A new crystalline form of cyclohexanecarboxamide and a process for its preparation

Abstract

The present invention provides a new crystalline form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (compound of formula (I)) and processes for its preparation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to a novel crystalline form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexaneformamide and its preparation method. Background Technology

[0002] RET (Rearranged during transfection) is a relatively rare proto-oncogene located on the long arm of human chromosome 10, encoding a receptor tyrosine kinase. This receptor spans both sides of the cell membrane and facilitates signal transduction by forming a protein complex. RET proteins play an important role in the development of the kidneys and gastrointestinal system. In various cancers, alterations to the RET gene lead to kinase activation, thereby driving tumor formation and growth. Initially, research found that RET gene alterations were associated with the development of papillary thyroid carcinoma; recent studies have shown that alterations to this gene have also been found in patients with non-small cell lung cancer (NSCLC), one of the deadliest cancers. Currently, no anticancer drugs that selectively target RET mutations or fusions have been approved globally. Although several marketed multi-kinase inhibitors (MKIs) can exert some inhibitory effects, their targeting specificity is low, their inhibitory effect on RET activity is limited, and they may also produce toxic side effects due to off-target effects. For example, in the treatment of NSCLC with RET fusions, the objective response rate (ORR) of these MKIs ranges from 28% to 47%, and the tumors quickly develop resistance mutations. Therefore, there is an urgent need for precision therapies that selectively target RET alterations and anticipated resistance mutations to provide durable clinical benefits.

[0003] Pralsetinib (also known as BLU667) is an oral, potent RET inhibitor developed by Blueprint Medicines Corporation. It exhibits high selectivity for RET fusions and mutations (including resistance mutations) and shows promising therapeutic potential in targeting RET mutations, fusions, and anticipated resistance mechanisms. Preclinical studies have shown that the compound of formula (I) has over 100 times greater selectivity for RET than most tested kinases and also demonstrates strong activity against common RET fusions, mutations, and anticipated resistance mutations. It can potently inhibit the growth of NSCLC, MTC, and colorectal cancer, including tumors resistant to other multi-kinase inhibitors (MKIs). In September 2020, the drug was approved by the US FDA for marketing under the brand name Gavreo. The chemical name of Pralsetinib is (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide, and its molecular structure is shown below:

[0004]

[0005] Patent WO2017079140 reports the compound of formula (I) but does not disclose information about its crystal form. The FDA reports that Pralsetinib is a BCS2 compound with low solubility and high permeability. Its solubility in aqueous media at pH 1.99 to pH 7.64 is 0.880 mg / mL to <0.001 mg / mL (0.880 mg / mL at pH 1.99 and <0.001 mg / mL at pH 7.64). Low solubility leads to low bioavailability. For drug development, the study of polymorphism is crucial. Different crystal forms can cause differences in drug solubility, stability, and flow properties, thus affecting drug safety and efficacy, and consequently leading to different clinical outcomes. To improve bioavailability and prepare stable, pharmaceutically suitable dosage forms, it is necessary to provide crystal forms with high solubility, high stability, and ease of preparation. Therefore, research on the crystal forms of this compound is urgently needed to find suitable crystal forms for drug development. Summary of the Invention

[0006] The purpose of this invention is to provide a new crystal form of the compound of formula (I) that is easy to prepare and has high stability, in order to meet the needs of drug research and industrial production.

[0007] In a first aspect, the present invention provides a crystal form of a compound of formula (I): the crystal form includes crystal form CM-I, crystal form CM-II, crystal form CM-III, crystal form CM-IV, crystal form CM-V, crystal form CM-VI, crystal form CM-VII and / or crystal form CM-VIII.

[0008]

[0009] Preferably, the crystal form is selected from the group consisting of: crystal form CM-I, crystal form CM-II, and crystal form CM-III;

[0010] Preferably, the XRPD diagram of the crystal form CM-I includes six or more 2θ values ​​selected from the group consisting of: 4.9°±0.2°, 6.8°±0.2°, 9.7°±0.2°, 12.7°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 19.7°±0.2°, and 22.9°±0.2°.

[0011] Preferably, the XRPD plot of the crystal form CM-I further includes one or more 2θ values ​​selected from the group consisting of: 13.9°±0.2°, 16.0°±0.2°, 17.1°±0.2°, 18.5°±0.2°, 19.2°±0.2°, 19.4°±0.2°, 20.5°±0.2°, 21.6°±0.2°, 23.5°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.5°±0.2°, 26.0°±0.2°, 27.8°±0.2°, 28.4°±0.2°, 29.3°±0.2°, and 29.7°±0.2°.

[0012] Preferably, the XRPD pattern of the crystal form CM-I includes six or more 2θ values ​​selected from the group consisting of: 4.9°±0.2°, 6.8°±0.2°, 9.7°±0.2°, 12.7°±0.2°, 13.6°±0.2°, 13.9°±0.2°, 14.8°±0.2°, 16.0°±0.2°, 17.1°±0.2°, 18.5°±0.2°, 19.2°±0.2°, ... Characteristic peaks are present at 19.4°±0.2°, 19.7°±0.2°, 20.5°±0.2°, 21.6°±0.2°, 22.9°±0.2°, 23.5°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.5°±0.2°, 26.0°±0.2°, 27.8°±0.2°, 28.4°±0.2°, 29.3°±0.2°, and 29.7°±0.2°.

[0013] Preferably, the crystal form CM-I has essentially the following characteristics:Figure 1 The XRPD diagram shown;

[0014] Preferably, the crystal form CM-I has essentially the following characteristics: Figure 2 The TGA diagram shown;

[0015] Preferably, the crystal form CM-I has essentially the following characteristics: Figure 3 The DSC diagram shown.

[0016] Preferably, the crystal form CM-I has essentially the following characteristics: Figure 4 shown 1 H NMR spectrum.

[0017] Preferably, the crystal form CM-I exhibits a weight loss of approximately 1.14% when heated to 100°C.

[0018] Preferably, the XRPD diagram of the crystal form CM-II includes three or more 2θ values ​​selected from the group consisting of: 9.0°±0.2°, 18.1°±0.2°, 20.8°±0.2°, and 25.1°±0.2°.

[0019] Preferably, the XRPD plot of the crystal form CM-II further includes one or more 2θ values ​​selected from the group consisting of: 3.9°±0.2°, 10.2°±0.2°, 11.3°±0.2°, 13.5°±0.2°, 15.5°±0.2°.

[0020] Preferably, the XRPD diagram of the crystal form CM-II includes six or more 2θ values ​​selected from the group consisting of: 3.9°±0.2°, 9.0°±0.2°, 10.2°±0.2°, 11.3°±0.2°, 13.5°±0.2°, 15.5°±0.2°, 18.1°±0.2°, 20.8°±0.2°, and 25.1°±0.2°.

[0021] Preferably, the XRPD plot of the crystal form CM-II further includes one or more 2θ values ​​selected from the group consisting of: 3.9°±0.2°, 6.9°±0.2°, 9.0°±0.2°, 10.3°±0.2°, 11.1°±0.2°, 11.3°±0.2°, 12.5°±0.2°, 13.5°±0.2°, 13.9°±0.2°, 15.1°±0.2°, 15.5° ±0.2°, 16.5°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.0°±0.2°, 20.8°±0.2°, 21.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 26.0°±0.2°, 29.6°±0.2°, 30.6°±0.2°, 32.0°±0.2°.

[0022] Preferably, the XRPD pattern of the crystal form CM-II includes six or more 2θ values ​​selected from the group consisting of: 3.9°±0.2°, 6.9°±0.2°, 9.0°±0.2°, 10.3°±0.2°, 11.1°±0.2°, 11.3°±0.2°, 12.5°±0.2°, 13.5°±0.2°, 13.9°±0.2°, 15.1°±0.2°, and 15.5°±0.2°. 16.5°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.0°±0.2°, 20.8°±0.2°, 21.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 25.1°±0.2°, 26.0°±0.2°, 29.6°±0.2°, 30.6°±0.2°, 32.0°±0.2°.

[0023] Preferably, the crystal form CM-II has essentially the following characteristics: Figure 9 The XRPD diagram shown;

[0024] Preferably, the crystal form CM-II has essentially the following characteristics: Figure 10 The TGA diagram shown;

[0025] Preferably, the crystal form CM-II has essentially the following characteristics: Figure 11 The DSC diagram shown;

[0026] Preferably, the crystal form CM-II has essentially the following characteristics: Figure 12 shown 1 H NMR spectrum.

[0027] Preferably, the crystal form CM-II has a weight loss of about 2.43% when heated to 100°C.

[0028] Preferably, the XRPD diagram of the crystal form CM-III includes three or more 2θ values ​​selected from the group consisting of: 5.6°±0.2°, 8.5°±0.2°, 10.8°±0.2°, and 14.3°±0.2°.

[0029] Preferably, the XRPD plot of the crystal form CM-III further includes one or more 2θ values ​​selected from the group consisting of: 11.3°±0.2°, 15.7°±0.2°, 20.0°±0.2°, and 23.0°±0.2°.

[0030] Preferably, the XRPD diagram of the crystal form CM-III includes six or more 2θ values ​​selected from the group consisting of: 5.6°±0.2°, 8.5°±0.2°, 10.8°±0.2°, 11.3°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 20.0°±0.2°, and 23.0°±0.2°.

[0031] Preferably, the XRPD plot of the crystal form CM-III further includes one or more 2θ values ​​selected from the group consisting of: 13.3°±0.2°, 15.3°±0.2°, 17.1°±0.2°, 18.0°±0.2°, 21.9°±0.2°, 24.3°±0.2°, and 25.8°±0.2°.

[0032] Preferably, the XRPD diagram of the crystal form CM-III includes six or more 2θ values ​​selected from the group consisting of: 5.6°±0.2°, 8.5°±0.2°, 10.8°±0.2°, 11.3°±0.2°, 13.3°±0.2°, 14.3°±0.2°, 15.3°±0.2°, 15.7°±0.2°, 17.1°±0.2°, 18.0°±0.2°, 20.0°±0.2°, 21.9°±0.2°, 23.0°±0.2°, 24.3°±0.2°, and 25.8°±0.2°.

[0033] Preferably, the crystal form CM-III has essentially the following characteristics: Figure 17 The XRPD diagram shown;

[0034] Preferably, the crystal form CM-III has essentially the following characteristics: Figure 18 The TGA diagram shown;

[0035] Preferably, the crystal form CM-III has essentially the following characteristics: Figure 19 The DSC diagram shown;

[0036] Preferably, the crystal form CM-III has essentially the following characteristics: Figure 20 shown 1 H NMR spectrum.

[0037] Preferably, the crystal form CM-III has a weight loss of about 4.45% when heated to 120°C.

[0038] Preferably, the crystal form CM-IV has characteristic peaks in its XRPD diagram at 2θ values ​​of 5.7°±0.2°, 9.2°±0.2°, 10.5°±0.2°, and 19.4°±0.2°.

[0039] Preferably, the crystal form CM-IV has characteristic peaks in its X-ray diffraction pattern at 2θ values ​​of 5.7°±0.2°, 9.2°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.8°±0.2°, 19.4°±0.2°, 22.2°±0.2°, and 24.6°±0.2°.

[0040] Preferably, the crystal form CM-IV also has characteristic peaks in its X-ray diffraction pattern at 2θ values ​​of 27.2°±0.2° and / or 28.0°±0.2°.

[0041] Preferably, the crystalline form CM-IV has characteristic peaks in its X-ray diffraction pattern at 2θ values ​​of 5.7°±0.2°, 9.2°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.8°±0.2°, 19.4°±0.2°, 22.2°±0.2°, 24.6°±0.2°, 27.2°±0.2°, and 28.0°±0.2°.

[0042] Preferably, the crystal form CM-IV has essentially the following characteristics: Figure 25 The XRPD diagram shown.

[0043] Preferably, the XRPD plot of the crystal form CM-V has characteristic peaks at 2θ values ​​of 5.9°±0.2°, 8.9°±0.2°, 10.3°±0.2°, and 17.3°±0.2°.

[0044] Preferably, the crystal form CM-V has essentially the following properties: Figure 26 The XRPD diagram shown.

[0045] Preferably, the crystal form CM-VI has characteristic peaks in its XRPD diagram at 2θ values ​​of 5.4°±0.2°, 8.0°±0.2°, 10.7°±0.2°, and 16.0°±0.2°.

[0046] Preferably, the crystal form CM-VI also has characteristic peaks in its XRPD pattern at 2θ values ​​of 5.8°±0.2°, and / or 8.7°±0.2°, and / or 11.7°±0.2°, and / or 13.3°±0.2°, and / or 14.6°±0.2°, and / or 18.7°±0.2°, and / or 20.4°±0.2°, 21.4°±0.2°, and / or 24.0°±0.2°, and / or 26.4°±0.2°, and / or 27.6°±0.2°, and / or 29.5°±0.2°, and / or 31.5°±0.2°.

[0047] Preferably, the crystal form CM-VI has characteristic peaks in its XRPD pattern at 2θ values ​​of 5.4°±0.2°, 8.0°±0.2°, 10.7°±0.2°, 16.0°±0.2°, 18.7°±0.2°, 20.4°±0.2°, 21.4°±0.2°, 24.0°±0.2°, 26.4°±0.2°, and 27.6°±0.2°.

[0048] Preferably, the crystal form CM-VI has characteristic peaks in its XRPD pattern at 2θ values ​​of 5.4°±0.2°, 5.8°±0.2°, 8.0°±0.2°, 8.7°±0.2°, 10.7°±0.2°, 11.7°±0.2°, 13.3°±0.2°, 14.6°±0.2°, 16.0°±0.2°, 18.7°±0.2°, 20.4°±0.2°, 21.4°±0.2°, 24.0°±0.2°, 26.4°±0.2°, 27.6°±0.2°, 29.5°±0.2°, and 31.5°±0.2°.

[0049] Preferably, the crystal form CM-VI has essentially the following characteristics: Figure 27 The XRPD diagram shown.

[0050] Preferably, the crystal form CM-VII has characteristic peaks in its XRPD diagram at 2θ values ​​of 2.9°±0.2°, 6.0°±0.2°, 8.0°±0.2°, and 9.8°±0.2°.

[0051] Preferably, the XRPD plot of the crystal form CM-VII also has characteristic peaks at one or more of the following 2θ values: 11.8°±0.2°, and / or 12.5°±0.2°, 14.2°±0.2°, and / or 15.2°±0.2°, and / or 16.4°±0.2°, and / or 16.8°±0.2°, and / or 17.2°±0.2°, and / or 17.6°±0.2°, and / or 18.3°±0.2°, and / or 19.1°±0.2°, and / or 19.7°±0.2°, and / or 21.4°±0.2°, and / or 22.0°±0.2°, and / or 24.5°±0.2°, and / or 24.9°±0.2°, and / or 26.1°±0.2°.

[0052] Preferably, the crystal form CM-VII has characteristic peaks in its XRPD diagram at 2θ values ​​of 2.9°±0.2°, 6.0°±0.2°, 8.0°±0.2°, 9.8°±0.2°, 11.8°±0.2°, 14.2°±0.2°, 17.2°±0.2°, and 17.6°±0.2°.

[0053] Preferably, the crystal form CM-VII has characteristic peaks in its XRPD diagram at 2θ values ​​of 2.9°±0.2°, 6.0°±0.2°, 8.0°±0.2°, 9.8°±0.2°, 11.8°±0.2°, 12.5°±0.2°, 14.2°±0.2°, 15.2°±0.2°, 16.4°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 18.3°±0.2°, 19.1°±0.2°, 19.7°±0.2°, 21.4°±0.2°, 22.0°±0.2°, 24.5°±0.2°, 24.9°±0.2°, and 26.1°±0.2°.

[0054] Preferably, the crystal form CM-VII has essentially the following characteristics: Figure 28 The XRPD diagram shown.

[0055] Preferably, the crystal form CM-VIII has characteristic peaks in its XRPD diagram at 2θ values ​​of 8.4°±0.2°, 10.9°±0.2°, 13.5°±0.2°, and 17.5°±0.2°.

[0056] Preferably, the XRPD pattern of the crystal form CM-VIII also has 2θ values ​​of 2.8°±0.2°, and / or 5.6°±0.2°, and / or 12.0°±0.2°, and / or 13.6°±0.2°, and / or 13.9°±0.2°, and / or 15.3°±0.2°, and / or 19.1°±0.2°, and / or 19.5°±0.2°. Characteristic peaks are present at °, and / or 19.9°±0.2°, and / or 20.9°±0.2°, and / or 21.5°±0.2°, and / or 22.0°±0.2°, and / or 22.8°±0.2°, and / or 24.0°±0.2°, and / or 25.4°±0.2°, and / or 27.5°±0.2°, and / or 29.0°±0.2°.

[0057] Preferably, the crystal form CM-VIII has characteristic peaks in its XRPD pattern at 2θ values ​​of 2.8°±0.2°, 5.6°±0.2°, 8.4°±0.2°, 10.9°±0.2°, 12.0°±0.2°, 13.5°±0.2°, 17.5°±0.2°, 19.9°±0.2°, 22.0°±0.2°, and 22.8°±0.2°.

[0058] Preferably, the crystal form CM-VIII has characteristic peaks in its XRPD pattern at 2θ values ​​of 2.8°±0.2°, 5.6°±0.2°, 8.4°±0.2°, 10.9°±0.2°, 12.0°±0.2°, 13.6°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 17.5°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 19.9°±0.2°, 20.9°±0.2°, 21.5°±0.2°, 22.0°±0.2°, 22.8°±0.2°, 24.0°±0.2°, 25.4°±0.2°, 27.5°±0.2°, and 29.0°±0.2°.

[0059] Preferably, the crystal form CM-VIII has essentially the following properties: Figure 29 The XRPD diagram shown.

[0060] A second aspect of the present invention provides a method for preparing the above-described crystal form, characterized in that,

[0061] The steps include: a) providing a solution of the compound raw material of formula (I) in a first solvent, adding a second solvent to the solution to induce crystallization, and collecting the precipitated solid to obtain the crystal form.

[0062] or,

[0063] The steps include: b) providing a solution of the compound raw material of formula (I) in a first solvent, adding the solution to a second solvent to crystallize, and collecting the precipitated solid to obtain the crystal form.

[0064] or,

[0065] The steps include: c) providing a solution of the compound raw material of formula (I) in a first solvent, treating the solution to obtain a solid, and collecting the obtained solid to obtain the crystal form; wherein the treatment includes stirring, volatilization or cooling.

[0066] Preferably, the first solvent includes alcohol solvents, ketone solvents, amide solvents, ester solvents, hydrocarbon solvents, ether solvents, or combinations thereof.

[0067] Preferably, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, or combinations thereof.

[0068] Preferably, the ketone solvent is selected from the group consisting of acetone, 2-butanone, methyl isobutyl ketone, N-methylpyrrolidone, or combinations thereof.

[0069] Preferably, the amide solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof.

[0070] Preferably, the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, n-propyl acetate, or combinations thereof.

[0071] Preferably, the hydrocarbon solvent is selected from the group consisting of chloroform, dichloromethane, nitromethane, n-heptane, cyclohexane, toluene, or combinations thereof.

[0072] Preferably, the ether solvent is selected from the group consisting of anisole, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or combinations thereof.

[0073] Preferably, the second solvent comprises water, dimethyl sulfoxide, nitromethane, or a combination thereof.

[0074] Preferably, the crystallization process is static crystallization.

[0075] Preferably, the settling process is carried out in a closed environment.

[0076] Preferably, the raw material of formula (I) is either crystalline or amorphous.

[0077] A third aspect of the present invention provides a pharmaceutical composition comprising: 1) a crystal form as described in the first aspect; and 2) a pharmaceutically acceptable carrier.

[0078] A fourth aspect of the invention provides the use of a pharmaceutical composition as described in the third aspect for treating RET-mutant cancers.

[0079] A fifth aspect of the invention provides the use of the crystal form as described in the first aspect, including: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a medicament for treating cancers caused by RET mutations.

[0080] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0081] Figure 1 This is the XRPD diagram of the crystal form CM-I of this invention.

[0082] Figure 2 This is the TGA diagram of the crystal form CM-I of this invention.

[0083] Figure 3 This is the DSC diagram of the crystal form CM-I of this invention.

[0084] Figure 4 It is the crystal form CM-I of this invention. 1 H NMR spectrum.

[0085] Figure 5A These are XRPD comparison images of the crystalline form CM-I of this invention after being placed at 25℃ / 60%RH, 25℃ / 92.5%RH, 40℃ / 75%RH, 40℃ / 92.5%RH and 60℃ / 75%RH for one month (from bottom to top, these are images before placement and after placement at 25℃ / 60%RH, 25℃ / 92.5%RH, 40℃ / 75%RH, 40℃ / 92.5%RH and 60℃ / 75%RH for one month).

[0086] Figure 5B These are XRPD comparison images of the mixture of crystal form CM-I and excipients of the present invention after being placed at 25℃ / 60%RH, 40℃ / 75%RH and 60℃ / 75%RH for 1 month (from bottom to top, the images are before placement and after placement at 25℃ / 60%RH, 40℃ / 75%RH and 60℃ / 75%RH for 1 month).

[0087] Figure 5C This is a comparison of the crystal form CM-I of the present invention before and after stirring in water for 24 hours (the lower figure is the XRPD image before stirring, and the upper figure is the XRPD image after stirring).

[0088] Figure 6 These are XRPD images of the CM-I crystal form of this invention before and after grinding (the top image is the XRPD image before grinding, and the bottom image is the XRPD image after grinding).

[0089] Figure 7 This is the DVS diagram of the crystal form CM-I of this invention.

[0090] Figure 8 These are XRPD images of the CM-I crystal form of this invention before and after DVS testing (the top image is the XRPD image before testing, and the bottom image is the XRPD image after testing).

[0091] Figure 9 This is the XRPD diagram of the crystal form CM-II of this invention.

[0092] Figure 10 This is the TGA diagram of the crystal form CM-II of this invention.

[0093] Figure 11 This is the DSC diagram of the crystal form CM-II of this invention.

[0094] Figure 12 It is the crystal form CM-II of this invention. 1 H NMR spectrum

[0095] Figure 13These are XRPD comparison images of the CM-II crystal form of the present invention after being placed at 25℃ / 60%RH, 25℃ / 92.5%RH, 40℃ / 75%RH, 40℃ / 92.5%RH and 60℃ / 75%RH for one month (from bottom to top, these are images before placement and after placement at 25℃ / 60%RH, 25℃ / 92.5%RH, 40℃ / 75%RH, 40℃ / 92.5%RH and 60℃ / 75%RH for one month).

[0096] Figure 14 These are XRPD images of the CM-II crystal form of this invention before and after grinding (the top image is the XRPD image before grinding, and the bottom image is the XRPD image after grinding).

[0097] Figure 15 This is the DVS diagram of the crystal form CM-II of this invention.

[0098] Figure 16 These are XRPD images of the CM-II crystal form of this invention before and after DVS testing (the upper image is the XRPD image before testing, and the lower image is the XRPD image after testing).

[0099] Figure 17 This is the XRPD diagram of the crystal form CM-III of this invention.

[0100] Figure 18 This is the TGA diagram of the crystal form CM-III of this invention.

[0101] Figure 19 This is the DSC diagram of the crystal form CM-III of this invention.

[0102] Figure 20 It is the crystal form CM-III of this invention. 1 H NMR spectrum

[0103] Figure 21A These are XRPD comparison images of the CM-III crystal form of the present invention after being placed at 25℃ / 60%RH, 25℃ / 92.5%RH, 40℃ / 75%RH, 40℃ / 92.5%RH and 60℃ / 75%RH for one month (from bottom to top, these are images before placement and after placement at 25℃ / 60%RH, 25℃ / 92.5%RH, 40℃ / 75%RH, 40℃ / 92.5%RH and 60℃ / 75%RH for one month).

[0104] Figure 21B These are XRPD comparison images of the mixture of crystal form CM-III and excipients of the present invention after being placed at 25℃ / 60%RH, 40℃ / 75%RH and 60℃ / 75%RH for 1 month (from bottom to top, the images are before placement and after placement at 25℃ / 60%RH, 40℃ / 75%RH and 60℃ / 75%RH for 1 month).

[0105] Figure 21C This is a comparison of the crystal form CM-III of the present invention before and after stirring in water for 24 hours (the lower figure is the XRPD image before stirring, and the upper figure is the XRPD image after stirring).

[0106] Figure 22 These are XRPD images of the CM-III crystal form of this invention before and after grinding (the top image is the XRPD image before grinding, and the bottom image is the XRPD image after grinding).

[0107] Figure 23 This is the DVS diagram of the crystal form CM-III of this invention.

[0108] Figure 24 These are XRPD images of the CM-III crystal form of this invention before and after DVS testing (the upper image is the XRPD image before testing, and the lower image is the XRPD image after testing).

[0109] Figure 25 This is the XRPD diagram of the crystal form CM-IV of this invention.

[0110] Figure 26 This is the XRPD diagram of the crystal form CM-V of this invention.

[0111] Figure 27 This is the XRPD diagram of the crystal form CM-VI of this invention.

[0112] Figure 28 This is the XRPD diagram of the crystal form CM-VII of this invention.

[0113] Figure 29 This is the XRPD diagram of the crystal form CM-VIII of this invention.

[0114] Figure 30A These are XRPD images of the CM-I crystal form of this invention before and after tableting (the top image is the XRPD image before tableting, and the bottom image is the XRPD image after tableting).

[0115] Figure 30B These are XRPD images of the CM-III crystal form of this invention before and after tableting (the top image is the XRPD image before tableting, and the bottom image is the XRPD image after tableting). Detailed Implementation

[0116] During their research, the inventors of this invention made a surprising discovery of a series of new crystal forms of the compound of formula (I). These crystal forms are simple to prepare, inexpensive, and have advantages in terms of stability and process development, which are of great significance for the future optimization and development of this drug.

[0117] the term

[0118] In this document, unless otherwise specified, all abbreviations have their conventional meanings as understood by those skilled in the art.

[0119] In this article, the compound of formula (I) is Pralsetinib, developed by Blueprint Pharmaceuticals, with the chemical name (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide, and its structure is as follows:

[0120]

[0121] Compound of formula (I) is also known as BLU667, or by the following chemical name: (1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide, or represented by the following structure:

[0122]

[0123] As used herein, unless otherwise specified, the term “formula (I) compound raw material” means the amorphous and / or various crystal forms of the formula (I) compound (including the various crystal forms and amorphous forms mentioned herein, and the crystal forms or amorphous forms mentioned in various published or unpublished documents or patents).

[0124] Preferably, the compound raw material of formula (I) used in this invention is BLU-667 prepared by the preparation method provided in the embodiments of this invention.

[0125] As used herein, “the crystal form of the present invention” refers to crystal forms CM-I, CM-II, CM-III, CM-IV, CM-V, CM-VI, CM-VII and CM-VIII of BLU-667 as described herein.

[0126] As used in this article, the "slow addition" method includes, but is not limited to: adding drop by drop, adding slowly along the container wall, etc.

[0127] General Method

[0128] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0129] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0130] All solvents used in this invention are analytical grade, with a water content of approximately 0.1%. The compounds of formula (I) used as raw materials in the examples were all purchased. All test methods used in this invention are general methods, and the test parameters are as follows:

[0131] XRPD plot determination method:

[0132] X-ray powder diffraction instrument: Bruker D2 Phaser X-ray powder diffractometer; radiation source Cu( ); Generator kv: 30kv; Generator mA: 10mA; Initial 2θ: 2.000°, Scan range: 2.0000~35.000°, Scan step size: 0.02°, Scan speed: 0.1s / step.

[0133] TGA determination method:

[0134] Thermogravimetric analysis (TGA) instrument: TGA55 from TA Instruments, USA; equilibration time before test: 2h; temperature range: 20~250℃; heating rate: 10℃ / min; nitrogen flow rate: 40mL / min.

[0135] DSC chart determination method:

[0136] Differential scanning calorimetry (DSC) instrument: TA Q2000 from TA Instruments, USA; temperature range: 20–250℃, heating rate: 10℃ / min, nitrogen flow rate: 50 mL / min.

[0137] Nuclear magnetic resonance hydrogen spectrum data ( 1 H NMR was obtained from a Bruker Avance II DMX 400 MHz nuclear magnetic resonance spectrometer. 2 mg of sample was weighed, dissolved in 0.6 mL of deuterated dimethyl sulfoxide, filtered, and the filtrate was added to an NMR tube for analysis.

[0138] DVS chart determination method:

[0139] Dynamic Moisture Adsorption Analyzer (DVS): TA Q5000 SA model from Thermomix, USA; Temperature: 25℃; Nitrogen flow rate: 50 mL / min; Mass change per unit time: 0.002% / min; Relative humidity range: 0%RH~90%RH.

[0140] Single-punch manual tablet press, model: ENERPAC.

[0141] In this invention, unless otherwise specified, the drying method used is a conventional drying method in the art. For example, in the embodiments of this invention, drying refers to vacuum drying or atmospheric pressure drying in a conventional drying oven. Generally, the drying time is 0.1–50 h or 1–30 h.

[0142] The main advantages of this invention are:

[0143] (1) Suitable crystal forms for drug preparation of compounds of formula (I) are provided. These crystal forms remain unchanged after grinding, tableting, and storage in water and under different temperature / humidity conditions for a period of time, demonstrating good crystal form stability. This indicates that these crystal forms are well adaptable to both wet and dry granulation, and are more conducive to the development of formulation processes.

[0144] (2) The crystal form provided by the present invention has low hygroscopicity, thus it has better tolerance to different humidity conditions, which facilitates packaging and storage while improving the quality of the medicines prepared subsequently.

[0145] (3) Compared with the prior art, the crystal form provided by the present invention has greater solubility, which is conducive to improving bioavailability and thus improving the clinical treatment effect.

[0146] (4) The crystal preparation method provided by the present invention is simple to operate, low in cost, and suitable for drug research and development and industrial production.

[0147] Pharmaceutical Compositions and Administration

[0148] Since the crystalline or amorphous forms of the present invention have excellent therapeutic and preventive effects on cancer or tumors, the crystalline or amorphous forms of the present invention, as well as pharmaceutical compositions containing the crystalline or amorphous forms of the present invention as the main active ingredient, can be used to treat and / or prevent anemia.

[0149] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the crystal form of the present invention and pharmaceutically acceptable excipients or carriers.

[0150] The term "safe and effective amount" refers to an amount of compound (or crystal form) sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the crystal form / dosage of the present invention, more preferably, 10-200 mg of the crystal form / dosage of the present invention. Preferably, "one dose" refers to one capsule or tablet.

[0151] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and incorporate the active ingredient of the invention without significantly reducing the efficacy of the active ingredient. 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, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0152] There are no particular limitations on the administration of the polymorphs or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0153] 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: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0154] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0155] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0156] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0157] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0158] Compositions for parenteral injection may comprise 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.

[0159] Dosage forms of the polymorphs of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0160] The crystal form of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0161] When using the pharmaceutical composition, a safe and effective amount of the polymorph of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0162] The present invention will be further illustrated by specific embodiments below, but these are not intended to limit the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

[0163] Example 1: Preparation of crystal form CM-I

[0164] 14 mg of compound (I) was weighed and dissolved in 0.5 mL of ethanol at 30 °C, and then filtered. The filtrate was stirred at 5 °C for 24 h, and a solid precipitated out. The obtained solid was crystalline form CM-I of compound (I). XRPD analysis was performed on the obtained solid, and its X-ray powder diffraction data are shown in Table 1. Its XRPD pattern is shown in... Figure 1 As shown; the obtained solid was subjected to TGA testing, and its spectrum is shown in the figure. Figure 2 As shown; the obtained solid was subjected to DSC testing, and its spectrum is shown in the figure. Figure 3 As shown; the obtained solid was subjected to... 1 H NMR testing, the spectrum is as follows Figure 4 As shown, the NMR data are: 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),9.51(s,1H),8.68(d,J=4.1Hz,1H),8.45(dd,J=17.2,5.1Hz,2H),7.99(dd,J=8.6,2.2Hz,1H),7.89(dd, J=15.6,6.4Hz,2H),5.17–4.98(m,1H),3.13(s,3H),2.62(d,J=42.2Hz,1H),2.22(d,J=13.8Hz,6H),2.10–1.52(m,9H),1.46(d,J=7.0Hz,3H).

[0165] Table 1

[0166] 2θ(°) relative strength 2θ(°) relative strength 4.9 35.9％ 20.5 8.2％ 6.8 6.0％ 21.6 1.6％ 9.7 15.5％ 22.9 25.5％ 12.7 64.1％ 23.5 11.9％ 13.6 100.0％ 23.7 13.8％ 13.9 13.8％ 24.5 1.4％ 14.8 20.3％ 25.5 1.9％ 16.0 37.5％ 26.0 21.1％ 17.1 1.3％ 27.8 5.9％ 18.5 8.1％ 28.4 1.3％ 19.2 12.2％ 29.3 4.3％ 19.4 21.5％ 29.7 5.7％ 19.6 57.8％

[0167] Example 2: Preparation of crystal form CM-II

[0168] Weigh 12 mg of compound (I), mix with 0.2 mL of methanol, filter, and place the filtrate in a 3 mL open glass vial. Add 3 mL of methyl tert-butyl ether to a 20 mL glass vial. Place the 3 mL glass vial containing the filtrate into the 20 mL glass vial containing the methyl tert-butyl ether, seal the 20 mL glass vial, and let it stand at 25 °C until a solid precipitates. The obtained solid is the crystal form CM-II of compound (I). XRPD testing was performed on the obtained solid, and its X-ray powder diffraction data are shown in Table 2. Its XRPD pattern is shown in... Figure 9 As shown; the obtained solid was subjected to TGA testing, and its spectrum is shown in the figure. Figure 10 As shown; the obtained solid was subjected to DSC testing, and its spectrum is shown in the figure. Figure 11 As shown; the obtained solid was subjected to... 1 H NMR testing, the spectrum is as follows Figure 12 As shown, the NMR data are: 1HNMR (400MHz, DMSO-d6) δ11.89(s,1H),9.52(s,1H),8.68(d,J=4.2Hz,1H),8.45(dd,J=17.7,5.1Hz,2H),7.99(dd,J=8.5,2.2Hz,1H),7.89(dd ,J=15.6,6.3Hz,2H),5.15–4.98(m,1H),3.13(s,3H),2.62(d,J=42.1Hz ,1H),2.22(d,J=13.8Hz,6H),2.07–1.52(m,9H),1.46(d,J=7.1Hz,3H).

[0169] Table 2

[0170]

[0171]

[0172] Example 3: Preparation of crystal form CM-III

[0173] 10 mg of compound (I) was dissolved in 1 mL of acetone, filtered, and 2 mL of water was slowly added to the filtrate. The solution was then placed in a sealed environment and allowed to stand at 28 °C until a solid precipitated. The obtained solid was crystalline form CM-III of compound (I). XRPD analysis was performed on the obtained solid, and its X-ray powder diffraction data are shown in Table 3. Its XRPD pattern is shown in... Figure 17 As shown; the obtained solid was subjected to TGA testing, and its spectrum is shown in the figure. Figure 18 As shown; the obtained solid was subjected to DSC testing, and its spectrum is shown in the figure. Figure 19 As shown; the obtained solid was subjected to... 1 H NMR testing, the spectrum is as follows Figure 20 As shown, the NMR data are: 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),9.52(s,1H),8.68(d,J=4.4Hz,1H),8.45(dd,J=17.9,5.1Hz,2H),7.99(dd,J=8.6,2.1Hz,1H),7.89(dd, J=15.4,6.3Hz,2H),5.15–4.90(m,1H),3.13(s,3H),2.62(d,J=42.2Hz,1H),2.22(d,J=13.7Hz,6H),2.12–1.51(m,9H),1.46(d,J=7.1Hz,3H).

[0174] Table 3

[0175] 2θ(°) relative strength 2θ(°) relative strength 5.6 100.0％ 17.2 16.3％ 8.5 61.0％ 18.0 11.3％ 10.8 53.2％ 20.0 25.3％ 11.3 45.3％ 20.2 20.4％ 13.3 57.4％ 21.9 24.6％ 14.2 59.1％ 23.0 16.5％ 15.3 4.6％ 24.2 9.4％ 15.7 7.6％ 25.8 6.6％

[0176] Example 4: Preparation of crystal form CM-IV

[0177] 10 mg of compound (I) was dissolved in 0.2 mL of tetrahydrofuran, filtered, and 1 mL of water was added dropwise to the filtrate. The mixture was stirred at 24 °C for 24 h, and a solid precipitated. The obtained solid was the crystal form CM-IV of compound (I). XRPD analysis was performed on the obtained solid, and its X-ray powder diffraction data are shown in Table 4. Its XRPD pattern is shown in... Figure 25 As shown.

[0178] Table 4

[0179] 2θ(°) relative strength 2θ(°) relative strength 5.7 12.3％ 19.4 11.0％ 6.4 2.7％ 22.2 5.8％ 9.2 100.0％ 24.6 5.5％ 10.5 38.7％ 27.2 7.9％ 14.5 3.8％ 28.0 2.9％ 17.8 36.2％

[0180] Example 5: Preparation of crystal form CMV

[0181] 9 mg of compound (I) was dissolved in 0.5 mL of chloroform and filtered. The filtrate was added dropwise to 3 mL of nitromethane at 24 °C. After the addition was complete, the mixture was stirred for 24 h, and a solid precipitated. The obtained solid was the crystal form CM-V of compound (I). XRPD tests were performed on the obtained solid, and its X-ray powder diffraction data are shown in Table 5. Its XRPD pattern is shown in... Figure 26 As shown.

[0182] Table 5

[0183] 2θ(°) relative strength 5.8 27.1％ 8.9 100.0％ 10.2 18.0％ 17.3 20.6％

[0184] Example 6: Preparation of crystal form CM-VI

[0185] 21 mg of compound (I) was dissolved in 0.3 mL of dimethyl sulfoxide, filtered, and the filtrate was left exposed at 25 °C until a solid precipitated. The resulting solid was crystalline form CM-VI. XRPD analysis was performed on the obtained solid, and its X-ray powder diffraction data are shown in Table 6. The XRPD pattern is shown in... Figure 27 As shown.

[0186] Table 6

[0187]

[0188]

[0189] Example 7: Preparation of crystal form CM-VII

[0190] 10 mg of compound (I) was dissolved in 0.5 mL of 1,4-dioxane / ethyl acetate (1:4, v / v), filtered, and the filtrate was slowly evaporated at 24 °C until a solid precipitated. The obtained solid was crystal form CM-VII. XRPD analysis was performed on the obtained solid, and its X-ray powder diffraction data are shown in Table 7. Its XRPD pattern is shown in... Figure 28 As shown.

[0191] Table 7

[0192] 2θ(°) relative strength 2θ(°) relative strength 2.9 18.0 17.2 76.7 6.0 29.6 17.6 51.6 8.0 41.2 18.3 26.5 9.8 55.0 19.1 31.5 11.8 38.5 19.7 28.8 12.5 8.0 21.4 26.3 14.2 100.0 22.0 12.4 15.2 28.8 24.5 40.3 16.4 27.4 24.9 29.5 16.8 71.8 26.1 47.2

[0193] Example 8: Preparation of crystal form CM-VIII

[0194] 11 mg of compound (I) was dissolved in 1 mL of 1,4-dioxane, filtered, and 2 mL of water was slowly added to the filtrate. The solution was then placed in a sealed environment and allowed to stand at 28 °C until a solid precipitated. The obtained solid was the crystal form CM-VIII of compound (I). XRPD analysis was performed on the obtained solid, and its X-ray powder diffraction data are shown in Table 8. Its XRPD pattern is shown in... Figure 29 As shown.

[0195] Table 8

[0196]

[0197]

[0198] Preparation Examples

[0199] Preparation of Pralsetinib raw material

[0200] Following the method disclosed in WO2017079140: HATU (162 mg, 0.427 mmol) was added to a solution of methyl 1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (0.23 mmol), (R)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethylamine hydrochloride (97 mg, 0.40 mmol), and DIEA (0.34 mL, 1.9 mmol) in DMF (3.8 mL). The reaction mixture was stirred for 10 minutes, then extracted with EtOAc and H2O. The organic layer was washed with a saturated aqueous NaCl solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (gradient elution of 0-10% methanol-dichloromethane with the addition of 2% triethylamine) to obtain an oily substance, which is the crude product of BLU-667. In this invention, it is preferred to use it as a raw material to prepare the above-mentioned crystal form.

[0201] Test case

[0202] Test Example 1: Crystal Form Stability

[0203] The crystal forms CM-I, CM-II, and CM-III prepared according to this invention were left exposed to the elements for 10 days or 1 month at 25℃ / 60%RH, 25℃ / 92.5%RH, 40℃ / 75%RH, 40℃ / 92.5%RH, and 60℃ / 75%RH, respectively. The crystal forms before and after exposure were then analyzed, and XRPD images of the crystal forms before and after exposure were obtained for comparison. The test results are shown in Tables 9.1 and 9.2. By comparing the XRPD images before and after exposure, it can be seen that the crystal forms CM-I, CM-II, and CM-III provided by this invention do not change after being exposed to the elements for 10 days or 1 month at 25℃ / 60%RH, 25℃ / 92.5%RH, 40℃ / 75%RH, 40℃ / 92.5%RH, and 60℃ / 75%RH, respectively, indicating that the crystal forms provided by this invention have good crystal form stability.

[0204] Table 9.1

[0205]

[0206] Table 9.2

[0207]

[0208] Test Example 2: Crystal form stability of products containing excipients

[0209] The crystalline forms CM-I and CM-III prepared according to this invention were mixed with excipients. The mass ratios of Pralsetinib and excipients were as follows: Pralsetinib 30%, citric acid 4%, hydroxypropyl methylcellulose 10%, magnesium stearate 2%, microcrystalline cellulose 21%, pregelatinized starch 21%, and sodium bicarbonate 12%. The mixtures were left exposed at 25℃ / 60%RH, 40℃ / 75%RH, and 60℃ / 75%RH for one month. The crystal forms before and after exposure were measured, and XRPD images of the solid crystal forms before and after exposure were obtained for comparison. The test results are shown in Table 10. By comparing the XRPD images before and after exposure, it can be seen that when the crystalline forms CM-I and CM-III provided by this invention are mixed with excipients, the crystal forms do not change after being exposed at 25℃ / 60%RH, 40℃ / 75%RH, and 60℃ / 75%RH for one month. This indicates that the crystal forms provided by this invention are relatively stable even when containing excipients and have good compatibility with them.

[0210] Table 10

[0211]

[0212] Test Example 3: Crystal Stability in Water

[0213] 10 mg of each of the crystal forms CM-I and CM-III prepared according to this invention were weighed into 1 mL of water. After stirring at 25°C for 24 h, the solids were collected, and XRPD was measured. XRPD images of the solid crystal forms before and after stirring were obtained for comparison. The test results are shown in Table 11. By comparing the XRPD images before and after stirring, it can be seen that the crystal forms CM-I and CM-III provided by this invention do not change in crystal form in water at 25°C for 24 h, indicating that the crystal forms provided by this invention have good crystal stability in water. This demonstrates the feasibility of wet granulation.

[0214] Table 11

[0215]

[0216] Test Example 4: Mechanical Stability

[0217] 50 mg of each of the crystal forms CM-I, CM-II, and CM-III prepared in the embodiments of this invention were weighed and ground in a mortar for 10 min. The ground solids were then subjected to XRPD testing. The XRPD comparison images of the crystal forms before and after grinding are shown in the figure. Figure 6 , Figure 14 , Figure 22 The grinding results are shown in Table 12. By comparing the XRPD images before and after grinding in each figure, it can be seen that the crystal forms CM-I, CM-II, and CM-III provided by the present invention do not change before and after grinding, indicating that the crystal forms provided by the present invention have good mechanical stability.

[0218] Table 12

[0219] Initial crystal form Grinding time Crystal form after grinding Does the crystal form change before and after grinding? Crystal form CM-I (Example 1) 10min Crystal form CM-I no Crystal form CM-II (Example 2) 10min Crystal form CM-II no Crystal form CM-III (Example 3) 10min Crystal form CM-III no

[0220] Test Example 5: Tableting Stability

[0221] Approximately 80 mg of the crystal forms CM-I and CM-III prepared according to this invention were weighed out. They were compressed into round, flat-punch tablets using a pressure of 10 kN. The XRPD of the samples was tested before and after tableting. Comparison of the XRPD images before and after tableting shows that the crystal forms of CM-I and CM-III remain unchanged after tableting, indicating good tableting stability.

[0222] Table 13

[0223]

[0224] Test Example 6: Compressibility

[0225] Approximately 80 mg of each of the three crystal forms CM-I, CM-II, and CM-III prepared according to this invention were weighed. Each was compressed into a round, flat-punched tablet using a pressure of 10 kN. After being placed at 25°C for 24 hours to allow complete recovery of elasticity, the radial breaking force (hardness, H) was tested using a tablet hardness tester. The diameter (D) and thickness (L) of the tablets were measured using vernier calipers. The tensile strength of the crystal forms at different hardness levels was calculated using the formula T = 2H / πDL * 9.8. Under a given pressure, a higher tensile strength indicates better compressibility. Specific results are shown in Table 14. The results indicate that crystal form CM-II has superior compressibility compared to crystal forms CM-I and CM-III.

[0226] Table 14

[0227] Crystal form Thickness (mm) Diameter (mm) Hardness (kgf) Tensile strength (MPa) CM-I (Example 1) 2 6 3.4 1.8 CM-II (Example 2) 2 6 4.0 2.1 CM-III (Example 3) 2 6 2.9 1.5

[0228] Test Example 7: Solubility

[0229] A certain amount of each of the three crystal forms CM-I, CM-II, and CM-III prepared according to this invention were respectively placed in a ~50mM HCl / KCl solution at pH 1.99 and stirred for 24 hours. The dissolution phenomenon was observed, and the corresponding solubility was calculated. Specific data are shown in Table 15. It can be seen that the solubility of the crystal forms CM-I, CM-II, and CM-III provided by this invention is greater than that of the crystal forms reported by the FDA, indicating good solubility.

[0230] Table 15

[0231]

[0232] Test Example 8: Hygroscopicity

[0233] Approximately 10 mg of each of the three crystal forms CM-I, CM-II, and CM-III obtained in Examples 1, 2, and 3 of this patent were used to test their hygroscopicity using a dynamic moisture adsorption (DVS) analyzer. The DVS graphs for CM-I, CM-II, and CM-III are shown below. Figure 7 , Figure 15 , Figure 23 In addition, XRPD tests were performed on crystal forms CM-I, CM-II, and CM-III before and after DVS testing, and their XRPD plots are shown below. Figure 8 , Figure 16 , Figure 24 The overall test results are shown in Table 16.

[0234] The DVS test results show that the moisture absorption of crystal forms CM-I, CM-II, and CM-III provided by this invention is all below 7% during the DVS test, indicating low hygroscopicity. The XRPD results show that the crystal forms of all crystal forms do not change before and after the DVS test.

[0235] Table 16

[0236] Initial crystal form Quality changes from 0% to 90% RH Test whether the crystal form changes after DVS Crystal form CM-I (Example 1) 1.0％ no Crystal form CM-II (Example 2) 6.8％ no Crystal form CM-III (Example 3) 3.7％ no

[0237] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A crystalline form of a compound of Formula (I): ###0001### Formula (I) and the crystalline form is selected from the group consisting of: crystalline form CM-I, crystalline form CM-II, and crystalline form CM-III. The XRPD pattern of the crystalline form CM-I includes three or more 2Θ values selected from the group consisting of: 4.9°±0.2°, 9.7°±0.2°, 12.7°±0.2°, 13.6°±0.2°. wherein The XRPD pattern of the crystalline form CM-II includes three or more 2Θ values selected from the group consisting of: 9.0°±0.2°, 18.1°±0.2°, 20.8°±0.2°, 25.1°±0.2°. The XRPD pattern of the crystalline form CM-III includes three or more 2Θ values selected from the group consisting of: 5.6°±0.2°, 8.5°±0.2°, 10.8°±0.2°, 14.3°±0.2°. The crystalline form is crystalline form CM-I and the XRPD pattern of the crystalline form CM-I includes all of the 2Θ values selected from the group consisting of: 4.9°±0.2°, 6.8°±0.2°, 9.7°±0.2°, 12.7°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 19.7°±0.2°, 22.9°±0.2°.

2. The crystal form as described in claim 1, characterized in that, The XRPD pattern of the crystalline form CM-I further includes one or more 2Θ values selected from the group consisting of: 13.9°±0.2°, 16.0°±0.2°, 17.1°±0.2°, 18.5°±0.2°, 19.2°±0.2°, 19.4°±0.2°, 20.5°±0.2°, 21.6°±0.2°, 23.5°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.5°±0.2°, 26.0°±0.2°, 27.8°±0.2°, 28.4°±0.2°, 29.3°±0.2°, 29.7°±0.2°.

3. The crystal form as described in claim 2, characterized in that, The crystalline form CM-I has one or more characteristics selected from the group consisting of:

4. The crystalline form of any one of claims 1 to 3, 1) the crystalline form CM-I has an XRPD pattern substantially as set forth in FIG. 1; 2) the crystalline form CM-I has a TGA pattern substantially as set forth in FIG. 2; 3) the crystalline form CM-I has a DSC pattern substantially as set forth in FIG. 3; The crystalline form is crystalline form CM-II and the XRPD pattern of the crystalline form CM-II includes all of the 2Θ values selected from the group consisting of: 3.9°±0.2°, 9.0°±0.2°, 10.2°±0.2°, 11.3°±0.2°, 13.5°±0.2°, 15.5°±0.2°, 18.1°±0.2°, 20.8°±0.2°, and 25.1°±0.2°. 4) the crystalline Form CM-I has a XRPD pattern substantially as shown in Figure 4 1 H NMR pattern.

5. The crystal form as described in claim 1, characterized in that, ​ 6. The crystal form as described in claim 5, characterized in that, The XRPD pattern of said crystalline form CM-II further comprises one or more 2Θ values selected from the group consisting of: 3.9°±0.2°, 6.9°±0.2°, 9.0°±0.2°, 10.3°±0.2°, 11.1°±0.2°, 11.3°±0.2°, 12.5°±0.2°, 13.5°±0.2°, 13.9°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.0°±0.2°, 20.8°±0.2°, 21.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 26.0°±0.2°, 29.6°±0.2°, 30.6°±0.2°, 32.0°±0.2°.

7. The crystal form according to any one of claims 1 and 5-6, characterized in that, Said crystalline form CM-II has one or more characteristics selected from the group consisting of: 1) said crystalline form CM-II has an XRPD pattern substantially as set out in Figure 9; 2) said crystalline form CM-II has a TGA pattern substantially as set out in Figure 10; 3) said crystalline form CM-II has a DSC pattern substantially as set out in Figure 11. 4) The Form CM-II has a XRPD pattern substantially as shown in Figure 12 1 H NMR pattern.

8. The crystal form as described in claim 1, characterized in that, said crystalline form is crystalline form CM-III, and the XRPD pattern of said crystalline form CM-III comprises all 2Θ values selected from the group consisting of: 5.6°±0.2°, 8.5°±0.2°, 10.8°±0.2°, 11.3°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 20.0°±0.2°, and 23.0°±0.2°.

9. The crystal form as described in claim 8, characterized in that, The XRPD pattern of said crystalline form CM-III further comprises one or more 2Θ values selected from the group consisting of: 13.3°±0.2°, 15.3°±0.2°, 17.1°±0.2°, 18.0°±0.2°, 21.9°±0.2°, 24.3°±0.2°, 25.8°±0.2°.

10. The crystal form according to any one of claims 1 and 8-9, characterized in that, Said crystalline form CM-III has one or more characteristics selected from the group consisting of: 1) said crystalline form CM-III has an XRPD pattern substantially as set out in Figure 17; 2) said crystalline form CM-III has a TGA pattern substantially as set out in Figure 18; 3) said crystalline form CM-III has a DSC pattern substantially as set out in Figure 19; 4) The Form CM-III has an XRPD pattern substantially as shown in FIG. 20 1 H NMR pattern.

11. A process for preparing a crystalline form according to any one of claims 1-10, wherein, (i) said crystalline form is crystalline form CM-I, and said process comprises: providing a solution of a starting material of a compound of formula (I) in a first solvent, subjecting said solution to a treatment to obtain a solid, and collecting the obtained solid to obtain said crystalline form; wherein said treatment comprises cooling; wherein said first solvent is ethanol; or, (i) said crystalline form is crystalline form CM-II, and said process comprises: providing a solution of a starting material of a compound of formula (I) in a first solvent, subjecting said solution to a treatment to obtain a solid, and collecting the obtained solid to obtain said crystalline form; wherein said treatment comprises cooling; wherein said first solvent is ethanol; or, (ii) the crystal form is crystal form CM-II, and the preparation method comprises the steps of: providing a solution of the compound of formula (I) raw material in a first solvent, adding a second solvent to the solution to perform crystallization, and collecting the precipitated solid to obtain the crystal form; wherein the first solvent is selected from methanol, and the second solvent is methyl tert-butyl ether; or, (iii) the crystal form is crystal form CM-III, and the preparation method comprises the steps of: providing a solution of the compound of formula (I) raw material in a first solvent, adding a second solvent to the solution to perform crystallization, and collecting the precipitated solid to obtain the crystal form; wherein the first solvent is selected from acetone, and the second solvent is water.

12. A pharmaceutical composition, characterized by, The composition comprises the crystal form of any one of claims 1-10 and a pharmaceutically acceptable carrier.

13. Use of the crystal form of any one of claims 1-10 in the preparation of a medicament for treating cancer caused by RET variation.

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