CN115703785A

CN115703785A - Novel crystal forms of compound and salt thereof, pharmaceutical composition and application

Info

Publication number: CN115703785A
Application number: CN202110934983.6A
Authority: CN
Inventors: 吴转; 易仕东; 王天明; 陈平运
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2021-08-13
Filing date: 2021-08-13
Publication date: 2023-02-17

Abstract

The invention provides crystal forms I, II and phosphate crystal forms I, II, III and mesylate crystal forms of 2- (1- (4- (5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- (hydroxymethyl) pyrazin-2-ylthio) -3-chloropyridin-2-yl) azetidin-3-yl) propan-2-ol, and pharmaceutical compositions and uses thereof.

Description

Novel crystal form, pharmaceutical composition and application of compound and salt thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a substituted pyrazine compound, in particular to different crystal forms of 2- (1- (4- (5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decane-8-yl) -6- (hydroxymethyl) pyrazine-2-yl sulfenyl) -3-chloropyridine-2-yl) azetidin-3-yl) propan-2-ol (hereinafter referred to as a compound of a formula (I)) and salts thereof, and a pharmaceutical composition containing the crystal forms and medical application thereof.

Background

SHP2 is a Protein Tyrosine Phosphatase (PTPs) encoded by the gene PTPN11 (protein tyrosine phosphatase non receptor 11), an intracellular non-receptor member of the PTPs family, which catalyzes the dephosphorylation reaction of tyrosine in proteins. SHP2 has two SH2 (src homology 2) domains (N-SH 2 at the N-terminus and C-SH2 at the C-terminus), a catalytic domain (PTP) and a C-terminal tail rich in proline groups and tyrosine phosphorylation sites. These two SH2 domains control subcellular localization and functional regulation of SHP 2. In the inactivated state, SHP2 is in a self-inhibitory state, and N-SH2 binds to PTP, thereby inhibiting phosphatase activity. However, under the stimulation of growth factors, cytokines or inflammatory factors, such as PDGF (PDGF-derived growth factor) and FGF (FGF growth factor), tyrosine residues Tyr542 (Y542) and Tyr580 (Y580) are phosphorylated and bound to N-SH2, so that the catalytic active site of the PTP domain is exposed, the self-inhibition state is released, and the PTP activity of SHP2 is activated, thereby initiating a signaling cascade initiated by tyrosine phosphorylation.

SHP2 is widely expressed in human body, and participates in multiple signal paths such as Ras-Erk, PI3K-Akt, jak-Stat, met, FGFR, EGFR and NF-kB, and further regulates physiological functions such as cell proliferation, differentiation, migration and apoptosis. The activating mutant of SHP2 is related to the occurrence of various diseases, such as Noonan syndrome (Noonan syndrome), breast cancer, melanoma and the like, and the over-expression of SHP2 can increase the risk of cancers, such as chronic granulocytic leukemia, mastocytosis, glioblastoma, lung cancer, breast cancer and the like, and the SHP2 has a wide role in different types of cancers and different development stages of the cancers. Therefore, there is a need for the use of SHP2 inhibitors for the prevention and/or treatment of cancer and other related diseases.

At present, compounds such as pyrimidinones, pyrazines, carboxylic acids, quinones, quinolines and indoles have been found to have the function of inhibiting the activity of SHP2 (for example, see WO2018013597 A1), and the present inventors have surprisingly found a series of substituted pyrazines through a large number of studies, which have high SHP2 inhibitory activity, can be used as an SHP2 inhibitor for preventing and/or treating SHP 2-related diseases, especially tumor diseases, and show good application prospects (PCT/CN 2021/099561).

Due to different crystal forms of solid drug compounds, the solubility, stability, fluidity and the like of the drugs can be different. Thereby affecting the safety and effectiveness of the pharmaceutical product containing the compound, resulting in differences in clinical efficacy. The discovery of new crystalline forms (including anhydrates, salt forms, etc.) of pharmaceutically active ingredients may result in greater processing advantages or provide materials with better physicochemical properties, e.g., storage stability, ease of processing, ease of purification, or as intermediate forms that facilitate conversion to other crystalline forms.

Therefore, research into different crystalline forms of SHP2 inhibitors to obtain more valuable SHP2 inhibitors is still needed in the art.

Disclosure of Invention

Problems to be solved by the invention

The invention aims to: novel crystalline forms, pharmaceutical compositions and uses of compounds of formula (I) and salts thereof are provided.

The chemical name of the compound of the formula (I) is: 2- (1- (4- (5- ((3s, 4s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- (hydroxymethyl) pyrazin-2-ylthio) -3-chloropyridin-2-yl) azetidin-3-yl) propan-2-ol having the formula:

means for solving the problems

In a first aspect, the present invention provides a crystalline form I of the compound of formula (I) having an X-ray powder diffraction pattern having characteristic peaks at 2 θ values of 4.8 + -0.2 °, 9.7 + -0.2 °, 12.3 + -0.2 °, 17.4 + -0.2 °, 19.0 + -0.2 ° and 19.9 + -0.2 °,

in some embodiments of the first aspect of the present invention, the compound of formula (I) has a crystalline form I that has an X-ray powder diffraction pattern further having characteristic peaks at least one of 2 Θ values of 13.8 ± 0.2 °, 17.0 ± 0.2 °, and 23.4 ± 0.2 °.

In some embodiments of the first aspect of the present invention, the X-ray powder diffraction pattern of crystalline form I of the compound of formula (I) further has a characteristic peak at least one of 2 Θ values of 17.2 ± 0.2 °, 17.8 ± 0.2 °, 21.5 ± 0.2 ° and 22.7 ± 0.2 °.

In some embodiments of the first aspect of the present invention, the crystalline form I of the compound of formula (I) has an XRPD pattern substantially as depicted in figure 1.

In a second aspect, the present invention also provides crystalline form II of the compound of formula (I) having an X-ray powder diffraction pattern having characteristic peaks at 2 θ values of 6.0. + -. 0.2 °, 6.4. + -. 0.2 °, 6.8. + -. 0.2 °, 9.0. + -. 0.2 °, 13.0. + -. 0.2 °, 17.8. + -. 0.2 ° and 18.4. + -. 0.2 °,

in some embodiments of the second aspect of the present invention, the X-ray powder diffraction pattern of form II of the compound of formula (I) further has characteristic peaks at least one of 2 Θ values of 15.6 ± 0.2 °, 17.4 ± 0.2 °, 19.6 ± 0.2 °, 20.4 ± 0.2 ° and 21.4 ± 0.2 °.

In some embodiments of the second aspect of the present invention, the X-ray powder diffraction pattern of form II of the compound of formula (I) further has characteristic peaks at 2 Θ values of at least one of 17.2 ± 0.2 °, 19.9 ± 0.2 ° and 24.6 ± 0.2 °.

In some embodiments of the second aspect of the present invention, the crystalline form II of the compound of formula (I) has an XRPD pattern substantially as shown in figure 4.

In a third aspect, the present invention also provides a phosphate salt of a compound of formula (I), preferably wherein the phosphate salt of the compound of formula (I) is in crystalline form I, having an X-ray powder diffraction pattern with characteristic peaks at 2 θ values of 3.6 ± 0.2 °, 10.9 ± 0.2 °, 12.1 ± 0.2 °, 15.2 ± 0.2 °, 15.8 ± 0.2 °, 16.5 ± 0.2 °, 18.0 ± 0.2 °, 20.1 ± 0.2 ° and 22.6 ± 0.2 °,

in some embodiments of the third aspect of the present invention, the compound of formula (I) has an X-ray powder diffraction pattern for phosphate form I further having characteristic peaks at least one of 2 Θ values of 11.9 ± 0.2 °, 18.1 ± 0.2 °, 21.0 ± 0.2 ° and 28.6 ± 0.2 °.

In some embodiments of the third aspect of the present invention, the X-ray powder diffraction pattern of the phosphate form I of the compound of formula (I) further has a characteristic peak at least one of 2 Θ values of 15.9 ± 0.2 °, 18.6 ± 0.2 °, 21.4 ± 0.2 ° and 24.4 ± 0.2 °.

In some embodiments of the third aspect of the present invention, the phosphate form I of the compound of formula (I) has an XRPD pattern substantially as shown in figure 7 or figure 19.

In a fourth aspect, the present invention also provides a phosphate salt of a compound of formula (I), preferably, the phosphate salt of a compound of formula (I) is present in form II having an X-ray powder diffraction pattern with characteristic peaks at 2 θ values of 6.7. + -. 0.2 °, 10.1. + -. 0.2 °, 10.4. + -. 0.2 °, 12.9. + -. 0.2 °, 14.6. + -. 0.2 °, 15.8. + -. 0.2 °, 17.1. + -. 0.2 °, 18.8. + -. 0.2 ° and 19.8. + -. 0.2 °,

in some embodiments of the fourth aspect of the present invention, the X-ray powder diffraction pattern of the phosphate form II of the compound of formula (I) also has a characteristic peak at least one of 2 Θ values of 12.3 ± 0.2 °, 16.6 ± 0.2 °, 19.4 ± 0.2 °, 20.8 ± 0.2 °, 23.3 ± 0.2 °, 24.6 ± 0.2 °.

In some embodiments of the fourth aspect of the present invention, the phosphate form II of the compound of formula (I) has an XRPD pattern substantially as shown in figure 11.

In a fifth aspect, the present invention also provides a phosphate salt of a compound of formula (I), preferably in form III, having an X-ray powder diffraction pattern with characteristic peaks at 2 Θ values of 3.6 ± 0.2 °, 10.5 ± 0.2 °, 12.9 ± 0.2 °, 13.8 ± 0.2 °, 15.7 ± 0.2 °, 16.6 ± 0.2 °, 18.1 ± 0.2 °, 20.4 ± 0.2 ° and 21.2 ± 0.2 °,

in some embodiments of the fifth aspect of the present invention, the X-ray powder diffraction pattern of phosphate form III of the compound of formula (I) also has a characteristic peak at least one of 2 Θ values of 11.9 ± 0.2 °, 17.3 ± 0.2 °, 19.2 ± 0.2 °, 21.6 ± 0.2 °, 24.0 ± 0.2 °, 24.6 ± 0.2 °, 26.4 ± 0.2 °.

In some embodiments of the fifth aspect of the present invention, the phosphate form III of the compound of formula (I) has an XRPD pattern substantially as shown in figure 12.

In a sixth aspect, the present invention also provides a mesylate salt of the compound of formula (I), preferably, the mesylate salt of the compound of formula (I) is present in crystalline form, and the crystalline form of the mesylate salt of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic peaks at 2 θ values of 4.5. + -. 0.2 °, 11.2. + -. 0.2 °, 13.9. + -. 0.2 °, 14.3. + -. 0.2 °, 14.7. + -. 0.2 °, 17.6. + -. 0.2 °, 19.5. + -. 0.2 °, 20.6. + -. 0.2 ° and 21.6. + -. 0.2 °,

in some embodiments of the sixth aspect of the present invention, the X-ray powder diffraction pattern of the crystalline mesylate salt form of the compound of formula (I) further has a characteristic peak at least one of 2 Θ values of 14.1 ± 0.2 °, 19.6 ± 0.2 °, 20.3 ± 0.2 °, 21.3 ± 0.2 °.

In some embodiments of the sixth aspect of the present invention, the crystalline form of the mesylate salt of the compound of formula (I) has an XRPD pattern substantially as shown in figure 15.

In a seventh aspect, the present invention also provides a pharmaceutical composition comprising at least one of the crystalline forms of the compound of formula (I) described above (e.g., crystalline form I or II of the compound of formula (I)), a phosphate salt of the compound of formula (I) (e.g., crystalline form I, II, or III phosphate salt of the compound of formula (I)), a mesylate salt of the compound of formula (I) (e.g., crystalline form mesylate salt of the compound of formula (I)), and one or more pharmaceutically acceptable carriers.

In an eighth aspect, the present invention provides the use of a crystalline form of the compound of formula (I) as described above (e.g., crystalline form I or II of the compound of formula (I)), a phosphate salt of the compound of formula (I) (e.g., crystalline form I, II, or III phosphate salt of the compound of formula (I)), a mesylate salt of the compound of formula (I) (e.g., crystalline form mesylate salt of the compound of formula (I)), or a pharmaceutical composition as a SHP2 inhibitor for the prevention and/or treatment of a disease or condition mediated at least in part by SHP2, preferably wherein the disease or condition mediated by SHP2 is cancer.

In a ninth aspect, the present invention provides the use of a crystalline form of the compound of formula (I) as described above (e.g., crystalline form I or II of the compound of formula (I)), a phosphate salt of the compound of formula (I) (e.g., crystalline form I, II or III of the phosphate salt of the compound of formula (I)), a mesylate salt of the compound of formula (I) (e.g., crystalline form mesylate salt of the compound of formula (I)), or a pharmaceutical composition, in the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by SHP2, preferably wherein the disease or condition mediated by SHP2 is cancer.

In a tenth aspect, the present invention provides a method for preventing and/or treating a disease or condition mediated at least in part by SHP2, comprising the steps of: administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a crystalline form of a compound of formula (I) (e.g., form I or II of a compound of formula (I)), a phosphate salt of a compound of formula (I) (e.g., form I, II, or III phosphate salt of a compound of formula (I)), a mesylate salt of a compound of formula (I) (e.g., a mesylate salt form of a compound of formula (I)), or a pharmaceutical composition; preferably, the disease or condition mediated by SHP2 is cancer.

ADVANTAGEOUS EFFECTS OF INVENTION

The compound of the formula (I) has good inhibition effect on SHP2, and has good properties of pharmacokinetics, safety and the like. In addition, it has been found that the use of certain solvents and/or processes results in crystalline forms of the compound of formula (I) or a salt thereof. These crystalline forms, including substantially pure forms and mixtures of substantially pure forms, exhibit one or more advantageous characteristics. For example, they may provide advantages in terms of bioavailability and stability, and are suitable for use as active ingredients in pharmaceutical formulations. In particular, various crystalline forms of the compounds of formula (I) and their phosphates and mesylates provide one or more advantages such as: improving the manufacturing process of the compound of formula (I), increasing the bioavailability and/or stability of the compound of formula (I), improving the solubility of the compound of formula (I), improving the hygroscopicity of the compound and/or improving the stability and extending the shelf life of pharmaceutical formulations comprising the compound of formula (I).

Drawings

Figure 1 shows the XRPD pattern of crystal I of the compound of formula (I) prepared in example 2.

Figure 2 shows the DSC profile of crystal I of the compound of formula (I) prepared in example 2.

Figure 3 shows a TGA profile of the crystal I of the compound of formula (I) prepared in example 2.

Figure 4 shows the XRPD pattern of crystal II of the compound of formula (I) prepared in example 5.

FIG. 5 shows a DSC spectrum of crystal II of the compound of formula (I) prepared in example 5.

Figure 6 shows a TGA profile of crystal II of the compound of formula (I) prepared in example 5.

Figure 7 shows the XRPD pattern of phosphate form I of the compound of formula (I) prepared in example 8.

Figure 8 shows a DSC profile of phosphate form I of the compound of formula (I) prepared in example 8.

Figure 9 shows a TGA profile of the phosphate crystalline form I of the compound of formula (I) prepared in example 8.

Figure 10 shows the PLM spectrum of phosphate form I of the compound of formula (I) prepared in example 8.

Figure 11 shows the XRPD pattern of phosphate form II of the compound of formula (I) prepared in example 10.

Figure 12 shows the XRPD pattern of phosphate form III of the compound of formula (I) prepared in example 11.

Figure 13 shows a DSC profile of phosphate form III of the compound of formula (I) prepared in example 11.

Figure 14 shows a TGA profile of the phosphate crystalline form III of the compound of formula (I) prepared in example 11.

Figure 15 shows the XRPD pattern of the mesylate salt form of the compound of formula (I) prepared in example 12.

Figure 16 shows a DSC profile of a crystalline form of the mesylate salt of the compound of formula (I) prepared in example 12.

Figure 17 shows a TGA profile of the mesylate salt crystalline form of the compound of formula (I) prepared in example 12.

Figure 18 shows a PLM spectrum of the mesylate salt form of the compound of formula (I) prepared in example 12.

Figure 19 shows the XRPD pattern of phosphate form I of the compound of formula (I) prepared in example 7.

Detailed Description

The invention will be described in further detail below with the understanding that the terminology is intended to be in the nature of words of description rather than of limitation.

General definitions and terms

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 to which this invention belongs. In case of conflict, the present application, including definitions provided herein, will control. When an amount, concentration, or other value or parameter is expressed in terms of a range, preferred range, or upper preferable numerical value and lower preferable numerical value, it is understood that any range defined by any pair of upper range limits or preferred numerical values in combination with any lower range limits or preferred numerical values is specifically disclosed, regardless of whether the range is specifically disclosed. Unless otherwise indicated, numerical ranges set forth herein are intended to include the endpoints of the ranges and all integers and fractions (decimal) within the range.

The terms "about" and "approximately," when used in conjunction with a numerical variable, generally mean that the value of the variable and all values of the variable are within experimental error (e.g., within 95% confidence interval for the mean) or within ± 10% of the specified value, or more.

The expressions "comprising" or similar expressions "including", "containing" and "having" and the like which are synonymous are open-ended and do not exclude additional, unrecited elements, steps or components. The expression "consisting of 8230comprises" excludes any element, step or ingredient not specified. The expression "consisting essentially of 8230comprises means that the scope is limited to the specified elements, steps or components, plus optional elements, steps or components that do not materially affect the basic and novel characteristics of the claimed subject matter. It is to be understood that the expression "comprising" covers the expressions "consisting essentially of and" consisting of 823030303030303030the expression "comprises" or "comprises" is used.

The terms "optionally" or "optionally" as used herein mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The "at least one position" includes at least one position, two positions, three positions, four positions, five positions, six positions, seven positions, eight positions and the like.

As used herein, a numerical range (e.g., "1-10"), and subranges thereof (e.g., "2-6," "6-10," "3-10," etc.), etc., encompasses any number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the stated numerical ranges.

As used herein, the term "solid form" refers to a solid state form of the compound of formula (I), e.g., may be a crystalline form or an amorphous form.

As used herein, the term "amorphous" refers to any solid substance that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques including XRPD crystal diffraction analysis, differential Scanning Calorimetry (DSC), solid-state nuclear magnetic resonance (ssNMR) spectroscopy, or a combination of these techniques. As demonstrated below, amorphous solids produce XRPD patterns without distinct diffraction signature peaks.

As used herein, the term "crystalline form" or "crystalline" refers to any solid substance that exhibits a three-dimensional ordering, as opposed to an amorphous solid substance, which produces a characteristic XRPD pattern having well-defined peaks.

As used herein, the term "seed" refers to an additive that can form nuclei in a crystallization process to accelerate or promote the growth of crystals of an enantiomer having the same crystal form or steric configuration as it is.

As used herein, the term "substantially pure" refers to the content of such crystals in the compound of formula (I) being about 95% by weight or more, preferably about 98% by weight or more, more preferably about 99% by weight or more, based on the total amount of the compound.

As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. XRPD patterns are generally characterized by peak position (abscissa) and/or peak intensity (ordinate).

As used herein, the term "diffraction angle" or "2 θ" refers to the peak position in degrees (°) set based on X-ray diffraction experiments, and is typically the abscissa unit in the diffraction pattern. If the reflection is diffracted when the incident beam makes an angle theta with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle of 2 theta. It should be understood that reference herein to particular 2 theta values for particular crystalline forms is intended to refer to 2 theta values (in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, cu-K α is used as the radiation source. The XRPD patterns herein are preferably collected in transmission mode at room temperature on an X' Pert 3X-ray powder diffraction analyzer. The instrument employs Cu-Ka irradiation. For example, the scanning voltage is 40kV, the current is 40mA, the scanning step size is 0.013 °, the counting time per step is 50 seconds, and the scanning range is 3.5 ° to 40 ° in the 2 θ interval.

As used herein, the term "substantially the same" with respect to X-ray diffraction peaks means that representative peak positions and intensity variations are taken into account. For example, those skilled in the art will appreciate that the peak position (2 θ) will show some variation, typically as much as 0.1-0.2 degrees, and that the instruments used to measure diffraction will also cause some variation. In addition, those skilled in the art will appreciate that relative peak intensities will vary due to inter-instrument variation as well as the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art.

As used herein, "the highest Peak temperature of the endothermic Peak" on the DSC diagram for a crystalline form means the Peak value representing the curve of the endothermic Peak of the DSC diagram. The highest peak temperature of the endothermic peak of the DSC test can cause some changes due to the purity, weight, particle size, test heating rate, instrument system errors and the like of a test product, and the provided numerical value can not be taken as an absolute value (reference document: guo Yonghui, yangning, lvyang. Differential scanning calorimetry is applied to crystal form drug research [ C ]. In China conference on research and development of crystal form drug research and development technology 2010.).

It will be appreciated that slightly different DSC profiles may be given with different types of equipment or with different test conditions. DSC profiles can be determined, for example, using a Mettler Toledo DSC1 or a TA DSC2500 differential scanning calorimeter. As used herein, the term "substantially the same" for a DSC profile will take into account representative characteristic peak locations. For example, one skilled in the art will appreciate that the characteristic peak positions will show some variation, typically up to 5 ℃. The temperature rise rate of the DSC test has a greater effect on the DSC profile for solid samples in which polymorphism is present. Under the condition of a faster temperature rise rate, the thermal hysteresis effect of the instrument is obvious, and the high-melting-point solid crystal form is not ready for recrystallization, so that the DSC chart usually only shows the melting endothermic peak of the low-melting-point crystal form. At moderate ramp rates, the DSC profile then shows two peaks: a melting endothermic peak of a low melting point crystal form and a melting endothermic peak of a high melting point crystal form; only at lower ramp rates, where the instrument thermal hysteresis is weak, will three peaks appear: melting peak of low melting point crystal form-recrystallization exothermic peak-melting endothermic peak of high melting point crystal. The skilled person will appreciate that the range of temperature rise rates associated with the different DSC profiles described above will vary depending on the weight, morphology, particle size and distribution of the test articles (Giron D. Thermal analysis and calorimetric methods in the characterization of polymorphs and solvents [ J ]. Thermochimica Acta,1995, 248 1-59..

"thermogravimetric analysis (TGA)" is a common method of determining the thermal stability of a compound. The TGA profile can be measured, for example, on a Mettler Toledo TGA1 instrument. The TGA can have an error within about ± 0.5 mass%. The term "substantially the same" means that such error variations are taken into account. Exemplary test conditions are a temperature range of 35-500 deg.C, a ramp rate of 10K/min, and a sweep gas of nitrogen (99.99%).

It will be appreciated that different types of equipment or with different test conditions may give slightly different XRPD patterns and characteristic peaks or different DSC patterns and characteristic peaks. The specific values provided are not to be taken as absolute values.

As used herein, the term "room temperature" refers to 20 ℃ ± 5 ℃.

As used herein, the term "preventing" refers to prophylactic administration to reduce the likelihood of or delay the onset of a disease or condition.

As used herein, the term "treatment" is intended to alleviate or eliminate the disease state or condition for which it is directed. It is also understood that treatment of the disease state or condition described includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant result.

Crystalline forms and processes for the preparation of compounds of formula (I) and salts thereof

Crystal form I of compound of formula (I) and preparation method thereof

The present invention provides a crystal I of the compound of formula (I) having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2 θ) at 4.8 ± 0.2 °, 9.7 ± 0.2 °, 12.3 ± 0.2 °, 17.4 ± 0.2 °, 19.0 ± 0.2 ° and 19.9 ± 0.2 °.

In some embodiments, the XRPD pattern of crystal I of the compound of formula (I) comprises characteristic peaks at diffraction angles (2 θ) of 4.8 ± 0.2 °, 9.7 ± 0.2 °, 12.3 ± 0.2 °, 13.8 ± 0.2 °, 17.0 ± 0.2 °, 17.4 ± 0.2 °, 19.0 ± 0.2 ° 19.9 ± 0.2 ° and 23.4 ± 0.2 °.

In some embodiments, the XRPD pattern of crystal I of the compound of formula (I) comprises characteristic peaks at diffraction angles (2 θ) of 4.8 ± 0.2 °, 9.7 ± 0.2 °, 12.3 ± 0.2 °, 13.8 ± 0.2 °, 17.0 ± 0.2 °, 17.2 ± 0.2 °, 17.4 ± 0.2 °, 17.8 ± 0.2 °, 19.0 ± 0.2 °, 19.9 ± 0.2 °, 21.5 ± 0.2 °, 22.7 ± 0.2 ° and 23.4 ± 0.2 °.

In a particularly preferred embodiment, the XRPD pattern of crystal I of said compound of formula (I) comprises characteristic peaks at diffraction angles (2 Θ) as shown in table 1 below, wherein the 2 Θ values have a range of error of ± 0.2 °:

TABLE 1

2θ(°)±0.2°	Strength%	2θ(°)±0.2°	Strength%
				4.77	56.29	21.48	18.39
5.85	7.26	21.78	15.13
				9.67	24.72	22.02	19.01
9.89	3.72	22.32	16.79
				10.09	6.00	22.73	23.40
10.26	4.04	23.36	26.46
				11.46	2.41	23.57	8.41
11.67	1.51	23.74	5.89
				12.32	44.82	24.29	6.89
12.62	4.79	24.89	5.26
				13.23	4.71	25.17	18.02
13.48	5.31	25.71	4.29
				13.81	13.57	25.97	2.68
14.05	3.14	26.62	1.88
				14.24	5.96	27.31	1.93
14.61	2.16	27.72	3.08
				14.83	3.80	27.93	6.40
16.01	7.71	28.85	3.01
				16.51	3.23	29.45	2.11
16.81	3.11	30.31	9.31
				17.05	30.64	30.99	5.88
17.20	23.99	31.47	1.54
				17.40	40.80	32.09	3.58
17.69	11.01	33.32	2.25
				17.83	21.99	33.70	3.79
17.99	19.40	34.19	1.68
				18.15	9.22	34.82	4.83
18.95	100.00	35.25	0.91
				19.28	5.45	35.84	2.21
19.55	4.64	36.51	0.92
				19.91	43.72	37.01	1.76
20.18	4.00	37.77	2.29
				20.55	2.50	38.35	0.98
20.83	16.90	39.29	0.83

In a more preferred embodiment, the XRPD pattern of crystal I of said compound of formula (I) comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 1. In a most preferred embodiment, the XRPD pattern of crystal I of the compound of formula (I) is as shown in figure 1.

In some embodiments, a Differential Scanning Calorimetry (DSC) profile of the crystals I of the compound of formula (I) is as shown in figure 2, with an endothermic peak beginning at about 125 ℃.

In some embodiments, the thermogravimetric analysis (TGA) profile of the crystals I of the compound of formula (I) is shown in figure 3 with a weight loss of about 1.02% at about 35 ℃ to 80 ℃ and onset of decomposition at about 230 ℃.

In some embodiments, the crystalline form I of the compound of formula (I) is obtained by any one of the following three methods:

(1) Amorphous solid of compound of formula (I) is mixed with isopropyl acetate, and the temperature is raised and lowered circularly, and the solid is collected. Preferably, the procedure of circularly increasing and decreasing the temperature is to shake for 1-4h at 40 ℃ and then for 1-4h at 20 ℃, and thus to circulate 10-15 times (for example, shake for 2h at 40 ℃ and then for 2h at 20 ℃ and thus to circulate 12 times);

(2) Dissolving an amorphous solid of the compound of formula (I) in an alcoholic solvent, volatilizing the solvent at room temperature, and collecting the solid. Preferably, the alcohol solvent is a monohydric alcohol, more preferably, the monohydric alcohol is selected from any one of methanol, ethanol, and propanol;

(3) After mixing the amorphous solid of the compound of formula (I) with dichloromethane, isopropyl acetate was added dropwise until turbid, and shaken at room temperature for 40-50 hours to collect the solid.

Crystal form II of compound of formula (I) and preparation method thereof

In another aspect, the present application provides crystalline form II of the compound of formula (I) having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2 θ) at 6.0 ± 0.2 °, 6.4 ± 0.2 °, 6.8 ± 0.2 °, 9.0 ± 0.2 °, 13.0 ± 0.2 °, 17.8 ± 0.2 ° and 18.4 ± 0.2 °.

In a preferred embodiment, the XRPD pattern for crystal II of the compound of formula (I) includes characteristic peaks at diffraction angles (2 θ) of 6.0 ± 0.2 °, 6.4 ± 0.2 °, 6.8 ± 0.2 °, 9.0 ± 0.2 °, 13.0 ± 0.2 °, 15.6 ± 0.2 °, 17.4 ± 0.2 °, 17.8 ± 0.2 °, 18.4 ± 0.2 °, 19.6 ± 0.2 °, 20.4 ± 0.2 ° and 21.4 ± 0.2 °.

In a more preferred embodiment, the XRPD pattern of crystal II of the compound of formula (I) comprises characteristic peaks at diffraction angles (2 θ) of 6.0 ± 0.2 °, 6.4 ± 0.2 °, 6.8 ± 0.2 °, 9.0 ± 0.2 °, 13.0 ± 0.2 °, 15.6 ± 0.2 °, 17.2 ± 0.2 °, 17.4 ± 0.2 °, 17.8 ± 0.2 °, 18.4 ± 0.2 °, 19.6 ± 0.2 °, 19.9 ± 0.2 °, 20.4 ± 0.2 °, 21.4 ± 0.2 °, 24.6 ± 0.2 °.

In a particularly preferred embodiment, the XRPD pattern of crystal II of said compound of formula (I) comprises characteristic peaks at diffraction angles (2 Θ) as shown in table 2 below, wherein the 2 Θ values have a range of error of ± 0.2 °:

TABLE 2

In a more preferred embodiment, the XRPD pattern of crystal II of said compound of formula (I) comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 4. In a most preferred embodiment, the XRPD pattern of crystal II of said compound of formula (I) is as shown in figure 4.

In some embodiments, a Differential Scanning Calorimetry (DSC) profile of the crystals II of the compound of formula (I) is as shown in figure 5, with an endothermic peak beginning at about 60 ℃.

In some embodiments, the thermogravimetric analysis (TGA) profile of the crystal II of the compound of formula (I) is as shown in figure 6, with a weight loss of about 2.70% at about 35 ℃ to 120 ℃ and onset of decomposition at about 230 ℃.

In some embodiments, the process for preparing the crystalline form II of the compound of formula (I) comprises: the amorphous solid of the compound of formula (I) is mixed with dichloromethane, then acetonitrile or n-heptane is added dropwise, shaking is carried out at room temperature for 40-50 hours, and the solid is collected.

Phosphate crystal form I of compound shown in formula (I) and preparation method thereof

In another aspect, the present application provides phosphate form I of the compound of formula (I) having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2 Θ) at 3.6 ± 0.2 °, 10.9 ± 0.2 °, 12.1 ± 0.2 °, 15.2 ± 0.2 °, 15.8 ± 0.2 °, 16.5 ± 0.2 °, 18.0 ± 0.2 °, 20.1 ± 0.2 ° and 22.6 ± 0.2 °.

In a preferred embodiment, the XRPD pattern of phosphate form I of the compound of formula (I) comprises characteristic peaks at diffraction angles (2 Θ) of 3.6 ± 0.2 °, 10.9 ± 0.2 °, 11.9 ± 0.2 °, 12.1 ± 0.2 °, 15.2 ± 0.2 °, 15.8 ± 0.2 °, 16.5 ± 0.2 °, 18.0 ± 0.2 °, 18.1 ± 0.2 °, 20.1 ± 0.2 °, 21.0 ± 0.2 °, 22.6 ± 0.2 °, 28.6 ± 0.2 °.

In a more preferred embodiment, the XRPD pattern of phosphate form I of the compound of formula (I) comprises characteristic peaks at diffraction angles (2 θ) of 3.6 ± 0.2 °, 10.9 ± 0.2 °, 11.9 ± 0.2 °, 12.1 ± 0.2 °, 15.2 ± 0.2 °, 15.8 ± 0.2 °, 15.9 ± 0.2 °, 16.5 ± 0.2 °, 18.0 ± 0.2 °, 18.1 ± 0.2 °, 18.6 ± 0.2 °, 20.1 ± 0.2 °, 21.0 ± 0.2 °, 21.4 ± 0.2 °, 22.6 ± 0.2 °, 24.4 ± 0.2 °, 28.6 ± 0.2 °.

In a particularly preferred embodiment, the XRPD pattern of the phosphate form I of the compound of formula (I) comprises characteristic peaks at the diffraction angles (2 Θ) of table 3 below, wherein the 2 Θ values have a range of error of ± 0.2 °:

TABLE 3

2θ(°)±0.2°	Strength%	2θ(°)±0.2°	Strength%
				3.63	100.00	24.01	9.21
7.36	1.71	24.44	29.23
				10.89	12.25	24.74	19.28
11.12	5.29	25.50	8.36
				11.88	12.82	26.22	7.38
12.11	14.68	26.57	17.86
				12.25	10.57	26.84	6.55
12.68	6.70	27.57	8.23
				12.84	11.22	28.02	3.53
13.37	3.54	28.61	23.12
				13.67	1.84	29.03	5.99
14.71	3.24	29.65	2.87
				15.18	87.75	30.10	1.53
15.48	4.34	30.84	4.68
				15.77	41.62	31.38	3.00
15.92	18.20	31.90	9.80
				16.48	44.53	32.21	4.26
16.91	8.29	33.05	1.46
				17.18	6.50	33.54	1.54
18.00	37.86	33.98	4.34
				18.14	36.43	34.30	1.68
18.63	10.17	34.78	6.23
				18.97	0.95	35.10	4.02
20.08	89.19	35.64	2.30
				20.98	20.56	35.94	3.29
21.36	31.66	36.58	1.78
				21.96	9.49	37.05	2.01
22.45	14.28	37.52	2.53
				22.64	35.42	37.94	2.70
23.02	5.13	38.66	2.76
				23.26	3.11	38.89	1.98
23.56	6.62	39.38	1.17

In a more preferred embodiment, the XRPD pattern of phosphate form I of the compound of formula (I) comprises peaks at diffraction angles (2 Θ) substantially the same as shown in figure 7 or figure 19. In a most preferred embodiment, the XRPD pattern of the phosphate form I of the compound of formula (I) is as shown in figure 7 or figure 19.

In some embodiments, the compound of formula (I) has a Differential Scanning Calorimetry (DSC) profile of form I phosphate as shown in figure 8, with an endothermic peak beginning at about 177 ℃.

In some embodiments, the compound of formula (I) has a thermogravimetric analysis (TGA) profile of the phosphate crystalline form I as shown in figure 9 with a weight loss of 1.97% at about 35 ℃ to 140 ℃ and onset of decomposition at about 180 ℃.

In some embodiments, the phosphate form I of the compound of formula (I) has a 1: 1 molar ratio of compound I to phosphoric acid.

In some embodiments, the process for preparing the phosphate form I of the compound of formula (I) comprises obtaining by either of two methods:

(1) Mixing amorphous solid of the compound of formula (I) with phosphoric acid solution, adding acetonitrile, circularly heating and cooling, and collecting solid. Preferably, the procedure of circularly increasing and decreasing the temperature is to shake at 35 ℃ for 1-4h, then shake at 15 ℃ for 1-4h, and thus cycle 20-40 times (for example, shake at 35 ℃ for 2h, then shake at 15 ℃ for 2h, and thus cycle 20 times) to obtain the phosphate crystal form I.

(2) Mixing an amorphous solid of the compound shown in the formula (I) with an alcohol solvent, heating to dissolve, then adding a phosphoric acid solution, adding phosphate crystal form I as a seed crystal, dropwise adding acetonitrile, cooling to room temperature, circularly heating and cooling, filtering, and collecting a solid. Preferably, the temperature of the heated supernatant is 50-70 ℃, e.g., 60 ℃. Preferably, the concentration of the phosphoric acid solution is 10-20mol/L. Preferably, the procedure of cycling up and down the temperature is to heat up to 50-70 ℃ (for example, 60 ℃) and then slowly cool down to room temperature (for example, 20 ℃), and thus cycle is 2-4 times (for example, first heat up to 60 ℃, then slowly cool down to 20 ℃, and so cycle is 2 times). Preferably, the alcohol solvent is selected from any one of methanol, ethanol or propanol.

Phosphate crystal form II of compound shown in formula (I) and preparation method thereof

In another aspect, the application provides a phosphate form II of the compound of formula (I) having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2 θ) at 6.7 ± 0.2 °, 10.1 ± 0.2 °, 10.4 ± 0.2 °, 12.9 ± 0.2 °, 14.6 ± 0.2 °, 15.8 ± 0.2 °, 17.1 ± 0.2 °, 18.8 ± 0.2 ° and 19.8 ± 0.2 °.

In a preferred embodiment, the XRPD pattern of the phosphate form II of the compound of formula (I) comprises characteristic peaks at diffraction angles (2 θ) of 6.7 ± 0.2 °, 10.1 ± 0.2 °, 10.4 ± 0.2 °, 12.3 ± 0.2 °, 12.9 ± 0.2 °, 14.6 ± 0.2 °, 15.8 ± 0.2 °, 16.6 ± 0.2 °, 17.1 ± 0.2 °, 18.8 ± 0.2 °, 19.4 ± 0.2 °, 19.8 ± 0.2 °, 20.8 ± 0.2 °, 23.3 ± 0.2 °, 24.6 ± 0.2 °.

In a more preferred embodiment, the X-ray powder diffraction pattern of the phosphate form II of the compound of formula (I) comprises peaks at diffraction angles (2 Θ) substantially the same as shown in figure 11. In a most preferred embodiment, the X-ray powder diffraction pattern of the phosphate form II of the compound of formula (I) is shown in figure 11.

In some embodiments, the process for preparing the phosphate form II of the compound of formula (I) comprises:

adding phosphate of the compound shown in the formula (I) into an alcohol solvent, heating to dissolve the phosphate, cooling and stirring, then dropwise adding a mixed solution of the alcohol solvent and acetonitrile, stirring for 8-12h, and collecting solids; preferably, the temperature of the heated solvent is 40-60 ℃; preferably, the alcohol solvent is selected from any one of methanol, ethanol or propanol.

Phosphate crystal form III of compound of formula (I) and preparation method thereof

In another aspect, the present application provides a phosphate form III of the compound of formula (I) having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2 θ) at 3.6 ± 0.2 °, 10.5 ± 0.2 °, 12.9 ± 0.2 °, 13.8 ± 0.2 °, 15.7 ± 0.2 °, 16.6 ± 0.2 °, 18.1 ± 0.2 °, 20.4 ± 0.2 ° and 21.2 ± 0.2 °.

In a preferred embodiment, the phosphate form III pattern of the compound of formula (I) includes characteristic peaks at diffraction angles (2 θ) of 3.6 ± 0.2 °, 10.5 ± 0.2 °, 11.9 ± 0.2 °, 12.9 ± 0.2 °, 13.8 ± 0.2 °, 15.7 ± 0.2 °, 16.6 ± 0.2 °, 17.3 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 20.4 ± 0.2 °, 21.2 ± 0.2 °, 21.6 ± 0.2 °, 24.0 ± 0.2 °, 24.6 ± 0.2 °, 26.4 ± 0.2 °.

In a more preferred embodiment, the X-ray powder diffraction pattern of the phosphate form III of the compound of formula (I) comprises peaks at diffraction angles (2 Θ) substantially the same as shown in figure 12. In a most preferred embodiment, the X-ray powder diffraction pattern of the phosphate form III of the compound of formula (I) is shown in figure 12.

In some embodiments, a Differential Scanning Calorimetry (DSC) profile of the phosphate form III of the compound of formula (I) is shown in figure 13, with an endothermic peak beginning at about 166 ℃.

In some embodiments, the thermogravimetric analysis (TGA) profile of the phosphate crystalline form III of the compound of formula (I) is as shown in figure 14, with no weight loss prior to decomposition and with decomposition beginning at about 180 ℃.

In some embodiments, the process for preparing the phosphate form III of the compound of formula (I) comprises:

the phosphate form II of the compound of formula (I) is dried at 30-40 ℃ for 2-4 hours and the solid is collected.

Crystalline mesylate of the compound of formula (I) and a process for its preparation

In another aspect, the application provides a crystalline mesylate salt of the compound of formula (I) having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2 θ) of 4.5 ± 0.2 °, 11.2 ± 0.2 °, 13.9 ± 0.2 °, 14.3 ± 0.2 °, 14.7 ± 0.2 °, 17.6 ± 0.2 °, 19.5 ± 0.2 °,20.6 ± 0.2 ° and 21.6 ± 0.2 °.

In a preferred embodiment, the XRPD pattern of the mesylate salt form of the compound of formula (I) includes characteristic peaks at diffraction angles (2 Θ) of 4.5 ± 0.2 °, 11.2 ± 0.2 °, 13.9 ± 0.2 °, 14.1 ± 0.2 °, 14.3 ± 0.2 °, 14.7 ± 0.2 °, 17.6 ± 0.2 °, 19.5 ± 0.2 °, 19.6 ± 0.2 °, 20.3 ± 0.2 °,20.6 ± 0.2 °, 21.3 ± 0.2 °, 21.6 ± 0.2 °.

In a more preferred embodiment, the XRPD pattern of the mesylate salt form of the compound of formula (I) comprises peaks at diffraction angles (2 Θ) substantially the same as shown in figure 15. In a most preferred embodiment, the X-ray powder diffraction pattern of the crystalline mesylate salt form of the compound of formula (I) is shown in figure 15.

In some embodiments, a Differential Scanning Calorimetry (DSC) pattern of the crystalline form of the mesylate salt of the compound of formula (I) is shown in figure 16, with an endothermic peak beginning at about 206 ℃.

In some embodiments, the thermogravimetric analysis (TGA) profile of the mesylate salt crystalline form of the compound of formula (I) is shown in figure 17 without weight loss prior to decomposition, with decomposition beginning at about 200 ℃.

In some embodiments, the process for preparing the crystalline form of the mesylate salt of the compound of formula (I) comprises:

weighing amorphous solid of the compound of formula (I), adding methanesulfonic acid, then adding isopropyl acetate, circularly heating and cooling, and collecting solid; preferably, the cyclic warming and cooling procedure is repeated 20-40 times by shaking at 35 ℃ for 1-4h and then at 15 ℃ for 1-4h (e.g., shaking at 35 ℃ for 2h and then at 15 ℃ for 2h and then at 20 times).

The invention is further illustrated by the following examples, which are intended only as illustrations for a better understanding of the invention, but are not intended to limit the scope of the invention.

The structure of the compound of the present invention or a salt thereof is represented by ¹ H NMR and/or MS. ¹ H NMR was carried out using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).

Characterization of the crystalline form

Each of the crystalline forms or amorphous forms prepared in the examples was characterized by X-ray powder diffraction (XRPD), differential Scanning Calorimetry (DSC), and thermogravimetric analysis (TGA).

The characterization method comprises the following steps:

(1)XRPD

XRPD patterns were collected for each crystalline form using a transmission mode on a PANalytacal X' Pert3 Powder X-ray Powder diffraction analyzer. Scanning 2 theta in the range of 3.5 DEG to 40 DEG (Cu-Ka emitter, wavelength

) The scanning current is 40mA, and the scanning voltage is 40KV. Successive transmission scans were performed at room temperature using an Absolute scan with a step size of 0.013 ℃ and a dwell time of 50s.

(2)DSC

And (3) adopting a TA DSC2500 differential scanning calorimeter to collect DSC spectra of various crystal forms according to a thermal analysis method of 0661 in the four-part rules of Chinese pharmacopoeia 2015 edition. The heating rate is 10 ℃/min, the initial temperature is 35.0 ℃, nitrogen is used as a purge gas, and the flow rate is 50ml/min. Weighing about 2-5 mg of the sample, spreading in a 60 mu l solid aluminum crucible, taking an empty aluminum crucible as a reference, and injecting for determination.

(3)TGA

TGA profiles of each crystalline form were collected using METTLER TOLEDO TGA 1. The test temperature range is 35 ℃ to 500 ℃, and the heating rate is 10 ℃/min. The test was purged with nitrogen at a flow rate of 50ml/min.

The method for testing the solubility of the sample comprises the following steps: placing different crystal forms or salt forms in a solvent, shaking at 25 deg.C for 4h, centrifuging at 7000rpm for 5min, collecting supernatant, and determining solubility by HPLC external standard method.

Vehicle to test solubility of samples:

the preparation method of the hydrochloric acid solution with the pH of 2.0 is as follows: taking a proper amount of ultrapure water, and adjusting the pH value to 2.0 by using hydrochloric acid to obtain the product.

The preparation method of the buffer solution with the pH of 7.4 is as follows: dissolving 1 piece of Invitrogen TM Phosphate Buffer Salin (PBS) and fixing the volume to 100ml to obtain the final product.

Examples

EXAMPLE 1 preparation of amorphous solid of Compound of formula (I)

The first step is as follows: preparation of 2- (1- (3-chloro-4-iodopyridin-2-yl) azetidin-3-yl) propan-2-ol (compound 1-3):

mixing compound 1-1 (25.0g, 97.1mmol), DMSO (200 mL), compound 1-2 (18.8g, 111.7mmol) and K ₂ CO ₃ (40.3 g,291.3 mmol) was mixed, and the mixture was heated to 80 ℃ to react for 4 hours. Cooled to room temperature, water and ethyl acetate were added, the product was extracted, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compounds 1-3 (36.7 g) which were used in the next reaction without purification.

The second step is that: preparation of 2-ethylhexyl 3- (3-chloro-2- (3- (2-hydroxyprop-2-yl) azetidin-1-yl) pyridin-4-ylsulfanyl) propionate (compound 1-4):

compounds 1-3 (36.7g, 93.68mmol), 2-ethylhexyl 3-mercaptopropionate (24.6g, 112.40mmol), DIPEA (24.2g, 187.4mmol), xantphos (542.0 mg, 0.94mmol) and Pd ₂ (dba) ₃ (428.9mg, 0.47mmol) was added to dioxane (300 mL), vacuum was applied, nitrogen was substituted three times, and the temperature was raised to 100 ℃ for 4 hours. Cooling to room temperature, filtering to remove solid, concentrating the filtrate to obtain crude product, and purifying by column chromatography to obtain compoundSubstance 1-4 (37.8 g, yield 86%).

The third step: preparation of sodium 3-chloro-2- (3- (2-hydroxypropan-2-yl) azetidin-1-yl) pyridin-4-thiophenol (compounds 1-5):

sodium methoxide (5.85g, 30% methanol solution) was added to a solution of compound 1-4 (12.00g, 27.1 mmol) in THF (120 mL) and reacted at 25 ℃ for 1 hour. The reaction mixture was concentrated to remove most of the solvent, dichloromethane (100 mL) and petroleum ether (50 mL) were added, stirred for 20 minutes, filtered, and the filter cake was dried under vacuum to give crude compounds 1-5 (7.85 g) which were used in the next reaction without purification.

The fourth step: preparation of methyl 3- ((3S, 4S) -4- (tert-butoxycarbonylamino) -3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- (3-chloro-2- (3- (2-hydroxypropan-2-yl) azetidin-1-yl) pyridin-4-ylthio) pyrazine-2-carboxylate (Compounds 1-7):

mixing compound 1-6 (5.00g, 10.30mmol), compound 1-5 (5.80g, 20.60mmol), cuI (0.98g, 5.15mmol), 1, 10-phenanthroline (1.02g, 5.15mmol) and K ₃ PO ₄ (4.37g, 20.6 mmol) was added to dioxane (100 mL) and the temperature was raised to 100 ℃ for reaction for 3 hours. Cooled to room temperature, insoluble material was filtered off, and the filtrate was concentrated to give a crude product, which was purified by column chromatography to give compound 1-7 (5.15 g, yield 71%).

The fifth step: preparation of tert-butyl (3S, 4S) -8- (5- (3- (2-hydroxyprop-2-yl) azetidin-1-yl) pyridin-4-ylsulfanyl) -3- (hydroxymethyl) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-ylcarbamate (Compounds 1-8):

compounds 1 to 7 (5.15g, 7.77mmol) were dissolved in ethanol (80 mL), calcium chloride (3.45g, 31.10mmol) was added, sodium borohydride (1.18g, 31.10mmol) was added in portions, and the mixture was slowly heated to 35 ℃ to react for 3 hours. Water (50 mL) was slowly added and citric acid water adjusted PH = 7-8, most of the ethanol was concentrated off, the product was extracted with ethyl acetate (150 mL), the organic phase was concentrated to dryness to give the crude product, which was purified by column chromatography to give compounds 1-8 (2.67 g, 51% yield).

And a sixth step: preparation of 2- (1- (4- (5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- (hydroxymethyl) pyrazin-2-ylthio) -3-chloropyridin-2-yl) azetidin-3-yl) propan-2-ol (Compound I):

compound 1-8 (40mg, 0.06mmol) was dissolved in dichloromethane (2 mL), TFA (4 mL) was added slowly, and the reaction was allowed to warm to 30 ℃ for 1 hour. Concentrating to remove solvent in the reaction solution to obtain crude product, and purifying by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% formic acid water solution).

MS(ESI)：m/z 535.2[M+H] ⁺ 。

¹ H-NMR(400MHz，DMSO-d ₆ )δ8.31(s，1H)，7.79(d，J＝5.6Hz，1H)，6.01(d，J＝5.2Hz，1H)，4.51(s，2H)，4.14-4.02(m，5H)，3.75-3.62(m，3H)，3.53(d，J＝8.4Hz，1H)，3.30-3.15(m，2H)，3.00(d，J＝5.2Hz，1H)，2.62(p，J＝7.6Hz，1H)，1.90-1.79(m，1H)，1.79-1.68(m，1H)，1.67-1.50(m，2H)，1.10(d，J＝6.4Hz，3H)，1.05(s，6H)。

EXAMPLE 2 Process for the preparation of crystalline form I of the Compound of formula (I)

100mg of an amorphous sample of the compound of formula (I) is weighed into 1000. Mu.L of isopropyl acetate, and the mixture is shaken first at 40 ℃ for 2h and then at 20 ℃ for 2h, and the temperature is repeatedly raised and lowered according to the program for 48h to obtain a solid, which is collected.

The solid is detected by XRPD, and the XRPD pattern of the obtained solid is shown in figure 1, namely the crystal I of the compound of the formula (I) of the invention.

The solid was subjected to DSC measurement, and the obtained DSC pattern was as shown in FIG. 2, and an endothermic peak began to appear at about 125 ℃.

TGA measurements were performed on the solids and the resulting TGA profile is shown in FIG. 3, with a weight loss of about 1.02% occurring between about 35℃ and 80℃ and the onset of decomposition at about 230℃.

EXAMPLE 3 Process for the preparation of crystalline form I of the Compound of formula (I)

20mg of an amorphous sample of the compound of formula (I) was weighed out, dissolved in 100. Mu.L of ethanol for clarification, evaporated at room temperature, the solvent removed and the solid collected.

XRPD analysis of the solid showed the product to be the same as crystal I from example 2.

EXAMPLE 4 Process for preparing crystalline form I of the Compound of formula (I)

20mg of an amorphous sample of the compound of formula (I) are weighed, 100. Mu.L of dichloromethane are added at room temperature, 600. Mu.L of isopropyl acetate are added dropwise, shaking is carried out at room temperature for 48h, and the solid is collected.

XRPD detection of the solid showed the product to be the same as crystal I obtained in example 2.

EXAMPLE 5 preparation of form II of the Compound of formula (I)

100mg of an amorphous sample of the compound of formula (I) is weighed, 300. Mu.L of dichloromethane is added at room temperature, 300. Mu.L of acetonitrile is added dropwise, shaking is carried out at room temperature for 48h, and the solid is collected.

The solid was subjected to XRPD detection, and the XRPD pattern of the obtained solid is shown in fig. 4, which is crystal II of the compound of formula (I) of the present invention.

DSC of the solid was determined and the resulting DSC spectrum was shown in FIG. 5, with an endothermic peak beginning at about 60 ℃.

TGA measurements were taken of the solids and the resulting TGA profile is shown in figure 6 with a weight loss of about 2.70% between about 35 ℃ and 120 ℃ and onset of decomposition at about 230 ℃.

EXAMPLE 6 preparation of crystalline form II of the Compound of formula (I)

20mg of an amorphous sample of the compound of formula (I) is weighed, 100. Mu.L of dichloromethane is added at room temperature, 200. Mu.L of n-heptane is added dropwise, shaking is carried out at room temperature for 48h, and the solid is collected.

XRPD analysis of the solid showed the product to be the same as crystal II from example 5.

EXAMPLE 7 preparation of phosphate form I of the Compound of formula (I)

And mixing the amorphous solid of the compound of 20mg with 1mol/L phosphoric acid solution of 37 mu L, then adding 1mL of acetonitrile, shaking for 2h at 35 ℃, then shaking for 2h at 15 ℃, circularly heating and cooling for 20 times according to the procedure, and collecting the solid to obtain the phosphate crystal form I.

The XRPD pattern of the resulting solid is shown in fig. 19, which is the phosphate form I of the compound of formula (I) of the present invention.

EXAMPLE 8 preparation of phosphate form I of the Compound of formula (I)

Weighing 4000mg of an amorphous sample of the compound shown in the formula (I), putting the amorphous sample into 45mL of ethanol, heating to 60 ℃ for clearing, adding 545 mu L of phosphoric acid solution with the concentration of 15 mol/L, adding the phosphate crystal form I of example 7 as a crystal seed, dropwise adding 90mL of acetonitrile, cooling to room temperature, then slowly cooling to 20 ℃ after heating to 60 ℃, crystallizing for 1h, filtering and collecting solid.

The XRPD pattern of the resulting solid is shown in fig. 7, which is the phosphate form I of the compound of formula (I) of the present invention.

DSC of the solid is determined and the DSC profile is shown in FIG. 8, where an endothermic peak begins to appear at about 177 ℃.

TGA measurements were taken of the solids and the resulting TGA profile is shown in figure 9 with a weight loss of about 1.97% between about 35 ℃ and 140 ℃ and onset of decomposition at about 180 ℃.

The solids were tested for PLM and the PLM profile obtained is shown in FIG. 10.

The phosphate crystal form I of the compound shown in the formula (I) is tested by an ion chromatography external standard method, and phosphoric acid and the compound shown in the formula (1) form salt in a molar ratio of 1: 1.

EXAMPLE 9 recrystallization of the phosphate form I of the Compound of formula (I)

Weighing 1000mg of phosphate crystal form I of the compound shown in the formula (I), adding the phosphate crystal form I into 6mL of anhydrous methanol, heating to 55 ℃ for clearing, cooling to 45 ℃, adding the phosphate crystal form I of example 7 as seed crystal, slowly cooling for crystallization to obtain white solid, and collecting the solid.

XRPD detection of the solid shows that the obtained product is the same as the phosphate crystal form I crystal obtained in example 7 or 8.

EXAMPLE 10 preparation of phosphate form II of the Compound of formula (I)

Weighing 2500mg of phosphate crystal form I of the compound shown in the formula (I), adding the phosphate crystal form I into 25mL of anhydrous methanol, dissolving at 40 ℃, concentrating until the phosphate is dry to obtain amorphous phosphate, adding the amorphous phosphate into 25mL of anhydrous methanol, dissolving at 40 ℃, cooling and stirring to obtain a solid, dropwise adding a mixed solution of methanol and acetonitrile (methanol: acetonitrile = 2: 1, v/v), stirring for 12h, filtering and collecting the solid.

XRPD detection of the solid showed that the XRPD pattern of the solid is shown in fig. 11, which is phosphate form II of the compound of formula (I) of the present invention.

EXAMPLE 11 preparation of phosphate form III of the Compound of formula (I)

1000mg of the phosphate crystals II of the compound of the formula (I) are weighed out and dried in a vacuum oven at 35 ℃ for 3h, and the solid is collected.

XRPD analysis of the solid gave an XRPD pattern as shown in figure 12, which is the phosphate form III of the compound of formula (I) of the present invention.

DSC analysis of the solid gave a DSC pattern as shown in FIG. 13, with an endothermic peak beginning at about 166 ℃.

TGA measurements were performed on the solids and the resulting TGA profile is shown in figure 14, with no weight loss before decomposition and onset of decomposition at about 180 ℃.

EXAMPLE 12 preparation of the mesylate salt form of the compound of formula (I)

Weighing 80mg of amorphous solid of the compound of the formula (I), adding 1.2 equivalents of methanesulfonic acid, adding 1.8mL of isopropyl acetate solvent, shaking for 2h at 35 ℃ and then for 2h at 15 ℃, repeating the above steps for 20 times, and collecting the solid.

The solid was subjected to XRPD analysis and the resulting XRPD pattern is shown in figure 15, which is the mesylate salt form of the compound of formula (I) of the invention.

DSC analysis of the solid gave a DSC pattern as shown in FIG. 16, with an endothermic peak beginning at about 206 ℃.

TGA measurements were taken of the solids and the resulting TGA profile is shown in figure 17 with no weight loss prior to decomposition and decomposition beginning at about 200 ℃.

The solids were tested for PLM and the PLM profile obtained is shown in FIG. 18.

Experimental example 1: solubility test

The solubility of the phosphate form I of the compound of formula (I) and the mesylate form of the compound of formula (I) was tested according to the test methods for solubility of the foregoing samples and the results were as follows:

the solubility of the phosphate form I of the compound of formula (I) is shown in table 4 below:

TABLE 4

PH	Solubility in water
		2.0	1.36mg/mL
7.4	1.20mg/mL

The solubility of the mesylate salt form of the compound of formula (I) is shown in table 5 below:

TABLE 5

PH	Solubility in water
		2.0	1.53mg/mL
7.4	2.37mg/mL

And (4) conclusion: the phosphate crystal form I of the compound shown in the formula (I) and the mesylate crystal form of the compound shown in the formula (I) obtained by the invention have certain solubility under acidic and neutral environments.

EXPERIMENTAL EXAMPLE 2 Competition experiments for the phosphate form I and phosphate form III of the Compound of formula (I)

10mg of the phosphate crystal form I of the compound of the formula (I) obtained in example 8 and 4 mg of the phosphate crystal form III of the compound of the formula (I) obtained in example 11 were weighed into the same 2mL centrifuge tube, shaken in a shaker for 20 hours under the conditions shown in the following table 6, and centrifuged to test XRPD, and the results were:

TABLE 6

Solvent/temperature	20℃	35℃
			MeOH ACN (volume ratio 1: 5)	Phosphate form I	Phosphate form I
MeOH: EA (volume ratio 1: 5)	Phosphate form I	Phosphate form I

And (4) conclusion: in the co-existence system of the phosphate form I and the phosphate form III of the compound of formula (I), the phosphate form III of the compound of formula (I) is transcrystallized to the phosphate form I of the compound of formula (I), which indicates that the phosphate form I of the compound of formula (I) is more stable than the phosphate form III of the compound of formula (I).

EXPERIMENTAL EXAMPLE 3 stability of the phosphate form I of the Compound of formula (I)

The phosphate crystal form of the compound of formula (I) was left for a period of time under different conditions for stability studies, and detected by high performance liquid chromatography, and the chemical purity was calculated according to peak area normalization, the results of which are shown in table 7 below.

Operating conditions of the high performance liquid chromatography: the chromatographic column is Waters Xbridge C8,4.6mm multiplied by 150mm,3.5 μm; the mobile phase is 10mM ammonium acetate water solution (pH5.5) and acetonitrile; the column temperature is 30 ℃; the flow rate is 1.0ml/min; the detection wavelength was 280nm.

TABLE 7

Condition	Time of standing	Chemical purity (%)
			Day 0	/	98.8
High temperature (60 ℃. + -. 2 ℃)	30 days	98.7
			High humidity (25 ℃. + -. 2 ℃, RH 92.5%. + -. 5%	30 days	98.7
Acceleration conditions (40 ℃. + -. 2 ℃ and RH 75%. + -. 5%)	30 days	98.7

The data in table 7 show that the purity of the phosphate form I of the compound of formula (I) does not change significantly under various conditions, indicating that the phosphate form I of the compound of formula (I) provided by the present invention has good physicochemical stability.

Claims

1. A crystalline form I of the compound of formula (I) characterized by an X-ray powder diffraction pattern having characteristic peaks at 2 theta values of 4.8 + -0.2 °, 9.7 + -0.2 °, 12.3 + -0.2 °, 17.4 + -0.2 °, 19.0 + -0.2 ° and 19.9 + -0.2 °,

preferably, the compound of formula (i) form i has an X-ray powder diffraction pattern also having characteristic peaks at least one of 2 Θ values of 13.8 ± 0.2 °, 17.0 ± 0.2 ° and 23.4 ± 0.2 °;

preferably, the compound of formula (i) in crystalline form i has an X-ray powder diffraction pattern further having characteristic peaks at 2 Θ values of at least one of 17.2 ± 0.2 °, 17.8 ± 0.2 °, 21.5 ± 0.2 ° and 22.7 ± 0.2 °;

preferably, the compound of formula (i) in crystalline form i has an XRPD pattern substantially as shown in figure 1.

2. A crystal form II of the compound of formula (I), characterized in that it has characteristic peaks in the 2 theta values of 6.0 + -0.2 °, 6.4 + -0.2 °, 6.8 + -0.2 °, 9.0 + -0.2 °, 13.0 + -0.2 °, 17.8 + -0.2 ° and 18.4 + -0.2 ° in its X-ray powder diffraction pattern,

preferably, the X-ray powder diffraction pattern of the compound of formula (I) in the form II also has characteristic peaks at least one of 2 theta values of 15.6 + -0.2 DEG, 17.4 + -0.2 DEG, 19.6 + -0.2 DEG, 20.4 + -0.2 DEG and 21.4 + -0.2 DEG;

preferably, the compound of formula (i) in form ii also has a characteristic peak in its X-ray powder diffraction pattern at least one of 2 Θ values of 17.2 ± 0.2 °, 19.9 ± 0.2 ° and 24.6 ± 0.2 °;

preferably, the crystalline form ii of the compound of formula (i) has an XRPD pattern substantially as shown in figure 4.

3. A phosphate salt of a compound of formula (I), wherein the phosphate salt of the compound of formula (I) is present in form I, characterized by an X-ray powder diffraction pattern having characteristic peaks at 2 θ values of 3.6 + -0.2 °, 10.9 + -0.2 °, 12.1 + -0.2 °, 15.2 + -0.2 °, 15.8 + -0.2 °, 16.5 + -0.2 °, 18.0 + -0.2 °, 20.1 + -0.2 ° and 22.6 + -0.2 °,

preferably, the compound of formula (I) has an X-ray powder diffraction pattern for the phosphate form I also having characteristic peaks at least one of 2 Θ values of 11.9 ± 0.2 °, 18.1 ± 0.2 °, 21.0 ± 0.2 ° and 28.6 ± 0.2 °;

preferably, the compound of formula (I) has an X-ray powder diffraction pattern of form I phosphate salt also having characteristic peaks at 2 Θ values of at least one of 15.9 ± 0.2 °, 18.6 ± 0.2 °, 21.4 ± 0.2 ° and 24.4 ± 0.2 °;

preferably, the phosphate form I of the compound of formula (I) has an XRPD pattern substantially as shown in figure 7 or figure 19.

4. A phosphate salt of a compound of formula (I), wherein the phosphate salt of the compound of formula (I) is present in crystalline form II, characterized by an X-ray powder diffraction pattern having characteristic peaks at 2 θ values of 6.7 + -0.2 °, 10.1 + -0.2 °, 10.4 + -0.2 °, 12.9 + -0.2 °, 14.6 + -0.2 °, 15.8 + -0.2 °, 17.1 + -0.2 °, 18.8 + -0.2 ° and 19.8 + -0.2 °,

preferably, the X-ray powder diffraction pattern of the phosphate form II of the compound of formula (i) also has characteristic peaks at least one of 2 Θ values of 12.3 ± 0.2 °, 16.6 ± 0.2 °, 19.4 ± 0.2 °, 20.8 ± 0.2 °, 23.3 ± 0.2 °, 24.6 ± 0.2 °;

preferably, the phosphate form II of the compound of formula (i) has an XRPD pattern substantially as shown in figure 11.

5. A phosphate salt of a compound of formula (I), wherein the phosphate salt of the compound of formula (I) is present in crystalline form III, characterized by an X-ray powder diffraction pattern having characteristic peaks at 2 θ values of 3.6 + -0.2 °, 10.5 + -0.2 °, 12.9 + -0.2 °, 13.8 + -0.2 °, 15.7 + -0.2 °, 16.6 + -0.2 °, 18.1 + -0.2 °, 20.4 + -0.2 ° and 21.2 + -0.2 °,

preferably, the X-ray powder diffraction pattern of the phosphate form iii of the compound of formula (i) also has characteristic peaks at least one of 2 Θ values of 11.9 ± 0.2 °, 17.3 ± 0.2 °, 19.2 ± 0.2 °, 21.6 ± 0.2 °, 24.0 ± 0.2 °, 24.6 ± 0.2 °, 26.4 ± 0.2 °;

preferably, the phosphate form iii of the compound of formula (i) has an XRPD pattern substantially as shown in figure 12.

6. A mesylate salt of a compound of formula (I), wherein the mesylate salt of the compound of formula (I) is present in crystalline form, characterized in that the crystalline form of the mesylate salt of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic peaks at 2 θ values of 4.5 + -0.2 °, 11.2 + -0.2 °, 13.9 + -0.2 °, 14.3 + -0.2 °, 14.7 + -0.2 °, 17.6 + -0.2 °, 19.5 + -0.2 °,20.6 + -0.2 ° and 21.6 + -0.2 °,

preferably, the X-ray powder diffraction pattern of the crystalline mesylate salt form of the compound of formula (i) also has characteristic peaks at 2 Θ values of at least one of 14.1 ± 0.2 °, 19.6 ± 0.2 °, 20.3 ± 0.2 °, 21.3 ± 0.2 °;

preferably, the crystalline form of the mesylate salt of the compound of formula (i) has an XRPD pattern substantially as shown in figure 15.

7. A pharmaceutical composition comprising at least one of the crystalline form I of the compound of formula (I) as defined in claim 1, the crystalline form II of the compound of formula (I) as defined in claim 2, the phosphate salt of the compound of formula (I) as defined in any one of claims 3 to 5, the mesylate salt of the compound of formula (I) as defined in claim 6, and one or more pharmaceutically acceptable carriers.

8. Use of the crystalline form I of the compound of formula (I) according to claim 1, the crystalline form II of the compound of formula (I) according to claim 2, the phosphate salt of the compound of formula (I) according to any one of claims 3 to 5, the mesylate salt of the compound of formula (I) according to claim 6 or the pharmaceutical composition according to claim 7 as an SHP2 inhibitor for the prevention and/or treatment of a disease or condition mediated at least in part by SHP2, preferably the disease or condition mediated by SHP2 is cancer.

9. Use of the crystalline form I of the compound of formula (I) according to claim 1, the crystalline form II of the compound of formula (I) according to claim 2, the phosphate salt of the compound of formula (I) according to any one of claims 3 to 5, the mesylate salt of the compound of formula (I) according to claim 6 or the pharmaceutical composition according to claim 7 for the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by SHP2, preferably wherein the disease or condition mediated by SHP2 is cancer.

10. A method for preventing and/or treating a disease or condition mediated at least in part by SHP2, comprising the steps of: administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of the crystalline form I of the compound of formula (I) according to claim 1, the crystalline form II of the compound of formula (I) according to claim 2, the phosphate salt of the compound of formula (I) according to any one of claims 3 to 5, the mesylate salt of the compound of formula (I) according to claim 6, or the pharmaceutical composition according to claim 7, preferably wherein the disease or disorder mediated by SHP2 is cancer.