CN113968843A - A new crystal form of cyclohexanecarboxamide and preparation method thereof - Google Patents

Abstract

The invention provides a novel crystal 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 a preparation method thereof.

Description

A new crystal form of cyclohexanecarboxamide and preparation method thereof

technical field

The invention relates to the field of medicinal chemistry, in particular to (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1 -New crystal form of methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide and its Preparation.

Background technique

RET (Rearranged during transfection) is a relatively rare proto-oncogene, which is located on the long arm of human chromosome 10 and encodes a receptor tyrosine kinase. The receptor spans both sides of the cell membrane and completes signaling by forming protein complexes. RET proteins play an important role in the development of the kidney and gastrointestinal system. In a variety of cancers, RET gene alterations lead to kinase activation that drives tumor formation and growth. Initially, RET gene alterations were found to be associated with the development of papillary thyroid cancer; recent studies have shown that alterations in this gene have also been found in patients with non-small cell lung cancer (NSCLC), one of the deadliest types of cancer. At present, there are no anticancer drugs that can selectively target RET mutations or fusions in the world. Although there are several multi-kinase inhibitors (MKIs) on the market that can play a certain inhibitory role, their target specificity is not high, their inhibitory effect on RET activity is limited, and they may also cause toxic side effects due to off-target effects. Taking the treatment of NSCLC with RET fusion as an example, the objective response rate (ORR) of these MKIs drugs is between 28% and 47%, and the tumor will soon develop resistance mutations. Therefore, there is an urgent need for precision therapies that selectively target RET alterations and expected resistance mutations to provide durable clinical benefit.

Pralsetinib (also known as BLU667) is an oral, potent and highly selective RET inhibitor developed by Blueprint Medicines Corporation (Blueprint Medicines Corporation) for RET fusions and mutations (including resistance mutations). The drug resistance mechanism shows a good therapeutic prospect. Preclinical studies have shown that compounds of formula (I) are more than 100-fold more selective for RET than most tested kinases, and are also highly active against common RET fusions, mutations, and expected drug resistance mutations. Inhibits the growth of NSCLC, MTC and colorectal cancer, including tumors resistant to other multikinase inhibitors (MKIs). In September 2020, the drug was approved by the US FDA under the trade name Gavreo. The chemical name for 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, its molecular structure is as follows:

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. The solubility in aqueous media from 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). Lower solubility results in lower bioavailability. For drug research and development, the study of polymorphism is a crucial content. Different crystal forms can cause equal differences in the solubility, stability and flow of the drug, thereby affecting the safety and efficacy of the drug, resulting in different clinical effects. In order to improve bioavailability and prepare stable dosage forms suitable for pharmaceutical use, it is necessary to provide crystal forms with high solubility, high stability and easy preparation. Therefore, it is urgent to carry out research on the crystal form of this compound to find a crystal form suitable for drug development.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a new crystal form of the compound of formula (I) that is easy to prepare and has high stability, so as to meet the needs of drug research and industrial production.

The first aspect of the present invention provides a crystal form of the 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 Form CM-V, Form CM-VI, Form CM-VI, Form CM-VII and/or Form CM-VIII.

Preferably, the crystal form is selected from the following group: crystal form CM-I, crystal form CM-II, crystal form CM-III;

Preferably, the XRPD pattern of the crystalline form CM-I comprises 6 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°, 22.9°±0.2°.

Preferably, the XRPD pattern of the crystalline form CM-I further comprises 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°.

Preferably, the XRPD pattern of the crystalline form CM-I comprises 6 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°, 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 There are characteristic peaks at °, 26.0°±0.2°, 27.8°±0.2°, 28.4°±0.2°, 29.3°±0.2°, 29.7°±0.2°.

Preferably, the crystal form CM-I has an XRPD pattern substantially as shown in FIG. 1 ;

Preferably, the crystal form CM-I has a TGA diagram substantially as shown in FIG. 2;

Preferably, the crystalline form CM-I has a DSC pattern substantially as shown in FIG. 3 .

Preferably, the crystalline form CM-I has a ¹ H NMR spectrum substantially as shown in FIG. 4 .

Preferably, the crystalline form CM-I has a weight loss of about 1.14% when heated to 100°C.

Preferably, the XRPD pattern of the crystal form CM-II includes 3 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 °.

Preferably, the XRPD pattern of the crystalline form CM-II further comprises 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°,.

Preferably, the XRPD pattern of the crystalline form CM-II comprises 6 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°, 25.1°±0.2°.

Preferably, the XRPD pattern of the 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°.

Preferably, the XRPD pattern of the crystal form CM-II comprises 6 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°, 25.1° ±0.2°, 26.0°±0.2°, 29.6°±0.2°, 30.6°±0.2°, 32.0°±0.2°.

Preferably, the crystal form CM-II has an XRPD pattern substantially as shown in FIG. 9;

Preferably, the crystal form CM-II has a TGA diagram substantially as shown in FIG. 10 ;

Preferably, the crystal form CM-II has a DSC chart substantially as shown in FIG. 11 ;

Preferably, the crystalline form CM-II has a ¹ H NMR spectrum substantially as shown in FIG. 12 .

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

Preferably, the XRPD pattern of the crystalline form CM-III includes 3 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 °.

Preferably, the XRPD pattern of the crystalline form CM-III further comprises one or more 2θ values selected from the group consisting of: 11.3°±0.2°, 15.7°±0.2°, 20.0°±0.2°, 23.0°±0.2° .

Preferably, the XRPD pattern of the crystalline form CM-III comprises 6 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°, 23.0°±0.2°.

Preferably, the XRPD pattern of the 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°.

Preferably, the XRPD pattern of the crystalline form CM-III comprises 6 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°, 25.8°±0.2°.

Preferably, the crystalline form CM-III has an XRPD pattern substantially as shown in Figure 17;

Preferably, the crystal form CM-III has a TGA diagram substantially as shown in FIG. 18 ;

Preferably, the crystalline form CM-III has a DSC chart substantially as shown in Figure 19;

Preferably, the crystalline form CM-III has a ¹ H NMR spectrum substantially as shown in FIG. 20 .

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

Preferably, the XRPD pattern of the crystal form CM-IV has characteristic peaks at 2θ values of 5.7°±0.2°, 9.2°±0.2°, 10.5°±0.2°, and 19.4°±0.2°.

Preferably, the X-ray diffraction pattern of the crystal form CM-IV has 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° have characteristic peaks.

Preferably, the X-ray diffraction pattern of the crystalline form CM-IV also has characteristic peaks at 27.2°±0.2° and/or 28.0°±0.2° in 2θ value.

Preferably, the X-ray diffraction pattern of the crystal form CM-IV has 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°, 28.0°±0.2° have characteristic peaks.

Preferably, the crystalline form CM-IV has an XRPD pattern substantially as shown in FIG. 25 .

Preferably, the XRPD pattern of the crystalline form CM-V has characteristic peaks at 2θ values of 5.9°±0.2°, 8.9°±0.2°, 10.3°±0.2°, 17.3°±0.2°.

Preferably, the crystalline form CM-V has an XRPD pattern substantially as shown in FIG. 26 .

Preferably, the XRPD pattern of the crystal form CM-VI has characteristic peaks at 2θ values of 5.4°±0.2°, 8.0°±0.2°, 10.7°±0.2° and 16.0°±0.2°.

Preferably, the XRPD pattern of the crystalline form CM-VI also has a 2θ value 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° 0.2°, and/or 27.6°±0.2°, and/or 29.5°±0.2°, and/or 31.5°±0.2° have characteristic peaks.

Preferably, the crystalline form CM-VI has an 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° There are characteristic peaks at ±0.2°, 21.4°±0.2°, 24.0°±0.2°, 26.4°±0.2°, and 27.6°±0.2°.

Preferably, the crystalline form CM-VI has an 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 There are characteristic peaks at °, 27.6°±0.2°, 29.5°±0.2°, and 31.5°±0.2°.

Preferably, the crystalline form CM-VI has an XRPD pattern substantially as shown in FIG. 27 .

Preferably, the crystal form CM-VII has characteristic peaks at 2.9°±0.2°, 6.0°±0.2°, 8.0°±0.2°, 9.8°±0.2° in its XRPD pattern.

Preferably, the crystalline form CM-VII, whose XRPD pattern also has 2θ values of 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° 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 Or one or more of 26.1°±0.2° have characteristic peaks.

Preferably, the crystalline form CM-VII has an XRPD pattern 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° There are characteristic peaks at ±0.2°, 17.2°±0.2°, and 17.6°±0.2°.

Preferably, the crystalline form CM-VII has an XRPD pattern 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 There are characteristic peaks at °, 19.7°±0.2°, 21.4°±0.2°, 22.0°±0.2°, 24.5°±0.2°, 24.9°±0.2°, 26.1°±0.2°.

Preferably, the crystalline form CM-VII has an XRPD pattern substantially as shown in FIG. 28 .

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

Preferably, the crystalline form CM-VIII has an XRPD pattern with a 2θ value 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°, 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 characteristic peaks at 27.5°±0.2°, and/or 29.0°±0.2°.

Preferably, the crystalline form CM-VIII has an 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° There are characteristic peaks at ±0.2°, 17.5°±0.2°, 19.9°±0.2°, 22.0°±0.2°, and 22.8°±0.2°.

Preferably, the crystalline form CM-VIII has an 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 There are characteristic peaks at °, 22.0°±0.2°, 22.8°±0.2°, 24.0°±0.2°, 25.4°±0.2°, 27.5°±0.2°, 29.0°±0.2°.

Preferably, the crystalline form CM-VIII has an XRPD pattern substantially as shown in FIG. 29 .

The second aspect of the present invention provides a method for preparing the above crystal form, characterized in that:

It comprises the steps of: a) providing a solution of the compound of formula (I) in a first solvent, adding a second solvent to the solution for crystallization, and collecting the precipitated solid to obtain the crystal form.

or,

It comprises the steps of: b) providing a solution of the raw material of the compound of formula (I) in the first solvent, adding the solution to the second solvent for crystallization, and collecting the precipitated solid to obtain the crystal form.

or,

It comprises the steps of: c) providing a solution of the compound 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 cool down.

Preferably, the first solvent includes an alcohol-based solvent, a ketone-based solvent, an amide-based solvent, an ester-based solvent, a hydrocarbon-based solvent, an ether-based solvent, or a combination thereof.

Preferably, the alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, or a combination thereof.

Preferably, the ketone solvent is selected from the group consisting of acetone, 2-butanone, methyl isobutyl ketone, N-methylpyrrolidone, or a combination thereof.

Preferably, the amide solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof.

Preferably, the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, n-propyl acetate, or a combination thereof.

Preferably, the hydrocarbon solvent is selected from the group consisting of chloroform, dichloromethane, nitromethane, n-heptane, cyclohexane, toluene, or a combination thereof.

Preferably, the ether solvent is selected from the group consisting of anisole, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

Preferably, the second solvent includes water, dimethyl sulfoxide, nitromethane, or a combination thereof.

Preferably, the crystallization process is standing crystallization.

Preferably, the standing is performed in a closed environment.

Preferably, the raw material of the compound of formula (I) is a crystalline or amorphous form of the compound of formula (I).

A third aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising: 1) the crystal form according to the first aspect; 2) a pharmaceutically acceptable carrier.

The fourth aspect of the present invention provides the use of the pharmaceutical composition according to the third aspect, which is used for the treatment of RET mutant cancer.

The fifth aspect of the present invention provides the use of the crystal form according to the first aspect, including: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a medicament for treating cancer caused by RET mutation.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to constitute new or preferred technical solutions. Due to space limitations, it is not repeated here.

Description of drawings

Fig. 1 is the XRPD pattern of the crystal form CM-I of the present invention.

Figure 2 is a TGA diagram of the crystal form CM-I of the present invention.

Figure 3 is the DSC chart of the crystal form CM-I of the present invention.

Fig. 4 is the ¹ H NMR spectrum of the crystal form CM-I of the present invention.

Figure 5A shows the crystal form CM-I of the present invention placed at 25°C/60%RH, 25°C/92.5%RH, 40°C/75%RH, 40°C/92.5%RH and 60°C/75%RH for 1 month XRPD comparison chart of (from bottom to top, before placing and placing 1 picture a month later).

Fig. 5B is the XRPD comparison chart of the mixture of crystal form CM-I and excipients of the present invention placed at 25°C/60%RH, 40°C/75%RH and 60°C/75%RH for 1 month (from bottom to top, respectively Figures before storage and after storage at 25°C/60%RH, 40°C/75%RH and 60°C/75%RH for 1 month).

Figure 5C is a comparison diagram of the crystal form CM-I of the present invention before and after stirring in water for 24 hours (the bottom picture is the XRPD pattern before stirring, and the top picture is the XRPD pattern after stirring).

6 is the XRPD pattern of the crystal form CM-I of the present invention before and after grinding (the upper picture is the XRPD pattern before grinding, and the lower picture is the XRPD pattern after grinding).

Fig. 7 is the DVS diagram of the crystal form CM-I of the present invention.

Fig. 8 is the XRPD figure before and after the DVS test of the crystal form CM-I of the present invention (the upper figure is the XRPD figure before the test, and the lower figure is the XRPD figure after the test)

Fig. 9 is the XRPD pattern of the crystal form CM-II of the present invention.

Figure 10 is a TGA diagram of the crystal form CM-II of the present invention.

Figure 11 is the DSC chart of the crystal form CM-II of the present invention.

Figure 12 is the ¹ H NMR spectrum of the crystal form CM-II of the present invention

Figure 13 shows the crystal form CM-II of the present invention placed at 25°C/60%RH, 25°C/92.5%RH, 40°C/75%RH, 40°C/92.5%RH and 60°C/75%RH for 1 month XRPD comparison chart of (from bottom to top, before placing and placing 1 picture a month later).

14 is the XRPD pattern of the crystal form CM-II of the present invention before and after milling (the upper figure is the XRPD pattern before milling, and the lower figure is the XRPD pattern after milling).

Figure 15 is a DVS diagram of the crystal form CM-II of the present invention.

16 is the XRPD pattern of the crystal form CM-II of the present invention before and after the DVS test (the upper picture is the XRPD pattern before the test, and the lower picture is the XRPD pattern after the test).

Figure 17 is the XRPD pattern of the crystal form CM-III of the present invention.

Figure 18 is a TGA diagram of the crystal form CM-III of the present invention.

Figure 19 is the DSC chart of the crystal form CM-III of the present invention.

Figure 20 is the ¹ H NMR spectrum of the crystal form CM-III of the present invention

Figure 21A shows the crystal form CM-III of the present invention placed at 25°C/60%RH, 25°C/92.5%RH, 40°C/75%RH, 40°C/92.5%RH and 60°C/75%RH for 1 month XRPD comparison chart of (from bottom to top, before placing and placing 1 picture a month later).

Figure 21B is a XRPD comparison diagram of the mixture of crystal form CM-III and excipients of the present invention placed at 25°C/60%RH, 40°C/75%RH and 60°C/75%RH for 1 month (from bottom to top, respectively Figures before storage and after storage at 25°C/60%RH, 40°C/75%RH and 60°C/75%RH for 1 month).

Figure 21C is a comparison diagram of the crystal form CM-III of the present invention before and after stirring in water for 24 hours (the bottom picture is the XRPD pattern before stirring, and the top picture is the XRPD pattern after stirring).

Figure 22 is the XRPD pattern of the crystal form CM-III of the present invention before and after milling (the upper figure is the XRPD pattern before milling, and the lower figure is the XRPD pattern after milling).

Figure 23 is a DVS diagram of the crystal form CM-III of the present invention.

24 is the XRPD pattern of the crystal form CM-III of the present invention before and after the DVS test (the upper picture is the XRPD pattern before the test, and the lower picture is the XRPD pattern after the test).

Figure 25 is the XRPD pattern of the crystal form CM-IV of the present invention.

Figure 26 is the XRPD pattern of the crystal form CM-V of the present invention.

Figure 27 is the XRPD pattern of the crystal form CM-VI of the present invention.

Figure 28 is an XRPD pattern of the crystal form CM-VII of the present invention.

Figure 29 is the XRPD pattern of the crystal form CM-VIII of the present invention.

30A is the XRPD pattern of the crystal form CM-I of the present invention before and after tableting (the upper picture is the XRPD pattern before tableting, and the lower picture is the XRPD pattern after tableting).

30B is the XRPD pattern of the crystal form CM-III of the present invention before and after tableting (the upper picture is the XRPD pattern before tableting, and the lower picture is the XRPD pattern after tableting).

Detailed ways

The inventors of the present invention have surprisingly discovered a series of new crystal forms of the compound of formula (I) in the course of research. These crystal forms are simple to prepare, low in cost, and have advantages in stability and process developability, which are of great significance to the optimization and development of the drug in the future.

the term

Herein, unless otherwise specified, each abbreviation has the conventional meaning understood by those skilled in the art.

In this paper, the compound of formula (I) is Pralsetinib developed by Blueprint Pharmaceuticals, chemical name (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridine -3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cycle Hexanecarboxamide, the structure is as follows:

The 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)pyridine -3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cycle Hexanecarboxamide, or represented by the following structure:

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

Preferably, the raw material of the compound of formula (I) used in the present invention is BLU-667 prepared according to the preparation method provided in the examples of the present invention.

As used herein, "crystalline form of the present invention" refers to BLU-667 Form CM-I, Form CM-II, Form CM-III, Form CM-IV, Form CM-III as described herein CM-V, Form CM-VI, Form CM-VII, and Form CM-VIII.

As used herein, the manner of "slow addition" includes, but is not limited to, dropwise addition, slow addition along the container wall, and the like.

general method

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

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 can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.

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

XRPD pattern determination method:

)；发生器(Generator)kv：30kv；发生器(Generator)mA：10mA；起始的2θ：2.000°，扫描范围：2.0000～35.000°，扫描步长0.02°，扫描速度0.1s/step。X-ray powder diffractometer: Bruker D2 Phaser X-ray powder diffractometer; radiation source Cu (

); Generator kv: 30kv; Generator mA: 10mA; Initial 2θ: 2.000°, scanning range: 2.0000-35.000°, scanning step size 0.02°, scanning speed 0.1s/step.

TGA chart determination method:

Thermogravimetric analysis (TGA) instrument: TGA55 from TA company in the United States; equilibration time before test: 2h; temperature range: 20-250°C; heating rate: 10°C/min; nitrogen flow rate: 40mL/min.

DSC chart determination method:

Differential scanning calorimetry (DSC) instrument: TA Q2000 type from TA company in the United States; temperature range: 20-250°C, heating rate: 10°C/min, nitrogen flow rate: 50 mL/min.

Hydrogen nuclear magnetic resonance data ( ¹ H NMR) were obtained from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 2 mg of the sample was weighed, dissolved in 0.6 mL of deuterated dimethyl sulfoxide, filtered, and the filtrate was added to a NMR tube for testing.

DVS chart determination method:

Dynamic Moisture Sorption (DVS) Instrument: TA Q5000 SA from TA Company, USA; Temperature: 25°C; Nitrogen Flow Rate: 50mL/min; Mass Change per Unit Time: 0.002%/min; Relative Humidity Range: 0%RH～90% RH.

Single punch manual tablet press, model: ENERPAC.

In the present invention, unless otherwise specified, the drying method is a conventional drying method in the field. For example, drying in the embodiments of the present invention refers to vacuum drying or normal pressure drying in a conventional drying oven. Generally, drying is performed for 0.1 to 50 hours or 1 to 30 hours.

The main advantages of the present invention are:

(1) The crystal forms of the compound of formula (I) suitable for preparing medicines are provided. These crystal forms are ground, tableted and placed in water and under different temperature/humidity conditions for a period of time, and the crystal forms remain unchanged and have good properties. Crystal stability. It shows that these crystal forms have good adaptability to both wet granulation and dry granulation, and are more conducive to the development of formulation technology.

(2) The crystal form provided by the present invention has low hygroscopicity, so it has better tolerance to different humidity environmental conditions, and improves the quality of the subsequently prepared medicine while being convenient for packaging and storage.

(3) Compared with the prior art, the crystal form provided by the present invention has greater solubility, which is beneficial to the improvement of bioavailability, thereby improving the clinical treatment effect.

(4) The preparation method of the crystal form provided by the present invention is simple and easy to operate, has low cost, and is suitable for drug research and development and industrial production.

Pharmaceutical compositions and methods of administration

Since the crystalline form or amorphous form of the present invention has excellent therapeutic and preventive effects on cancer or tumors, the crystalline form or amorphous form of the present invention and a pharmaceutical composition containing the crystalline form or amorphous form of the present invention as a main active ingredient can be used for the treatment and/or prevention of anemia.

The pharmaceutical composition of the present invention comprises the crystal form of the present invention and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.

Wherein, "safe and effective amount" refers to: the amount of the compound (or crystal form) is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the crystal form/dose of the present invention, more preferably, 10-200 mg of the crystal form/dose of the present invention. Preferably, the "one dose" is a capsule or tablet.

)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties 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 (such as Tween)

), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

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

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, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that may be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.

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 employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.

Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions, in addition to the active ingredient, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

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.

Dosage forms of the polymorphs of the 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 if necessary.

The crystalline forms of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When using the pharmaceutical composition, a safe and effective amount of the polymorphic form of the present invention is suitable for mammals (such as humans) in need of treatment, wherein the dose is a pharmaceutically effective dose when administered, and for a 60kg body weight human For example, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The following will further illustrate the present invention through specific examples, which are not intended to limit the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Example 1: Preparation of crystal form CM-I

14 mg of the compound of formula (I) was weighed and dissolved in 0.5 mL of ethanol at 30° C., and filtered. The filtrate was stirred at 5° C. for 24 h, and a solid was precipitated. The obtained solid was the compound of formula (I) in crystal form CM-I. The obtained solid is tested by XRPD, and its X-ray powder diffraction data is shown in Table 1, and its XRPD pattern is shown in Figure 1; the obtained solid is tested by TGA, and its spectrum is shown in Figure 2; DSC test, its spectrum is shown in Figure 3; ¹ H NMR test is performed on the obtained solid, and its spectrum is shown in Figure 4, nuclear magnetic data: ¹ H NMR (400MHz, DMSO-d ₆ )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).

Table 1

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%

Example 2: Preparation of crystal form CM-II

12 mg of the compound of formula (I) was weighed, mixed with 0.2 mL of methanol, filtered, and the filtrate was placed in a 3 mL open glass vial. In a 20 mL large glass vial was added 3 mL of methyl tert-butyl ether. The 3mL glass vial containing the filtrate was placed in a 20mL glass vial containing methyl tert-butyl ether, the 20mL glass vial was sealed, and allowed to stand at 25°C until a solid was precipitated, and the obtained solid was the compound of formula (I) Form CM-II. The obtained solid is tested by XRPD, and its X-ray powder diffraction data is shown in Table 2, and its XRPD pattern is shown in Figure 9; the obtained solid is tested by TGA, and its spectrum is shown in Figure 10; DSC test, its spectrum is shown in Figure 11; ¹ H NMR test is performed on the obtained solid, and its spectrum is shown in Figure 12, nuclear magnetic data: ¹ HNMR (400MHz, DMSO-d ₆ )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=7.1 Hz, 3H).

Table 2

Example 3: Preparation of crystal form CM-III

10 mg of the compound of formula (I) was weighed and dissolved in 1 mL of acetone, filtered, and 2 mL of water was slowly added to the filtrate, then the solution was placed in a closed environment and allowed to stand at 28° C. until solids were precipitated. The obtained solid is the crystalline form CM-III of the compound of formula (I). The obtained solid was tested by XRPD, and its X-ray powder diffraction data was shown in Table 3, and its XRPD pattern was shown in Figure 17; the obtained solid was tested by TGA, and its spectrum was shown in Figure 18; DSC test, its spectrum is shown in Figure 19; ¹ H NMR test is performed on the obtained solid, and its spectrum is shown in Figure 20, nuclear magnetic data: ¹ H NMR (400MHz, DMSO-d ₆ )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=7.1 Hz, 3H).

table 3

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%

Example 4: Preparation of crystal form CM-IV

10 mg of the compound of formula (I) was weighed and dissolved in 0.2 mL of tetrahydrofuran, filtered, and 1 mL of water was added dropwise to the filtrate, stirred at 24° C. for 24 h, and a solid was precipitated. The obtained solid is the crystalline form CM-IV 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 4, and its XRPD pattern is shown in FIG. 25 .

Table 4

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%

Example 5: Preparation of crystal form CM-V

9 mg of the compound of formula (I) was weighed and dissolved in 0.5 mL of chloroform, filtered, and the filtrate was dropped into 3 mL of nitromethane at 24°C. The obtained solid is the crystalline form CM-V 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, and its XRPD pattern is shown in Figure 26 .

table 5

2θ(°) Relative Strength 5.8 27.1% 8.9 100.0% 10.2 18.0% 17.3 20.6%

Example 6: Preparation of crystal form CM-VI

21 mg of the compound of formula (I) was dissolved in 0.3 mL of dimethyl sulfoxide, filtered, and the filtrate was left open at 25° C. until a solid was precipitated. The obtained solid is crystal form CM-VI. The obtained solid was tested by XRPD, and its X-ray powder diffraction data is shown in Table 6, and its XRPD pattern is shown in FIG. 27 .

Table 6

Example 7: Preparation of crystal form CM-VII

10 mg of the compound of formula (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 was precipitated. The obtained solid is crystal form CM-VII. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data is shown in Table 7, and its XRPD pattern is shown in Figure 28 .

Table 7

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

Example 8: Preparation of crystal form CM-VIII

11 mg of the compound of formula (I) was weighed and dissolved in 1 mL of 1,4-dioxane, filtered, and 2 mL of water was slowly added to the filtrate, and then the solution was placed in a closed environment and allowed to stand at 28° C. until a solid precipitated. The obtained solid is the crystalline form CM-VIII 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 8, and its XRPD pattern is shown in Figure 29 .

Table 8

Preparation Examples

Preparation of Pralsetinib Raw Materials

Referring to the method disclosed in WO2017079140: HATU (162 mg, 0.427 mmol) was added to 1-methoxy 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine Methyl-2-yl)cyclohexanecarboxylate (0.23 mmol), (R)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine 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 saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (gradient elution 0-10% methanol-dichloromethane, added with 2% triethylamine) to obtain an oily product, which is the crude product of BLU-667, which is preferably used in the present invention as The above crystal forms are prepared from the starting materials.

test case

Test Example 1: Crystal Form Stability

The crystal form CM-I, crystal form CM-II and crystal form CM-III prepared by the present invention were respectively heated at 25°C/60%RH, 25°C/92.5%RH, 40°C/75%RH and 40°C/92.5°C. %RH and 60°C/75%RH were left open for 10 days or 1 month, the crystal forms before and after storage were detected, and the XRPD patterns of the crystal forms before and after storage were obtained for comparison. The test results are shown in Table 9.1 and Table 9.2. By comparing the XRPD patterns before and after placement in each figure, it can be seen that the crystal form CM-I, crystal form CM-II and crystal form CM-III provided by the present invention are at 25°C/60%RH, 25°C/92.5%RH, 40°C Under the conditions of /75%RH, 40°C/92.5%RH and 60°C/75%RH, the crystal form does not change after being left open for 10 days or 1 month, indicating that the crystal form provided by the present invention has good crystal form stability .

Table 9.1

Table 9.2

Test Example 2: Crystal Form Stability with Excipients

The crystal form CM-I and crystal form CM-III prepared by the present invention are respectively mixed with auxiliary materials. The mass proportions of Pralsetinib and excipients are: Pralsetinib 30%, citric acid 4%, hydroxypropyl methylcellulose 10%, magnesium stearate 2%, microcrystalline cellulose 21%, pregelatinized starch 21% and Sodium Bicarbonate 12%. The crystal forms were tested before and after being placed at 25°C/60%RH, 40°C/75%RH and 60°C/75%RH for 1 month, and the XRPD patterns of the solid crystal forms before and after being placed were obtained for comparison. . The test results are shown in Table 10. By comparing the XRPD patterns before and after placement in each figure, it can be seen that when the crystal form CM-I and crystal form CM-III provided by the present invention are mixed with excipients, the temperature is 25°C/60%RH, 40°C/75%RH and 60°C/ Under 75% RH, the crystal form does not change after being left open for 1 month, indicating that the crystal form provided by the present invention is also relatively stable when it contains auxiliary materials, and has good compatibility with the auxiliary materials.

Table 10

Test Example 3: Crystal Form Stability in Water

Weigh 10 mg of the crystalline form CM-I and crystalline form CM-III prepared by the present invention in 1 mL of water, stir at 25° C. for 24 h, collect the solid, detect XRPD, and obtain the XRPD images of the solid crystal form before and after stirring for comparison. . The test results are shown in Table 11. By comparing the XRPD patterns before and after stirring in each figure, it can be seen that the crystal form CM-I and crystal form CM-III provided by the present invention do not change at 25° C. in water for 24 hours, indicating that the crystal form provided by the present invention is in water. It has good crystal stability. Possibility of wet granulation.

Table 11

Test Example 4: Mechanical Stability

Weigh 50 mg of the crystal form CM-I, crystal form CM-II, and crystal form CM-III prepared in the embodiment of the present invention, respectively, and grind them in a mortar for 10 min. The ground solids are tested by XRPD, and the crystal form XRPD before and after grinding is compared. Figures are shown in Figure 6, Figure 14, and Figure 22, respectively, and the grinding results are shown in Table 12. By comparing the XRPD patterns before and after grinding in each figure, it can be seen that the crystal form CM-I, crystal form CM-II and crystal form CM-III provided by the present invention do not change before and after grinding, indicating that the crystal form provided by the present invention has Good mechanical stability.

Table 12

starting crystal form grinding time Crystalline after grinding Whether the crystal form changes before and after grinding Crystal form CM-I (Example 1) 10min Form CM-I no Crystal form CM-II (Example 2) 10min Form CM-II no Crystal form CM-III (Example 3) 10min Form CM-III no

Test Example 5: Tablet Stability

About 80 mg of crystal form CM-I and crystal form CM-III prepared by the present invention were weighed respectively. Compressed into circular flat punched tablets with a pressure of 10 kN, respectively, and tested the XRPD of the samples before and after tableting. By comparing the XRPD patterns before and after tableting in each figure, it can be seen that the crystal forms of crystal form CM-I and crystal form CM-III remain unchanged after tableting, and have good tableting stability.

Table 13

Test Example 6: Compressibility

About 80 mg of crystal form CM-I, crystal form CM-II and crystal form CM-III prepared by the present invention were weighed respectively. They were respectively compressed into round flat punched tablets with a pressure of 10kN. It was placed at 25° C. for 24 hours, and the radial crushing force (hardness, H) was measured by a tablet hardness tester after it fully recovered its elasticity. Diameter (D) and thickness (L) of the tablets were measured using vernier calipers. Through the formula T=2H/πDL*9.8, the tensile strength of the crystal form under different hardness is calculated. Under a certain pressure, the greater the tensile strength, the better the compressibility. The specific results are shown in Table 14. The results show that the crystalline form CM-II has better compressibility than the crystalline forms CM-I and CM-III.

Table 14

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

Test Example 7: Solubility

Take a certain amount of the crystal form CM-I, crystal form CM-II and crystal form CM-III prepared by the present invention respectively in ~50mM HCl/KCl solution with pH 1.99, stir for 24h, observe the dissolution phenomenon, and calculate The corresponding solubility, the specific data are shown in Table 15. It can be seen that the solubility of the crystal form crystal form CM-I, crystal form CM-II and crystal form CM-III provided by the present invention are all higher than the crystal form reported by FDA, and have better solubility.

Table 15

Test Example 8: Humidity

Take about 10 mg of crystal form CM-I, crystal form CM-II and crystal form CM-III obtained in Example 1, Example 2 and Example 3 in this patent respectively, and use a dynamic moisture absorption instrument (DVS) to test its hygroscopicity. . The DVS diagrams of crystal form CM-I, crystal form CM-II and crystal form CM-III are shown in Figure 7, Figure 15, and Figure 23, respectively. In addition, XRPD tests were performed on the crystal form CM-I, crystal form CM-II and crystal form CM-III before and after the DVS test, respectively, and the XRPD patterns are shown in Figure 8, Figure 16, and Figure 24, respectively. The overall test results are shown in Table 16.

It can be seen from the DVS test results that the crystalline form CM-I, crystalline form CM-II, and crystalline form CM-III provided by the present invention have a moisture absorption capacity of less than 7% during the DVS test process, and have low hygroscopicity; The results showed that all crystal forms did not change before and after the DVS test.

Table 16

starting crystal form 0～90%RH mass change Whether the crystal form has changed after testing 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

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

1. A crystal form of the compound represented by formula (I):

2. The crystal form of claim 1, wherein the crystal form is selected from the group consisting of crystal form CM-I, crystal form CM-II, crystal form CM-III; Wherein, the XRPD pattern of the crystal form CM-I includes 3 or more 2θ values selected from the following group: 4.9°±0.2°, 9.7°±0.2°, 12.7°±0.2°, 13.6°±0.2° ; The XRPD of the crystal form CM-II comprises 3 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 3 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°. 3. The crystal form of claim 2, wherein the crystal form CM-1 has one or more features selected from the group consisting of: 1) The XRPD pattern of the crystal form CM-I includes 6 or more 2θ values selected from the following group: 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°, 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°, 29.7°±0.2°; 2) The crystal form CM-I has an XRPD pattern basically as shown in Figure 1; 3) The crystal form CM-I has a TGA diagram as shown in Figure 2; 4) The crystal form CM-I has a DSC diagram as shown in FIG. 3; 5) The crystalline form CM-I has a ¹ H NMR spectrum substantially as shown in FIG. 4 . 4. The crystal form of claim 2, wherein the crystal form CM-II has one or more features selected from the group consisting of: 1) The XRPD pattern of the crystal form CM-II includes 6 or more 2θ values selected from the following group: 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°, 25.1°± 0.2°, 26.0°±0.2°, 29.6°±0.2°, 30.6°±0.2°, 32.0°±0.2°; 2) The crystal form CM-II has an XRPD pattern substantially as shown in Figure 9; 3) The crystal form CM-II has a TGA diagram as shown in FIG. 10 ; 4) The crystal form CM-II has a DSC chart as shown in FIG. 11 ; 5) The crystal form CM-II has a ¹ H NMR spectrum substantially as shown in FIG. 12 . 5. The crystal form of claim 2, wherein the crystal form CM-III has one or more features selected from the group consisting of: 1) The XRPD pattern of the crystal form CM-III includes 6 or more 2θ values selected from the following group: 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°, 25.8°±0.2°; 2) The crystal form CM-III has an XRPD pattern substantially as shown in Figure 17; 3) The crystal form CM-III has a TGA diagram substantially as shown in Figure 18; 4) The crystal form CM-III has a DSC chart as shown in FIG. 19 ; 5) The crystal form CM-III has a ¹ H NMR spectrum substantially as shown in FIG. 20 . 6. crystal form as claimed in claim 1 is characterized in that, described crystal form is selected from following group: crystal form CM-IV, crystal form CM-V, crystal form CM-VI, crystal form CM-VII, crystal form Type CM-VIII; Wherein, the XRPD pattern of the crystal form CM-IV includes 3 or more 2θ values selected from the following group: 5.7°±0.2°, 9.2°±0.2°, 10.5°±0.2°, 19.4°±0.2° ; The XRPD pattern of the crystalline form CM-V includes 3 or more 2θ values selected from the following group: 5.9°±0.2°, 8.9°±0.2°, 10.3°±0.2°, 17.3°±0.2°; The XRPD pattern of the crystal form CM-VI includes 3 or more 2θ values selected from the group consisting of 5.4°±0.2°, 8.0°±0.2°, 10.7°±0.2°, 16.0°±0.2°; The XRPD pattern of the crystal form CM-VII includes 3 or more 2θ values selected from the following group: 2.9°±0.2°, 6.0°±0.2°, 8.0°±0.2°, 9.8°±0.2°; The XRPD pattern of the crystalline form CM-VIII includes 3 or more 2θ values selected from the group consisting of 8.4°±0.2°, 10.9°±0.2°, 13.5°±0.2°, 17.5°±0.2°. 7. The crystal form of claim 6, wherein the crystal form has one or more features selected from the group consisting of: 1) The XRPD pattern of the crystal form CM-IV includes 6 or more 2θ values selected from the group consisting 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°, 28.0°±0.2°; 2) The crystal form CM-IV has an XRPD pattern substantially as shown in Figure 25; 3) The XRPD pattern of the crystalline form CM-V includes 6 or more 2θ values selected from the following group: 5.9°±0.2°, 8.9°±0.2°, 10.3°±0.2°, 17.3°±0.2° ; 4) The crystal form CM-V has an XRPD pattern substantially as shown in Figure 26; 5) The XRPD pattern of the crystal form CM-VI includes 6 or more 2θ values selected from the following group: 2θ values are 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°, 31.5°±0.2°; 6) The crystal form CM-VI has an XRPD pattern substantially as shown in Figure 27; 7) The XRPD pattern of the crystal form CM-VII includes 6 or more 2θ values selected from the following group: 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°, 26.1°±0.2° 8) The crystal form CM-VII has an XRPD pattern substantially as shown in Figure 28; 9) The XRPD pattern of the crystal form CM-VIII includes 6 or more 2θ values selected from the following group: 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°, 29.0°±0.2°; 10) The crystal form CM-VIII has an XRPD pattern substantially as shown in FIG. 29 . 8. a preparation method of the crystal formation as described in any one of claim 1-7, is characterized in that, It comprises the steps of: a) providing a solution of the raw material of the compound of formula (I) in a first solvent, adding a second solvent to the solution for crystallization, and collecting the precipitated solid to obtain the crystal form; or, It comprises the steps of: b) providing a solution of the raw material of the compound of formula (I) in the first solvent, adding the solution to the second solvent for crystallization, and collecting the precipitated solid to obtain the crystal form; or, It comprises the steps of: c) providing a solution of the compound 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 cool down. 9. A pharmaceutical composition, characterized in that, the composition comprises the crystal form of any one of claims 1-7 and a pharmaceutically acceptable carrier. 10. Use of the crystal form according to claims 1-7, comprising: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a medicament for treating cancer caused by RET mutation.

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