CN111777595A

CN111777595A - Novel crystal form of cyclohexane carboxamide compound and preparation method thereof

Info

Publication number: CN111777595A
Application number: CN202010710201.6A
Authority: CN
Inventors: 彭欢; 张凤杰; 张良
Original assignee: Shanghai Acebright Pharmaceuticals Group Co ltd; SHANGHAI XIMAI MEDICAL TECHNOLOGY CO LTD
Current assignee: Shanghai Acebright Pharmaceuticals Group Co ltd; SHANGHAI XIMAI MEDICAL TECHNOLOGY CO LTD; Shanghai Cdymax Pharmaceuticals Co Ltd
Priority date: 2020-07-22
Filing date: 2020-07-22
Publication date: 2020-10-16
Also published as: WO2022017478A1; CN113968843A

Abstract

The invention provides a novel crystal form of (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) pyrimidine-2-yl) cyclohexane carboxamide (a compound of formula (I)) and a preparation method thereof.

Description

Novel crystal form of cyclohexane carboxamide compound and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, and in particular relates to a novel crystal form of (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) pyrimidine-2-yl) cyclohexane carboxamide and a preparation method thereof.

Background

Ret (recovered during transformation) is a relatively rare protooncogene, located on the long arm of human chromosome 10, that encodes a receptor tyrosine kinase. The receptor crosses both sides of the cell membrane and completes signaling by forming a protein complex. The RET protein plays an important role in the development of the renal and gastrointestinal systems. In many cancers, RET gene alterations lead to kinase activation, driving tumor formation and growth. Initially, RET gene alterations were found to be associated with the development of papillary thyroid carcinoma; recent studies have shown that alterations in this gene have also been found in non-small cell lung cancer (NSCLC) patients, one of the most lethal cancer species. Currently, no anticancer drugs that selectively target RET mutations or fusions are approved worldwide. Although several multikinase inhibitors (MKIs) drugs are available on the market to play a certain inhibitory role, they have low targeting specificity and limited inhibitory effect on RET activity, and may also produce toxic side effects due to off-target effects. In the case of treatment of NSCLC with RET fusion, the Objective Remission Rate (ORR) of these MKIs drugs is between 28% and 47%, and tumors soon develop resistance mutations. Therefore, there is an urgent need for accurate therapies that selectively target changes in RET and prospective drug resistance mutations to provide long-lasting clinical benefit.

BLU667 is a developed oral, potent and highly selective RET inhibitor to RET fusions and mutations (including resistance mutations) from Blueprint medicins Corporation showing good therapeutic prospects in targeting RET mutations, fusions and expected resistance mechanisms. Preclinical studies have shown that the compounds of formula (I) are more than 100 times selective for RET than most detected kinases, and also possess potent activity against common RET fusions, mutations and prospective drug-resistant mutations, and are potent inhibitors of NSCLC, MTC and colorectal cancer growth, including tumors that develop resistance to other multi-kinase inhibitors (MKIs). The chemical name of BLU667 is (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, the molecular structure of which is shown below:

in the prior art, no crystal forms of the compound of formula (I) have been reported. Patent WO2017079140 reports on compounds of formula (I) but does not disclose information about their crystalline forms. For drug development, research on polymorphism is a crucial element. The difference of crystal forms can cause the equal difference of solubility, stability and flow of the drug, thereby affecting the safety and effectiveness of the drug and further causing the difference of clinical effects. In order to prepare a stable, pharmaceutically suitable dosage form, it is desirable to provide a crystalline form that is highly stable and easy to prepare. Therefore, research on the crystal form of the compound is urgently needed to find a crystal form suitable for drug development.

Disclosure of Invention

The invention aims to provide a novel crystal form of a compound shown in a formula (I) which is easy to prepare and high in stability so as to meet the requirements of pharmaceutical research and industrial production.

In a first aspect of the invention, there is provided a crystalline form of a compound of formula (I): the crystal form comprises a crystal form CM-I, CM-II, a crystal form CM-III, a crystal form CM-IV, a crystal form CM-V, CM-VI, a crystal form CM-VII and/or a crystal form CM-VIII.

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

preferably, the XRPD pattern of said crystalline form CM-I comprises 6 or more than 62 Θ values selected from the group consisting of: 4.9 degrees +/-0.2 degrees, 6.8 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees, 13.6 degrees +/-0.2 degrees, 14.8 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees and 22.9 degrees +/-0.2 degrees.

Preferably, the XRPD pattern of said crystalline form CM-I comprises 6 or more than 62 Θ values selected from the group consisting of: the characteristic of the peak at 2 theta values of 4.9 +/-0.2 degrees, 6.8 +/-0.2 degrees, 9.7 +/-0.2 degrees, 12.7 +/-0.2 degrees, 13.6 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.8 +/-0.2 degrees, 16.0 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.2 +/-0.2 degrees, 19.4 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.5 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.5 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.0 +/-0.2 degrees, 27.8 +/-0.2 degrees, 28.4 +/-0.2 degrees, 29.3 +/-0.2 degrees.

Preferably, the crystalline form CM-I has an XRPD pattern substantially as shown in figure 1;

preferably, the crystalline form CM-I has a TGA profile substantially as shown in figure 2;

preferably, the crystalline form CM-I has a DSC profile substantially as shown in figure 3.

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

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

Preferably, the XRPD pattern of said crystalline form CM-II comprises 3 or more than 32 Θ values selected from the group consisting of: 9.0 degrees +/-0.2 degrees, 18.1 degrees +/-0.2 degrees, 20.8 degrees +/-0.2 degrees and 25.1 degrees +/-0.2 degrees.

Preferably, the XRPD pattern of said crystalline form CM-II comprises 6 or more than 62 Θ values selected from the group consisting of: 3.9 degrees +/-0.2 degrees, 9.0 degrees +/-0.2 degrees, 10.2 degrees +/-0.2 degrees, 11.3 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees, 15.5 degrees +/-0.2 degrees, 18.1 degrees +/-0.2 degrees, 20.8 degrees +/-0.2 degrees and 25.1 degrees +/-0.2 degrees.

Preferably, the XRPD pattern of said crystalline form CM-II comprises 6 or more than 62 Θ values selected from the group consisting of: 3.9 +/-0.2 degrees, 6.9 +/-0.2 degrees, 9.0 +/-0.2 degrees, 10.3 +/-0.2 degrees, 11.1 +/-0.2 degrees, 11.3 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.5 +/-0.2 degrees, 13.9 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.5 +/-0.2 degrees, 16.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.1 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 21.4 +/-0.2 degrees, 22.7 +/-0.2 degrees, 24.3 +/-0.2 degrees, 25.1 +/-0.2 degrees, 26.0 degrees, 29.6 +/-0.2 degrees, 2.6 +/-0.2 degrees, 2 degrees.

Preferably, the crystalline form CM-II has an XRPD pattern substantially as shown in figure 9;

preferably, the crystalline form CM-II has a TGA profile substantially as shown in figure 10;

preferably, said crystalline form CM-II has a DSC profile substantially as shown in figure 11;

preferably, the crystalline form CM-II has a structure substantially as shown in FIG. 12¹H NMR spectrum.

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

Preferably, the XRPD pattern of said crystalline form CM-III comprises 3 or more than 32 Θ values selected from the group consisting of: 5.6 degrees +/-0.2 degrees, 8.5 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees and 14.3 degrees +/-0.2 degrees.

Preferably, the XRPD pattern of said crystalline form CM-III comprises 6 or more than 62 Θ values selected from the group consisting of: 5.6 degrees +/-0.2 degrees, 8.5 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 11.3 degrees +/-0.2 degrees, 14.3 degrees +/-0.2 degrees, 15.7 degrees +/-0.2 degrees, 20.0 degrees +/-0.2 degrees and 23.0 degrees +/-0.2 degrees.

Preferably, the XRPD pattern of said crystalline form CM-III comprises 6 or more than 62 Θ values selected from the group consisting of: 5.6 degrees +/-0.2 degrees, 8.5 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 11.3 degrees +/-0.2 degrees, 13.3 degrees +/-0.2 degrees, 14.3 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees, 15.7 degrees +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 18.0 degrees +/-0.2 degrees, 20.0 degrees +/-0.2 degrees, 21.9 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees, 24.3 degrees +/-0.2 degrees and 25.8 degrees +/-0.2 degrees.

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

preferably, the crystalline form CM-III has a TGA profile substantially as shown in figure 18;

preferably, the crystalline form CM-III has a DSC profile substantially as shown in figure 19;

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

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

Preferably, the XRPD pattern of the crystal form CM-IV has characteristic peaks at 2 theta values of 5.7 DEG +/-0.2 DEG, 9.2 DEG +/-0.2 DEG, 10.5 DEG +/-0.2 DEG and 19.4 DEG +/-0.2 deg.

Preferably, the X-ray diffraction pattern of the crystal form CM-IV has characteristic peaks at 2 theta values of 5.7 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 10.5 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 17.8 degrees +/-0.2 degrees, 19.4 degrees +/-0.2 degrees, 22.2 degrees +/-0.2 degrees and 24.6 degrees +/-0.2 degrees.

Preferably, the X-ray diffraction pattern of the crystal form CM-IV has characteristic peaks at 2 theta values of 5.7 +/-0.2 degrees, 9.2 +/-0.2 degrees, 10.5 +/-0.2 degrees, 14.5 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.4 +/-0.2 degrees, 22.2 +/-0.2 degrees, 24.6 +/-0.2 degrees, 27.2 +/-0.2 degrees and 28.0 +/-0.2 degrees.

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

Preferably, the XRPD pattern of the crystalline form CM-V has characteristic peaks at 2 theta values of 5.9 DEG +/-0.2 DEG, 8.9 DEG +/-0.2 DEG, 10.3 DEG +/-0.2 DEG and 17.3 DEG +/-0.2 deg.

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

Preferably, the XRPD pattern of the crystal form CM-VI has characteristic peaks at 2 theta values of 5.4 +/-0.2 degrees, 8.0 +/-0.2 degrees, 10.7 +/-0.2 degrees and 16.0 +/-0.2 degrees.

Preferably, the XRPD pattern of the crystal form CM-VI has characteristic peaks at 2 theta values of 5.4 +/-0.2 degrees, 8.0 +/-0.2 degrees, 10.7 +/-0.2 degrees, 16.0 +/-0.2 degrees, 18.7 +/-0.2 degrees, 20.4 +/-0.2 degrees, 21.4 +/-0.2 degrees, 24.0 +/-0.2 degrees, 26.4 +/-0.2 degrees and 27.6 +/-0.2 degrees.

Preferably, the XRPD pattern of the crystal form CM-VI has characteristic peaks at 2 theta values of 5.4 +/-0.2 degrees, 5.8 +/-0.2 degrees, 8.0 +/-0.2 degrees, 8.7 +/-0.2 degrees, 10.7 +/-0.2 degrees, 11.7 +/-0.2 degrees, 13.3 +/-0.2 degrees, 14.6 +/-0.2 degrees, 16.0 +/-0.2 degrees, 18.7 +/-0.2 degrees, 20.4 +/-0.2 degrees, 21.4 +/-0.2 degrees, 24.0 +/-0.2 degrees, 26.4 +/-0.2 degrees, 27.6 +/-0.2 degrees, 29.5 +/-0.2 degrees and 31.5 +/-0.2 degrees.

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

Preferably, the XRPD pattern of the crystal form CM-VII has characteristic peaks at 2 theta values of 2.9 +/-0.2 degrees, 6.0 +/-0.2 degrees, 8.0 +/-0.2 degrees and 9.8 +/-0.2 degrees.

Preferably, the XRPD pattern of the crystal form CM-VII has characteristic peaks at 2 theta values of 2.9 +/-0.2 degrees, 6.0 +/-0.2 degrees, 8.0 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.8 +/-0.2 degrees, 14.2 +/-0.2 degrees, 17.2 +/-0.2 degrees and 17.6 +/-0.2 degrees.

Preferably, the XRPD pattern of the crystal form CM-VII has characteristic peaks at 2 theta values of 2.9 +/-0.2 degrees, 6.0 +/-0.2 degrees, 8.0 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.8 +/-0.2 degrees, 12.5 +/-0.2 degrees, 14.2 +/-0.2 degrees, 15.2 +/-0.2 degrees, 16.4 +/-0.2 degrees, 16.8 +/-0.2 degrees, 17.2 +/-0.2 degrees, 17.6 +/-0.2 degrees, 18.3 +/-0.2 degrees, 19.1 +/-0.2 degrees, 19.7 +/-0.2 degrees, 21.4 +/-0.2 degrees, 22.0 +/-0.2 degrees, 24.5 +/-0.2 degrees, 24.9 +/-0.2 degrees and 26.1 +/-0.2 degrees.

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

Preferably, the XRPD pattern of the crystal form CM-VIII has characteristic peaks at 2 theta values of 8.4 +/-0.2 degrees, 10.9 +/-0.2 degrees, 13.5 +/-0.2 degrees and 17.5 +/-0.2 degrees.

Preferably, the XRPD pattern of the crystal form CM-VIII has characteristic peaks at 2 theta values of 2.8 +/-0.2 degrees, 5.6 +/-0.2 degrees, 8.4 +/-0.2 degrees, 10.9 +/-0.2 degrees, 12.0 +/-0.2 degrees, 13.5 +/-0.2 degrees, 17.5 +/-0.2 degrees, 19.9 +/-0.2 degrees, 22.0 +/-0.2 degrees and 22.8 +/-0.2 degrees.

Preferably, the XRPD pattern of the crystal form CM-VIII has characteristic peaks at 2 theta values of 2.8 +/-0.2 degrees, 5.6 +/-0.2 degrees, 8.4 +/-0.2 degrees, 10.9 +/-0.2 degrees, 12.0 +/-0.2 degrees, 13.6 +/-0.2 degrees, 13.9 +/-0.2 degrees, 15.3 +/-0.2 degrees, 17.5 +/-0.2 degrees, 19.1 +/-0.2 degrees, 19.5 +/-0.2 degrees, 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.8 +/-0.2 degrees, 24.0 +/-0.2 degrees, 25.4 +/-0.2 degrees, 27.5 +/-0.2 degrees, 29.0 +/-0.2 degrees.

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

In a second aspect of the invention, there is provided a process for preparing the above crystalline form, characterized in that,

the method comprises the following steps: a) providing a solution of a compound raw material shown in the formula (I) in a first solvent, adding a second solvent into the solution for crystallization, and collecting precipitated solids to obtain the crystal form.

Alternatively, the first and second electrodes may be,

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

Alternatively, the first and second electrodes may be,

the method comprises the following steps: c) providing a solution of a 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 comprises stirring, volatilizing or cooling.

Preferably, the first solvent includes an alcohol solvent, a ketone solvent, an amide solvent, an ester solvent, a hydrocarbon solvent, an ether 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-based solvent is selected from the group consisting of: n, N-dimethylformamide, 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 combinations thereof.

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

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

Preferably, the second solvent comprises 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 compound of formula (I) is starting from a compound of formula (I) in crystalline or amorphous form.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: 1) a crystalline form as described in the first aspect; 2) a pharmaceutically acceptable carrier.

In a fourth aspect of the invention, there is provided a use of the pharmaceutical composition according to the third aspect for the treatment of RET variant cancer.

In a fifth aspect of the invention, there is provided a use of the crystalline form of the first aspect, comprising: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a medicament for treating cancer caused by RET variation.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

Figure 1 is an XRPD pattern of crystalline form CM-I of the present invention.

Figure 2 is a TGA profile of crystalline form CM-I of the present invention.

FIG. 3 is a DSC of crystalline form CM-I of the present invention.

FIG. 4 is a diagram of the crystalline form CM-I of the present invention¹H NMR spectrum.

Figure 5A is an XRPD comparison of form CM-I of the present invention at 25 ℃/92.5% relative humidity for 10 days (top panel is an XRPD pattern prior to placement and bottom panel is an XRPD pattern after placement).

Figure 5B is an XRPD comparison of form CM-I of the present invention at 40 ℃/75% relative humidity for 10 days (top panel is an XRPD pattern prior to placement and bottom panel is an XRPD pattern after placement).

Figure 6 is an XRPD pattern of crystalline form CM-I of the invention before and after milling (upper panel is an XRPD pattern before milling and lower panel is an XRPD pattern after milling).

FIG. 7 is a DVS plot of crystalline form CM-I of the present invention.

FIG. 8 is an XRPD pattern of the crystalline form of the invention before and after testing for DVS (the upper panel is an XRPD pattern before testing and the lower panel is an XRPD pattern after testing)

Figure 9 is an XRPD pattern of crystalline form CM-II of the present invention.

Figure 10 is a TGA profile of crystalline form CM-II of the present invention.

FIG. 11 is a DSC of crystalline form CM-II of the present invention.

FIG. 12 is a drawing of the crystalline form CM-II of the present invention¹H NMR spectrum

Figure 13A is an XRPD comparison of crystalline form CM-II of the present invention at 25 ℃/92.5% relative humidity for 10 days (top panel is an XRPD pattern prior to placement and bottom panel is an XRPD pattern after placement).

Figure 13B is an XRPD comparison of crystalline form CM-II of the present invention at 40 ℃/75% relative humidity for 10 days (top panel is an XRPD pattern prior to placement and bottom panel is an XRPD pattern after placement).

Figure 14 is an XRPD pattern of crystalline form CM-II of the invention before and after milling (upper panel is an XRPD pattern before milling and lower panel is an XRPD pattern after milling).

FIG. 15 is a DVS plot of crystalline form CM-II of the present invention.

Figure 16 is an XRPD pattern of crystalline form CM-II of the invention before and after DVS testing (top panel is an XRPD pattern before testing and bottom panel is an XRPD pattern after testing).

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

Figure 18 is a TGA profile of crystalline form CM-III of the present invention.

Figure 19 is a DSC diagram of crystalline form CM-III of the present invention.

FIG. 20 is a crystalline form of CM-III of the present invention¹H NMR spectrum

Figure 21A is an XRPD comparison of crystalline form CM-III of the present invention at 25 ℃/92.5% relative humidity for 10 days (top panel is an XRPD pattern prior to placement and bottom panel is an XRPD pattern after placement).

Figure 21B is an XRPD comparison of crystalline form CM-III of the present invention at 40 ℃/75% relative humidity for 10 days (top panel is an XRPD pattern prior to placement and bottom panel is an XRPD pattern after placement).

Figure 22 is an XRPD pattern of crystalline form CM-III of the invention before and after milling (upper panel is an XRPD pattern before milling and lower panel is an XRPD pattern after milling).

Figure 23 is a DVS plot of crystalline form CM-III of the present invention.

Figure 24 is an XRPD pattern of crystalline form CM-III of the invention before and after DVS testing (top panel is an XRPD pattern before testing and bottom panel is an XRPD pattern after testing).

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

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

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

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

FIG. 29 is an XRPD pattern for crystalline form CM-VIII of the present invention.

Detailed Description

The inventors of the present invention have surprisingly discovered a series of novel crystalline forms of the compound of formula (I) during the course of their research. The crystal forms are simple to prepare, low in cost, have advantages in aspects of stability, process developability and the like, and have important significance for optimizing and developing the medicine in the future.

Term(s) for

In this context, each abbreviation is used in the conventional sense understood by those skilled in the art, unless otherwise specified.

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

Preferably, the starting compound of formula (I) employed in the present invention is BLU-667 prepared according to the methods of preparation provided in the examples of the present invention.

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

As used herein, the manner of "slow addition" includes, but is not limited to: dropwise, slowly along the vessel wall, etc.

General procedure

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

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

XRPD pattern determination method:

x-ray powder diffraction instrument: bruker D2 Phaser X-ray powder diffractometer; radiation source

Generator (Generator) kv: 30 kv; generator (Generator) mA: 10 mA; initial 2 θ: 2.000 °, scan range: 2.0000-35.000 degrees, a scanning step size of 0.02 degrees and a scanning speed of 0.1 s/step.

TGA profile determination method:

thermogravimetric analysis (TGA) instrument: TGA55 from TA USA; equilibration time before testing: 2 h; temperature range: 20-250 ℃; heating rate: 10 ℃/min; nitrogen flow rate: 40 mL/min.

DSC chart measurement method:

differential Scanning Calorimetry (DSC) instrument: TA Q2000 by TA, USA; temperature range: 20-250 ℃, heating rate: 10 ℃/min, nitrogen flow rate: 50 mL/min.

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

DVS graph measurement method:

dynamic moisture sorption instrument (DVS) instrument: TA Q5000 SA from TA of America; temperature: 25 ℃; nitrogen flow rate: 50 mL/min; change in mass per unit time: 0.002%/min; relative humidity range: 0% RH to 90% RH.

In the present invention, the method for drying is a conventional drying method in the art unless otherwise specified, for example, drying in the examples of the present invention means drying in vacuum or drying under normal pressure in a conventional drying oven. Generally, the drying is carried out for 0.1 to 50 hours or 1 to 30 hours.

The main advantages of the invention are:

(1) provides crystal forms of the compound shown in the formula (I) suitable for preparing medicaments, and the crystal forms have better crystal form stability and mechanical stability and are more beneficial to preparation and storage of preparation products.

(2) The crystal form has lower hygroscopicity, so that the crystal form has better tolerance to different humidity environment conditions, is convenient to package and store, and simultaneously improves the quality of subsequently prepared medicines.

(3) The preparation method of the crystal form provided by the 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 prophylactic effects on cancer or tumor, the crystalline form or amorphous form of the present invention and a pharmaceutical composition comprising the crystalline form or amorphous form of the present invention as a main active ingredient can be used for treating and/or preventing anemia.

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

Wherein "safe and effective amount" means: the amount of the compound (or crystalline form) is sufficient to significantly ameliorate the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 to 2000mg of the crystalline form/dosage of the present invention, more preferably, 10 to 200mg of the crystalline form/dosage of the present invention. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

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 the following: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells 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 delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to 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 ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, 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 nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the polymorphic forms 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 which may be required if necessary.

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

When the pharmaceutical composition is used, a safe and effective amount of the polymorphic substance of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1-2000mg, preferably 20-500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

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

Example 1: preparation of crystalline form CM-I

14mg of the compound of the formula (I) are weighed out, dissolved in 0.5mL of ethanol at 30 ℃ and filtered. And (3) standing the filtrate at 5 ℃ and stirring for 24h, and separating out a solid, wherein the obtained solid is the compound of the formula (I) in a crystal form CM-I. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 1, and the XRPD pattern of which is shown in fig. 1; TGA testing was performed on the resulting solid, the spectrum of which is shown in figure 2; subjecting the obtained solid to DSC test, wherein the spectrum is shown in figure 3; subjecting the obtained solid to¹H NMR measurement, spectrum as shown in fig. 4, nuclear magnetic data:¹H NMR(400MHz,DMSO-d₆)11.89(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 crystalline form CM-II

12mg of the compound of formula (I) are weighed, mixed with 0.2mL of methanol, filtered and the filtrate placed in a 3mL open glass vial. In a 20mL glass vial was added 3mL of methyl tert-butyl ether. And (3) putting the 3mL glass bottle containing the filtrate into a 20mL glass bottle containing methyl tert-butyl ether, sealing the 20mL glass bottle, and standing at 25 ℃ until a solid is separated out, wherein the obtained solid is the compound of the formula (I) in the crystal form CM-II. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 2, and the XRPD pattern of which is shown in fig. 9; TGA testing was performed on the resulting solid, the spectrum of which is shown in figure 10; subjecting the obtained solid to DSC test, and its spectrum is shown in FIG. 11; subjecting the obtained solid to¹H NMR measurement, spectrum as shown in fig. 12, nuclear magnetic data:¹HNMR(400MHz,DMSO-d₆)11.89(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)。

TABLE 2

Example 3: preparation of crystalline form CM-III

10mg of the compound of formula (I) are weighed out and dissolved in 1mL of acetone, filtered, 2mL of water are slowly added to the filtrate, and the solution is placed in a closed environment and allowed to stand at 28 ℃ until a solid precipitates. The obtained solid is a compound of a formula (I) in a crystal form CM-III. The resulting solid was subjected to XRPD testing, with X-ray powder diffraction data as shown in table 3 and an XRPD pattern as shown in figure 17; TGA testing was performed on the resulting solid, the spectrum of which is shown in figure 18; the obtained solid is subjected to DSC test, and the spectrum is shown in figure 19; subjecting the obtained solid to¹H NMR measurement, spectrum as shown in fig. 20, nuclear magnetic data:¹H NMR(400MHz,DMSO-d₆)11.89(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)。

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 crystalline form CM-IV

10mg of the compound of the formula (I) was dissolved in 0.2mL of tetrahydrofuran, filtered, and 1mL of water was added dropwise to the filtrate, followed by stirring at 24 ℃ for 24 hours to precipitate a solid. The obtained solid is a compound of formula (I) in a crystal form CM-IV. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 4, and the 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 crystalline form CM-V

Weighing 9mg of the compound of the formula (I) and dissolving in 0.5mL of chloroform, filtering, dripping the filtrate into 3mL of nitromethane at 24 ℃, stirring the mixed solution for 24h after dripping, and separating out solid. The obtained solid is a compound of formula (I) in a crystal form CM-V. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 5, and the XRPD pattern is shown in fig. 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 crystalline form CM-VI

21mg of the compound of formula (I) is dissolved in 0.3mL of dimethyl sulfoxide, filtered and the filtrate is left open at 25 ℃ until a solid precipitates. The obtained solid is the crystal form CM-VI. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 6, and the XRPD pattern is shown in fig. 27.

TABLE 6

Example 7: preparation of crystalline form CM-VII

10mg of the compound of formula (I) are dissolved in 0.5mL1, 4-dioxane/ethyl acetate (1:4, v/v), filtered and the filtrate is slowly evaporated at 24 ℃ until a solid precipitates. The obtained solid is the crystal form CM-VII. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 7, and the XRPD pattern is shown in fig. 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 crystalline form CM-VIII

11mg of the compound of formula (I) are weighed out and dissolved in 1mL1, 4-dioxane, filtered, 2mL water are slowly added to the filtrate, and the solution is placed in a closed environment and left to stand at 28 ℃ until a solid precipitates. The solid obtained is the compound of formula (I) in crystal form CM-VIII. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 8, and the XRPD pattern is shown in fig. 29.

TABLE 8

Preparation examples

Preparation of BLU-667 starting Material

Reference is made to the process disclosed in WO 2017079140: HATU (1.62g, 4.27mmol) was added to (1S,4R) -1-methoxy 4- (4-methyl-6- ((5-methyl-1H-pyrazole-3)-yl) amino) pyrimidin-2-yl) cyclohexanecarboxylic acid methyl ester (2.3mmol), (R) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethylamine hydrochloride (970mg, 4.0mmol) and DIEA (3.4mL, 19mmol) in DMF (38 mL). The reaction mixture was stirred for 10min, then with EtOAc and H₂O extraction, the organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (gradient elution 0-10% methanol-dichloromethane with 2% triethylamine) to give an oil, a crude product of BLU-667, which is preferably used in the present invention as a starting material for the preparation of the above crystalline form.

Test example

Test example 1 stability of Crystal form

The prepared crystal forms CM-I, CM-II and CM-III are respectively placed in an open air for 10 days at the conditions of 25 ℃/92.5% RH and 40 ℃/75% RH, the crystal forms before and after placement are detected, and XRPD patterns of the crystal forms before and after placement are respectively obtained for comparison. The results are shown in Table 9. By comparing XRPD patterns before and after the crystal forms are placed in the figures, the crystal forms of the CM-I, CM-II and the CM-III provided by the invention do not change after being placed in an open environment for 10 days under the conditions of 25 ℃/92.5% RH or 40 ℃/75% RH, which shows that the crystal forms provided by the invention have good crystal form stability.

TABLE 9

Test example 2: mechanical stability

50mg of the crystalline forms CM-I, CM-II and CM-III prepared in the examples of the present invention were weighed and ground in a mortar for 10min, and XRPD test was performed on the ground solid, and comparative patterns of the crystalline forms XRPD before and after grinding are shown in FIG. 6, FIG. 14 and FIG. 22, respectively, and the grinding results are shown in Table 10. As can be seen by comparing XRPD patterns before and after grinding in the figures, the crystal forms CM-I, CM-II and CM-III provided by the invention have no change before and after grinding, which shows that the crystal forms provided by the invention have good mechanical stability.

Watch 10

Test example 3: moisture-wicking property

About 10mg of the crystalline forms CM-I, CM-II and CM-III obtained in example 1, example 2 and example 3 of the present patent were measured for hygroscopicity by a dynamic moisture sorption instrument (DVS). The DVS diagrams of the crystal forms CM-I, CM-II and CM-III are shown in FIG. 7, FIG. 15 and FIG. 23 respectively. In addition, the XRPD patterns of the crystalline forms CM-I, CM-II and CM-III before and after DVS testing are shown in fig. 8, fig. 16, and fig. 24, respectively. The overall test results are shown in table 11.

According to the DVS test result, the moisture absorption amount of the crystal forms CM-I, CM-II and CM-III provided by the invention in the DVS test process is below 7%, and the crystal forms have lower moisture absorption; as can be seen from the XRPD results, all forms did not change form before and after DVS testing.

TABLE 11

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A crystalline form of a compound of formula (I):

2. the crystalline form of claim 1, wherein the crystalline 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 said crystalline form CM-I comprises 3 or more than 32 Θ values selected from the group consisting of: 4.9 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees and 13.6 degrees +/-0.2 degrees;

the XRPD of crystalline form CM-II comprises 3 or more than 32 Θ values selected from the group consisting of: 9.0 degrees +/-0.2 degrees, 18.1 degrees +/-0.2 degrees, 20.8 degrees +/-0.2 degrees and 25.1 degrees +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-III comprises 3 or more than 32 Θ values selected from the group consisting of: 5.6 degrees +/-0.2 degrees, 8.5 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees and 14.3 degrees +/-0.2 degrees.

3. The crystalline form of claim 2, wherein the crystalline form CM-I has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-I comprises 6 or more than 62 Θ values selected from the group consisting of: 4.9 +/-0.2 degrees, 6.8 +/-0.2 degrees, 9.7 +/-0.2 degrees, 12.7 +/-0.2 degrees, 13.6 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.8 +/-0.2 degrees, 16.0 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.2 +/-0.2 degrees, 19.4 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.5 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.5 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.0 +/-0.2 degrees, 27.8 +/-0.2 degrees, 28.4 +/-0.2 degrees, 29.3 +/-0.2 degrees.

2) The crystalline form CM-I has an XRPD pattern substantially as shown in figure 1;

3) the crystalline form CM-I has a TGA profile substantially as shown in figure 2;

4) the crystalline form CM-I has a DSC profile substantially as shown in figure 3.

5) Said crystalline form CM-I having a structure substantially as shown in FIG. 4¹H NMR spectrum.

4. The crystalline form of claim 2, wherein the crystalline form CM-II has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-II comprises 6 or more 2 Θ values selected from the group consisting of: 3.9 +/-0.2 degrees, 6.9 +/-0.2 degrees, 9.0 +/-0.2 degrees, 10.3 +/-0.2 degrees, 11.1 +/-0.2 degrees, 11.3 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.5 +/-0.2 degrees, 13.9 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.5 +/-0.2 degrees, 16.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.1 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 21.4 +/-0.2 degrees, 22.7 +/-0.2 degrees, 24.3 +/-0.2 degrees, 25.1 +/-0.2 degrees, 26.0 degrees, 29.6 +/-0.2 degrees, 2.6 +/-0.2 degrees, 2 degrees.

2) The crystalline form CM-II has an XRPD pattern substantially as shown in figure 9;

3) the crystalline form CM-II has a TGA profile substantially as shown in figure 10;

4) said crystalline form CM-II having a DSC profile substantially as shown in figure 11;

5) said crystalline form CM-II having a structure substantially as shown in FIG. 12¹H NMR spectrum.

5. The crystalline form of claim 2, wherein the crystalline form CM-III has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystalline form CM-III comprises 6 or more 2 Θ values selected from the group consisting of: 5.6 degrees +/-0.2 degrees, 8.5 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 11.3 degrees +/-0.2 degrees, 13.3 degrees +/-0.2 degrees, 14.3 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees, 15.7 degrees +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 18.0 degrees +/-0.2 degrees, 20.0 degrees +/-0.2 degrees, 21.9 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees, 24.3 degrees +/-0.2 degrees and 25.8 degrees +/-0.2 degrees.

2) The crystalline form CM-III has an XRPD pattern substantially as shown in figure 17;

3) the crystalline form CM-III has a TGA profile substantially as shown in figure 18;

4) the crystalline form CM-III has a DSC profile substantially as shown in figure 19;

5) said crystalline form CM-III having a structure substantially as shown in figure 20¹H NMR spectrum.

6. The crystalline form of claim 1, wherein the crystalline form is selected from the group consisting of: crystal form CM-IV, crystal form CM-V, crystal form CM-VI, crystal form CM-VII, crystal form CM-VIII;

wherein the XRPD pattern of crystalline form CM-IV comprises 3 or more than 32 Θ values selected from the group consisting of: 5.7 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 10.5 degrees +/-0.2 degrees and 19.4 degrees +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-V comprises 3 or more than 32 Θ values selected from the group consisting of: 5.9 degrees +/-0.2 degrees, 8.9 degrees +/-0.2 degrees, 10.3 degrees +/-0.2 degrees and 17.3 degrees +/-0.2 degrees;

the XRPD pattern of the crystalline form CM-VI comprises 3 or more than 32 Θ values selected from the group consisting of: 5.4 degrees +/-0.2 degrees, 8.0 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees and 16.0 degrees +/-0.2 degrees;

the crystalline form CM-VII having an XRPD pattern comprising 3 or more 2 θ values selected from the group consisting of: 2.9 degrees +/-0.2 degrees, 6.0 degrees +/-0.2 degrees, 8.0 degrees +/-0.2 degrees and 9.8 degrees +/-0.2 degrees;

the XRPD pattern of crystalline form CM-VIII comprises 3 or more than 32 Θ values selected from the group consisting of: 8.4 degrees +/-0.2 degrees, 10.9 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees and 17.5 degrees +/-0.2 degrees.

7. The crystalline form of claim 6, wherein the crystalline form has one or more characteristics selected from the group consisting of:

1) the XRPD pattern of the crystal form CM-IV comprises 6 or more than 62 theta values selected from the group consisting of 5.7 DEG +/-0.2 DEG, 9.2 DEG +/-0.2 DEG, 10.5 DEG +/-0.2 DEG, 14.5 DEG +/-0.2 DEG, 17.8 DEG +/-0.2 DEG, 19.4 DEG +/-0.2 DEG, 22.2 DEG +/-0.2 DEG, 24.6 DEG +/-0.2 DEG, 27.2 DEG +/-0.2 DEG and 28.0 DEG +/-0.2 DEG;

2) the crystalline form CM-IV has an XRPD pattern substantially as shown in figure 25;

3) the XRPD pattern of the crystalline form CM-V comprises 6 or more 2 Θ values selected from the group consisting of: 5.9 degrees +/-0.2 degrees, 8.9 degrees +/-0.2 degrees, 10.3 degrees +/-0.2 degrees and 17.3 degrees +/-0.2 degrees.

4) The crystalline form CM-V has an XRPD pattern substantially as shown in figure 26;

5) the XRPD pattern of the crystalline form CM-VI comprises 6 or more 2 Θ values selected from the group consisting of: the 2 theta values are 5.4 DEG +/-0.2 DEG, 5.8 DEG +/-0.2 DEG, 8.0 DEG +/-0.2 DEG, 8.7 DEG +/-0.2 DEG, 10.7 DEG +/-0.2 DEG, 11.7 DEG +/-0.2 DEG, 13.3 DEG +/-0.2 DEG, 14.6 DEG +/-0.2 DEG, 16.0 DEG +/-0.2 DEG, 18.7 DEG +/-0.2 DEG, 20.4 DEG +/-0.2 DEG, 21.4 DEG +/-0.2 DEG, 24.0 DEG +/-0.2 DEG, 26.4 DEG +/-0.2 DEG, 27.6 DEG +/-0.2 DEG, 29.5 DEG +/-0.2 DEG and 31.5 DEG +/-0.2 DEG;

6) the crystalline form CM-VI has an XRPD pattern substantially as shown in figure 27;

7) the XRPD pattern of the crystalline form CM-VII comprises 6 or more 2 Θ values selected from the group consisting of: 2.9 degrees +/-0.2 degrees, 6.0 degrees +/-0.2 degrees, 8.0 degrees +/-0.2 degrees, 9.8 degrees +/-0.2 degrees, 11.8 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees, 14.2 degrees +/-0.2 degrees, 15.2 degrees +/-0.2 degrees, 16.4 degrees +/-0.2 degrees, 16.8 degrees +/-0.2 degrees, 17.2 degrees +/-0.2 degrees, 17.6 degrees +/-0.2 degrees, 18.3 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 22.0 degrees +/-0.2 degrees, 24.5 degrees +/-0.2 degrees, 24.9 degrees +/-0.2 degrees, 26.1 degrees +/-0.2 degrees

8) The crystalline form CM-VII has an XRPD pattern substantially as shown in figure 28;

9) the XRPD pattern of crystalline form CM-VIII comprises 6 or more than 62 Θ values selected from the group consisting of: 2.8 degrees +/-0.2 degrees, 5.6 degrees +/-0.2 degrees, 8.4 degrees +/-0.2 degrees, 10.9 degrees +/-0.2 degrees, 12.0 degrees +/-0.2 degrees, 13.6 degrees +/-0.2 degrees, 13.9 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 19.5 degrees +/-0.2 degrees, 19.9 degrees +/-0.2 degrees, 20.9 degrees +/-0.2 degrees, 21.5 degrees +/-0.2 degrees, 22.0 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees, 24.0 degrees +/-0.2 degrees, 25.4 degrees +/-0.2 degrees, 27.5 degrees +/-0.2 degrees and 29.0 degrees +/-0.2 degrees.

10) The crystalline form CM-VIII has an XRPD pattern substantially as shown in figure 29.

8. A process for preparing the crystalline form of any of claims 1 to 7,

Alternatively, the first and second electrodes may be,

9. A pharmaceutical composition comprising the crystalline form of any one of claims 1-7 and a pharmaceutically acceptable carrier.

10. Use of the crystalline form of 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 variation.