Crystal form of pyrimidine formamide compound and preparation method thereof

Abstract

The invention provides a crystal form of a pyrimidine formamide compound and a preparation method thereof. Specifically, the invention provides a novel crystal form of 2-(2-boric acid-5-trifluoromethoxy-benzyl sulfydryl)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide (formula I) and a preparation method of the novel crystal form of 2-(2-boric acid-5-trifluoromethoxy-benzyl sulfydryl)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide (formula I). More specifically, the invention provides crystal forms A, B, C and G of a compound SX-682 as shown in a formula (I) and a preparation method thereof. The crystal form provided by the invention has the advantages in at least one aspect of solubility, melting point, stability, dissolution rate, hygroscopicity, tabletting stability, fluidity, safety, purification effect, preparation research and development, industrial production and the like, and has very important significance for future development of a compound of formula (I). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a crystal form of a pyrimidinecarboxamide compound and a preparation method thereof, and specifically relates to a crystal form Form A, B, C, G of 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide and a preparation method thereof. Background Art

[0002] Chemokines are a class of small cytokines or signaling proteins secreted by cells that have the ability to induce directional chemotaxis of nearby reactive cells. Chemokine receptors are a class of seven-transmembrane G protein-coupled receptors (GPCRs) that mediate the function of chemokines. They can be selectively expressed on the surface of target cells, usually on the cell membranes of immune cells, neutrophils, endothelial cells, etc. Chemokines exert their biological effects by interacting with G protein-coupled transmembrane receptors. They play an important role in mediating cell migration, proliferation, and resisting pathogen invasion, and are closely related to the occurrence and development of inflammation and cancer in the immune environment.

[0003] Chemokines are a subfamily of cytokines responsible for immune cell trafficking and lymphoid tissue development. It is reported that there are 50 different chemokines to date, which can be divided into four major categories, namely C, CC, CXC and CX3C chemokines, based on the position of the first two cysteine ​​residues in their main protein structure. Each immune cell subset has a different chemokine receptor expression pattern, which makes them respond differently to chemokines and migrate according to the specific needs of each environment. In cancer, they play a key role in the pattern of immune cell migration into tumors. In addition, chemokines can directly target non-immune cells in the tumor microenvironment, including tumor cells, stromal cells and vascular endothelial cells. Therefore, chemokines are involved in a variety of cancer development processes, such as angiogenesis, metastasis, cancer cell proliferation, stemness and invasiveness, and are key determinants of disease progression, with a great impact on patient prognosis and treatment response. Because chemokines have important regulatory functions in cancer cells and immune infiltrating cells, chemokine ligands and their receptors have become very powerful therapeutic targets.

[0004] SX-682 is a pyrimidine carboxamide compound, and the biopharmaceutical company Syntrix Pharmaceuticals is conducting a Phase I study (NCT04245397) for the treatment of patients with myelodysplastic syndrome (MDS) who have disease progression or are intolerant to previous treatment. As a dual allosteric inhibitor targeting CXCR1 and CXCR2, SX-682 can block the recruitment of tumor myeloid-derived suppressor cells and enhance T cell activation and anti-tumor immunity.

[0005] The chemical name of SX-682 is 2-(2-boric acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide, and its molecular structure is shown below:

[0006]

[0007] Patent US8969365 (B2) reports the compound of formula (I) and its synthesis process, but does not disclose relevant information about the solid form or crystalline form of the compound of formula (I). The inventors prepared the compound of formula (I) according to the method of the patent and obtained a yellow-white substance, which is a crystal and is named Form I. The crystal stability of Form I was studied and it was found that the crystal form was kinetically unstable.

[0008] For drug development, the study of polymorphs is a crucial content. Different crystal forms can cause differences in drug solubility, stability, uniformity, and fluidity, thereby affecting the safety and effectiveness of the drug, and further leading to different clinical effects. In order to obtain a stable dosage form suitable for pharmaceutical use, it is necessary to provide a crystal form with high stability and industrial production.

[0009] Therefore, there is an urgent need in the art to screen polymorphs of the compound of formula (I) and develop polymorphs with excellent stability under different temperature, humidity and mechanical conditions, low production cost and simple preparation method to meet the needs of drug development, formulation preparation and industrial production. Summary of the invention

[0010] The purpose of the present invention is to provide a crystal form and a preparation method thereof with excellent stability under different temperature, humidity and mechanical force conditions, low production cost and simple preparation method.

[0011] The technical solution adopted by the present invention to solve the above technical problems is as follows:

[0012] The present invention provides a crystalline form Form A of a pyrimidinecarboxamide compound having a structure as shown in formula (I),

[0013]

[0014] The X-ray powder diffraction pattern includes 3 or more 2θ values ​​selected from the following: 5.8°±0.2°, 11.4°±0.2°, 16.5°±0.2°, 21.2°±0.2°.

[0015] As a preferred embodiment, the crystalline form Form A includes 6 or more 2θ values ​​selected from the following in the X-ray powder diffraction pattern: 5.8°±0.2°, 8.1°±0.2°, 11.4°±0.2°, 11.8°±0.2°, 12.9°±0.2°, 13.1°±0.2°, 14.9°±0.2°, 16.5°±0.2°, 17.7°±0.2°, 18.2°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 20.0°±0.2°, 21.2°±0.2°, 21.8°±0.2°, 22.3°±0.2°, 23.1°±0.2°, 23.8°±0.2°, 24.3°±0.2°, 24.6°±0.2 °, 24.9°±0.2°, 26.0°±0.2°, 26.6°±0.2°, 27.1°±0.2°, 28.0°±0.2°, 28.6°±0.2°, 29.1°±0.2°, 29.3°±0.2°, 30.0°±0.2°, 30.3°±0.2°, 30.8°±0.2°, 31.5°±0.2°, 32.1°±0.2°, 32.7°±0.2°, 33.4°±0.2°, 33.8°±0.2°, 34.7°±0.2°, 34.9°±0.2°, 35.5°±0.2°, 36.5°±0.2°, 37.0°±0.2°, 38.0°±0.2°.

[0016] As a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form Form A is as follows: Figure 1 Its thermogravimetric analysis (TGA) curve is shown in Figure 2 As shown, or its differential scanning calorimetry (DSC) curve is as shown Figure 3 As shown, or its H NMR spectrum ( 1 H NMR) Figure 4 shown.

[0017] The present invention also provides a crystalline form Form B of a pyrimidinecarboxamide compound having a structure as shown in formula (I), wherein the X-ray powder diffraction pattern thereof comprises 3 or more 2θ values ​​selected from the following: 9.2°±0.2°, 12.2°±0.2°, 16.0°±0.2°, 18.4°±0.2°, and 25.7°±0.2°.

[0018] As a preferred embodiment, the crystalline form Form B includes 6 or more 2θ values ​​selected from the following in the X-ray powder diffraction pattern: 4.6°±0.2°, 8.2°±0.2°, 9.2°±0.2°, 10.5°±0.2°, 12.2°±0.2°, 14.0°±0.2°, 16.0°±0.2°, 16.5°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 22.4°±0.2°, 23.3°±0.2°, 24.0°±0.2 °, 24.3°±0.2°, 24.6°±0.2°, 24.9°±0.2°, 25.7°±0.2°, 26.4°±0.2°, 26.6°±0.2°, 27.7°±0.2°, 28.3°±0.2°, 29.1°±0.2°, 30.8°±0.2°, 31.9°±0.2°, 32.4°±0.2°, 32.8°±0.2°, 33.6°±0.2°, 34.5°±0.2°, 35.4°±0.2°, 36.6°±0.2°, and 37.3°±0.2°.

[0019] As a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form Form B is as follows: Figure 5 shown.

[0020] As a preferred embodiment, its thermogravimetric analysis (TGA) curve is as follows Figure 6 As shown, or its differential scanning calorimetry (DSC) curve is as shown Figure 7 As shown, or its H NMR spectrum ( 1 H NMR) Figure 8 shown.

[0021] The present invention also provides a crystalline form Form C of a pyrimidinecarboxamide compound having a structure as shown in formula (I), wherein the X-ray powder diffraction pattern thereof comprises 3 or more 2θ values ​​selected from the following: 3.9°±0.2°, 10.2°±0.2°, 15.7°±0.2°, 20.7°±0.2°, and 22.7°±0.2°.

[0022] As a preferred embodiment, the crystalline form Form C includes 6 or more 2θ values ​​selected from the following in the X-ray powder diffraction pattern: 3.9°±0.2°, 5.0°±0.2°, 6.7°±0.2°, 10.2°±0.2°, 14.9°±0.2°, 15.7°±0.2°, 16.9°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.8 °±0.2°, 19.3°±0.2°, 19.6°±0.2°, 20.7°±0.2°, 21.4°±0.2°, 21.8°±0.2°, 22.7°±0.2°, 23.6°±0.2°, 24.6°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 28.8°±0.2°.

[0023] As a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form Form C is as follows: Fig. 9 shown.

[0024] As a preferred embodiment, its differential scanning calorimetry (DSC) curve is as follows: Fig.10 shown.

[0025] The present invention also provides a crystalline form Form G of a pyrimidinecarboxamide compound having a structure as shown in formula (I), wherein the X-ray powder diffraction pattern thereof comprises 3 or more 2θ values ​​selected from the following: 10.8°±0.2°, 15.2°±0.2°, 17.6°±0.2°, 22.8°±0.2°, and 24.2°±0.2°.

[0026] As a preferred embodiment, the crystalline form Form G includes 6 or more 2θ values ​​selected from the following in the X-ray powder diffraction pattern: 10.8°±0.2°, 11.4°±0.2°, 12.4°±0.2°, 13.3°±0.2°, 14.8°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 16.3°±0.2°, 17.6°±0.2°, 18.9°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.2°±0.2°, 20.6°±0.2°, 21. .3°±0.2°, 21.8°±0.2°, 22.1°±0.2°, 22.8°±0.2°, 23.5°±0.2°, 24.2°±0.2°, 25.1°±0.2°, 25.6°±0.2°, 26.2°±0.2°, 27.3°±0.2°, 28.8°±0.2°, 30.1°±0.2°, 30.8°±0.2°, 32.1°±0.2°, 35.3°±0.2°, 35.9°±0.2°, 38.7°±0.2°.

[0027] As a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form Form G is as follows: Fig.11 shown.

[0028] As a preferred embodiment, its thermogravimetric analysis (TGA) curve is as follows Fig.12 As shown, or its differential scanning calorimetry (DSC) curve is as shown Fig.13 shown.

[0029] The present invention also provides a method for preparing the crystal form Form A, Form B, Form C or Form G: the method comprises the steps of: a) providing a solution of a raw material of a compound of formula (I) in a solvent one, adding a solvent two to the solution for treatment to obtain a target crystal form;

[0030] Alternatively, the method comprises the steps of: b) providing a solution of a raw material of a compound of formula (I) in a solvent one, adding the solution into a solvent two for treatment to obtain a target crystal form;

[0031] Alternatively, the method comprises the steps of: c) providing a solution or dispersion of a raw material of the compound of formula (I) in solvent one and / or solvent two, and treating the solution or dispersion to obtain a target crystal form;

[0032] Wherein, the treatment method comprises one or more of the following steps: stirring, heating, volatilization, cooling, freeze drying;

[0033] The solvent 1 and the solvent 2 are each independently selected from the following group: alcohol solvents, ketone solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ether solvents, acid solvents, water, or a combination thereof.

[0034] As a preferred embodiment, the alcohol solvent is selected from the following group: n-propanol, methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, 2-ethoxyethanol, cyclohexanol, n-pentanol, or a combination thereof;

[0035] The ketone solvent is selected from the group consisting of methyl isobutyl ketone, acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof; the ester solvent is selected from the group consisting of ethyl formate, ethyl acetate, isopropyl acetate, isobutyl acetate, or a combination thereof;

[0036] The hydrocarbon solvent is selected from the group consisting of chloroform, dichloromethane, n-heptane, cyclohexane, methylcyclohexane, toluene, xylene, cumene, n-hexane, n-pentane, or a combination thereof;

[0037] The nitrile solvent is selected from acetonitrile;

[0038] The ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether, 1,4-dioxane, 1,3-dioxolane, or a combination thereof;

[0039] The acid solvent is selected from the group consisting of formic acid, acetic acid, propionic acid, or a combination thereof.

[0040] As a preferred embodiment, the method for preparing the crystal form Form A comprises the following steps:

[0041] Method 1, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of solvent 1, filtering, adding an appropriate amount of solvent 2 or adding the filtrate to an appropriate amount of solvent 2, stirring, crystallizing, filtering, and vacuum drying to obtain the pyrimidinecarboxamide compound having the crystal form Form A, wherein the solvent 1 is selected from acetic acid or isobutyl acetate, the solvent 2 is selected from water or n-pentane, and the crystallization method is dissolution crystallization;

[0042] Method 2, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of solvent 3, filtering, and freeze-drying to obtain the pyrimidinecarboxamide compound having the crystal form Form A, wherein the solvent 3 is selected from a binary solvent of tert-butanol and water.

[0043] As a preferred embodiment, the method for preparing the crystal form Form B comprises the following steps:

[0044] Method 1, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of solvent 1, filtering, adding an appropriate amount of solvent 2, stirring, crystallizing, filtering, and vacuum drying to obtain the pyrimidinecarboxamide compound having the crystal form Form B, wherein the solvent 1 is selected from acetonitrile, the solvent 2 is selected from water, and the crystallization method is dissolution crystallization;

[0045] Method 2, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of solvent 3, filtering, volatilizing, and crystallizing to obtain the pyrimidinecarboxamide compound having the crystal form Form B, wherein the solvent 3 is selected from a binary solvent of ethyl formate and methylcyclohexane; and the crystallization method is evaporative crystallization;

[0046] Method three, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of solvent four, stirring, filtering to obtain the pyrimidinecarboxamide compound having the crystal form Form B, wherein the solvent four is selected from a binary solvent of methyl tert-butyl ether and n-heptane; the method is suspension beating.

[0047] As a preferred embodiment, the method for preparing the crystal form Form C comprises the following steps:

[0048] The pyrimidinecarboxamide compound shown in formula (I) is heated to obtain the pyrimidinecarboxamide compound having the crystal form Form C; the heating temperature reaches 180-200°C, preferably 190°C.

[0049] As a preferred embodiment, the method for preparing the crystal form Form G comprises the following steps:

[0050] The pyrimidinecarboxamide compound shown in formula (I) is dissolved in an appropriate amount of solvent, stirred, and filtered to obtain the pyrimidinecarboxamide compound having the crystal form Form G, wherein the solvent is selected from a mixture of methyl isobutyl ketone and anisole.

[0051] The present invention also provides a pharmaceutical composition, comprising the following components: 1) at least one of the crystalline forms Form A, B, C, and G; and

[0052] 2) One or more pharmaceutically acceptable carriers, diluents or excipients.

[0053] As a preferred embodiment, it is suitable for administration via a route selected from oral, parenteral, topical, transdermal and pulmonary.

[0054] As a preferred embodiment, it is an oral dosage form selected from the following: pills, tablets, capsules, emulsions, suspensions, microsuspensions, sticky paper capsules, dustings, powders, freeze-dried powders, granules and lozenges.

[0055] The present invention also provides a use of the crystal form Form A, crystal form Form B, crystal form Form C, and crystal form Form G in preparing a drug for treating a CXCR1 / 2 chemokine-mediated disease, wherein the disease is inflammation or a tumor disease, and the inflammation is selected from any one of rheumatoid arthritis, stroke, ischemia-reperfusion injury, psoriasis, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, asthma, cystic fibrosis, airway hyperresponsiveness, bronchiectasis, bronchiolitis, chronic bronchitis, cor pulmonale, dyspnea, emphysema, hyperinflation, hyperoxia-induced inflammation, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, small airway disease, ventilation-perfusion mismatch, or myelodysplastic syndrome; and the tumor disease is selected from any one of pancreatic cancer, pancreatic ductal adenocarcinoma, metastatic cancer, non-small cell lung cancer, melanoma, or other advanced solid tumors.

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] (1) Provided are crystal forms of the compound of formula (I) suitable for preparing drugs. These crystal forms remain unchanged after being ground and placed in water and under different temperature / humidity conditions for a period of time, and have good crystal stability. These crystal forms have good adaptability to wet granulation, dry granulation or other dosage forms, and are conducive to the development of formulation technology.

[0058] (2) The crystal form provided by the present invention has low hygroscopicity and thus has good tolerance to different humidity environmental conditions, which facilitates the packaging and storage of drugs and significantly reduces the cost of drug transportation and storage.

[0059] (3) In the process of preparing the crystal form of the present invention, non-toxic or low-toxic solvents can be selected, and the preparation methods are all conventional crystallization methods that can be industrially produced. By controlling the process parameters, the particle size, crystal form and crystal habit can be controlled, thereby obtaining a stable and high-quality product. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 This is the XRPD diagram of the crystalline form Form A of the present invention.

[0061] Figure 2 It is the TGA chart of the crystal form Form A of the present invention.

[0062] Figure 3 It is the DSC graph of the crystal form Form A of the present invention.

[0063] Figure 4 It is the crystal form A of the present invention 1 H NMR spectrum.

[0064] Figure 5 It is the XRPD pattern of the crystalline form Form B of the present invention.

[0065] Figure 6 It is the TGA chart of the crystal form Form B of the present invention.

[0066] Figure 7 It is the DSC graph of the crystal form Form B of the present invention.

[0067] Figure 8 It is the crystal form B of the present invention 1 H NMR spectrum.

[0068] Fig. 9 This is the XRPD diagram of the crystalline form Form C of the present invention.

[0069] Fig.10 It is the DSC graph of the crystal form Form C of the present invention.

[0070] Fig.11It is the XRPD pattern of the crystalline form Form G of the present invention.

[0071] Fig.12 It is the TGA chart of the crystal form Form G of the present invention.

[0072] Fig.13 It is the DSC graph of the crystal form Form G of the present invention.

[0073] Fig.14 This is the XRPD diagram of the crystalline Form I prepared by the inventor according to the compound preparation example of patent US8969365 (B2).

[0074] Fig.15 It is the XRPD comparison diagram of the crystal form Form A of the present invention placed at 25°C / <10% RH for 1 month (from bottom to top, the diagrams are before placement and after placement at 25°C / <10% RH for 1 month respectively).

[0075] Fig.16 It is a comparison of XRPD diagrams of the crystal form Form A of the present invention placed at 25°C / 60% RH for 1 month (from bottom to top, diagrams before placement and after placement at 25°C / 60% RH for 1 month, respectively).

[0076] Fig.17 It is a comparison of XRPD diagrams of the crystal form Form A of the present invention placed at 25°C / 92.5% RH for 1 month (from bottom to top, diagrams before placement and after placement at 25°C / 92.5% RH for 1 month, respectively).

[0077] Fig.18 It is a comparison of XRPD diagrams of the crystal form Form A of the present invention placed at 40°C / <10% RH for 1 month (from bottom to top, diagrams before placement and after placement at 40°C / <10% RH for 1 month, respectively).

[0078] Fig.19 It is a comparative XRPD diagram of the crystal form Form A of the present invention placed at 40°C / 60% RH for 1 month (from bottom to top, the diagrams are respectively before placement and after placement at 40°C / <60% RH for 1 month).

[0079] Fig. 20 It is a comparative XRPD diagram of the crystal form Form A of the present invention placed at 40°C / 92.5% RH for 1 month (from bottom to top, the diagrams are before placement and after placement at 40°C / 92.5% RH for 1 month, respectively).

[0080] Fig.21 It is the XRPD comparison diagram of the crystal form Form B of the present invention placed at 25°C / <10% RH for 1 month (from bottom to top, the diagrams are before placement and after placement at 25°C / <10% RH for 1 month respectively).

[0081] Fig. 22 It is the XRPD comparison diagram of the crystal form Form B of the present invention placed at 25°C / 60% RH for 1 month (from bottom to top, the diagrams are before placement and after placement at 25°C / 60% RH for 1 month respectively).

[0082] Fig.23 It is a comparison of XRPD diagrams of the crystal form Form B of the present invention placed at 25°C / 92.5% RH for 1 month (from bottom to top, diagrams before placement and after placement at 25°C / 92.5% RH for 1 month, respectively).

[0083] Fig.24 It is the XRPD comparison diagram of the crystal form Form B of the present invention placed at 40°C / <10% RH for 1 month (from bottom to top, the diagrams are before placement and after placement at 40°C / <10% RH for 1 month respectively).

[0084] Fig.25 It is the XRPD comparison diagram of the crystal form Form B of the present invention placed at 40°C / 60% RH for 1 month (from bottom to top, the diagrams are before placement and after placement at 40°C / <60% RH for 1 month respectively).

[0085] Fig.26 It is a comparison of XRPD diagrams of the crystal form Form B of the present invention placed at 40°C / 92.5% RH for 1 month (from bottom to top, diagrams before placement and after placement at 40°C / 92.5% RH for 1 month, respectively).

[0086] Fig. 27 The XRPD comparison diagram of Form I placed at 25°C / 60% RH for 1 day (from bottom to top, the diagrams are before placement and after placement at 25°C / 60% RH for 1 day, respectively).

[0087] Fig.28 This is a comparison of XRPD diagrams of the crystal form Form A of the present invention before and after stirring in water for one week (from top to bottom are the diagrams before stirring and after stirring in water for one week, respectively).

[0088] Fig.29 This is a comparison of XRPD diagrams of the crystalline form Form B of the present invention before and after stirring in water for one week (from top to bottom are the diagrams before stirring and after stirring in water for one week, respectively).

[0089] Fig.30 This is a comparison of XRPD images of Form I before and after stirring in water for 10 minutes (from top to bottom are the images before stirring and after stirring in water for 10 minutes, respectively).

[0090] Fig.31It is an XRPD comparison diagram of the mixed crystals of Form A and Form B of the present invention before and after stirring in water for 1 week at 25°C (from top to bottom, respectively, the mixed crystals when stirred for 1 hour, Form A of the present invention, the mixed crystals after stirring in water for 1 week, and Form B of the present invention).

[0091] Fig.32 This is a comparison of XRPD diagrams of the crystal form Form A of the present invention before and after grinding for 10 minutes (from top to bottom are the diagrams before grinding and after grinding for 10 minutes, respectively).

[0092] Fig.33 This is a comparison of XRPD diagrams of the crystal form Form B of the present invention before and after grinding for 10 minutes (from top to bottom are the diagrams before grinding and after grinding for 10 minutes, respectively).

[0093] Fig.34 This is the XRPD comparison chart of Form I before and after grinding for 10 minutes (from top to bottom are the charts before grinding and after grinding for 10 minutes respectively).

[0094] Fig.35 It is a DVS diagram of the crystal form Form A of the present invention.

[0095] Fig.36 It is a DVS diagram of the crystalline form Form B of the present invention.

[0096] Fig.37 1 is the XRPD diagram of the crystal form Form A of the present invention before and after the DVS test (from top to bottom are the XRPD diagrams before and after the test, respectively).

[0097] Fig.38 1 is the XRPD diagram of the crystal form Form B of the present invention before and after the DVS test (from top to bottom are the XRPD diagrams before and after the test, respectively). DETAILED DESCRIPTION

[0098] After extensive and in-depth research and a large number of screenings, the inventors have developed a series of crystal forms of the compound of formula (I). These crystal forms are simple to prepare and low in cost, and some specific crystal forms (such as crystal form Form A, crystal form Form B, etc.) have obvious advantages in crystal stability, stability in water, mechanical stability, compressibility, process developability, etc., which are of great significance to the optimization and development of the drug in the future.

[0099] General Definitions and Terms

[0100] Unless otherwise specified herein, each abbreviation has a common meaning understood by those skilled in the art.

[0101] In this article, the compound of formula (I) is SX-682 developed by Syntrix Pharmaceuticals, with a chemical name of 2-(2-boronic acid-5-trifluoromethoxy-benzylmercapto)-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide, and has the following structural formula:

[0102]

[0103] As used herein, unless otherwise specified, the term "raw material of the compound of formula (I)" refers to the amorphous form and / or various crystalline forms of the compound of formula (I) (including the various crystalline forms and amorphous forms mentioned herein, and the crystalline forms or amorphous forms mentioned in various published or unpublished documents or patents).

[0104] As used herein, unless otherwise specified, the method of adding a solvent or a solution is direct pouring, adding at a uniform speed, or slowly dropping.

[0105] Polymorph

[0106] Solids exist in either amorphous or crystalline form. In the case of crystalline form, the molecules are positioned in a three-dimensional lattice. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, which are known as "polymorphs". Different polymorphs of a given substance may differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal shape, packing mode, fluidity and / or solid state stability.

[0107] crystallization

[0108] The solubility limit of the compound of interest can be exceeded by operating the solution, thereby completing production-scale crystallization. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature and then cooling the solution to below the saturation limit. Alternatively, the liquid volume can be reduced by boiling, atmospheric evaporation, vacuum drying or by some other methods. The solubility of the compound of interest can be reduced by adding an antisolvent or a solvent or a mixture of such solvents in which the compound has a low solubility. Another alternative is to adjust the pH value to reduce solubility. For a detailed description of the crystallization, see Crystallization, the third edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

[0109] If it is desired that salt formation and crystallization occur simultaneously, the addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting materials. Likewise, completion of the synthesis reaction in a medium in which the final desired form is less soluble than the reactants may result in direct crystallization of the final product.

[0110] Optimization of crystallization can include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One embodiment is to dissolve the compound of interest in a solvent at an elevated temperature, followed by the controlled addition of an appropriate volume of antisolvent to bring the system just below saturation levels. At this point, seeds of the desired form can be added (while maintaining the integrity of the seeds) and the system cooled to complete crystallization.

[0111] Crystal form of the present invention

[0112] As used herein, "the crystalline form of the present invention" refers to the crystalline form Form A, crystalline form Form B, crystalline form Form C, crystalline form Form G or a combination thereof as described herein.

[0113] Pharmaceutical compositions and methods of use

[0114] Since the crystal form of the present invention or SX-682 (amorphous) prepared from the crystal form of the present invention has excellent therapeutic effects and is used to treat CXCR1 / 2 chemokine-mediated diseases, the crystal form of the present invention or SX-682 (amorphous) prepared from the crystal form of the present invention and a pharmaceutical composition containing the crystal form of the present invention or SX-682 (amorphous) prepared from the crystal form of the present invention as a main active ingredient can be used to treat CXCR1 / 2 chemokine-mediated diseases.

[0115] The pharmaceutical composition of the present invention comprises the crystal form of the present invention or SX-682 (amorphous form) prepared from the crystal form of the present invention within a safe and effective amount, and a pharmaceutically acceptable excipient or carrier.

[0116] Among them, "safe and effective amount" means: the amount of the compound (or crystal form or amorphous form) is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1 to 2000 mg of the crystal form of the present invention per dose, and more preferably, contains 2.5 to 200 mg of the crystal form of the present invention per dose. Preferably, the "one dose" is one capsule or tablet.

[0117] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0118] The administration method of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0119] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0120] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be formed into microcapsules with one or more of the above-mentioned excipients.

[0121] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0122] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0123] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0124] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0125] Dosage forms of the polymorphs of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0126] The crystal form of the present invention or SX-682 (amorphous form) prepared from the crystal form of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0127] When using the pharmaceutical composition, a safe and effective amount of the crystal form of the present invention or SX-682 (amorphous form) prepared from the crystal form of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 2.5 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of skilled physicians.

[0128] General Methods

[0129] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for which specific conditions are not specified in the following examples are usually performed under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0130] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0131] The solvents used in the present invention are all analytically pure and have a water content of about 0.1%. The raw materials used as the compounds of formula (I) in the examples are all purchased. All the test methods of the present invention are general methods, and the test parameters are as follows:

[0132] XRPD pattern determination method:

[0133] X-ray powder diffraction (XRPD) instrument: Bruker D2 Phaser X-ray powder diffractometer; radiation source Generator kV: 30 kV; Generator mA: 10 mA; Starting 2θ: 3.000°, Scanning range: 3.0000-40.000°, Scanning step 0.02°, Scanning speed 0.1 s / step.

[0134] TGA diagram determination method:

[0135] Thermogravimetric analysis (TGA) instrument: TGA2 from METTLER TOLEDO, Switzerland; heating rate: 10°C / min; nitrogen flow rate: 50 mL / min.

[0136] DSC graph determination method:

[0137] Differential Scanning Calorimetry (DSC) instrument: DSC 3 from METTLER TOLEDO, Switzerland; heating rate: 10°C / min, nitrogen flow rate: 50 mL / min.

[0138] H NMR data ( 1 H NMR) was collected on a Bruker A4ance II DMX 400M HZ NMR spectrometer. 5 mg of sample was weighed, dissolved in 0.6 mL of deuterated dimethyl sulfoxide, filtered, and the filtrate was added to the NMR tube for testing.

[0139] DVS diagram determination method:

[0140] Dynamic moisture sorption instrument (DVS) instrument: Discovery SA model from TA Company, USA; temperature: 25°C; nitrogen flow rate: 50 mL / min; mass change per unit time: 0.002% / min; relative humidity range: 0% RH to 90% RH.

[0141] In the present invention, unless otherwise specified, the drying method used is a conventional drying method in the art, for example, in the embodiments of the present invention, drying refers to vacuum drying or normal pressure drying in a conventional drying oven. Generally, the drying time is 0.1 to 50 hours or 1 to 30 hours.

[0142] Example 1: Preparation of Crystalline Form A

[0143] Weigh 10.5 mg of the compound of formula (I) and dissolve it in 0.2 mL of acetic acid at 30°C, filter it, add 2 mL of water to the filtrate, stir it at 30°C for 24 hours, and solid precipitates, filter it, and dry it in vacuum at 25°C for 18 hours. The solid obtained is Form A.

[0144] The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 1, and its spectrum is shown in Figure 1 As shown; the obtained solid was subjected to TGA test, and its spectrum was as shown Figure 2 The obtained solid was subjected to DSC test, and its spectrum was as shown Figure 3 As shown; the obtained solid is subjected to 1 H NMR test, its spectrum is as follows Figure 4 As shown, NMR data: 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.09(s,2H),8.34(bs,2H),7.76(dd,J=9.1, 5.0Hz, 2H), 7.65 (d, J = 8.2Hz, 1H), 7.46 (s, 1H), 7.23 (t, J = 8.9Hz, 3H), 4.70 (s, 2H).

[0145] Table 1

[0146]

[0147]

[0148] Example 2: Preparation of Crystalline Form A

[0149] 10.1 mg of the compound of formula (I) was weighed and dissolved in 0.2 mL of isobutyl acetate at 25°C, filtered, and the filtrate was added to 2 mL of n-pentane and stirred at 25°C for 2 hours. Solid precipitated and filtered. The solid was placed at 25°C and vacuum dried for 24 hours. The obtained solid was Form A. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 2.

[0150] Table 2

[0151] Peak number 2θ(°) Relative strength (%) 1 5.9 5.7 2 8.3 7.5 3 11.6 27.8 4 11.9 9.8 5 13.0 7.9 6 13.2 13.1 7 16.6 100.0 8 17.8 17.8 9 18.4 8.9 10 18.8 12.1 11 21.3 55.1 12 21.9 2.9 13 23.2 4.2 14 24.0 11.4 15 24.6 5.9 16 25.0 4.3 17 26.6 10.1 18 27.9 3.8 19 29.4 1.9 20 30.5 4.2 21 32.2 3.6 22 33.5 4.9 23 34.8 2.7 24 35.6 4.0 25 36.5 7.2

[0152] Example 3: Preparation of Crystalline Form A

[0153] 10.5 mg of the compound of formula (I) was weighed and dissolved in 1.0 mL of tert-butyl alcohol / water (4:1, v / v) at 22° C., filtered, and the filtrate was freeze-dried to obtain a white powdery solid, which was Form A. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 3.

[0154] Table 3

[0155]

[0156]

[0157] Example 4: Preparation of Crystal Form B

[0158] Weigh 10.3 mg of the compound of formula (I) and dissolve it in 0.2 mL of acetonitrile at 22°C, filter it, add 2 mL of water to the filtrate, stir it at 24°C for 16 hours, and solid precipitates, filter it, and dry it in vacuum at 25°C for 24 hours. The solid obtained is Form B.

[0159] The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 4, and its spectrum is shown in Figure 5 As shown; the obtained solid was subjected to TGA test, and its spectrum was as shown Figure 6 The obtained solid was subjected to DSC test, and its spectrum was as shown Figure 7 As shown; the obtained solid is subjected to 1 H NMR test, its spectrum is as follows Figure 8 As shown, NMR data: 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.09(s,2H),8.34(s,2H),7.76(dd,J=9.0,5 .0Hz,2H),7.65(d,J=8.2Hz,1H),7.46(s,1H),7.23(t,J=8.9Hz,3H),4.70(s,2H).

[0160] Table 4

[0161] Peak number 2θ(°) Relative strength (%) 1 4.6 2.4 2 8.2 4.2 3 9.2 6.9 4 10.5 0.5 5 12.2 8.9 6 14.0 1.4 7 16.0 16.6 8 16.5 8.6 9 18.1 10.8 10 18.4 100.0 11 19.7 3.2 12 20.2 4.2 13 21.1 1.3 14 22.4 2.6 15 23.3 3.5 16 24.0 1.7 17 24.3 6.7 18 24.6 3.4 19 24.9 15.8 20 25.7 22.2 21 26.4 5.5 22 26.6 2.3 23 27.7 4.5 24 28.3 3.5 25 29.1 1.8 26 30.8 0.8 27 31.9 1.5 28 32.4 8.6 29 32.8 1.1 30 33.6 8.5 31 34.5 0.9 32 35.4 0.8 33 36.6 0.6 34 37.3 0.7

[0162] Example 5: Preparation of Crystal Form B

[0163] 10.3 mg of the compound of formula (I) was weighed and dissolved in 1.0 mL of ethyl formate / methylcyclohexane (4:1, v / v) at 25° C., filtered, and the filtrate was slowly evaporated at 24.5° C. / 70% RH. After the solvent was evaporated, a solid was precipitated, and the obtained solid was the crystalline form Form B of the compound of formula (I). The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 5.

[0164] Table 5

[0165] Peak number 2θ(°) Relative strength (%) 1 4.6 10.0 2 8.3 2.7 3 9.3 18.7 4 12.2 14.6 5 14.1 1.7 6 16.1 20.8 7 16.6 6.2 8 18.1 22.4 9 18.4 100.0 10 19.7 5.0 11 20.3 8.6 12 22.4 6.7 13 23.3 10.2 14 24.4 4.0 15 24.6 11.7 16 25.0 12.5 17 25.7 19.2 18 26.4 12.2 19 26.7 2.4 20 27.8 4.9 21 28.3 7.8 22 29.2 3.6 23 30.9 1.9 24 32.0 1.2 25 32.4 6.4 26 32.8 5.3 27 33.6 11.8 28 34.5 2.6

[0166] Example 6: Preparation of Crystal Form B

[0167] 10.0 mg of the compound of formula (I) was weighed and suspended in 0.5 mL of methyl tert-butyl ether / n-heptane (1:9, v / v) at 25° C., stirred at −20° C. for 14 h, and filtered. The obtained solid was the crystalline form B of the compound of formula (I). The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 6.

[0168] Table 6

[0169]

[0170]

[0171] Example 7: Preparation of Crystal Form C

[0172] 7.9 mg of the compound of formula (I) was weighed and heated to 190° C. The obtained solid was crystal form Form C. The obtained solid was subjected to XRPD test. Its X-ray powder diffraction data is shown in Table 7. Its spectrum is shown in Fig. 9 The obtained solid was subjected to DSC test, and its spectrum was as shown Fig.10 shown.

[0173] Table 7

[0174]

[0175]

[0176] Example 8: Preparation of Crystal Form G

[0177] 10.1 mg of the compound of formula (I) was weighed and dissolved in 0.5 mL of methyl isobutyl ketone / anisole (1:9, v / v), stirred at -20°C for 16 h, and filtered. The obtained solid was the crystalline form Form G. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 8, and its spectrum is shown in Fig.11 As shown; the obtained solid was subjected to TGA test, and its spectrum was as shown Fig.12 The obtained solid was subjected to DSC test, and its spectrum was as shown Fig.13 shown.

[0178] Table 8

[0179]

[0180]

[0181] Comparative Example 1

[0182] Preparation of SX-682 compound

[0183] Referring to the method disclosed in US8969365 (B2), 2-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethoxy-benzylmercapto]-pyrimidine-5-carboxylic acid (4-fluorophenyl)-amide (5.66 g, 10.3 mmol, 1 eq) was dissolved in methanol (100 mL), and 4.5 M aqueous potassium bifluoride (11.5 mL, 5 eq) was filled in the reaction vessel, and the solution was stirred for 1 hour. Methanol was then removed by rotary evaporation at room temperature, and the obtained mixture of yellow and yellow-white solids was suspended in acetone, and the suspension was gravity filtered to remove insoluble salts to obtain a clear yellow solution. The solution was added to water and placed in a refrigerator. After cooling for about 1.5 hours, a yellow-white precipitate was collected by vacuum filtration, rinsed with water, and vacuum dried overnight. The obtained yellow-white solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 9, and its spectrum is shown in Table 9. Fig.14 shown.

[0184] Table 9

[0185]

[0186]

[0187] Test Example 1: Crystal Stability

[0188] The crystal forms Form A and Form B prepared by the present invention and the crystal form Form I prepared by the method disclosed in US8969365 (B2) were placed open for a certain period of time under different conditions, and XRPD detection was performed on the crystal forms before and after the placement, and the XRPD patterns of the crystal forms before and after the placement were compared. The specific results are shown in Table 10.

[0189] Table 10

[0190]

[0191]

[0192] By comparing the XRPD patterns before and after placement in each figure, it can be seen that the crystal forms Form A and Form B provided by the present invention do not change in crystal form after being exposed for 30 days at 25°C / <10% RH, 25°C / 60% RH, 25°C / 92.5% RH, 40°C / <10% RH, 40°C / 60% RH and 40°C / 92.5% RH, indicating that the crystal form of the present invention has excellent stability at different temperatures / humidities; while the crystal form Form I is exposed for 1 day at 25°C / 60% RH and is converted into the crystal form Form B of the present invention, indicating that the crystal form is kinetically unstable.

[0193] Test Example 2: Crystal stability in water

[0194] 20 mg of the crystal form Form A and the crystal form Form B prepared by the present invention were weighed respectively in 2 mL of water, stirred at 25° C. for 1 week, and then the solid was collected and XRPD was detected. The XRPD patterns of the solid crystal forms before and after stirring were compared. The specific results are shown in Table 11.

[0195] Table 11

[0196]

[0197]

[0198] By comparing the XRPD diagrams before and after stirring in each figure, it can be seen that the crystal forms Form A and Form B provided by the present invention are stirred in water at 25°C for 1 week respectively, and the crystal forms do not change, indicating that the crystal forms of the present invention have good stability in water and are feasible for wet granulation, suspension or other liquid preparations; after stirring Form I in water for 10 minutes, it turns into the crystal form Form A of the present invention, indicating that the crystal form I has poor crystal stability in water. The mixed crystals of the crystal forms A and B of the present invention are stirred in water at 25°C for 1 week and completely turned into Form B, indicating that Form B has better thermodynamic stability than Form A in water at 25°C.

[0199] Test Example 3: Mechanical Stability

[0200] 50 mg of the crystal form Form A and the crystal form Form B prepared by the present invention were weighed in a mortar, ground for 10 min, and then the solid was collected and XRPD was detected. The XRPD patterns of the solid crystal forms before and after grinding were compared. The specific results are shown in Table 12.

[0201] Table 12

[0202]

[0203] By comparing the XRPD patterns before and after grinding in each figure, it can be seen that the crystal forms A and B provided by the present invention do not change in crystal form before and after grinding, indicating that the crystal forms of the present invention have good mechanical stability. However, the crystal form I changes in crystal form before and after grinding, and turns into an amorphous form after grinding. After the amorphous form is placed at 25°C / 92.5% RH for 1 week, the surface of the sample turns yellow, and it becomes a viscous jelly after being pressed with a spoon.

[0204] Test Example 4: Moisture absorption

[0205] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Appendix XIX J of the 2010 edition of the Chinese Pharmacopoeia, Guidelines for Drug Hygroscopicity Test):

[0206] Deliquescence: Absorbing enough water to form a liquid;

[0207] Very hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0208] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0209] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0210] No or almost no hygroscopicity: weight gain due to moisture absorption is less than 0.2%.

[0211] 10 mg of each of the crystal form A and the crystal form B prepared by the present invention were taken, and their hygroscopicity was tested by a dynamic moisture sorption instrument (DVS), and then samples were taken for XRPD measurement. The DVS images of the crystal form A and the crystal form B are shown in Fig.35 and Fig.36 The overall test results are shown in Table 13.

[0212] Table 13

[0213]

[0214] It can be seen from the DVS test results that the crystal forms Form A and Form B provided by the present invention have low hygroscopicity; from the XRPD results, it can be seen that the crystal forms Form A and Form B do not change before and after the DVS test, which shows that the crystal forms Form A and Form B of the present invention have the ability to withstand high humidity environments.

[0215] The above are only some preferred embodiments of the present invention, and the present invention is not limited to the contents of the embodiments. For those skilled in the art, various changes and modifications can be made within the scope of the technical solution of the present invention, and any changes and modifications made are within the protection scope of the present invention.

Claims

1. A crystalline form A of a pyrimidinecarboxamide compound having a structure as shown in formula (I), characterized in that: The X-ray powder diffraction pattern includes 3 or more 2θ values ​​selected from the following: 5.8°±0.2°, 11.4°±0.2°, 16.5°±0.2°, 21.2°±0.2°.

2. The crystal form Form A according to claim 1, characterized in that: The crystalline form Form A comprises 6 or more 2θ values ​​selected from the following in the X-ray powder diffraction pattern: 5.8°±0.2°, 8.1°±0.2°, 11.4°±0.2°, 11.8°±0.2°, 12.9°±0.2°, 13.1°±0.2°, 14.9°±0.2°, 16.5°±0.2°, 17.7°±0.2°, 18.2°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 20.0°±0.2°, 21.2°±0.2°, 21.8°±0.2°, 22.3°±0.2°, 23.1°±0.2°, 23.8°±0.2°, 24.3°±0.2°, 24.6°±0.2°. 2°, 24.9°±0.2°, 26.0°±0.2°, 26.6°±0.2°, 27.1°±0.2°, 28.0°±0.2°, 28.6°±0.2°, 29.1°±0.2°, 29.3°±0.2°, 30.0°±0.2°, 30.3°±0.2°, 30.8°±0.2 °, 31.5°±0.2°, 32.1°±0.2°, 32.7°±0.2°, 33.4°±0.2°, 33.8°±0.2°, 34.7°±0.2°, 34.9°±0.2°, 35.5°±0.2°, 36.5°±0.2°, 37.0°±0.2°, 38.0°±0.2°.

3. The crystal form Form A according to claim 1 or 2, characterized in that: The X-ray powder diffraction (XRPD) pattern of the crystalline form Form A is shown in FIG1 .

4. A crystalline form B of a pyrimidinecarboxamide compound having a structure as shown in formula (I), characterized in that: The X-ray powder diffraction pattern includes 3 or more 2θ values ​​selected from the following: 9.2°±0.2°, 12.2°±0.2°, 16.0°±0.2°, 18.4°±0.2°, 25.7°±0.2°.

5. The crystal form Form B according to claim 4, characterized in that: The crystalline form Form B comprises 6 or more 2θ values ​​selected from the following in the X-ray powder diffraction pattern: 4.6°±0.2°, 8.2°±0.2°, 9.2°±0.2°, 10.5°±0.2°, 12.2°±0.2°, 14.0°±0.2°, 16.0°±0.2°, 16.5°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 22.4°±0.2°, 23.3°±0.2°, 24.0°±0.2 °, 24.3°±0.2°, 24.6°±0.2°, 24.9°±0.2°, 25.7°±0.2°, 26.4°±0.2°, 26.6°±0.2°, 27.7°±0.2°, 28.3°±0.2°, 29.1°±0.2°, 30.8°±0.2°, 31.9°±0.2°, 32.4°±0.2°, 32.8°±0.2°, 33.6°±0.2°, 34.5°±0.2°, 35.4°±0.2°, 36.6°±0.2°, and 37.3°±0.2°.

6. The crystal form Form B according to claim 4 or 5, characterized in that: The X-ray powder diffraction (XRPD) pattern of the crystalline form Form B is shown in FIG5 .

7. A crystalline form Form C of a pyrimidinecarboxamide compound having a structure as shown in formula (I), characterized in that: The X-ray powder diffraction pattern includes 3 or more 2θ values ​​selected from the following: 3.9°±0.2°, 10.2°±0.2°, 15.7°±0.2°, 20.7°±0.2°, 22.7°±0.2°.

8. The crystal form Form C according to claim 7, characterized in that: The crystalline form Form C comprises 6 or more 2θ values ​​selected from the following in the X-ray powder diffraction pattern: 3.9°±0.2°, 5.0°±0.2°, 6.7°±0.2°, 10.2°±0.2°, 14.9°±0.2°, 15.7°±0.2°, 16.9°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.8 °±0.2°, 19.3°±0.2°, 19.6°±0.2°, 20.7°±0.2°, 21.4°±0.2°, 21.8°±0.2°, 22.7°±0.2°, 23.6°±0.2°, 24.6°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 28.8°±0.2°.

9. The crystal form Form C according to claim 7 or 8, characterized in that: The X-ray powder diffraction (XRPD) pattern of the crystalline form Form C is shown in FIG9 .

10. A crystalline form Form G of a pyrimidinecarboxamide compound having a structure as shown in formula (I), characterized in that: The X-ray powder diffraction pattern includes 3 or more 2θ values ​​selected from the following: 10.8°±0.2°, 15.2°±0.2°, 17.6°±0.2°, 22.8°±0.2°, 24.2°±0.2°.

11. The crystal form Form G according to claim 10, characterized in that: The crystalline form Form G comprises 6 or more 2θ values ​​selected from the following in the X-ray powder diffraction pattern: 10.8°±0.2°, 11.4°±0.2°, 12.4°±0.2°, 13.3°±0.2°, 14.8°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 16.3°±0.2°, 17.6°±0.2°, 18.9°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.2°±0.2°, 20.6°±0.2°, 21. .3°±0.2°, 21.8°±0.2°, 22.1°±0.2°, 22.8°±0.2°, 23.5°±0.2°, 24.2°±0.2°, 25.1°±0.2°, 25.6°±0.2°, 26.2°±0.2°, 27.3°±0.2°, 28.8°±0.2°, 30.1°±0.2°, 30.8°±0.2°, 32.1°±0.2°, 35.3°±0.2°, 35.9°±0.2°, 38.7°±0.2°.

12. The crystal form Form G according to claim 10 or 11, characterized in that: The X-ray powder diffraction (XRPD) pattern of the crystalline form Form G is shown in FIG11 .

13. A method for preparing the crystalline form Form A according to any one of claims 1 to 3, the crystalline form Form B according to any one of claims 4 to 6, the crystalline form Form C according to any one of claims 7 to 9, or the crystalline form Form G according to any one of claims 10 to 12, characterized in that: The method comprises the steps of: a) providing a solution of a raw material of a compound of formula (I) in a solvent one, adding a solvent two to the solution for treatment to obtain a target crystal form; or, The method comprises the steps of: b) providing a solution of a raw material of a compound of formula (I) in a solvent one, and adding the solution into a solvent two for treatment to obtain a target crystal form; or, The method comprises the steps of: c) providing a solution or dispersion of a raw material of a compound of formula (I) in solvent one and / or solvent two, and treating the solution or dispersion to obtain a target crystal form; Wherein, the treatment method comprises one or more of the following steps: stirring, heating, volatilization, cooling, freeze drying; The solvent 1 and the solvent 2 are each independently selected from the following group: alcohol solvents, ketone solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ether solvents, acid solvents, water, or a combination thereof.

14. The method according to claim 13, characterized in that The alcohol solvent is selected from the group consisting of n-propanol, methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, 2-ethoxyethanol, cyclohexanol, n-pentanol, or a combination thereof; The ketone solvent is selected from the group consisting of methyl isobutyl ketone, acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof; the ester solvent is selected from the group consisting of ethyl formate, ethyl acetate, isopropyl acetate, isobutyl acetate, or a combination thereof; The hydrocarbon solvent is selected from the group consisting of chloroform, dichloromethane, n-heptane, cyclohexane, methylcyclohexane, toluene, xylene, cumene, n-hexane, n-pentane, or a combination thereof; The nitrile solvent is selected from acetonitrile; The ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether, 1,4-dioxane, 1,3-dioxolane, or a combination thereof; The acid solvent is selected from the group consisting of formic acid, acetic acid, propionic acid, or a combination thereof.

15. The method according to claim 13 or 14, characterized in that The preparation method of the crystal form Form A comprises the following steps: Method 1, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of solvent 1, filtering, adding an appropriate amount of solvent 2 or adding the filtrate to an appropriate amount of solvent 2, stirring, crystallizing, filtering, and vacuum drying to obtain the pyrimidinecarboxamide compound having the crystal form Form A, wherein the solvent 1 is selected from acetic acid or isobutyl acetate, the solvent 2 is selected from water or n-pentane, and the crystallization method is dissolution crystallization; Method 2, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of mixed solvent 3, filtering, and freeze-drying to obtain the pyrimidinecarboxamide compound having the crystal form Form A, wherein the mixed solvent 3 is selected from a binary solvent of tert-butanol and water.

16. The method according to claim 13 or 14, characterized in that The preparation method of the crystal form Form B comprises the following steps: Method 1, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of solvent 1, filtering, adding an appropriate amount of solvent 2, stirring, crystallizing, filtering, and vacuum drying to obtain the pyrimidinecarboxamide compound having the crystal form Form B, wherein the solvent 1 is selected from acetonitrile, the solvent 2 is selected from water, and the crystallization method is dissolution crystallization; Method 2, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of solvent 3, filtering, volatilizing, and crystallizing to obtain the pyrimidinecarboxamide compound having the crystal form Form B, wherein the mixed solvent 3 is selected from a binary solvent of ethyl formate and methylcyclohexane; and the crystallization method is evaporative crystallization; Method three, dissolving the pyrimidinecarboxamide compound shown in formula (I) in an appropriate amount of solvent four, stirring, filtering to obtain the pyrimidinecarboxamide compound having the crystal form Form B, wherein the solvent four is selected from a binary solvent of methyl tert-butyl ether and n-heptane; the method is suspension beating.

17. The method according to claim 13 or 14, characterized in that The preparation method of the crystal form Form C comprises the following steps: The pyrimidinecarboxamide compound shown in formula (I) is heated to obtain the pyrimidinecarboxamide compound having the crystal form Form C; the heating temperature reaches 180-200°C, preferably 190°C.

18. The method according to claim 13 or 14, characterized in that The preparation method of the crystal form Form G comprises the following steps: The pyrimidinecarboxamide compound shown in formula (I) is dissolved in an appropriate amount of solvent, stirred, and filtered to obtain the pyrimidinecarboxamide compound having the crystal form Form G, wherein the solvent is selected from a binary solvent of methyl isobutyl ketone and anisole.

19. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the following components: 1) at least one of the crystalline form Form A of the compound of formula (I) according to any one of claims 1 to 3, the crystalline form Form B of the compound of formula (I) according to any one of claims 4 to 6, the crystalline form Form C of the compound of formula (I) according to any one of claims 7 to 9, or the crystalline form Form G of the compound of formula (I) according to any one of claims 10 to 12; and 2) One or more pharmaceutically acceptable carriers, diluents or excipients.

20. The pharmaceutical composition according to claim 19, which is suitable for administration by a route selected from oral, parenteral, topical, transdermal and pulmonary.

21. The pharmaceutical composition according to claim 19 or 20, which is in an oral dosage form selected from the group consisting of pills, tablets, capsules, emulsions, suspensions, microsuspensions, rice paper capsules, dustings, powders, freeze-dried powders, granules and lozenges.

22. The crystalline form A of the compound of formula (I) according to any one of claims 1 to 3, the crystalline form B of the compound of formula (I) according to any one of claims 4 to 6, the crystalline form C of the compound of formula (I) according to any one of claims 7 to 9, or the crystalline form Form C of the compound of formula (I) according to any one of claims 10 to 12 The use of G in the preparation of a medicament for treating a CXCR1 / 2 chemokine-mediated disease, wherein the disease is an inflammation or a tumor disease, wherein the inflammation is selected from any one of rheumatoid arthritis, stroke, ischemia-reperfusion injury, psoriasis, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, asthma, cystic fibrosis, airway hyperresponsiveness, bronchiectasis, bronchiolitis, chronic bronchitis, cor pulmonale, dyspnea, emphysema, hyperinflation, hyperoxia-induced inflammation, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, small airway disease, ventilation-perfusion mismatch, or myelodysplastic syndrome; and the tumor disease is selected from any one of pancreatic cancer, pancreatic ductal adenocarcinoma, metastatic cancer, non-small cell lung cancer, melanoma, or other advanced solid tumors.

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