), and further e.g., 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), e.g. 1 (0.5-1.5), e.g. 1:1;

when the acid is 1, 5-naphthalene disulfonic acid, the molar ratio of said compound of formula I to 1, 5-naphthalene disulfonic acid is 1 (0.5-2), e.g. 1 (0.5-1.5), e.g. 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), e.g. 1 (0.5-1.5), e.g. 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), e.g. 1 (0.5-1.5), and further e.g. 1:1.

In a sixth aspect the present invention provides a crystalline form a of the hydrochloride salt of the compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ with diffraction peaks at 13.2577 ± 0.2 °, 19.0205 ± 0.2 °, 26.6619 ± 0.2 ° and 24.4646 ± 0.2 °; the hydrochloride of the compound shown as the formula I is as described above;

in a preferred embodiment, form a of the hydrochloride salt of the compound of formula I; 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, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, further 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, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, 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 crystalline form a of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern in terms of 2θ, substantially as shown in figure 4.

In a preferred embodiment, the thermal gravimetric analysis of form a of the hydrochloride salt of the compound of formula I exhibits a weight loss of 6% to 8% (e.g., 7.1%) when initially heated to 110±5 ℃, and a weight loss of 7% to 9% (e.g., 7.9%) when heated from 110±5 ℃ to 200±5 ℃ (the weight loss is the percentage of the weight of the sample that was reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the hydrochloride salt of the compound of formula I, form a, has a differential scanning calorimetry pattern with endothermic peaks at 115.4 ± 5 ℃ and 185.0 ± 5 ℃; and/or, an exothermic peak at 218.3 ℃ ± 5 ℃.

In a preferred embodiment, the hydrochloride salt of the compound of formula I, form a, has a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 5.

In a seventh aspect the present invention provides a crystalline form B of the hydrochloride salt of the compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ with diffraction peaks at 11.2971 ± 0.2 °, 4.1094 ± 0.2 °, 16.0047 ± 0.2 ° and 18.5553 ± 0.2 °; the hydrochloride of the compound shown as the formula I is as described above;

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

In a preferred embodiment, form B of the hydrochloride salt of the compound of formula I, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, further 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, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, 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 crystalline form B of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern in terms of 2θ angles substantially as shown in figure 7.

In a preferred embodiment, the thermogravimetric analysis of form B of the hydrochloride salt of the compound of formula I loses 4% to 6% (e.g., 4.8%) by initial heating to 150±5 ℃, from 150±5 ℃ to 230±5 ℃, and the sample loses 6.5% to 8.5% (e.g., 7.6%) (the percentage of weight loss is the percentage of weight of the sample that was reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the hydrochloride salt of the compound of formula I, form B, has a differential scanning calorimetry trace with an endotherm at 223.0±5 ℃.

In a preferred embodiment, the hydrochloride salt of the compound of formula I, form B, has a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 8.

In an eighth aspect, the present invention provides a crystalline form C of the hydrochloride salt of the compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ with diffraction peaks at 21.5443 ± 0.2 °, 27.3605 ± 0.2 °, 10.0792 ± 0.2 ° and 18.8112 ± 0.2 °; the hydrochloride of the compound shown as the formula I is as described above;

in a preferred embodiment, form C of the hydrochloride salt of the compound of formula I; wherein the mol ratio of the compound of the formula I to the hydrochloric acid is 1 (0.9-1.0); for example 1:0.9.

In a preferred embodiment, form C of the hydrochloride salt of the compound of formula I, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, further 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 hydrochloride of the compound of formula I in form C 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: 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 crystalline form C of the hydrochloride salt of the compound of formula I has an X-ray powder diffraction pattern in terms of 2θ angles substantially as shown in figure 10.

In a preferred embodiment, the thermogram of form C of the hydrochloride salt of the compound of formula I loses weight 1.5% -3% (e.g., 2.2%) at 150±5 ℃ and 6.5% -8.5% (e.g., 7.5%) at 150 ℃ to 250 ℃ (the weight loss is the percentage of the weight of the sample that is reduced to the weight of the sample before this weight loss).

In a preferred embodiment, the hydrochloride salt of the compound of formula I, form C, has a differential scanning calorimetry trace with an endotherm at 248.2±5 ℃.

In a preferred embodiment, the hydrochloride salt of the compound of formula I, form C, has a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 11.

In a ninth aspect, the present invention provides a crystal form a of the phosphate of the compound of formula I, wherein the X-ray powder diffraction pattern expressed as 2θ degrees has diffraction peaks at 12.8284 ±0.2°, 21.1193 ±0.2°, 22.7554 ±0.2° and 12.4119 ±0.2°; the phosphate of the compound shown as the formula I is as described above;

In a preferred embodiment, form a of the phosphate salt 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 1:1.3.

In a preferred embodiment, the phosphate salt of the compound of formula I, form a, 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: 24.1820 ±0.2°, 19.6004 ±0.2°, 24.9449 ±0.2°, 17.7015 ±0.2° and 25.7812 ±0.2°.

Preferably, the phosphate salt of the compound of formula I, form a, has an X-ray powder diffraction pattern expressed in terms of 2θ, 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 crystalline form a of the phosphate salt of the compound of formula I has an X-ray powder diffraction pattern in terms of 2θ angles substantially as shown in figure 13.

In a preferred embodiment, the phosphate salt of the compound of formula I in form a has a thermogravimetric analysis with a weight loss of 1% to 3% (e.g., 2.1%) at 65±5 ℃ when initially heated, and a weight loss of 2% to 4% (e.g., 2.8%) for the sample when heated from 65±5 ℃ to 125±5 ℃ (the weight loss is the percentage of the weight of the sample that was reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the phosphate salt of the compound of formula I, form A, has a differential scanning calorimetry pattern with endothermic peaks at one or more of 81.7+ -5deg.C, 92.1+ -5deg.C and 139.2+ -5deg.C.

In a preferred embodiment, the phosphate salt of the compound of formula I in form a has a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 14.

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

in a preferred embodiment, form a of the fumarate salt of the compound of formula I; 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, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, further 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, which has an X-ray powder diffraction pattern expressed in terms of 2θ angles, 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, form a of the fumarate salt of the compound of formula I has an X-ray powder diffraction pattern in terms of 2θ angles substantially as shown in figure 16.

In a preferred embodiment, the fumarate salt of the compound of formula I, form a, has a thermogravimetric analysis with a weight loss of 2% to 4% (e.g., 2.6%) at initial heating to 150±5 ℃, and a weight loss of 19% to 22% (e.g., 21.2%) for the sample at heating from 150±5 ℃ to 240±5 ℃ (the weight loss is the percentage of the weight of the sample reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the fumarate salt of the compound of formula I, form A, has a differential scanning calorimetry trace with an endotherm at 224.7+ -5deg.C.

In a preferred embodiment, form a of the fumarate salt of the compound of formula I is characterized by a differential scanning thermogram and thermogram substantially as shown in figure 17.

In an eleventh aspect, the present invention provides a crystal form a of the 1, 5-naphthalene disulfonate of the compound of the formula I, wherein the X-ray powder diffraction pattern expressed as 2θ has diffraction peaks 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 shown in the formula I is as described above;

In a preferred embodiment, 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, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, further 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, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, 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, crystalline form a of the 1, 5-naphthalene disulfonate of the compound of formula I has an X-ray powder diffraction pattern in terms of 2Θ substantially as shown in figure 19.

In a preferred embodiment, the crystalline form a of the 1, 5-naphthalene disulfonate of the compound of formula I has a thermogravimetric analysis of 2.5% to 4.5% (e.g., 3.5%) weight loss at initial heating to 130±5 ℃, and 1.5% to 3.5% (e.g., 2.6%) weight loss of the sample at from 130±5 ℃ to 175±5 ℃ (the weight loss is the percentage of the weight of the sample reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the crystalline form A of the 1, 5-naphthalene disulfonate of the compound of formula I has a differential scanning calorimetry trace with endothermic peaks at one or more of 57.7.+ -. 5 ℃, 82.9.+ -. 5 ℃, 166.9.+ -. 5 ℃ and 211.1.+ -. 5 ℃.

In a preferred embodiment, form a of the 1, 5-naphthalene disulfonate of the compound of formula I has a differential scanning thermogram and thermogram substantially as shown in figure 20.

In a twelfth aspect, the present invention provides a crystalline form B of the 1, 5-naphthalene disulfonate of the compound of formula I described above, having an X-ray powder diffraction pattern expressed in terms of 2Θ having diffraction peaks at 15.0980 ±0.2°, 20.3818 ±0.2°, 13.6481 ±0.2° and 24.7069 ±0.2°;

in a preferred embodiment, 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, crystalline form B of the 1, 5-naphthalene disulfonate of the compound of formula I, having an X-ray powder diffraction pattern expressed in terms of 2Θ, further having 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, which has an X-ray powder diffraction pattern expressed in terms of 2θ, 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, crystalline form B of the 1, 5-naphthalene disulfonate of the compound of formula I has an X-ray powder diffraction pattern in terms of 2Θ substantially as shown in figure 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 of 3.5% to 5.5% (e.g., 4.3%) weight loss when initially heated to 200±5℃ (the weight loss percentage is the percentage of the weight of the sample reduced to the weight of the sample prior to this weight loss).

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

In a preferred embodiment, form B of the 1, 5-naphthalene disulfonate of the compound of formula I has a differential scanning calorimetry and thermogram substantially as shown in figure 23.

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

In a preferred embodiment, form a of the p-toluenesulfonate salt 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, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, further 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, which has an X-ray powder diffraction pattern expressed in terms of 2θ, 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 crystalline form a of the p-toluenesulfonate salt of the compound of formula I has an X-ray powder diffraction pattern in terms of 2θ angles substantially as shown in figure 25.

In a preferred embodiment, the p-toluenesulfonate salt of the compound of formula I, form A, has a thermogravimetric analysis of 3.5% -5.5% (e.g., 4.3%) sample weight loss when initially heated to 75+ -5deg.C, from 75+ -5deg.C to 120+ -5deg.C, and a sample weight loss of 5% -7% (e.g., 6.1%) (the weight loss percentage is the weight of the sample reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the crystalline form a of the p-toluenesulfonate salt of the compound of formula I has a differential scanning calorimetry trace with an endotherm at 111.1±5 ℃.

In a preferred embodiment, form a of the p-toluenesulfonate salt of the compound of formula I has a differential scanning thermogram and thermogram substantially as shown in figure 26.

In a fourteenth aspect the present invention provides a crystalline form a of the hydrobromide salt of a compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ with diffraction peaks at 4.1403 ± 0.2 °, 11.1940 ± 0.2 °, 27.3198 ± 0.2 ° and 17.4698 ± 0.2 °; the hydrobromide of the compound shown in the formula I is as described above;

in a preferred embodiment, form a of the hydrobromide salt of the 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.

In a preferred embodiment, the crystalline form a of the hydrobromide salt of the compound of formula I, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, further 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, which has an X-ray powder diffraction pattern expressed in terms of 2Θ, further has diffraction peaks at the following 2Θ angles: 25.5412 ±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 in terms of 2Θ, substantially as shown in figure 28.

In a preferred embodiment, the thermal gravimetric analysis of form a of the hydrobromide salt of the compound of formula I exhibits a weight loss of 4.5% -6.5% (e.g., 5.6%) at initial heating to 200±5% (the weight loss percentage is the percentage of the weight of the sample reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the crystalline form A of the hydrobromide of the compound of formula I has a differential scanning calorimetry trace with endothermic peaks at one or more of 97.7+ -5deg.C, 179.4+ -5deg.C, 230.7+ -5deg.C and 254.9+ -5deg.C.

In a preferred embodiment, the crystalline form a of the hydrobromide salt of the compound of formula I has a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 29.

In a fifteenth aspect the present invention provides a crystalline form a of the maleate salt of the compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ having diffraction peaks at 4.4590 ± 0.2 °, 10.0991 ± 0.2 °, 13.6435 ± 0.2 ° and 20.6462 ± 0.2 °; the maleate salt of the compound shown as the 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 maleate salt of the compound of formula I, form a, 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: 25.9433 ±0.2°, 17.3036 ±0.2°, 26.3520 ±0.2°, 18.2594 ±0.2° and 17.8271 ±0.2°.

Preferably, the maleate salt of the compound of formula I, form a, 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: 15.0805 ±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 in terms of 2Θ substantially as shown in figure 31.

In a preferred embodiment, the maleate salt of the compound of formula I in form a has a thermogravimetric analysis of 2.5% to 3.5% (e.g., 2.8%) weight loss at initial heating to 150±5 ℃ from 150 ℃ to 230 ℃ and a sample weight loss of 19% to 21% (e.g., 19.3%) (the weight loss is the percentage of the weight of the sample reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the maleate salt of the compound of formula I, form A, has a differential scanning calorimetry trace with an endotherm at 200.3+ -20deg.C.

In a preferred embodiment, the maleate salt of the compound of formula I, form A, has a differential scanning calorimetry trace with an endotherm at 200.3+ -5deg.C.

In a preferred embodiment, the maleate salt of the compound of formula I is in form a, having a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 32.

In a sixteenth aspect the present invention provides a crystalline form E of the maleate salt of the compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ having diffraction peaks at 4.4072 ± 0.2 °, 13.3026 ± 0.2 °, 27.4367 ± 0.2 ° and 21.9948 ± 0.2 °; the maleate salt of the compound shown as the 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 maleate salt of the compound of formula I has a crystalline form E, which 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: 20.1322 ±0.2°, 18.1840 ±0.2°, 12.8549 ±0.2°, 22.7709 ±0.2° and 13.6555 ±0.2°.

Preferably, the maleate salt of the compound of formula I has a crystalline form E, which 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°.

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 in terms of 2θ angles substantially as shown in figure 34.

In a preferred embodiment, the maleate salt of the compound of formula I in form E has a thermogravimetric analysis of 2.5% to 4.5% (e.g. 3.4%) weight loss at initial heating to 150±5 ℃, from 150 ℃ to 250 ℃ and a sample weight loss of 19% to 21% (e.g. 19.7%) (the weight loss percentage is the weight of the sample reduced to the weight of the sample before this weight loss).

In a preferred embodiment, the maleate salt of the compound of formula I is in form E, which has a differential scanning calorimetry trace with an endotherm at 194.2.+ -. 5 ℃.

In a preferred embodiment, the maleate salt of the compound of formula I is in form E, having a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 35.

In a seventeenth aspect the present invention provides a crystalline form F of the maleate salt of the compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ having diffraction peaks at 10.9668 ± 0.2 °, 7.8002 ± 0.2 °, 6.1349 ± 0.2 ° and 12.3076 ± 0.2 °; the maleate salt of the compound shown as the 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 maleate salt of the compound of formula I, form F, 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: 17.6068 ±0.2°, 16.7364 ±0.2°, 25.6746 ±0.2°, 23.5852 ±0.2° and 20.2850 ±0.2°.

Preferably, the maleate salt of the compound of formula I, form F, 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°.

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 in terms of 2Θ substantially as shown in figure 37.

In a preferred embodiment, the maleate salt of the compound of formula I in form F has a thermogravimetric analysis of 2% to 4% (e.g., 2.9%) weight loss at 150±5 ℃ when initially heated, from 150 ℃ to 250 ℃ and a sample weight loss of 17.5% to 19.5% (e.g., 18.7%) (the weight loss percentage is the weight of the sample reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the maleate salt of the compound of formula I, form F, has a differential scanning calorimetry pattern with endothermic peaks at one or more of 65.3+ -5deg.C, 81.7+ -5deg.C and 180.8 + -5deg.C.

In a preferred embodiment, the maleate salt of the compound of formula I is in form F, having a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 38.

In an eighteenth aspect, the present invention provides a crystalline form H of the maleate salt of the compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ with diffraction peaks at 4.5619 ±0.2°, 13.5614 ±0.2°, 13.0298 ±0.2° and 10.2862 ±0.2°; the maleate salt of the compound shown as the 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 maleate salt of the compound of formula I has a crystalline form H, which 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: 18.3628 ±0.2°, 25.9556 ±0.2°, 26.6709 ±0.2°, 20.7641 ±0.2° and 12.4688 ±0.2°.

Preferably, the maleate salt of the compound of formula I has a crystalline form H, which 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°.

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 in terms of 2θ substantially as shown in figure 40.

In a preferred embodiment, the maleate salt of the compound of formula I in form H has a thermogravimetric analysis of 1% to 2% (e.g., 1.4%) weight loss at initial heating to 150±5 ℃ and 16.5% to 18.5% (e.g., 17.4%) weight loss of the sample at heating from 150 ℃ to 250 ℃ (the weight loss is the percentage of the weight of the sample reduced to the weight of the sample prior to this weight loss).

In a preferred embodiment, the maleate salt of the compound of formula I, form H, has a differential scanning calorimetry trace with an endotherm at 188.6.+ -. 5 ℃.

In a preferred embodiment, the maleate salt of the compound of formula I is in form H, having a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 41.

In a nineteenth aspect, the present invention provides a crystalline form I of the maleate salt of the compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ having 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 shown as the 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 maleate salt of the compound of formula I has a crystalline form I, an X-ray powder diffraction pattern expressed in terms of 2θ, and 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 maleate salt of the compound of formula I has a crystalline form I, an X-ray powder diffraction pattern expressed in terms of 2θ angles, and 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 crystalline form I of the maleate salt of the compound of formula I has an X-ray powder diffraction pattern in terms of 2θ angles substantially as shown in figure 43.

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

In a preferred embodiment, the maleate salt of the compound of formula I has a differential scanning calorimetry trace with endothermic peaks at 112.9 + -5 ℃ and 202.5 + -5 ℃; and/or, an exothermic peak at 161.5.+ -. 5 ℃.

In a preferred embodiment, the maleate salt of the compound of formula I is in form I, having a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 44.

In a twentieth aspect the present invention provides a crystalline form J of the maleate salt of the compound of formula I having an X-ray powder diffraction pattern in degrees 2Θ having diffraction peaks at 5.4594 ±0.2°, 25.5787 ±0.2°, 17.8675 ±0.2° and 10.5280 ±0.2°; the maleate salt of the compound shown as the 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 maleate salt of the compound of formula I, form J, 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: 15.7099 + -0.2 °, 27.1774 + -0.2 °, 23.6955 + -0.2 °, 9.4120 + -0.2 ° and 8.9158 + -0.2 °;

preferably, the maleate salt of the compound of formula I has a crystalline form J, which 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°.

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 in terms of 2-theta angles substantially as shown in figure 46.

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

In a preferred embodiment, the maleate salt of the compound of formula I, form J, has a differential scanning calorimetry trace with an endotherm at 193.7±5 ℃; and/or, there is an exothermic peak at 162.1.+ -. 5 ℃.

In a preferred embodiment, the maleate salt of the compound of formula I is in form J, having a differential scanning thermogram and thermogravimetric analysis substantially as shown in figure 47.

The crystalline forms of the BTK inhibitors of the invention and pharmaceutically acceptable salts thereof and methods of preparing the crystalline forms of the pharmaceutically acceptable salts thereof can be obtained in crystalline form by a number of methods as known in the art.

In a twenty-first aspect of the present invention, a process for preparing the crystalline form a of the maleate salt of the compound of formula I as described above is provided, comprising the steps of: and (3) 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 solvent is ketone solvent (preferably acetone, 2-butanone, methyl isobutyl ketone, N-methylpyrrolidone) and/or ester solvent (preferably ethyl acetate).

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

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.

The crystallization mode can be performed under stirring (such as suspension stirring).

After the crystallization is completed, separation may be performed according to a conventional operation method in the art, such as centrifugation or filtration.

In a twenty-second aspect, the present invention provides a crystalline form a of maleate salt prepared according to the process for preparing crystalline form a of maleate salt of a compound of formula I as described above.

In a twenty-third aspect of the present invention, there is provided a process for preparing the crystalline form E of the maleate salt of the compound of formula I as described above, comprising the steps of: 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 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, n-heptane.

In a twenty-fourth aspect, the present invention provides a crystalline form E of maleate salt prepared according to the process for the preparation of crystalline form E of maleate salt of a compound of formula I as described above.

In a twenty-fifth aspect of the present invention, there is provided a process for the preparation of form F of the maleate salt of a compound of formula I as described above, comprising the steps of: and (3) at the temperature of 10-30 ℃, forming a suspension of a maleate crystal form A sample of the compound of the formula I in a solvent, and crystallizing to obtain a 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 an ether solvent and water, and the ether solvent is preferably tetrahydrofuran or 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.

In a twenty-sixth aspect, the present invention provides a crystalline form F of maleate salt prepared according to the process for preparing crystalline form F of maleate salt of a compound of formula I as described above.

In a twenty-seventh aspect, the present invention provides a process for preparing form H of maleic acid of a compound of formula I, comprising the steps of: 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.

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.

In a twenty-eighth aspect, the present invention provides a crystalline form H of maleate salt prepared according to the process for preparing crystalline form H of maleate salt of a compound of formula I as described above.

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

The thirty-third aspect of the present invention provides the use of substance B in the manufacture of a medicament for the prevention and/or treatment of a disease or condition; the substance B is the above pharmaceutical composition, the above crystal form of the compound of formula I (one or more of the above crystal form A of the free base of the compound of formula I, the above crystal form C of the free base of the compound of formula I, the above crystal form D of the free base of the compound of formula I and the above crystal form E of the free base of the compound of formula I), the above pharmaceutically acceptable salt of the compound of formula I or the above crystal form of the pharmaceutically acceptable salt of the compound of formula I (the above crystal form A of the hydrochloride of the compound of formula I, the above crystal form B of the hydrochloride of the compound of formula I, the above crystal form C of the hydrochloride of the compound of formula I, the above crystal form A of the phosphate of the compound of formula I) one or more of the above-described compound fumarate salt form a of formula I, the above-described compound 1, 5-naphthalene disulfonate salt form B of formula I, the above-described compound p-toluenesulfonate salt form a of formula I, the above-described compound hydrobromide salt form a of formula I, the above-described compound maleate salt form E of formula I, the above-described compound maleate salt form F of formula I, the above-described compound maleate salt form H of formula I, the above-described compound maleate salt form I of formula I, and the above-described compound maleate salt form J of formula I.

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

The amount of substance B is a therapeutically effective amount.

In a thirty-first aspect, the present invention provides the use of the crystalline form of the compound of formula I and the acid salts thereof and the crystalline form of the acid salts thereof or the pharmaceutical composition in the preparation of a BTK inhibitor.

In a preferred embodiment, the crystalline form of the compound of formula I and the acid salts thereof and the crystalline form of the acid salts thereof are present in a therapeutically and/or prophylactically effective amount in a pharmaceutical composition or medicament.

In a preferred embodiment, the disease or condition is selected from the group consisting of: heterologous immune diseases, autoimmune diseases, inflammatory diseases, and cancers.

In a preferred embodiment, the heterologous immune disease, autoimmune disease, inflammatory disease may be selected from the group consisting of: rheumatic diseases, glomerulonephritis, goodpasture syndrome, atherosclerosis, autoimmune blood diseases, autoimmune gastritis, autoimmune inflammatory bowel disease, irritable bowel syndrome, allograft rejection, chronic thyroiditis, graves 'disease, sjogren's disease, scleroderma, diabetes, hepatitis, pancreatitis, primary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, dermatomyositis, contact dermatitis, eczema, vasculitis, chronic renal insufficiency, stevens-Johnson syndrome, inflammatory pain, idiopathic diarrhea, cachexia, sarcoidosis, guillain-Barre syndrome, uveitis, conjunctivitis, otitis, periodontal disease, parkinson's disease, alzheimer's disease, septic shock, interstitial pulmonary fibrosis, asthma, bronchitis, rhinitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary fibrosis, chronic pulmonary disease, and chronic pulmonary disease or other inflammatory diseases of the airways.

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

In a preferred embodiment, the cancer may be selected from the group consisting of: small Lymphocytic Lymphoma (SLL), acute Lymphoblastic Leukemia (ALL), chronic Lymphocytic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute promyelocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, fahrenheit macroglobulinemia, follicular lymphoma, multiple myeloma, mantle Cell Lymphoma (MCL), marginal Zone Lymphoma (MZL), non-hodgkin's lymphoma.

Definition and description of terms

All documents cited herein are incorporated by reference in their entirety and are incorporated by reference herein to the extent they are not inconsistent with this invention. Furthermore, various terms and phrases used herein have a common meaning known to those skilled in the art, and even though they are still intended to be described and explained in greater detail herein, the terms and phrases used herein should not be construed to be inconsistent with the ordinary meaning in the sense of the present invention.

The polymorph of a compound of formula 1 according to the invention exhibits an X-ray powder diffraction characteristic peak expressed in terms of 2θ, wherein "±0.20°" is the allowed measurement error range.

Polymorphs of the compounds of formula I of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions.

The term "composition" as used herein is intended to include products comprising the specified amounts of the respective specified ingredients, as well as any product that results, directly or indirectly, from combination of the specified amounts of the respective specified ingredients.

Polymorphs of the compounds of formula I of the present invention can be prepared by one skilled in the art into suitable pharmaceutical compositions using known pharmaceutical carriers. The pharmaceutical compositions may be specifically formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.

The pharmaceutical compositions may be formulated into a variety of dosage forms for convenient administration, e.g., oral formulations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders) may be administered immediately after addition of the drug vehicle prior to injection.

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

When used for the above therapeutic and/or prophylactic uses, the total daily amount of polymorphs of the compounds of formula I and pharmaceutical compositions of the present invention must be decided by the physician within the scope of sound medical judgment. For any particular patient, the particular therapeutically effective dose level will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; age, weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound employed; duration of treatment; a medicament for use in combination with or simultaneously with the particular compound employed; and similar factors well known in the medical arts. For example, it is common in the art to start doses of the compound at levels below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

As used herein, "polymorph" or "polymorph" refers to a crystalline form having the same chemical composition but different spatial arrangements of molecules, atoms and/or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement 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, both polymorphs may be mono-or reciprocal. For a monomutable system, the relative stability between the two solid phases remains unchanged upon a change in temperature. In contrast, in a reciprocal system, there is a transition temperature where the stability of the two phases is reversed ((Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids" (1999) ISBN:) -8247-0237). The phenomenon in which such compounds exist in different crystal structures is called drug polymorphism.

The term "room temperature" or "RT" as used herein refers to an ambient temperature of 20 to 25 ℃ (68-77 DEG F).

Abbreviations description: meOH: methanol; 2-MeTHF: 2-methyltetrahydrofuran; etOH: ethanol; 1,4-Dioxane:1, 4-dioxane; IPA: isopropyl alcohol; ACN: acetonitrile; acetone: acetone; DCM: dichloromethane; MIBK: methyl isobutyl ketone: tolutene: toluene; etOAc: ethyl acetate; n-Heptane: n-heptane; IPAc: isopropyl acetate; DMSO: dimethyl sulfoxide; MTBE: methyl tertiary butyl ether; DMAc: dimethylacetamide; THF: tetrahydrofuran; NMP N-methylpyrrolidone.

On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.

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

The invention has the positive progress effects that: the crystal forms of the BTK inhibitor, the acid salt thereof and the crystal forms of the acid salt thereof have the advantages of high activity, low hygroscopicity and good stability, and have very important significance for drug development.

Drawings

Figure 1 is an XRPD pattern of the free base form a of the compound of formula I.

FIG. 2 is a TGA/DSC spectrum of the free base form A of the compound of formula I.

FIG. 3 is a free base form A of a compound of formula I ¹ H NMR spectrum.

Fig. 4 is an XRPD pattern of hydrochloride salt form a of the compound of formula I.

FIG. 5 is a TGA/DSC spectrum of the hydrochloride form A of the compound of formula I.

FIG. 6 is a hydrochloride salt of the compound of formula I, form A ¹ H NMR spectrum.

Fig. 7 is an XRPD pattern of hydrochloride salt form B of the compound of formula I.

FIG. 8 is a TGA/DSC spectrum of form B of the hydrochloride salt of the compound of formula I.

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

Fig. 10 is an XRPD pattern of hydrochloride form C of the compound of formula I.

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

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

Fig. 13 is an XRPD pattern of phosphate form a of the compound of formula I.

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

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

Fig. 16 is an XRPD pattern of fumarate salt form a of compound of formula I.

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

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

FIG. 19 is an XRPD pattern for 1, 5-naphthalenedisulfonate form A of the compound of formula I.

FIG. 20 is a TGA/DSC spectrum of crystalline form A of 1, 5-naphthalene disulfonate of the compound of formula I.

FIG. 21 is a crystalline form A of 1, 5-naphthalene disulfonate of a compound of formula I ¹ H NMR spectrum.

FIG. 22 is an XRPD pattern for 1, 5-naphthalenedisulfonate form B of the compound of formula I.

FIG. 23 is a TGA/DSC spectrum of crystalline form B of 1, 5-naphthalene disulfonate of the compound of formula I.

FIG. 24 is a crystalline form B of 1, 5-naphthalene disulfonate of a compound of formula I ¹ H NMR spectrum.

Fig. 25 is an XRPD pattern of p-toluenesulfonate salt form a of compound of formula I.

FIG. 26 is a TGA/DSC spectrum of p-toluenesulfonate form A of the compound of formula I.

FIG. 27 is a crystalline form A of p-toluenesulfonate salt of a compound of formula I ¹ H NMR spectrum.

Fig. 28 is an XRPD pattern of hydrobromide crystalline form a of compound of formula I.

FIG. 29 is a TGA/DSC spectrum of hydrobromide form A of the compound of formula I.

FIG. 30 is a hydrobromide salt of a compound of formula I, form A ¹ H NMR spectrum.

Fig. 31 is an XRPD pattern of maleate salt form a of the compound of formula I.

FIG. 32 is a TGA/DSC spectrum of maleate form A of the compound of formula I.

FIG. 33 is a maleate salt form A of a compound of formula I ¹ H NMR spectrum.

Fig. 34 is an XRPD pattern of maleate salt form E of compound of formula I.

FIG. 35 is a TGA/DSC spectrum of maleate form E of the compound of formula I.

FIG. 36 is a maleate salt form E of a compound of formula I ¹ H NMR spectrum.

Fig. 37 is an XRPD pattern of maleate salt form F of compound of formula I.

FIG. 38 is a TGA/DSC spectrum of maleate form F of the compound of formula I.

FIG. 39 is a maleate salt form F of a compound of formula I ¹ H NMR spectrum.

Fig. 40 is an XRPD pattern of maleate salt form H of compound of formula I.

FIG. 41 is a TGA/DSC spectrum of maleate form H of the compound of formula I.

FIG. 42 is a maleate salt form H of a compound of formula I ¹ H NMR spectrum.

Fig. 43 is an XRPD pattern of maleate salt form I of compound of formula I.

FIG. 44 is a TGA/DSC spectrum of maleate salt form I of the compound of formula I.

FIG. 45 is a maleate salt of a compound of formula I form I ¹ H NMR spectrum.

Fig. 46 is an XRPD pattern of maleate salt form J of compound of formula I.

FIG. 47 is a TGA/DSC spectrum of maleate form J of the compound of formula I.

FIG. 48 is a maleate salt form J of a compound of formula I ¹ H NMR spectrum.

Fig. 49 is an XRPD pattern of free base form C of compound of formula I.

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

FIG. 51 is a free base form C of a compound of formula I ¹ H NMR spectrum.

Fig. 52 is an XRPD pattern of free base form D of compound of formula I.

FIG. 53 is a TGA/DSC spectrum of the free base form D of the compound of formula I.

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

Fig. 55 is an XRPD pattern of free base form E of compound of formula I.

FIG. 56 is a TGA/DSC spectrum of the free base form E of the compound of formula I.

FIG. 57 is a free base form E of a compound of formula I ¹ H NMR spectrum.

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

Fig. 59 is an XRPD overlay before and after pressure stability of maleate salt form a of the compound of formula I.

FIG. 60 is an XRPD pattern for the compound of formula I obtained in preparation 1.

FIG. 61 is an X-ray single crystal diffraction pattern of the compound of formula I obtained in preparation example 1.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Apparatus and method

The obtained solid sample is analyzed by various detection analysis methods, such as powder X-ray diffraction (XRPD), differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA), dynamic moisture adsorption (DVS), hydrogen spectrum liquid nuclear magnetism ¹ H Solution NMR)。

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

TABLE 1 XRPD test parameters (I/II)

(2) Thermogravimetric analysis (TGA) and Differential Scanning Calorimeter (DSC): TGA and DSC plots were taken on a TA Discovery 5500 thermogravimetric analyzer and a TA Discovery 2500 differential scanning calorimeter, respectively, and the table lists the test parameters.

TABLE 2 TGA and DSC test parameters

(3) Dynamic moisture adsorption (DVS): dynamic moisture sorption (DVS) curves were collected on DVS intricic of SMS (Surface Measurement Systems). LiCl, mg (NO) ₃ ) ₂ And deliquescence point correction of KCl. DVS test parameters are listed in the table.

TABLE 3 DVS test parameters

(4) Hydrogen spectrum liquid nuclear magnetism ¹ H Solution NMR): collecting hydrogen spectrum liquid nuclear magnetic spectrum on Bruker 400M nuclear magnetic resonance apparatus, DMSO-d ₆ As a solvent.

(5) High Performance Liquid Chromatography (HPLC): purity and solubility in the assay were measured by Agilent 1260 high performance liquid chromatograph and the analytical conditions are shown in the table.

TABLE 4 high performance liquid chromatography test conditions for purity testing

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(7) Ion Chromatography (IC): the ion content was analyzed in the test using a ThermoFisher ICS-1100 ion chromatograph, with specific conditions shown in the Table.

TABLE 5 ion chromatography conditions and parameters

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

It will be appreciated that additional values may be obtained using other types of instruments that function the same as the instruments described above or using different test conditions than those used in the present invention, and therefore, the values recited should not be considered absolute values. Those skilled in the art will appreciate that the above parameters used to characterize the physical properties of crystals may vary slightly due to instrument errors or operator differences, and therefore are only used to aid in characterizing the polymorphs provided by the present invention and are not to be considered as limiting.

Preparation example 1 preparation of Compounds of formula I

Step one: (S) -2- (hydroxymethyl) -2- ((5-nitro-1- (benzenesulfonyl) -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), silver (II) oxide (3.97 g,17.15 mmol) and deuterated methyl iodide (2.49 g,17.15 mmol) were added and the reaction stirred at 35℃for 48 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the cake was washed with ethyl acetate (20 mL). The obtained filtrate is concentrated in vacuo to obtain (S) -2- (((methoxy-d 3) methyl) -2- ((5-nitro-1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) amino) deuterated methyl propionate (520 mg,1.14mmol, 100% yield) as a yellow solid. ES-API [ M+H ]] ⁺ ＝455.1。

Step two: (S) -2- (((methoxy-d 3) methyl) -2- ((5-nitro-1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) amino) deuterated methyl propionate (520 mg,1.14 mmol) was dissolved in acetic acid (10 mL), iron powder (447 mg,8.01 mmol) was added and the reaction stirred at 90℃for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the cake was washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo and the crude product obtained was purified by flash column chromatography (ethyl acetate/petroleum ether: 0-100%) to give (S) -2- ((methoxy-d 3) methyl) -2- (methyl-d 3) -7- (benzenesulfonyl) -1,2,4, 7-tetrahydro-3H-pyrrolo [3',2':5, 6) ]Pyrido [3,4-b]Pyrazin-3-one (350 mg,0.87mmol, 78% yield) as a pale yellow solid. ES-API [ M+H ]] ⁺ ＝393.2。

Step three: (S) -2- ((methoxy-d 3) methyl) -2- (methyl-d 3) -7- (benzenesulfonyl) -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 stirred at 65℃for 6 hours. The reaction solution was cooled to room temperature, adjusted to ph=8 with dilute hydrochloric acid (1.0M), then 20mL of saturated sodium bicarbonate solution was added, and extracted with ethyl acetate (100 mL). The organic phase was washed successively with saturated sodium bicarbonate solution (20 mL) for one timeTwice, washing with saturated saline (20 mL), drying and concentrating to obtain (S) -2- (((methoxy-d 3) methyl) -2- (methyl-d 3) -1,2,4, 7-tetrahydro-3H-pyrrolo [3',2':5, 6)]Pyrido [3,4-b]Pyrazin-3-one (225 mg,0.89mmol, 100% yield) as a white solid. ES-API [ M+H ]] ⁺ ＝253.1。

Step four: (S) -2- (((methoxy-d 3) methyl) -2- (methyl-d 3) -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 0deg.C, potassium hydroxide (350 mg,6.24 mmol) was added and the reaction stirred at room temperature for 16 hours, the reaction solution was adjusted to pH=8 with dilute hydrochloric acid (1.0M), extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (30 mL), dried and concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-8%) to give (2S) -9- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -2- ((methoxy-d 3) methyl) -2- (methyl-d 3) -1,2,4, 7-tetrahydro-3H-pyrrolo [3',2':5,6 ] ]Pyrido [3,4-b]Pyrazin-3-one (200 mg,0.412mmol, 46% yield) was a pale yellow solid. ES-API [ M+H ]] ⁺ ＝485.1。

Step five: (2S) -9- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -2- ((methoxy-d 3) methyl) -2- (methyl-d 3) -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) and 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (281mg, 1.24 mmol) was added at room temperature, and the reaction was stirred at room temperature for 2 hours. To the reaction solution, a saturated sodium sulfite solution (10 mL) and a saturated sodium bicarbonate solution (10 mL) were added to quench the reaction, followed by extraction with ethyl acetate (50 mL). The organic phase was washed successively with saturated sodium bicarbonate solution (20 mL), saturated brine (20 mL), dried and concentrated, and the crude product was purified by preparative HPLC to give (S) -9- (2-chloro-4-phenoxybenzoyl) -2- (methoxy-d 3) methyl) -2- (methyl-d 3) -1,2,4, 7-tetrahydro-3H-pyrrolo [3',2':5,6]Pyrido [3,4-b]Pyrazin-3-one (compound of formula I, 76mg, 38% yield) 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＝8.5Hz,1H),7.48(t,J＝8.5Hz,2H),7.25(t,J＝7.5Hz,1H),7.20–7.16(m,3H),7.02(dd,J＝8.5,2.5Hz,1H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H).ES-API:[M+H] ⁺ = 483.1. XPRD characterization shows that the product is amorphous. The XPRD results are shown in FIG. 60.

Single crystal cultivation: a sample of the compound of formula I (100 mg) was weighed, heated with ethanol/water (1:1) solvent to dissolve the sample, and slowly evaporated at room temperature to give a single crystal. X-ray single crystal diffraction testing was performed by a Bruker D8 Venture instrument. The results are shown in Table 6 and FIG. 61 below.

TABLE 6

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Biological testing

Test example 1: enzyme assay for BTK and BTK C481S

1000X compound 3-fold gradient stock solution was prepared using DMSO and reaction buffer (50mM HEPES,pH7.5,0.0015% Briji-35,2mM DTT,10mM MgCl) ₂ ) 100-fold dilution to 10X stock of compound, transfer 10X stock of compound into 384 well plates. The enzymatic reactions were established with BTK Kinase Enzyme System (Promega Catalog#V2941) or BTK (C481S) Kinase Enzyme System (Promega Catalog#VA 7033). First, 2 Xenzyme solution containing 10nM BTK or 10nM BTK C481S was prepared with reaction buffer and added to the plate and incubated with the compound for 10 minutes. Then, a 2.5 Xsubstrate solution containing ATP (125. Mu.M), poly (Glu 4, tyr 1) (0.05. Mu.g/. Mu.L) was prepared with a reaction buffer and added to the plate, and reacted at 20℃for 90 minutes. Finally, kinase activity was measured according to the experimental procedure provided by ADP-GloTM kinase Assay kit (Promega, # V9101) and finally luminescence values were read. DMSO was used as the maximum signal value and no enzyme was added as the minimum signal value. Calculation of the CompoundInhibition ratio (%) = (maximum signal value-compound signal value)/(maximum signal value-minimum signal value) ×100% of the compound, compound gradient dilution concentration and corresponding enzyme activity inhibition ratio were fitted using XLFit four-parameter method, and IC was calculated ₅₀ Values. As a result, the compound of formula I has higher inhibition activity to BTK or BTK (C481S) kinase, and IC to BTK ₅₀ IC with a value of 10.6nM for BTK (C481S) ₅₀ The value was 12.5nM.

Test example 2: P-BTK cell assay

The first day: HEK293 cells (ADDEBIO, T0011001) in logarithmic growth phase were collected by enzyme EDTA digestion, counted and 2E6 cells were inoculated in 10cm dishes and cultured overnight. The following day: a mixture containing 6ug of WT-BTK/C481S-BTK plasmid and 18 ul of FuGENE HD transfection reagent was prepared using 1000 ul of Opti-MEM, respectively, and after standing at room temperature for 10 minutes, the mixture was slowly added to a petri dish with a pipette and incubated overnight. Third day: the petri dish enzyme EDTA digested cells were removed, counted and 1E4 cells were seeded in 96 well cell culture plates and cultured overnight. Compound 3.16-fold gradient concentration stock solution of 1000X was prepared using DMSO and left standing at room temperature. Fourth day: the prepared 1000X compound stock solution was taken out, and diluted 200 times to 5X compound stock solution using a medium, and 5X compound stock solution was added to each cell culture well at a final concentration of 1X and a DMSO content of 0.1%. DMSO was used as experimental control. After two hours of incubation with the compound, the residual medium was removed. mu.L of cell lysis buffer was added to each well, and the mixture was allowed to stand on ice for 30 minutes, followed by ultrasonic lysis with ice water for 5 minutes. After diluting the cell lysate in proportion, 80. Mu.L of the mixture was transferred to ELISA plates, and 80. Mu.L of cell lysis buffer was added to blank wells. After incubation for 2 hours in an incubator at 37℃the plates were removed and the antibody incubation and chromogenic termination was completed according to the PathScan P-Btk (Y223) Sandwich ELISA Kit (Cell signaling #23843 CA) protocol and the OD was read. Inhibition (%) = (OD) of compound was calculated _Control –OD _{Compounds of formula (I)} )/(OD _Control –OD _{Blank space} ) 100% and IC was calculated by fitting the compound gradient dilution concentration and the corresponding cell proliferation inhibition rate using Prism 8 four-parameter method ₅₀ Values. As a result, the compound of formula I is directed against BTK or BTK(C481S) phosphorylation level has high inhibitory activity on BTK IC ₅₀ IC with a value of 17.00nM for BTK (C481S) phosphorylation ₅₀ The value was 39.20nM.

Test example 3: TMD-8 proliferation inhibition experiment

TMD-8 cells were grown as diffuse large B lymphoma (Minghuage, MZ-0832) in 10% FBS+1% PS1640 medium. On the first day, cells in the logarithmic growth phase were counted and inoculated with 600 TMD-8 cells in 384-well cell culture plates and cultured overnight. The next day, 3-fold gradient concentration stock of 400X compound was made up with DMSO, diluted 40-fold to 10X compound stock with medium, 10X compound stock was added to each cell culture well at a final concentration of 1X and DMSO content of 0.25%. DMSO was used as experimental control and medium as blank. Culture was continued for three days after addition of the compound. On the fifth day, 25. Mu.L of ADP-Glo was added to each well, and after incubation for 10 minutes, the chemiluminescent value (RLU value) was read. Cell proliferation inhibition (%) = (RLU) was calculated _Control -RLU _{Compounds of formula (I)} )/(RLU _Control -RLU _{Blank space} ) X 100% and IC was calculated by fitting the compound gradient dilution concentration and the corresponding cell proliferation inhibition ratio using XLFIT four parameter method ₅₀ Values. As a result, the compound of the present invention has a high inhibitory activity against TMD-8 and IC against TMD-8 ₅₀ The value was 72.77nM.

EXAMPLE 1 preparation of the free base form A of the Compound of formula I

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

TABLE 7

EXAMPLE 2 preparation of Compound of formula I hydrochloride form A

About 20mg of a sample of the compound of formula I (prepared in preparation 1) and 37% hydrochloric acid (1:2, molar ratio of the feed) were weighed into an HPLC vial, 0.5mL of ethyl acetate was added, after stirring at room temperature for 3 days, the solid was centrifuged and dried at room temperature under vacuum overnight to obtain the hydrochloride form A of the compound of formula I; XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 4, 5 and 6. TGA results showed that the sample weight loss was 7.1% when heated to 110 ℃, from 110 ℃ to 200 ℃, and 7.9%; DSC showed that the sample had 2 endothermic peaks observed at 115.4℃and 185.0℃at peak temperature and 1 exothermic peak observed at 218.3℃at peak temperature. The IC/HPLC test results showed a molar ratio of hydrochloric acid to free form of 1.0:1. The X-ray powder diffraction data for the hydrochloride salt form a of the compound of formula I are shown in table 8 below.

TABLE 8

EXAMPLE 3 preparation of Compound of formula I hydrochloride form B

About 20mg of a sample of the compound of formula I (prepared in preparation 1) and 37% hydrochloric acid (1:2, molar ratio of the feed) were weighed into an HPLC vial, 0.5mL of acetone was added, stirred overnight at room temperature, and after centrifugation the solid was dried overnight at room temperature under vacuum to obtain the hydrochloride crystalline form B of the compound of formula I; XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 7, 8 and 9, respectively. TGA results showed that the sample weight loss was 4.8% when heated to 150℃and 7.6% when heated from 150℃to 230 ℃The method comprises the steps of carrying out a first treatment on the surface of the DSC showed that the sample observed 1 endothermic peak at 223.0deg.C (peak temperature). The IC/HPLC test results showed a molar ratio of hydrochloric acid to free form of 1.0:1. The X-ray powder diffraction data for the hydrochloride salt form B of the compound of formula I are shown in table 9 below.

TABLE 9

EXAMPLE 4 preparation of Compound hydrochloride form C of formula I

About 20mg of the compound of formula I (prepared in preparation 1) and 1N hydrochloric acid (1:2, molar ratio of the feed) were weighed into an HPLC vial, 0.5mL of acetone was added, and after stirring overnight at room temperature, the solid was centrifuged and dried overnight at room temperature under vacuum to obtain the hydrochloride form C of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 10, fig. and fig. respectively. TGA results showed that the sample weight loss was 2.2% when heated to 150 ℃, from 150 ℃ to 250 ℃, and 7.5%; DSC showed that the sample observed 1 endothermic peak at 248.2 ℃ (peak temperature). The IC/HPLC test results showed a molar ratio of hydrochloric acid to free form of 0.9:1. The X-ray powder diffraction data for the hydrochloride salt form C of the compound of formula I are shown in table 10 below.

Table 10

EXAMPLE 5 preparation of the phosphate Crystal form A of the Compound of formula I

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

TABLE 11

EXAMPLE 6 preparation of Compound fumarate salt form A of formula I

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

Table 12

EXAMPLE 7 preparation of Compound 1, 5-naphthalenedisulfonate form A of formula I

About 20mg of the compound of formula I (obtained from preparation 1) and an equimolar amount of 1, 5-naphthalenedisulfonic acid were weighed into an HPLC vial, 0.5mL of acetonitrile/water (19:1, v/v) was added, and after stirring at room temperature for 3 days, the solid was centrifuged and dried under vacuum at room temperature overnight to obtain 1, 5-naphthalenedisulfonate crystalline form A of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 19, fig. 20, and fig. 21, respectively. TGA results showed that the sample weight loss was 3.5% when heated to 130 ℃, from 130 ℃ to 175 ℃, and 2.6%; DSC showed that the sample was at 57.7℃and 82.4 endothermic peaks were observed at 9 ℃,166.9 ℃ and 211.1 ℃ (peak temperature). ¹ H NMR results showed that the molar ratio of 1, 5-naphthalenedisulfonic acid to free form in this sample was about 0.7:1, and no acetonitrile solvent residue was observed. The X-ray powder diffraction data for crystalline form a of the 1, 5-naphthalene disulfonate of the compound of formula I are shown in table 13 below.

TABLE 13

EXAMPLE 8 preparation of Compound 1, 5-naphthalenedisulfonate form B of formula I

About 20mg of the compound of formula I (obtained from preparation 1) and an equimolar amount of 1, 5-naphthalenedisulfonic acid were weighed into an HPLC vial, 0.5mL of acetone was added, and after stirring at room temperature for 3 days, the solid was centrifuged and dried at room temperature under vacuum overnight to obtain 1, 5-naphthalenedisulfonate crystalline form B of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 22, 23 and 24, respectively. TGA results showed that the sample weight loss was 4.3% when the temperature was raised to 200 ℃; DSC showed that 3 endothermic peaks were observed at 57.0 ℃,82.5 ℃ and 276.1 ℃ (peak temperature). ¹ H NMR results showed that the molar ratio of 1, 5-naphthalenedisulfonic acid to free form in this sample was about 0.7:1, and no acetonitrile solvent residue was observed. The X-ray powder diffraction data for crystalline form B of the 1, 5-naphthalene disulfonate of the compound of formula I are shown in table 14 below.

TABLE 14

EXAMPLE 9 preparation of the para-toluenesulfonate salt of Compound of formula I form A

About 20mg of the compound of formula I (from preparation 1) and an equimolar amount of p-toluenesulfonic acid were weighed into an HPLC vial, 0.5mL acetonitrile/water (19:1, v/v) was added and stirred at room temperatureAfter stirring for 3 days, the solid was centrifuged and dried overnight at room temperature under vacuum to obtain the p-toluenesulfonate salt form a of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 25, 26 and 27, respectively. TGA results showed that the sample weight loss was 4.3% when heated to 75 ℃, from 75 ℃ to 120 ℃, and 6.1%; DSC showed that the sample observed 1 endothermic peak at 111.1deg.C (peak temperature). ¹ H NMR results showed that the molar ratio of p-toluenesulfonic acid to free form in the sample was 1.0:1, and no solvent residue of acetonitrile was observed. The X-ray powder diffraction data for p-toluenesulfonate salt form a of the compound of formula I are shown in table 15 below.

TABLE 15

EXAMPLE 10 preparation of Compound hydrobromide form A of formula I

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

Table 16

EXAMPLE 11 preparation of Compound maleate form A of formula I

About 20mg of the compound of formula I (obtained from preparation 1) and an equimolar amount of maleic acid are weighed into an HPLC vial, 0.5mL of acetone solution is added,after stirring at room temperature for 3 days, the solid was centrifuged and dried at room temperature under vacuum overnight to obtain the maleate salt form a of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 31, 32 and 33. TGA results showed that the sample weight loss was 2.8% when heated to 150 ℃, from 150 ℃ to 230 ℃, and 19.3%; DSC showed that the sample observed 1 endothermic peak at 200.3 ℃ (peak temperature). ¹ H NMR results showed that the molar ratio of maleic acid to free form in this sample was about 1.0:1. The compound of formula I maleate salt form a, having X-ray powder diffraction data as shown in table 17 below.

TABLE 17

EXAMPLE 12 preparation of maleate salt form E of Compound of formula I

A20 mg sample of maleate form A (prepared from example 11) was weighed into a 3mL vial, 0.2-1.8 mL of tetrahydrofuran solvent was added for dissolution, another 20mL vial was added with about 4mL of n-heptane antisolvent, and after placing the 3mL vial containing the filtrate in the 20mL vial, the 20mL vial was sealed and allowed to stand at room temperature. When solid precipitation is observed, the solid is collected to give maleate salt form E of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 34, 35 and 36, respectively. TGA results showed that the sample was heated from room temperature to 150 ℃ and the sample weight loss was 3.4%, from 150 ℃ to 250 ℃ and the sample weight loss was 19.7%. DSC results showed that 1 endothermic peak was observed at 194.2℃for this sample. ¹ H NMR results showed that the molar ratio of maleic acid to free form in this sample was 1.0:1. Maleate salt form E of the compound of formula I, X-ray powder diffraction data for which are shown in table 18 below.

TABLE 18

EXAMPLE 13 preparation of maleate salt form F of Compound of formula I

A20 mg sample of maleate form A (prepared from example 11) was weighed into an HPLC vial, 0.5mL of tetrahydrofuran/water (957:43, v/v) solvent was added, the resulting suspension was magnetically stirred at room temperature for about 7 days, and the solid was centrifuged to give maleate form F of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 37, 38 and 39, respectively. TGA results showed that the sample was heated from room temperature to 150 ℃ and the sample weight loss was 2.9%, from 150 ℃ to 250 ℃ and the sample weight loss was 18.7%. DSC results showed that 3 endothermic peaks were observed at 65.3 ℃,81.7 ℃ and 180.8 ℃ (peak temperature) for the sample. ¹ H NMR results showed that the molar ratio of maleic acid to free form in this sample was 1.0:1. The X-ray powder diffraction data for maleate salt form F of compound I are shown in table 19 below.

TABLE 19

EXAMPLE 14 preparation of maleate form H of Compound of formula I

A20 mg sample of maleate form A (prepared from example 11) was weighed into a 3mL vial, 0.2-1.8 mL of tetrahydrofuran solvent was added for dissolution, another 20mL vial was added with about 4mL of methyl tert-butyl ether antisolvent, and after placing the 3mL vial containing the filtrate in the 20mL vial, the 20mL vial was sealed and allowed to stand at room temperature. When solid precipitation is observed, the solid is collected to give the maleate salt form H of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 40, 41 and 42, respectively. TGA results showed that the sample was heated from room temperature to 150 ℃ and the sample weight loss was 1.4%, from 150 ℃ to 250 ℃ and the sample weight loss was 17.4%. DSC results showed that 1 endothermic peak was observed at 188.6deg.C (peak temperature) for the sample. ¹ H NMR (results show that the molar ratio of maleic acid to free form in the sample was 1.0:1. Crystal form identification of maleate form H was performed by VT-XRPD, sample was N ₂ Purging for 20min, heating to 150No change in the crystalline form was observed at any of the temperatures below 30 ℃. The compound of formula I maleate form H, having X-ray powder diffraction data as shown in table 20 below.

Table 20

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EXAMPLE 15 preparation of maleate salt form I of Compound of formula I

A100 mL round bottom flask was charged with a sample of maleate form A (1 g, prepared from example 11), tetrahydrofuran (30 mL) and the system refluxed for clearing. Naturally cooling to room temperature, and separating out solid. Concentrating by rotary evaporation until the residual tetrahydrofuran is 20 mL. The oil bath was warmed to 80 ℃ and stirred for 0.5 hour, cooled naturally to room temperature and stirred overnight. Filtration and drying gives 780mg of off-white solid as maleate form I of the compound of formula I. The XRPD and TGA/DSC and 1H NMR characterization results are shown in FIG. 43, FIG. 44, and FIG. 45, respectively. TGA results showed that the sample was heated from room temperature to 130 ℃ and the sample weight loss was 3.5%, from 130 ℃ to 250 ℃ and the sample weight loss was 20.2%. DSC results showed that the sample observed 2 endothermic peaks at 112.9 ℃ and 202.5 ℃ (peak temperature) and 1 exothermic peak at 161.5 ℃ (peak temperature). ¹ H NMR results showed that the molar ratio of maleic acid to free form in this sample was 1.0:1. The compound of formula I maleate salt form I, has X-ray powder diffraction data as shown in table 21 below.

Table 21

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EXAMPLE 16 preparation of Compound maleate form J of formula I

Maleate form I (prepared from example 15) was heated to 130 ℃, cooled to room temperature and exposed to air to obtain maleate form J of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 46, 47 and 48, respectively. TGA results showed that the sample was heated from room temperature to 150 ℃ and the sample weight loss was 6.4%, from 150 ℃ to 250 ℃ and the sample weight loss was 20.5%. DSC results showed that the sample observed 1 endothermic peak at 193.7 ℃ (peak temperature) and 1 exothermic peak at 162.1 ℃ (peak temperature). ¹ H NMR results showed that the molar ratio of maleic acid to free form in this sample was 1.0:1. And carrying out humidity induction test on the maleate crystal form J, and standing the maleate crystal form J under 80% RH for overnight, wherein the maleate crystal form J is unchanged, so that the maleate crystal form J is relatively stable under high humidity conditions. The X-ray powder diffraction data for maleate salt form J of compound I are shown in table 22 below.

Table 22

EXAMPLE 17 preparation of the free base form C of the Compound of formula I

A20 mg sample of maleate form A (prepared from example 11) was weighed into a 20mL vial and dissolved in 0.2-3.0 mL of methanol solvent (undissolved system was filtered into another vial using a 0.45 μm PTFE filter head), water antisolvent was added to the clear solution and stirred dropwise until solids precipitated, or after the total amount of antisolvent had been added to 10.0mL, the sample without solids precipitated was transferred to magnetic stirring at 5℃and, if solids still did not precipitate, transferred to room temperature for evaporation. And (3) separating out solids by centrifugation to obtain the free base crystal form C of the compound of the formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 49, 50, and 51. TGA results showed 2.7% weight loss of the sample when heated to 200 ℃; DSC results showed that the sample observed 1 endothermic peak at 329.3 ℃ (peak temperature) and 1 exothermic peak at 311.3 ℃ (peak temperature). Crystalline form C of the free base of the compound of formula IThe X-ray powder diffraction data are shown in table 23 below.

Table 23

EXAMPLE 18 preparation of the free base form D of the Compound of formula I

A20 mg sample of maleate form A (prepared from example 11) was weighed into a 3mL vial, 0.2-1.8 mL dimethylacetamide solvent was added to dissolve, another 20mL vial was taken and approximately 4mL of water was added to the anti-solvent, after placing the 3mL vial containing the filtrate in the 20mL vial with the opening, the 20mL vial was sealed and allowed to stand at room temperature. When solid precipitation is observed, the solid is collected to give the free base form D of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 52, 53 and 54, respectively. TGA results showed that the sample was heated from room temperature to 150 ℃ and the sample weight loss was 4.1%, from 150 ℃ to 230 ℃ and the sample weight loss was 7.1%. DSC results showed that the samples observed 2 endothermic peaks at 175.3 ℃ and 328.9 ℃ (peak temperature). The compound of formula I, form D, has X-ray powder diffraction data as shown in table 24 below.

Table 24

EXAMPLE 19 preparation of the free base form E of the Compound of formula I

A20 mg sample of maleate form A (prepared from example 11) was weighed into an HPLC vial, 0.5mL of 1, 4-dioxane/water (1:2, v/v) solvent was added, and the mixture was stirred in suspension at 50℃for 3 days to obtain the free base form E of the compound of formula I. XRPD and TGA/DSC ¹ The H NMR characterization results are shown in fig. 55, 56 and 57, respectively. TGA results showed that the sample was heated from room temperature to 80 ℃ and the sample weight loss was 1.8%; the sample lost weight by heating from 80 ℃ to 180 ℃ was 16.8%. DSC results showed that the samples observed 2 endothermic peaks at 144.5 ℃ and 329.1 ℃ (peak temperature). Crystalline form E of the free base of the compound of formula I, X-rays thereofThe line powder diffraction data are shown in table 25 below.

Table 25

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EXAMPLE 20 preparation of Compound maleate form A of formula I

To a 250mL round bottom flask was added the compound of formula I (7.4 g, from preparation 1) and ethyl acetate (100 mL) and stirred at room temperature; a solution of maleic acid (1.86 g) in ethyl acetate (50 mL) was added dropwise to give a suspension, which was stirred at room temperature for 4 hours; the reaction solution was filtered and the filter cake dried to give 8.8g of an off-white solid which was characterized by XRPD, TGA/DSC, each pattern being substantially the same as in example 11. The solid thus obtained is the maleate salt of the compound of formula I, form A.

EXAMPLE 21 preparation of Compound maleate form A of formula I

To the reaction vessel were added the compound of formula I (570 g, from preparation 1) and ethyl acetate (17L), and stirred at room temperature; dripping ethyl acetate (2.85L) solution of maleic acid (144 g) to obtain suspension, heating to 50-60 ℃, and stirring the suspension for 4-5 hours; heating was stopped, naturally cooled to room temperature with stirring, stirred for 16-24 hours, filtered and the filter cake dried to give 678g of an off-white solid, which was characterized by XRPD, TGA/DSC, each pattern being substantially the same as in example 11. The solid thus obtained is the maleate salt of the compound of formula I, form A.

Moisture permeability

The hygroscopicity of a sample of maleate form a of the compound of formula I (obtained in example 21) was evaluated by DVS test at 25 ℃ between 0% rh and 95% rh. The DVS test results are shown in fig. 58. The results show that the moisture adsorption of the maleate form A sample at 25 ℃/80% RH is 0.13%, the maleate form A sample has almost no hygroscopicity, and the forms of the maleate form A sample before and after the DVS test are consistent.

Pressure stability

A sample of maleate form a of the compound of formula I (obtained in example 20) was subjected to a pressure stability test using a SYP-5BS manual tablet press, the following steps being followed: weighing 100mg of maleate crystal form A sample in a die of a press, tabletting by using 350MPa pressure for 1min, and testing XRPD by using a sample. XRPD of the sample before and after pressure stability is shown in fig. 59, and the results indicate that the form of maleate form a is unchanged before and after pressure stability.

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

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:

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,

(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.