Substituted amino 6-membered nitrogen heterocyclic compound salts and their crystal forms, preparation methods and applications

Abstract

The present invention provides a salt of a substituted amino 6-membered nitrogen heterocyclic compound and its crystalline form, preparation method and application. Specifically, the present invention provides a dihydrochloride salt of the compound of formula (I), which can be prepared in crystalline form, and preferably, the crystalline form has the advantages of good solubility, low hygroscopicity, stable quality and stable crystalline form, and therefore, compared with the compound of formula (I) or other salts, it is easier to develop drugs. [Formula 1] JPEG2025507196000017.jpg41169

Description

Detailed Description of the Invention

[0001] This application claims priority from a prior application filed by the applicant with the State Intellectual Property Office of the People's Republic of China on March 18, 2022, bearing patent application number 202210268968.7 and entitled "Substituted amino six-membered nitrogen heterocyclic compound salts and their crystalline forms, preparation methods and applications." The above prior application is incorporated herein by reference in its entirety.

[0002] [Technical field] The present invention relates to the field of medicinal chemistry, specifically to the salts of substituted amino six-membered nitrogen heterocyclic compounds and their crystal forms, preparation methods and applications.

[0003] [Background technology] Fibroblast growth factor receptors (FGFRs) are important molecular typing targets for tumors and are abnormally activated in several types of tumors, especially some refractory tumors and tumors with Chinese characteristics. Currently, many clinical studies targeting FGFR inhibitors are in the early stages, and FGFR inhibitors under clinical study mainly target multiple targets, have weak inhibitory activity against FGFR, and often have enhanced antagonistic effects against human vascular endothelial growth factor receptor (Kinase insert domain containing receptor, KDR), resulting in severe adverse reactions, which greatly limits the application of inhibitors targeting FGFR antitumor effects and the maximization of clinical therapeutic effects. However, FGFR and KDR have the ability to be activated compensatory, suggesting that they mediate drug resistance compensatory to each other. In fact, it has been reported that activation of FGFR is a drug resistance mechanism of KDR inhibitors, and the tumor-promoting effect of enhanced immune inhibition of the KDR family has gradually been revealed in recent years. Therefore, the development of inhibitors that co-target FGFR and KDR has important clinical potential.

[0004] It cannot be ignored that in recent years, tumor treatment is not limited to tumor cells themselves, but the role of the tumor microenvironment, which is functionally indivisible as a whole, in promoting tumor progression and mediating drug resistance has attracted great attention. Among them, tumor-associated macrophages (TAMs) are important microenvironmental stromal cells, which not only directly inhibit effector T cells from exerting their killing effect and synergistically promote the microenvironment of tumor immune inhibitors, but also promote intratumoral angiogenesis, thereby promoting tumor cell growth and metastasis at multiple stages and mediating tumor drug resistance. Among them, colony-stimulating factor 1 receptor (CSF-1R) is expressed in macrophages and is crucial for the differentiation and proliferation survival of TAMs toward an M2 polarized phenotype. Based on this, by simultaneously targeting FGFR / KDR / CSF-1R, it can not only antagonize tumor cells themselves, but also regulate the tumor microenvironment, which is helpful in antagonizing tumors at multiple stages, remodeling the immune suppressive microenvironment of the body, and delaying the occurrence of acquired drug resistance.

[0005] The compound of formula (I) is a novel FGFR / CSF1R / KDR targeting small molecule inhibitor developed based on the above mechanism, and preclinical pharmacological studies have shown that it has relatively good therapeutic effects in multiple tumor models. [ka]

[0006] PCT patent document WO2017 / 140269A1 discloses the structure of the compound of formula (I) and a method for preparing the same, as well as the use of the drug for preventing and / or treating diseases associated with FGFR.

[0007] PCT patent document WO2021 / 170078A1 discloses the use of compounds of formula (I) as CSF-1R inhibitors.

[0008] None of the above patent documents studies the specific salt forms of the compound of formula (I) and their crystalline forms and preparations. Summary of the Invention

[0009] The compound of formula (I) is a drug molecule of an entirely new compound, and by carrying out a systematic study on its salt forms and crystalline forms, the inventors have surprisingly found a drug form that is optimal for drug development.

[0010] The present inventors have found that the compound of formula (I) obtained according to the prior art has poor druggability due to its own physicochemical properties, for example, the solubility of the compound of formula (I) is relatively low, etc. Therefore, in order to meet the needs of better pharmaceuticals, further research on the drug form of the compound of formula (I) is necessary.

[0011] In order to solve the above problems, the present invention provides a dihydrochloride salt of a compound of formula (I), the dihydrochloride salt of the compound of formula (I) having the structure shown in formula (II): [ka]

[0012] According to an embodiment of the present invention, the dihydrochloride salt of the compound of formula (I) above is in solid form.

[0013] According to an embodiment of the present invention, the dihydrochloride salt of the compound of formula (I) above is in crystalline form.

[0014] The present invention further provides crystalline Form I of the dihydrochloride salt of compound of formula (I), having characteristic peaks in X-ray powder diffraction, expressed in degrees 2θ, using Cu-Kα radiation, at 5.0±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2° and 25.2±0.2°.

[0015] According to an embodiment of the present invention, the crystalline form I of the dihydrochloride salt of the compound of formula (I) has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 5.0±0.2°, 10.4±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 23.4±0.2° and 25.2±0.2° using Cu-Kα radiation.

[0016] According to an embodiment of the present invention, the crystalline form I of the dihydrochloride salt of compound of formula (I) has characteristic peaks in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation at 5.0±0.2°, 10.4±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2° and 25.2±0.2°.

[0017] According to an embodiment of the present invention, the crystalline form I of the dihydrochloride salt of compound of formula (I) has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 5.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, 26.6±0.2° using Cu-Kα radiation.

[0018] According to an embodiment of the present invention, the crystalline form I of the dihydrochloride salt of the compound of formula (I) above has X-ray powder diffraction, expressed at 2θ angles using Cu-Kα radiation, of 5.0±0.2°, 10.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.7±0.2°, 17.4±0.2° and 18. It has characteristic peaks at 0±0.2°, 19.3±0.2°, 20.1±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, 26.6±0.2°, 28.6±0.2°, and 30.1±0.2°.

[0019] According to an embodiment of the present invention, the crystalline form I of the dihydrochloride salt of the compound of formula (I) above has an X-ray powder diffraction pattern (XRPD) essentially as shown in FIG. 1 or FIG.

[0020] In some embodiments, the crystalline form I of the dihydrochloride salt of the compound of Formula (I) has X-ray powder diffraction analysis data essentially as set forth in Tables 2 or 3.

[0021] According to an embodiment of the present invention, the thermogravimetric analysis curve of the crystalline form I of the dihydrochloride salt of the compound of formula (I) above has a weight loss of 1.17% between 25°C and 200°C.

[0022] According to an embodiment of the present invention, the differential scanning calorimetry spectrum of the crystalline form I of the dihydrochloride salt of the compound of formula (I) above shows that it begins to melt decompose at 285-300°C.

[0023] According to an embodiment of the present invention, the crystalline form I of the dihydrochloride salt of the compound of formula (I) above has a TGA-DSC spectrum essentially as shown in FIG.

[0024] The present invention relates to a method for preparing the dihydrochloride salt of the compound of formula (I) above, comprising the steps of: The present invention further provides a method for preparing the compound of formula (I), comprising the steps of adding the compound of formula (I) and a solvent to a reaction flask, slowly adding hydrochloric acid, stirring, isolating the resulting solid, and drying to obtain the dihydrochloride salt of the compound of formula (I), wherein the molar ratio of the hydrochloric acid to the compound of formula (I) is 1.5-3:1.

[0025] According to an embodiment of the present invention, the molar ratio of said hydrochloric acid to the compound of formula (I) is 1.8-2.5:1, for example, 2:1.

[0026] According to an embodiment of the present invention, the solvent is any one selected from the group consisting of water, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, methanol, tetrahydrofuran-water (V:V=19:1), and tetrahydrofuran.

[0027] In some embodiments, when the solvent is selected from dimethyl sulfoxide or tetrahydrofuran-water (V:V=19:1), the preparation method further comprises adding a poor solvent, and the poor solvent is preferably methyl tert-butyl ether.

[0028] The present invention relates to a method for preparing crystalline form I of the dihydrochloride salt of the compound of formula (I) above, comprising the steps of: The present invention further provides a method for preparing the compound of formula (I) and a solvent, comprising the steps of adding hydrochloric acid slowly into a reaction flask, optionally adding seed crystals of crystalline form I, and stirring, crystallizing, isolating and drying to obtain crystalline form I of the dihydrochloride salt of the compound of formula (I), wherein the molar ratio of the hydrochloric acid to the compound of formula (I) is 1.5-3:1, and the solvent is any one selected from the group consisting of water, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, methanol and tetrahydrofuran-water (V:V=19:1).

[0029] According to an embodiment of the present invention, when the solvent is selected from dimethyl sulfoxide or tetrahydrofuran-water (V:V=19:1), the preparation method further includes a step of adding a poor solvent, the poor solvent is preferably methyl tert-butyl ether, the volume ratio of the dimethyl sulfoxide to methyl tert-butyl ether is preferably 20-30:8, more preferably 25:8, and the volume ratio of the tetrahydrofuran-water (V:V=19:1) to methyl tert-butyl ether is preferably 45-55:8, more preferably 50:8.

[0030] According to an embodiment of the present invention, the molar ratio of said hydrochloric acid to the compound of formula (I) is 1.8-2.5:1, for example, 2:1.

[0031] According to an embodiment of the present invention, the crystallization temperature is 10 to 35°C, and preferably 20 to 30°C.

[0032] According to an embodiment of the present invention, the crystallization time is 1 to 72 hours, preferably 3 to 48 hours, and more preferably 5 to 24 hours.

[0033] According to an embodiment of the invention, the separation step comprises separating the resulting precipitate from the crystallization liquid using a suitable method such as filtration, centrifugation, or the like.

[0034] According to an embodiment of the present invention, the drying method may be any suitable known method, preferably reduced pressure (vacuum) drying. Specific drying conditions are, for example, a temperature of preferably 20 to 70°C, more preferably 30 to 45°C, a pressure of preferably a degree of vacuum >0.090 MPa, and a drying time of preferably 10 to 50 hours, more preferably 20 to 40 hours. Regardless of which drying method is used, it is preferable that the residual amount of solvent in the obtained product satisfies the quality standard.

[0035] The compound of the above formula (I) of the present invention can be prepared by referring to the methods disclosed in the prior art, for example, PCT patent document WO2017 / 140269A1.

[0036] The present invention further provides a pharmaceutical composition comprising the dihydrochloride salt of the compound of formula (I) as above or crystalline Form I of the dihydrochloride salt of the compound of formula (I) as above, and a pharma- ceutically acceptable carrier.

[0037] The present invention further provides the use of the dihydrochloride salt of compound of formula (I) or its crystalline form I, or said pharmaceutical composition, in the manufacture of a medicament for preventing and / or treating a disease associated with the activity or expression of FGFR, KDR and / or CSF-1R, preferably, said associated disease is a tumor-associated disease, and said tumor-associated disease is selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, bladder cancer, urinary tract transitional cell carcinoma, gastric cancer (including gastroesophageal junction adenocarcinoma), pancreatic cancer, prostate cancer, colorectal cancer, myeloma, multiple myeloma, acute myeloid leukemia, liver cancer, melanoma, thyroid cancer, liver cancer, head and neck cancer, renal cell carcinoma, glioblastic carcinoma, testicular cancer and / or cholangiocarcinoma.

[0038] The drugs are administered in an effective amount to a "subject" or "patient." The "subject" and "patient" include all members of the animal kingdom, including, but not limited to, mammals (e.g., mice, rats, cats, monkeys, dogs, horses, pigs, etc.) and humans.

[0039] The present invention further provides the dihydrochloride salt of compound of formula (I) or its crystalline form I, or said pharmaceutical composition, for treating a disease associated with the activity or expression of FGFR, KDR and / or CSF-1R, preferably, said associated disease is a tumor-associated disease, and said tumor-associated disease is selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, bladder cancer, urinary tract transitional cell carcinoma, gastric cancer (including gastroesophageal junction adenocarcinoma), pancreatic cancer, prostate cancer, colorectal cancer, myeloma, multiple myeloma, acute myeloid leukemia, liver cancer, melanoma, thyroid cancer, liver cancer, head and neck cancer, renal cell carcinoma, glioblastic carcinoma, testicular cancer and / or cholangiocarcinoma.

[0040] The present invention further provides a method for preventing and / or treating a disease associated with the activity or expression of FGFR, KDR and / or CSF-1R, comprising administering to a subject or patient in need thereof a therapeutically effective amount of the dihydrochloride salt of the compound of formula (I) or its crystalline form I, or a pharmaceutical composition comprising the dihydrochloride salt of the compound of formula (I) or the crystalline form I of the dihydrochloride salt of the compound of formula (I), wherein the disease associated with the activity or expression of FGFR, KDR and / or CSF-1R is a tumor-associated disease, which may be selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, bladder cancer, urinary tract transitional cell carcinoma, gastric cancer (including gastroesophageal junction adenocarcinoma), pancreatic cancer, prostate cancer, colorectal cancer, myeloma, multiple myeloma, acute myeloid leukemia, liver cancer, melanoma, thyroid cancer, liver cancer, head and neck cancer, renal cell carcinoma, glioblastic carcinoma, testicular cancer and / or cholangiocarcinoma.

[0041] [Definitions and Explanations] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings: A particular word or term, unless specifically defined, should not be considered indefinite or unclear but should be understood in its ordinary sense.

[0042] The solid forms of the dihydrochloride salt of the compound of formula (I) referred to in this application include crystalline and amorphous forms of the dihydrochloride salt of the compound of formula (I).

[0043] The crystalline forms of the dihydrochloride salt of the compound of formula (I) referred to in this application include anhydrous and non-aqueous solvent-free forms, hydrate forms, non-aqueous solvate forms, and co-crystalline forms of the dihydrochloride salt of the compound of formula (I).

[0044] The above "room temperature" is room temperature in the usual sense in the art, generally 10 to 30°C, preferably 25°C±5°C.

[0045] In the X-ray powder diffraction pattern, the term "essentially" or "essentially as shown in the figure" refers to a crystalline form that is essentially pure and in which at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks appear in the provided pattern in the X-ray powder diffraction pattern. Furthermore, when the content of a crystalline form in a product slowly decreases, some of the diffraction peaks assigned to that crystalline form in the X-ray powder diffraction pattern may be reduced due to the detection sensitivity of the instrument. In addition, for any given crystalline form, there may be slight errors in the positions of the peaks, which are well known in the field of crystallography. For example, the positions of the peaks may shift due to temperature changes during sample analysis, sample movement, or instrument calibration, and the measurement error of the 2θ values ​​is sometimes about ±0.3°, and usually about ±0.2°. Therefore, this error should be taken into consideration when determining the structure of each crystalline form, and the terms "essentially" or "essentially as shown in the figures" are intended to encompass such variations in diffraction peak positions, which are ±0.3°, preferably ±0.2°.

[0046] In a DSC spectrum or a TGA spectrum, the term "essentially" or "essentially as shown in the figure" refers to a thermal transition onset temperature, endothermic peak temperature, exothermic peak temperature, melting point, weight loss onset temperature, or weight loss end temperature, etc., in successive analyses for the same crystalline form of the same compound, the error is typically about 5° C., usually within about 3° C. When a compound or a crystalline form thereof is described as having a certain thermal transition onset temperature, endothermic peak temperature, exothermic peak temperature, melting point, weight loss onset temperature, or weight loss end temperature, etc., the error refers to that temperature ±5° C.

[0047] The term "tumor" includes benign tumors, malignant tumors, and borderline tumors, of which malignant tumors are also collectively called cancer.

[0048] As used herein, the term "prevention," when applied to a disease or condition (e.g., cancer), refers to the ability of a compound or drug (e.g., a pharmaceutical composition product claimed by the present invention) to reduce the frequency of symptoms of, or delay the onset of, a medical condition in a subject in vivo, as compared to a subject not administered the compound or drug.

[0049] The term "treatment" as used herein refers to the alleviation, relieving or amelioration of the symptoms of a disease or condition, the amelioration of symptoms caused by a potential metabolic event, the inhibition of a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, inducing regression of a disease or condition, alleviating pathology caused by a disease or condition, or preventing the symptoms of a disease or condition.

[0050] The term "pharmaceutically acceptable carrier" refers to a carrier or adjuvant that has no significant irritating effect on an organism and does not impair the biological activity and performance of the active compound.

[0051] All of the solvents used in the present invention are commercially available and can be used without further purification.

[0052] [Beneficial Effects] The present invention provides a dihydrochloride salt of the compound of formula (I), particularly crystalline form I. The inventors have found that the dihydrochloride salt, particularly crystalline form I, is easy to dry, has good solubility, stable quality, thermodynamically stable, and facilitates drug discovery.

[0053] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an XRPD spectrum of crystalline form I of the dihydrochloride salt of compound of formula (I) obtained in Example 2. FIG. 2 is an XRPD spectrum of crystalline form I of the dihydrochloride salt of compound of formula (I) obtained in Example 3. FIG. 3 is a TGA-DSC spectrum of crystalline form I of the dihydrochloride salt of compound of formula (I) obtained in Example 3. FIG. 4 is a comparative XRPD diagram of crystalline form I of the dihydrochloride salt of compound of formula (I) obtained in Example 3 before and after polishing.

[0054] [Mode for carrying out the invention] The technical solution of the present invention will be described in more detail with reference to the following specific examples. The following examples are merely for illustrative purposes and should not be construed as limiting the scope of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the present invention.

[0055] Unless otherwise specified, all materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0056] In the following examples, the measurement conditions for X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic moisture sorption / desorption analysis (DVS) are as follows: 1. X-ray powder diffraction (XRPD) measurement conditions Equipment: German BRUKER D8 Advance X-ray powder diffractometer. Conditions: Cu-Kα radiation (λ = 1.5418 Å), tube pressure 40 kV, tube current 40 mA, 2θ scan range 3-40°, scan step length 0.02° (2θ), scan speed 10 s / step, and sample pan with zero background sample pan. Method: Place the sample in a zero-background monocrystalline silicon sample pan, gently press it flat with a spoon, and then measure it.

[0057] 2. Thermogravimetric analysis (TGA) test conditions Equipment: Discovery TGA 55. Conditions: temperature range from room temperature to 350°C, heating rate 10°C / min, purge gas nitrogen gas, flow rate in equilibrium chamber: 40 mL / min, flow rate in sample chamber: 25 mL / min. Method: 1-5 mg of sample is placed into a tared open aluminum sample pan and the sample volume is automatically weighed in the TGA furnace. The sample is heated to the final temperature at a rate of 10 °C / min and analyzed using the data analysis software TRIOS.

[0058] 3. Differential Scanning Calorimetry (DSC) Equipment: Discovery DSC 250. Conditions: temperature range 25 to 350°C, heating rate 10°C / min, purge gas was nitrogen gas with a flow rate of 50 mL / min. Method: 1-3 mg samples are accurately weighed into perforated aluminum sample pans and the exact mass of the sample is recorded. Analysis is performed using the data analysis software TRIOS.

[0059] 4. Dynamic moisture sorption and desorption analysis (DVS) Equipment: DVS Intrinsic plus (SMS, UK). Method: Approximately 30 mg of sample is placed into a tared sample basket, the sample weight is automatically measured, and the sample is analyzed according to the parameters in Table 1 below. [Table 1]

[0060] Example 1: High-throughput screening of salt formation of compounds of formula (I) Based on the pKa of the compound of formula (I), 12 acids, namely, sulfuric acid, phosphoric acid, maleic acid, glutamic acid, tartaric acid, fumaric acid, citric acid, malic acid, ascorbic acid, succinic acid, adipic acid, and hydrochloric acid, were selected for salt formation high-throughput screening experiments, and 8 solvent systems were selected, namely, A: water, B: water / acetonitrile at a volume ratio of 1:1, C: water / methanol at a volume ratio of 1:1, D: water / acetone at a volume ratio of 1:1, E: water / methanol at a volume ratio of 1:9, F: water / acetone at a volume ratio of 1:9, G: methanol, and H: acetone.

[0061] Testing Method: After dissolving the compound of formula (I), add it to a 96-well plate, and determine the volume of counterion added according to the molar amount of the compound of formula (I) added and the number of counterion functional groups. The heating time and temperature can be determined according to the specific situation (generally 40°C, 1 hour). In order to ensure that there is a certain pressure when reacting in the bottle, it is necessary to ensure the absolute sealing of the sample in the process of uniform mixing, vortexing and heating, and at least a silicone resin inner pad is required in the entire process.

[0062] The specific operation steps are as follows: 1) Prepare 0.02 mol / L solutions of each acid (except glutamic acid) in tetrahydrofuran-methanol (V:V=1:1). Glutamic acid is an aqueous solution. 2) preparing a 0.01 mol / L solution of the compound of formula (I) in tetrahydrofuran-methanol (V:V=1:1); 3) Add 1 mL of hydrochloric acid and 0.5 mL of other acid, then add 1 mL of each of the compounds of formula (I); 4) adding 0.5 mL of each acid, followed by adding 0.5 mL of each compound of formula (I); 5) After vortexing, the mixture was reacted in an oven at 40°C for 1 hour, the organic solvent was evaporated at room temperature, and finally the mixture was dried under reduced pressure at 50°C.

[0063] The experimental results show that the compound of formula (I) cannot form salts with glutamic acid and ascorbic acid, but can form salts with other acids to obtain solids, among which the salts with better solid state are dihydrochloride, phosphate, maleate, tartrate and fumarate.

[0064] Example 2: Crystalline Form I of the dihydrochloride salt of the compound of formula (I) and its preparation The compound of formula (I) (0.52 g, which can be prepared by referring to Preparation Example 10 of WO2017 / 140269A1) and 25 mL of methanol were added to a reaction flask, stirred, and after the system was uniformly dispersed, 1.2 mL of 2 mol / L hydrochloric acid methanol solution was added dropwise while stirring, and stirred uniformly and crystallized for 5 h. The obtained solid was suction filtered, dried in vacuum at 30 ° C for 12 h until it reached a constant weight, and then the material was vacuum dried at 45 ° C until the solvent residue passed, obtaining 0.53 g of crystals.

[0065] The ion chromatography result showed that the chloride ion content in the obtained crystal sample was 11.7%, and the theoretical chloride ion content of the dihydrochloride salt of the compound of formula (I) was 12.2%, indicating that the obtained crystal was the dihydrochloride salt, and the crystal was named "crystal form I", whose XRPD characterization spectrum is as shown in FIG. 1, and the characterization data are as shown in Table 2. [Table 2]

[0066] Example 3: Crystalline Form I of the dihydrochloride salt of the compound of formula (I) and its preparation The compound of formula (I) (1.0432 g, which can be prepared by referring to Preparation Example 10 of WO2017 / 140269A1) and 3 mL of purified water were added to the reaction flask, and the mixture was stirred until the system was uniformly dispersed. Then, 0.35 mL of 37% concentrated hydrochloric acid and 1.8 mL of 2N hydrochloric acid prepared with pure water were added dropwise, and the mixture was stirred until completely dissolved. Then, 0.01 g of the crystal form I sample obtained in Example 2 was added as a seed crystal at 20-30°C, and the mixture was stirred for 20-24 h to crystallize. The obtained solid was filtered by suction, dried in vacuum at 30°C for 12 h until it reached a constant weight, and the material was further dried in vacuum at 45°C until the solvent residue passed, to obtain 1.112 g of crystal form I.

[0067] The obtained crystalline form I exhibits good crystallinity, and its XRPD characterization spectrum is shown in Figure 2, and the characterization data are shown in Table 3. Its TGA-DSC spectrum is shown in Figure 3, and the TGA measurement results show that the crystalline form I sample does not contain water of crystallization or non-aqueous crystallization solvent. [Table 3]

[0068] Example 4: Preparation of crystalline form I of the dihydrochloride salt of compound of formula (I) in different solvent conditions With reference to the preparation method of Example 3, the following solvent system was used to prepare crystalline form I of the dihydrochloride salt of compound of formula (I), and the results are shown in Table 4 below. [Table 4]

[0069] Example 5: Preparation of amorphous dihydrochloride salt of compound of formula (I) With reference to the preparation method of Example 3, the dihydrochloride salt of compound of formula (I) was prepared using the following solvent system to obtain an amorphous product, and the results are shown in Table 5 below. [Table 5]

[0070] Example 6: Preparation of other crystalline forms of the hydrochloride salt of the compound of formula (I) With reference to the preparation method of Example 3, the hydrochloride salt of the compound of formula (I) was prepared using the following solvent system, and the results are shown in Table 6 below. [Table 6]

[0071] Comparative Example 1: Preparation of other salts of the compound of formula (I) In a 25 mL bottle containing 5 mL of 0.02 mol / mL acids (phosphoric acid, maleic acid, tartaric acid, fumaric acid) in tetrahydrofuran-methanol (volume ratio 1:1), 10 mL of 0.01 mol / mL solution of the compound of formula (I) in tetrahydrofuran-methanol (volume ratio 1:1) was added in order and vortexed to mix uniformly. The four solutions obtained above were left to react for 1 h under the condition of 40°C. The reaction solution was evaporated to dryness and dried at 50°C for 3 to 4 h. The phosphate, maleate, tartrate and fumarate salts of the compound of formula (I) were obtained.

[0072] Measurement Example 1: Solubility Experiment of the Compound of Formula (I) and Its Salts The solubilities of the compound of formula (I) (which can be prepared by referring to Preparation Example 10 of WO2017 / 140269A1), the samples obtained in Example 3 and Comparative Example 1 in deionized water and Na2HPO4-citrate buffer (pH 4.6) medium were measured, and the experimental results are shown in Table 7. [Table 7]

[0073] Measurement example 2: Water adsorption and desorption experiment In order to determine the moisture absorption performance of various different salt forms, a dynamic moisture sorption apparatus (DVS) was used to carry out moisture adsorption and desorption experiments on the samples obtained in Example 3 and Comparative Example 1 at a temperature of 25°C and a relative humidity of 40 to 80%, and the experimental results are shown in Table 8. [Table 8]

[0074] Measurement example 3: Solid state stability study of crystalline form I of the dihydrochloride salt The physical and chemical stability of the crystalline form I sample of the dihydrochloride salt obtained in Example 3 when left at 40°C / 75% RH (open) and 60°C (in a sample bottle with a lid) for 7 days, and when left at room temperature / 92.5% RH (open) for 10 days, were examined, and the experimental results are shown in Table 9 below. The results show that when crystalline form I is left at 40°C / 75% RH (open) and 60°C (in a sample bottle with a lid) for 7 days, its purity and crystalline form do not change obviously, and when left at 92.5% RH (open) for 10 days, its crystalline form does not change obviously. Crystal form I shows that its physical and chemical properties are stable under the measurement conditions. [Table 9]

[0075] Measurement example 4: Solid polishing stability experiment (1) Solvent drop polishing The sample (crystal form I) obtained in Example 3 was polished by dropping the following solvents, and the experimental results in Table 10 show that the crystal form does not change. [Table 10]

[0076] (2) Solid polishing 20 mg of the sample of Example 3 was weighed into the grinding bowl and ground for 2 and 5 minutes, respectively, before XRPD characterization. The experimental results show that the crystal form of the sample remains unchanged after grinding (see FIG. 4).

[0077] Measurement Example 5: Efficacy test of the dihydrochloride of the compound of formula (I) against a human lung cancer NCI-H1581 subcutaneously transplanted tumor model in nude mice 1) Experimental drug: a sample of crystalline form I of the dihydrochloride salt of compound of formula (I) obtained in Example 3.

[0078] 2) Cell line Human lung cancer NCI-H1581 cell line (preserved in the Shanghai Institute of Materia Medica, Chinese Academy of Sciences) was inoculated subcutaneously into the right axilla of nude mice, with a cell inoculation volume of 5 × 10 6 The mice were inoculated with the transplanted tumor directly after the tumor was formed.

[0079] 3) Experimental Method Actively growing tumor tissue was cut into approximately 1.5 mm 3 The tumors were sheared into small pieces and inoculated subcutaneously into the right axilla of nude mice under aseptic conditions. The diameters of the tumors inoculated subcutaneously into nude mice were measured using a caliper, and the tumors had an average volume of approximately 150–160 mm. 3 After the animals had grown to 10 mg / kg, the animals were randomly divided into groups. The sample groups of Example 3 were orally administered with 10 mg / kg, 5 mg / kg, or 2.5 mg / kg once a day for two consecutive weeks. The solvent control group (AZD4547) was orally administered with 12.5 mg / kg once a day for two consecutive weeks. During the entire experimental process, the diameter of the transplanted tumor was measured twice a week, and the mice were weighed at the same time. The formula for calculating tumor volume (TV) was TV=1 / 2×a×b. 2 where a and b represent length and width, respectively. Based on the measurement results, the relative tumor volume (RTV) was calculated using the formula RTV=Vt / V0, where V0 is the tumor volume measured at the time of administration in separate cages (d0), and Vt is the tumor volume at each measurement. The evaluation index of antitumor activity is the relative tumor growth rate T / C (%), using the formula T / C (%)=(TRTV / CRTV)×100%, where TRTV is the treatment group RTV, and CRTV is the negative control group RTV.

[0080] 4) Results The experimental results are shown in Table 11. The sample of Example 3 was orally administered at 10 mg / kg, 5 mg / kg and 2.5 mg / kg once a day for two consecutive weeks, and had a significant inhibitory effect on the growth of human lung cancer NCI-H1581 subcutaneously transplanted tumor in nude mice. During the experimental period, the condition of the animals in each group was good, and no mice died.

[0081] [Table 11]

[0082] [ka]

[0083] In summary, the dihydrochloride salt of the compound of formula (I) of the present invention, particularly crystalline form I, has good solubility, low hygroscopicity, stable quality, stable crystalline form, and is easy for drug development.

[0084] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should be included in the claims of the present invention. [Brief description of the drawings]

[0085] [Figure 1] 1 is an XRPD spectrum of crystalline form I of the dihydrochloride salt of compound of formula (I) obtained in Example 2. [Diagram 2] 1 is an XRPD spectrum of crystalline form I of the dihydrochloride salt of compound of formula (I) obtained in Example 3. [Diagram 3] 1 is a TGA-DSC spectrum of crystalline form I of the dihydrochloride salt of compound of formula (I) obtained in Example 3. [Figure 4] FIG. 2 is a comparative XRPD diagram of crystalline form I of the dihydrochloride salt of compound of formula (I) obtained in Example 3 before and after polishing.

Claims

1. The dihydrochloride salt of the compound of formula (I), 【Chemistry 1】

2. The dihydrochloride salt of the compound of formula (I) according to claim 1, characterized in that said dihydrochloride salt is in solid form, preferably in crystalline form.

3. Crystalline form I of the dihydrochloride salt of the compound of formula (I), which has characteristic peaks in the X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation at 5.0±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2° and 25.2±0.2°; Preferably, said crystalline form I of the dihydrochloride salt of compound of formula (I) has characteristic peaks in X-ray powder diffraction, expressed in 2θ angles using Cu-Kα radiation, at 5.0±0.2°, 10.4±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 23.4±0.2° and 25.2±0.2°; More preferably, said crystalline form I of the dihydrochloride salt of compound of formula (I) has characteristic peaks in X-ray powder diffraction, expressed in 2θ angles, using Cu-Kα radiation at 5.0±0.2°, 10.4±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2° and 25.2±0.2°.

2. The compound of formula (I) according to claim 1 , wherein the crystalline form I of the dihydrochloride salt is

4. X-ray powder diffraction, expressed in 2θ angles, using Cu-Kα radiation, had characteristic peaks at 5.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, and 26.6±0.2°. Preferably, the X-ray powder diffraction, expressed in 2θ angles using Cu-Kα radiation, has characteristic peaks at 5.0±0.2°, 10.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.7±0.2°, 17.4±0.2°, 18.0±0.2°, 19.3±0.2°, 20.1±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, 26.6±0.2°, 28.6±0.2°, 30.1±0.2°, Crystalline form I of the dihydrochloride salt of compound of formula (I) according to claim 3.

5. Using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern (XRPD) essentially as shown in FIG. 1 or FIG. 2; and / or the thermogravimetric analysis curve of said crystalline form I has a weight loss of 1.17% from 25° C. to 200° C.; and / or the differential scanning calorimetry spectrum of the crystalline form I shows an onset of melt decomposition at 285-300° C.; and / or the crystalline form I has a TGA-DSC spectrum essentially as shown in FIG. Crystalline form I of the dihydrochloride salt of compound of formula (I) according to claim 3 or 4, characterized in that

6. A method for preparing crystalline form I of the dihydrochloride salt of compound of formula (I) according to any one of claims 3 to 5, comprising the steps of: adding compound of formula (I) and a solvent into a reaction flask; slowly adding hydrochloric acid; optionally adding seed crystals of crystalline form I; and stirring, crystallizing, isolating and drying to obtain crystalline form I, wherein the molar ratio of hydrochloric acid to compound of formula (I) is 1.5-3:1; and the solvent is any one selected from the group consisting of water, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, methanol and tetrahydrofuran-water (V:V=19:1).

7. When the solvent is selected from dimethyl sulfoxide or tetrahydrofuran-water (V:V=19:1), the preparation method further includes the step of adding a poor solvent, the poor solvent is preferably methyl tert-butyl ether, the volume ratio of the dimethyl sulfoxide to methyl tert-butyl ether is preferably 20-30:8, more preferably 25:8, the volume ratio of the tetrahydrofuran-water (V:V=19:1) to methyl tert-butyl ether is preferably 45-55:8, more preferably 50:8; Preferably, the molar ratio of hydrochloric acid to the compound of formula (I) is 1.8-2.5:1; Preferably, the temperature of the crystallization is between 10 and 35° C., preferably between 20 and 30° C. Preferably, the crystallization time is from 1 to 72 hours, preferably from 3 to 48 hours, more preferably from 5 to 24 hours. A process for preparing the crystalline form I of the dihydrochloride salt of compound of formula (I) according to claim 6.

8. A pharmaceutical composition comprising the dihydrochloride salt of the compound of formula (I) as defined in claim 1 or 2 or crystalline form I of the dihydrochloride salt of the compound of formula (I) as defined in any one of claims 3 to 5, and a pharma- ceutically acceptable carrier therefor.

9. Use of the dihydrochloride salt of compound of formula (I) according to claim 1 or 2 or crystalline form I of the dihydrochloride salt of compound of formula (I) according to any one of claims 3 to 5 in the manufacture of a medicament for the treatment and / or prevention of a disease associated with the activity or expression of FGFR, KDR and / or CSF-1R.

10. 10. The use according to claim 9, characterized in that the associated disease is a tumor-associated disease selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, bladder cancer, transitional cell carcinoma of the urinary tract, gastric cancer (including gastroesophageal junction adenocarcinoma), pancreatic cancer, prostate cancer, colorectal cancer, myeloma, multiple myeloma, acute myeloid leukemia, liver cancer, melanoma, thyroid cancer, liver cancer, head and neck cancer, renal cell carcinoma, glioblastoma, testicular cancer, and / or bile duct cancer.

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